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http://www.ncbi.nlm.nih.gov/pubmed/28427100 | 1. Neuropediatrics. 2017 Aug;48(4):262-272. doi: 10.1055/s-0037-1601860. Epub
2017 Apr 20.
Dystrophinopathies and Limb-Girdle Muscular Dystrophies.
Domingos J(1), Sarkozy A(1), Scoto M(1), Muntoni F(1).
Author information:
(1)UCL Great Ormond Street Institute of Child Health, Department of Molecular
Neurosciences, Dubowitz Neuromuscular Centre and Great Ormond Street Hospital,
London, United Kingdom.
Muscular dystrophies are a heterogeneous group of inherited diseases. The
natural history of these disorders along with their management have changed
mainly due to a better understanding of their pathophysiology, the evolution of
standards of care, and new treatment options. Dystrophinopathies include both
Duchenne's and Becker's muscular dystrophies, but in reality they are a spectrum
of muscle diseases caused by mutations in the gene that encodes the protein
dystrophin. Duchenne's muscular dystrophy is the most common form of inherited
muscle disease of childhood. The current standards of care considerably prolong
independent ambulation and survival. Several therapeutic options either aiming
at substituting/correcting the primary protein defect or limiting the
progression of the dystrophic process are currently being explored in clinical
trials.Limb-girdle muscular dystrophies (LGMDs) are rare and heterogeneous
conditions, characterized by weakness and wasting of the pelvic and shoulder
girdle muscles. Originally classified into dominant and recessive, > 30 genetic
forms of LGMDs are currently recognized. Further understanding of the pathogenic
mechanisms of LGMD will help identifying novel therapeutic approaches that can
be tested in clinical trials.
Georg Thieme Verlag KG Stuttgart · New York.
DOI: 10.1055/s-0037-1601860
PMID: 28427100 [Indexed for MEDLINE]
Conflict of interest statement: Disclosure The authors report no conflicts of
interest in this work. |
http://www.ncbi.nlm.nih.gov/pubmed/35748699 | 1. N Engl J Med. 2022 Aug 11;387(6):514-524. doi: 10.1056/NEJMoa2205416. Epub
2022 Jun 25.
Fazirsiran for Liver Disease Associated with Alpha(1)-Antitrypsin Deficiency.
Strnad P(1), Mandorfer M(1), Choudhury G(1), Griffiths W(1), Trautwein C(1),
Loomba R(1), Schluep T(1), Chang T(1), Yi M(1), Given BD(1), Hamilton JC(1), San
Martin J(1), Teckman JH(1).
Author information:
(1)From the Department of Internal Medicine III, University Hospital, RWTH
(Rheinisch-Westfälische Technische Hochschule) Aachen, Health Care Provider of
the European Reference Network on Rare Liver Disorders (ERN RARE-LIVER), Aachen,
Germany (P.S., C.T.); the Division of Gastroenterology and Hepatology,
Department of Internal Medicine III, Medical University of Vienna, ERN
RARE-LIVER, Vienna (M.M.); the Department of Respiratory Medicine, Royal
Infirmary of Edinburgh University Hospital, University of Edinburgh, Edinburgh
(G.C.), and the Department of Hepatology, Addenbrooke's Hospital, Cambridge
University Hospitals NHS Foundation Trust, Cambridge (W.G.) - both in the United
Kingdom; the Division of Gastroenterology, University of California San Diego
School of Medicine, La Jolla (R.L.), and Arrowhead Pharmaceuticals, Pasadena
(T.S., T.C., M.Y., B.D.G., J.C.H., J.S.M.) - both in California; and the
Departments of Pediatrics and Biochemistry and Molecular Biology, Saint Louis
University School of Medicine, St. Louis (J.H.T.).
BACKGROUND: Alpha1-antitrypsin (AAT) deficiency results from carriage of a
homozygous SERPINA1 "Z" mutation (proteinase inhibitor [PI] ZZ). The Z allele
produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and
can lead to progressive liver disease and fibrosis. This open-label, phase 2
trial investigated the safety and efficacy of fazirsiran, an RNA interference
therapeutic, in patients with liver disease associated with AAT deficiency.
METHODS: We assigned adults with the PI ZZ genotype and liver fibrosis to
receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8
patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4
and then every 12 weeks. The primary end point was the change from baseline to
week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations,
which were measured by means of liquid chromatography-mass spectrometry.
RESULTS: All the patients had reduced accumulation of Z-AAT in the liver (median
reduction, 83% at week 24 or 48). The nadir in serum was a reduction of
approximately 90%, and treatment was also associated with a reduction in
histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9,
with higher scores indicating a greater globule burden] at baseline to 2.3 at
week 24 or 48). All cohorts had reductions in liver enzyme concentrations.
Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in
2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to
trial or drug discontinuation. Four serious adverse events (viral myocarditis,
diverticulitis, dyspnea, and vestibular neuronitis) resolved.
CONCLUSIONS: In this small trial, fazirsiran was associated with a strong
reduction of Z-AAT concentrations in the serum and liver and concurrent
improvements in liver enzyme concentrations. (Funded by Arrowhead
Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.).
Copyright © 2022 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2205416
PMID: 35748699 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36121164 | 1. Percept Mot Skills. 2023 Feb;130(1):221-238. doi: 10.1177/00315125221128129.
Epub 2022 Sep 19.
Gait and Sit-To-Stand Motor Compensation Strategies in Children and Adolescents
With Duchenne Muscular Dystrophy.
Dazzi MAR(1), Sá CDSC(2).
Author information:
(1)Fisioterapeuta, 28105Mestre em Ciências Pela Universidade Federal de São
Paulo, São Paulo, Brazil.
(2)Doutora do Curso de Fisioterapia, Departamento de Ciências do Movimento
Humano, 58804Universidade Federal de São Paulo, São Paulo, Brazil.
Duchenne Muscular Dystrophy (DMD), the most common form of muscular dystrophies,
is characterized by progressive and generalized muscle weakness. The weakness of
the trunk and other muscle groups leads these patients to perform motor
compensation strategies to maintain their lower limb functionality for gait
quality and for tasks such as getting up from a sitting position. In this
cross-sectional observational study, we described and quantified trunk, gait,
and sit-to-stand motor compensation strategies in different stages of this
disease. Thirty-one ambulatory 5-18-year-old children and adolescents with a
diagnosis of DMD, underwent cognitive assessment with the Mental
Mini-Examination (MMSE) and motor assessment with the Vignos scale, Segmental
Assessment of Trunk Control (SATCo-BR), Timed Up and Go test (TUG Test), and
10-m walk test. We found strong correlations between trunk and gait
compensations, and identified motor compensation strategies characteristic of
certain DMD classifications. Also, these lower limb and trunk compensations
related to disease staging (Vignos) such that compensations were fewer for
patients at relatively better disease staging.
DOI: 10.1177/00315125221128129
PMID: 36121164 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35693619 | 1. J Thorac Dis. 2022 May;14(5):1504-1514. doi: 10.21037/jtd-22-501.
Long chain noncoding RNA-ROR promotes hypoxic injury of cardiomyocytes by
targeting the miR-145/HAX-1 axis.
Yang Y(1), Tang Q(1), Li Y(1), Dai L(1), Li M(1), Fu Y(1).
Author information:
(1)Department of Cardiovascular Medicine, Chongqing General Hospital, Chongqing,
China.
BACKGROUND: Long non-coding RNAs (lncRNAs) are a class of non-protein coding
RNAs greater than 200 nucleotides (nt) in length which have been shown to be
significantly highly expressed in the heart tissue of mice undergoing thoracic
aortic arch constriction (TAC). Micro RNAs (miRNAs) are a class of
non-protein-coding RNAs. Many miRNAs have been reported to play a key role in
the progression of myocardial hypertrophy. In this study, we aimed to
investigate whether lncRNA reprogramming regulators (ROR) promotes hypoxic
injury in cardiomyocytes by targeting and regulating the miR-145/HS1-associated
protein X-1 (HAX-1) axis.
METHODS: A mouse model of myocardial hypertrophy was established by conventional
TAC method, and the cardiomyocytes were isolated. We transfected pcDNA3.0-ROR
vector, pcDNA3.0-HAX-1 vector plasmid, and miR-145 simulant into cardiomyocytes
with Lipofectamine 2000. Luciferase reporter gene was used to analyze the
targeting relationship between genes.
RESULTS: The expression of ROR in hypertrophic myocardium was significantly
increased after phenylephrine (PE) intervention. After transfection with si-ROR,
the ROR expression in hypertrophic cardiomyocytes treated with PE decreased
significantly. Levels of lactate dehydrogenase (LDH), malondialdehyde (MDA),
creatine kinase (CK) decreased and superoxide dismutase (SOD) increased. The
expression of miR-145 in cardiomyocytes was significantly down-regulated after
PE treatment. In hypertrophic cardiomyocytes, after up-regulating the expression
of miR-145, the relative messenger ribonucleic acid (mRNA) and protein
expressions of atrial natriuretic peptide (ANP) and B-type natriuretic peptide
(BNP) induced by PE decreased. Compared with the miR-NC group, wild type
(WT)-ROR activity in the miR-145 group was significantly inhibited (P<0.05), and
mutant (MUT)-ROR activity had no significant change (P>0.05). When
cardiomyocytes were transfected with HAX-1 3'URT WT vector along with miR-145
simulant, miR-145 inhibitor, and their respective controls. Compared with the
control groups, the luciferase activity of cells transfected with simulant was
significantly decreased (P<0.05), and increased in inhibitor group (P<0.05).
Transfection of HAX-1 3'URT mutant vector did not show this phenomenon. ROR was
negatively correlated with miR-145 expression and positively correlated with
HAX-1 mRNA.
CONCLUSIONS: The lncRNA ROR can promote the expression of HAX-1 by competitive
binding with miR-145, so as to promote the pathophysiological process of
myocardial hypertrophy.
2022 Journal of Thoracic Disease. All rights reserved.
DOI: 10.21037/jtd-22-501
PMCID: PMC9186230
PMID: 35693619
Conflict of interest statement: Conflicts of Interest: All authors have
completed the ICMJE uniform disclosure form (available at
https://jtd.amegroups.com/article/view/10.21037/jtd-22-501/coif). The authors
have no conflicts of interest to declare. |
http://www.ncbi.nlm.nih.gov/pubmed/35882940 | 1. Sci Rep. 2022 Jul 26;12(1):12740. doi: 10.1038/s41598-022-17086-2.
Substantial impact of 3-iodothyronamine (T1AM) on the regulations of fluorescent
thermoprobe-measured cellular temperature and natriuretic peptide expression in
cardiomyocytes.
Takahashi H(1), Nagoshi T(2), Kimura H(1), Tanaka Y(1), Yasutake R(1), Oi Y(1),
Yoshii A(1), Tanaka TD(1), Kashiwagi Y(1), Yoshimura M(1).
Author information:
(1)Division of Cardiology, Department of Internal Medicine, The Jikei University
School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
(2)Division of Cardiology, Department of Internal Medicine, The Jikei University
School of Medicine, 3-25-8, Nishi-Shimbashi, Minato-ku, Tokyo, 105-8461, Japan.
tnagoshi@jikei.ac.jp.
There is growing interest in 3-iodothyronamine (T1AM), an active thyroid hormone
metabolite, that induces negative inotropic and chronotropic actions in the
heart and exerts systemic hypothermic action. We explored the direct impact of
T1AM on cardiomyocytes with a focus on the regulation of the intracellular
temperature and natriuretic peptide (NP) expression. A thermoprobe was
successfully introduced into neonatal rat cardiomyocytes, and the
temperature-dependent changes in the fluorescence intensity ratio were measured
using a fluorescence microscope. After one-hour incubation with T1AM, the degree
of change in the fluorescence intensity ratio was significantly lower in
T1AM-treated cardiomyocytes than in equivalent solvent-treated controls
(P < 0.01), indicating the direct hypothermic action of T1AM on cardiomyocytes.
Furthermore, T1AM treatment upregulated B-type NP (BNP) gene expression
comparable to treatment with endothelin-1 or phenylephrine. Of note, ERK
phosphorylation was markedly increased after T1AM treatment, and inhibition of
ERK phosphorylation by an MEK inhibitor completely cancelled both T1AM-induced
decrease in thermoprobe-measured temperature and the increase in BNP expression.
In summary, T1AM decreases fluorescent thermoprobe-measured temperatures
(estimated intracellular temperatures) and increases BNP expression in
cardiomyocytes by activating the MEK/ERK pathway. The present findings provide
new insight into the direct myocardial cellular actions of T1AM in patients with
severe heart failure.
© 2022. The Author(s).
DOI: 10.1038/s41598-022-17086-2
PMCID: PMC9325765
PMID: 35882940 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/12732268 | 1. Prog Biophys Mol Biol. 2003 May-Jul;82(1-3):57-66. doi:
10.1016/s0079-6107(03)00005-1.
Stretch-modulation of second messengers: effects on cardiomyocyte ion transport.
Kudoh S(1), Akazawa H, Takano H, Zou Y, Toko H, Nagai T, Komuro I.
Author information:
(1)Department of Cardiology, Kanazawa Medical University, 1-1 Daigaku,
Uchinada-cho, Kawakita-gun, 920-0265, Ishikawa, Japan.
In cardiomyocytes, mechanical stress induces a variety of hypertrophic responses
including an increase in protein synthesis and a reprogramming of gene
expression. Recently, the calcium signaling has been reported to play an
important role in the development of cardiac hypertrophy. In this article, we
report on the role of the calcium signaling in stretch-induced gene expression
in cardiomyocytes. Stretching of cultured cardiomyocytes up-regulates the
expression of brain natriuretic peptide (BNP). Intracellular calcium-elevating
agents such as the calcium ionophore A23187, the calcium channel agonist
BayK8644 and the sarcoplasmic reticulum calcium-ATPase inhibitor thapsigargin
up-regulate BNP gene expression. Conversely, stretch-induced BNP gene expression
is suppressed by EGTA, stretch-activated ion channel inhibitors,
voltage-dependent calcium channel antagonists, and long-time exposure to
thapsigargin. Furthermore, stretch increases the activity of calcium-dependent
effectors such as calcineurin and calmodulin-dependent kinase II, and inhibitors
of calcineurin and calmodulin-dependent kinase II significantly attenuated
stretch-induced hypertrophy and BNP expression. These results suggest that
calcineurin and calmodulin-dependent kinase II are activated by calcium influx
and subsequent calcium-induced calcium release, and play an important role in
stretch-induced gene expression during the development of cardiac hypertrophy.
DOI: 10.1016/s0079-6107(03)00005-1
PMID: 12732268 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29859763 | 1. Peptides. 2019 Jan;111:18-25. doi: 10.1016/j.peptides.2018.05.012. Epub 2018
May 31.
Atrial and brain natriuretic peptides: Hormones secreted from the heart.
Nakagawa Y(1), Nishikimi T(2), Kuwahara K(3).
Author information:
(1)Department of Cardiovascular Medicine, Kyoto University Graduate School of
Medicine, Japan.
(2)Department of Cardiovascular Medicine, Kyoto University Graduate School of
Medicine, Japan; Department of Internal Medicine, Wakakusa-Tatsuma
Rehabilitation Hospital, Japan.
(3)Department of Cardiovascular Medicine, Shinshu University School of Medicine,
Japan. Electronic address: kkuwah@shinshu-u.ac.jp.
The natriuretic peptide family consists of three biologically active peptides:
atrial natriuretic peptide (ANP), brain (or B-type) natriuretic peptide (BNP),
and C-type natriuretic peptide (CNP). Among these, ANP and BNP are secreted by
the heart and act as cardiac hormones. Both ANP and BNP preferentially bind to
natriuretic peptide receptor-A (NPR-A or guanylyl cyslase-A) and exert similar
effects through increases in intracellular cyclic guanosine monophosphate (cGMP)
within target tissues. Expression and secretion of ANP and BNP are stimulated by
various factors and are regulated via multiple signaling pathways. Human ANP has
three molecular forms, α-ANP, β-ANP, and proANP (or γ-ANP), with proANP
predominating in healthy atrial tissue. During secretion proANP is
proteolytically processed by corin, resulting in secretion of bioactive α-ANP
into the peripheral circulation. ProANP and β-ANP are minor forms in the
circulation but are increased in patients with heart failure. The human BNP
precursor proBNP is proteolytically processed to BNP1-32 and N-terminal proBNP
(NT-proBNP) within ventricular myocytes. Uncleaved proBNP as well as mature
BNP1-32 and NT-proBNP is secreted from the heart, and its secretion is increased
in patients with heart failure. Mature BNP, its metabolites including BNP3-32,
BNP4-32, and BNP5-32, and proBNP are all detected as immunoreactive-BNP by the
current BNP assay system. We recently developed an assay system that
specifically detects human proBNP. Using this assay system, we observed that
miR30-GALNTs-dependent O-glycosylation in the N-terminal region of proBNP
contributes to regulation of the processing and secretion of proBNP from the
heart.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
DOI: 10.1016/j.peptides.2018.05.012
PMID: 29859763 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14574050 | 1. Heart Fail Rev. 2003 Oct;8(4):315-20. doi: 10.1023/a:1026182912461.
B-type natriuretic peptide: physiologic role and assay characteristics.
Azzazy HM(1), Christenson RH.
Author information:
(1)Departments of Pathology and Medical & Research Technology, University of
Maryland School of Medicine, Baltimore, USA.
The discovery of cardiac natriuretic peptides two decades ago has lead to
considerable research to investigate their biochemical and physiological
properties. Clearly the heart is not just a pump but is also an endocrine organ
that together with the kidneys control volume overload. The natriuretic peptides
are a group of structurally similar but genetically distinct peptides that
exhibit diverse actions in cardiovascular, renal, and endocrine homeostasis.
Atrial natriuretic peptide (ANP) and brain (or B-type) natriuretic peptide (BNP)
are of myocardial cell origin. BNP is released mainly from the left ventricle in
response to volume overload and has become the first biochemical marker for the
identification of individuals with congestive heart failure (CHF). The
development of assays, including rapid point-of-care tests, has made BNP
measurement a clinical reality.
DOI: 10.1023/a:1026182912461
PMID: 14574050 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/14987573 | 1. Eur J Heart Fail. 2004 Mar 15;6(3):257-60. doi: 10.1016/j.ejheart.2003.12.015.
Essential biochemistry and physiology of (NT-pro)BNP.
Hall C(1).
Author information:
(1)Research Institute for Internal Medicine, University of Oslo, Rikshospitalet,
0037 Oslo, Norway. Christian.hall@klinmed.uio.no
Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide
hormone originally isolated from porcine brain tissue. The human BNP gene is
located on chromosome 1 and encodes the prohormone proBNP. The biologically
active BNP and the remaining part of the prohormone, NT-proBNP (76 amino acids)
can be measured by immunoassay in human blood. Cardiac myocytes constitute the
major source of BNP related peptides. The main stimulus for peptide synthesis
and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been
shown to produce BNP. Other neurohormones may stimulate cardiac BNP production
in different cardiac cell types. In contrast to atrial natriuretic peptides
(ANP/NT-proANP), which originate mainly from atrial tissue, BNP related peptides
are produced mainly from ventricular myocytes. Ventricular (NT-pro)BNP
production is strongly upregulated in cardiac failure and locally in the area
surrounding a myocardial infarction. In peripheral organs BNP binds to the
natriuretic peptide receptor type A causing increased intracellular cGMP
production. The biological effects include diuresis, vasodilatation, inhibition
of renin and aldosterone production and of cardiac and vascular myocyte growth.
In mice BNP gene knockout leads to cardiac fibrosis, gene over-expression to
hypotension and bone malformations. BNP is cleared from plasma through binding
to the natriuretic peptide clearance receptor type C, but it seems relatively
resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance
mechanisms for NT-proBNP await further study. While the plasma concentration of
NT-proBNP and BNP is approximately equal in normal controls, NT-proBNP plasma
concentration is 2-10 times higher than BNP in patients with heart failure. This
relative change in peptide levels may be explained by shifts in cardiac
secretion and/or clearance mechanisms.
DOI: 10.1016/j.ejheart.2003.12.015
PMID: 14987573 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30135320 | 1. Circ J. 2018 Sep 25;82(10):2455-2461. doi: 10.1253/circj.CJ-18-0824. Epub 2018
Aug 21.
Cutting Edge of Brain Natriuretic Peptide (BNP) Research - The Diversity of BNP
Immunoreactivity and Its Clinical Relevance.
Kuwahara K(1), Nakagawa Y(2), Nishikimi T(2)(3).
Author information:
(1)Department of Cardiovascular Medicine, Shinshu University School of Medicine.
(2)Department of Cardiovascular Medicine, Kyoto University Graduate School of
Medicine.
(3)Department of Internal Medicine, Wakakusa-Tatsuma Rehabilitation Hospital.
Brain (or B-type) natriuretic peptide (BNP) is a cardiac hormone produced in the
heart and an established biochemical marker for heart failure (HF) because the
level in plasma increases in proportion to disease severity. Recently, the
diversity of BNP molecular forms in the peripheral circulation, which includes
mature BNP (BNP1-32) and its metabolites (BNP3-32, BNP4-32, and BNP5-32), was
demonstrated. Moreover, studies showed that unprocessed BNP prohormone (proBNP)
is also secreted from the heart, and its secretion is increased in patients with
HF. Interestingly, BNP1-32, its metabolites, and proBNP are all detected as
immunoreactive BNP by the currently available BNP assay system. Current
N-terminal proBNP (NT-proBNP) assay systems also can react to both NT-proBNP and
proBNP. In addition, the N-terminal region of proBNP and NT-proBNP are often
O-glycosylated, which may result in underestimation of total NT-proBNP level,
which includes both glycosylated and non-glycosylated NT-proBNP, by the
NT-proBNP assay system. More recently, we have shown that miR30-GALNT-dependent
O-glycosylation in the N-terminal region of proBNP affects the processing of
proBNP and contributes to its secretion from the heart. The level of proBNP
relative to BNP (proBNP/BNP ratio) in the coronary sinus is higher in patients
with more severe HF. The proBNP/BNP ratio and the deglycosylated NT-proBNP level
may be new and clinically useful biomarkers of HF.
DOI: 10.1253/circj.CJ-18-0824
PMID: 30135320 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/30120963 | 1. Peptides. 2019 Jan;111:3-17. doi: 10.1016/j.peptides.2018.08.006. Epub 2018
Aug 16.
Natriuretic peptides in human heart: Novel insight into their molecular forms,
functions, and diagnostic use.
Matsuo A(1), Nagai-Okatani C(2), Nishigori M(1), Kangawa K(3), Minamino N(4).
Author information:
(1)Omics Research Center, National Cerebral and Cardiovascular Center, Suita,
Osaka 565-8565, Japan.
(2)Biotechnology Research Institute for Drug Discovery, National Institute of
Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8568, Japan.
(3)Research Institute, National Cerebral and Cardiovascular Center, Suita, Osaka
565-8565, Japan.
(4)Omics Research Center, National Cerebral and Cardiovascular Center, Suita,
Osaka 565-8565, Japan. Electronic address: minamino@ncvc.go.jp.
Among the three natriuretic peptides, atrial/A-type natriuretic peptide (ANP)
and brain/B-type natriuretic peptide (BNP) are primarily produced by, and
secreted from, heart tissue. They maintain cardiovascular homeostasis by binding
to natriuretic peptide receptor-A. Since plasma ANP and BNP concentrations, as
well as expression, are elevated in response to increased body fluid volume and
pressure load on the heart wall, these peptides are widely utilized as
diagnostic biomarkers for evaluating heart failure. Regardless of their high
utility, differences in their molecular forms between healthy and diseased
subjects and how these relate to pathophysiology have not well been examined.
Recent studies have shown that the circulating molecular forms of ANP and BNP
are not uniform; bioactive α-ANP is the major ANP form, whereas the weakly
active proBNP is the major BNP form. The relative ratios of the different
molecular forms are altered under different pathophysiological conditions. These
facts indicate that detailed measurements of each form may provide useful
information on the pathophysiological state of heart tissue. Here, we revisit
the relationship between the molecular forms of, and pathophysiological
alterations in, human ANP and BNP and discuss the possible utility of the
measurement of each of the molecular forms. The third peptide, C-type
natriuretic peptide, activates natriuretic peptide receptor-B, but little is
known about its production and function in the heart because of its extremely
low levels. However, through recent studies, its role in the heart is gradually
becoming clear. Here, we summarize its molecular forms, assay systems, and
functions in the heart.
Copyright © 2018 Elsevier Inc. All rights reserved.
DOI: 10.1016/j.peptides.2018.08.006
PMID: 30120963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/16689366 | 1. Nihon Rinsho. 2006 May;64(5):861-4.
[Plasma B-type natriuretic peptide (BNP) measuring].
[Article in Japanese]
Ashizawa N(1), Yano K.
Author information:
(1)Division of Cardiovascular Medicine, Graduate School of Biomedical Sciences,
Nagasaki University.
Brain or B-type natriuretic peptide (BNP) is a potent natriuretic, diuretic and
vasorelaxant peptide and inhibits sympathetic tone, the
renin-angiotensin-aldosterone system, and synthesis of vasoconstrictive
molecules. The major source of plasma BNP is the cardiac ventricles. Elevated
plasma BNP concentrations correlate with increased left ventricular (LV) filling
pressure. Therefore BNP is a useful biomarkers as a screening tool for LV
dysfunction. It also is a strong diagnostic indicator for both systolic and
diastolic LV dysfunction. Measurement of plasma BNP is proved to be not only an
efficient but also a cost effective screening tool for identifying patients with
acute dyspnea of unknown etiology.
PMID: 16689366 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/8025996 | 1. Circulation. 1994 Jul;90(1):195-203. doi: 10.1161/01.cir.90.1.195.
Localization and mechanism of secretion of B-type natriuretic peptide in
comparison with those of A-type natriuretic peptide in normal subjects and
patients with heart failure.
Yasue H(1), Yoshimura M, Sumida H, Kikuta K, Kugiyama K, Jougasaki M, Ogawa H,
Okumura K, Mukoyama M, Nakao K.
Author information:
(1)Division of Cardiology, Kumamoto University School of Medicine, Japan.
BACKGROUND: B-type or brain natriuretic peptide (BNP) is a novel natriuretic
peptide secreted from the heart that forms a peptide family with A-type or
atrial natriuretic peptide (ANP), and its plasma level has been shown to be
increased in patients with congestive heart failure. This study was designed to
examine the sources and mechanisms of the secretion of BNP in comparison with
those of ANP in control subjects and in patients with heart failure.
METHODS AND RESULTS: We measured the plasma levels of BNP as well as ANP in 16
patients with dilated cardiomyopathy (11 men and 5 women; mean age, 59 years)
and 18 control subjects (9 men and 9 women; mean age, 54 years) by sampling
blood from the femoral vein, the aortic root, the anterior interventricular vein
(AIV), and the coronary sinus using the newly developed immunoradiometric assay
systems. In the control subjects, there was no significant difference in the
plasma ANP level between the aortic root and the AIV (24.0 +/- 5.2 pg/mL versus
32.2 +/- 17.0 pg/mL), but there was a highly significant step-up of the level
between the AIV and the coronary sinus (32.2 +/- 17.0 pg/mL versus 371.4 +/-
111.1 pg/mL, P < .001). In contrast, there was a significant step-up of the
plasma BNP level between the aortic root and the AIV (8.6 +/- 6.4 pg/mL versus
19.0 +/- 11.5 pg/mL, P < .01) but not between the AIV and the coronary sinus
(19.0 +/- 11.5 pg/mL versus 28.8 +/- 14.0 pg/mL). On the other hand, in patients
with dilated cardiomyopathy, there was a significant step-up in the plasma ANP
level between the aortic root and the AIV (280.6 +/- 183.7 pg/mL versus 612.3
+/- 431.6 pg/mL, P < .01) and between the AIV and the coronary sinus (612.3 +/-
431.6 pg/mL versus 1229.0 +/- 772.7 pg/mL, P < .01). There was a significant
step-up in the plasma BNP level between the aortic root and the AIV (268.4 +/-
293.2 pg/mL versus 511.6 +/- 458.1 pg/mL, P < .01) but not between the AIV and
the coronary sinus (511.6 +/- 458.1 pg/mL versus 529.7 +/- 455.3 pg/mL) in
patients with dilated cardiomyopathy. The arteriovenous difference at the AIV of
the plasma level of BNP had a significant positive correlation with left
ventricular end-systolic volume index (r = 0.859, P < .001) and a significant
negative correlation with left ventricular ejection fraction (r = -.735, P <
.001).
CONCLUSIONS: We conclude that (1) BNP is secreted mainly from the left ventricle
in normal adult humans as well as in patients with left ventricular dysfunction,
whereas ANP is secreted from atria in normal adult humans and also from the left
ventricle in patients with left ventricular dysfunction; (2) secretion of BNP as
well as ANP from the left ventricle increases in proportion to the severity of
the left ventricular dysfunction, suggesting that the secretions of ANP and BNP
from the left ventricle are regulated mainly by wall tension of the left
ventricle; and (3) the peripheral plasma levels of ANP and BNP reflect the
secretion rate of these hormones from the left ventricle and may be used as a
marker of the degree of left ventricular dysfunction in patients with left
ventricular dysfunction.
DOI: 10.1161/01.cir.90.1.195
PMID: 8025996 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10519161 | 1. Proc Assoc Am Physicians. 1999 Sep-Oct;111(5):406-16. doi:
10.1111/paa.1999.111.5.406.
The natriuretic peptides in heart failure: diagnostic and therapeutic
potentials.
Chen HH(1), Burnett JC Jr.
Author information:
(1)Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo
Clinic and Foundation, Rochester, MN 55905, USA.
The natriuretic peptides are a group of structurally similar but genetically
distinct peptides that have diverse actions in cardiovascular, renal, and
endocrine homeostasis. Atrial natriuretic peptide (ANP) and brain natriuretic
peptide (BNP) are of myocardial cell origin and C-type natriuretic peptide (CNP)
is of endothelial origin. ANP and BNP bind to the natriuretic peptide-A receptor
(NPR-A), which, via 3',5'-cyclic guanosine monophosphate (cGMP), mediates
natriuresis, vasodilation, renin inhibition, antimitogenesis, and lusitropic
properties. CNP lacks natriuretic actions but possesses vasodilating and
growth-inhibiting actions via the guanylyl cyclase-linked natriuretic peptide-B
receptor (NPR-B). All three peptides are cleared by the natriuretic peptide-C
receptor (NPR-C) and are degraded by the ectoenzyme neutral endopeptidase 24.11
(NEP), both of which are widely expressed in the kidneys, lungs, and the
vascular wall. Congestive heart failure (CHF) represents a pathological state in
which the activation of the natriuretic peptides exceeds those of all other
states. In this brief review, we will attempt to provide an update on important
issues regarding natriuretic peptides in CHF, with a focus on their functional
importance as a beneficial humoral response in asymptomatic left ventricular
dysfunction (LVD), the mechanisms of natriuretic peptide hyporesponsiveness in
severe heart failure, the diagnostic and prognostic significance of the
natriuretic peptides in CHF, and the therapeutic potential of the natriuretic
peptides in this multiorgan syndrome.
DOI: 10.1111/paa.1999.111.5.406
PMID: 10519161 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29978892 | 1. Compr Physiol. 2018 Jun 18;8(3):1211-1249. doi: 10.1002/cphy.c180002.
Natriuretic Peptides and Normal Body Fluid Regulation.
Bie P(1).
Author information:
(1)Department of Cardiovascular and Renal Research, Institute of Molecular
Medicine, University of Southern Denmark, Odense, Denmark.
Natriuretic peptides are structurally related, functionally diverse hormones.
Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)
are delivered predominantly by the heart. Two C-type natriuretic peptides (CNPs)
are paracrine messengers, notably in bone, brain, and vessels. Natriuretic
peptides act by binding to the extracellular domains of three receptors, NPR-A,
NPR-B, and NPR-C of which the first two are guanylate cyclases. NPR-C is coupled
to inhibitory proteins. Atrial wall stress is the major regulator of ANP
secretion; however, atrial pressure changes plasma ANP only modestly and
transiently, and the relation between plasma ANP and atrial wall tension (or
extracellular volume or sodium intake) is weak. Absence and overexpression of
ANP-related genes are associated with modest blood pressure changes. ANP
augments vascular permeability and reduces vascular contractility, renin and
aldosterone secretion, sympathetic nerve activity, and renal tubular sodium
transport. Within the physiological range of plasma ANP, the responses to
step-up changes are unimpressive; in man, the systemic physiological effects
include diminution of renin secretion, aldosterone secretion, and cardiac
preload. For BNP, the available evidence does not show that cardiac release to
the blood is related to sodium homeostasis or body fluid control. CNPs are not
circulating hormones, but primarily paracrine messengers important to
ossification, nervous system development, and endothelial function. Normally,
natriuretic peptides are not powerful natriuretic/diuretic hormones; common
conclusions are not consistently supported by hard data. ANP may provide
fine-tuning of reno-cardiovascular relationships, but seems, together with BNP,
primarily involved in the regulation of cardiac performance and remodeling. ©
2017 American Physiological Society. Compr Physiol 8:1211-1249, 2018.
Copyright © 2018 American Physiological Society. All rights reserved.
DOI: 10.1002/cphy.c180002
PMID: 29978892 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/12084525 | 1. Peptides. 2002 May;23(5):935-40. doi: 10.1016/s0196-9781(02)00004-9.
Human bone marrow endothelial cells: a new identified source of B-type
natriuretic peptide.
Bordenave L(1), Georges A, Bareille R, Conrad V, Villars F, Amédée J.
Author information:
(1)U-443-INSERM, Université Victor Segalen Bordeaux 2, 146 rue Léo Saignat,
Bordeaux, France. laurence.bordenave@u-bordeaux2.fr
B-type natriuretic peptide (BNP) is a hormone mainly secreted by cardiac
ventricle myocytes and which is increased in cardiac diseases. Moreover, BNP
expression has been shown in various cell/tissue types. Six different human
endothelial cell (EC) culture models arising from macro and microcirculation
either primary cultures or cell lines were cultured and screened for BNP
presence and secretion. All cell types expressed BNP mRNA while only the ECs
arising from bone marrow stromal compartment secreted high amounts of BNP
protein. This report is the first to identify ECs as a new source of BNP.
However, BNP secretion is limited to a particular EC type.
DOI: 10.1016/s0196-9781(02)00004-9
PMID: 12084525 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35181864 | 1. Infection. 2022 Jun;50(3):771-774. doi: 10.1007/s15010-022-01779-x. Epub 2022
Feb 18.
High titer of antibody against the SARS-CoV-2 spike protein among patients
receiving neutralizing antibody cocktail therapy with REGN-COV.
Sasaki H(1), Miyata N(2), Yoshimura Y(2), Tachikawa N(2).
Author information:
(1)Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital,
1-1, Mitsuzawanishimachi, Yokohama City, Kanagawa, Japan.
sasaki.hiro.21@gmail.com.
(2)Department of Infectious Diseases, Yokohama Municipal Citizen's Hospital,
1-1, Mitsuzawanishimachi, Yokohama City, Kanagawa, Japan.
PURPOSE: Casirivimab/imdevimab (REGN-COV), a cocktail of neutralizing antibodies
against the receptor-binding domain of the severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) spike protein, was shown to be an effective treatment
and post-exposure prophylaxis measure for coronavirus disease 2019 (COVID-19).
We assessed the antibody titers among patients who received REGN-COV with the
purpose of evaluating this therapeutic and prophylactic option from the
serological point of view.
METHODS: We collected serological data of patients with COVID-19 who were
treated with REGN-COV 1200 mg (casirivimab 600 mg/imdevimab 600 mg). Antibody
titers were assessed within 24 h before and within 48 h after the administration
of REGN-COV using ARCHITECT SARS-CoV-2 immunoglobulin (Ig)G (IgGNC), which is
against nucleocapsid protein, and ARCHITECT SARS-CoV-2 IgG II Quant (IgGSP),
which is against spike protein.
RESULTS: A total of nine patients were evaluated. IgGSP was elevated after
REGN-COV administration with a median of 208,370 Arbitrary Units/mL while
simultaneous IgGNC remained low. With the simple linear regression model, the
IgGSP after the REGN-COV administration was correlated with the reciprocal of
ideal body weight.
CONCLUSION: The high titer of IgGSP supports the clinical benefit of therapeutic
and prophylactic use of REGN-COV from the serological point of view.
© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.
DOI: 10.1007/s15010-022-01779-x
PMCID: PMC8856927
PMID: 35181864 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/34318930 | 1. Cochrane Database Syst Rev. 2021 Jul 28;7(7):CD015017. doi:
10.1002/14651858.CD015017.pub2.
Ivermectin for preventing and treating COVID-19.
Popp M(1), Stegemann M(2), Metzendorf MI(3), Gould S(4), Kranke P(1), Meybohm
P(1), Skoetz N(5), Weibel S(1).
Author information:
(1)Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine,
University Hospital Wuerzburg, Wuerzburg, Germany.
(2)Department of Infectious Diseases and Respiratory Medicine, Charité -
Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and
Humboldt-Universität zu Berlin, Berlin, Germany.
(3)Cochrane Metabolic and Endocrine Disorders Group, Institute of General
Practice, Medical Faculty of the Heinrich-Heine-University Düsseldorf,
Düsseldorf, Germany.
(4)Royal Liverpool University Hospital, Liverpool, UK.
(5)Cochrane Cancer, Department I of Internal Medicine, Center for Integrated
Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University
Hospital Cologne, University of Cologne, Cologne, Germany.
Update in
Cochrane Database Syst Rev. 2022 Jun 21;6:CD015017. doi:
10.1002/14651858.CD015017.pub3.
Comment in
Nature. 2022 Jan;601(7892):167. doi: 10.1038/d41586-022-00025-6.
BACKGROUND: Ivermectin, an antiparasitic agent used to treat parasitic
infestations, inhibits the replication of viruses in vitro. The molecular
hypothesis of ivermectin's antiviral mode of action suggests an inhibitory
effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
replication in the early stages of infection. Currently, evidence on efficacy
and safety of ivermectin for prevention of SARS-CoV-2 infection and COVID-19
treatment is conflicting.
OBJECTIVES: To assess the efficacy and safety of ivermectin compared to no
treatment, standard of care, placebo, or any other proven intervention for
people with COVID-19 receiving treatment as inpatients or outpatients, and for
prevention of an infection with SARS-CoV-2 (postexposure prophylaxis).
SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science
(Emerging Citation Index and Science Citation Index), medRxiv, and Research
Square, identifying completed and ongoing studies without language restrictions
to 26 May 2021.
SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing
ivermectin to no treatment, standard of care, placebo, or another proven
intervention for treatment of people with confirmed COVID-19 diagnosis,
irrespective of disease severity, treated in inpatient or outpatient settings,
and for prevention of SARS-CoV-2 infection. Co-interventions had to be the same
in both study arms. We excluded studies comparing ivermectin to other
pharmacological interventions with unproven efficacy.
DATA COLLECTION AND ANALYSIS: We assessed RCTs for bias, using the Cochrane risk
of bias 2 tool. The primary analysis excluded studies with high risk of bias. We
used GRADE to rate the certainty of evidence for the following outcomes 1. to
treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening
or improvement, adverse events, quality of life, duration of hospitalization,
and viral clearance; 2. to treat outpatients with mild COVID-19: mortality,
clinical worsening or improvement, admission to hospital, adverse
events, quality of life, and viral clearance; (3) to prevent SARS-CoV-2
infection: SARS-CoV-2 infection, development of COVID-19 symptoms, adverse
events, mortality, admission to hospital, and quality of life.
MAIN RESULTS: We found 14 studies with 1678 participants investigating
ivermectin compared to no treatment, placebo, or standard of care. No study
compared ivermectin to an intervention with proven efficacy. There were nine
studies treating participants with moderate COVID-19 in inpatient settings and
four treating mild COVID-19 cases in outpatient settings. One study investigated
ivermectin for prevention of SARS-CoV-2 infection. Eight studies had an
open-label design, six were double-blind and placebo-controlled. Of the 41 study
results contributed by included studies, about one third were at overall high
risk of bias. Ivermectin doses and treatment duration varied among included
studies. We identified 31 ongoing and 18 studies awaiting classification until
publication of results or clarification of inconsistencies. Ivermectin compared
to placebo or standard of care for inpatient COVID-19 treatment We are uncertain
whether ivermectin compared to placebo or standard of care reduces or increases
mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2
studies, 185 participants; very low-certainty evidence) and clinical worsening
up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR
0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low-certainty
evidence) or need for supplemental oxygen (0 participants required supplemental
oxygen; 1 study, 45 participants; very low-certainty evidence), adverse events
within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very
low-certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51
to 6.48; 2 studies, 159 participants; very low-certainty evidence). Ivermectin
may have little or no effect compared to placebo or standard of care on clinical
improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73
participants; low-certainty evidence) and duration of hospitalization (mean
difference (MD) -0.10 days, 95% CI -2.43 to 2.23; 1 study; 45 participants;
low-certainty evidence). No study reported quality of life up to 28 days.
Ivermectin compared to placebo or standard of care for outpatient COVID-19
treatment We are uncertain whether ivermectin compared to placebo or standard of
care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05;
2 studies, 422 participants; very low-certainty evidence) and clinical worsening
up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study,
398 participants; very low-certainty evidence) or non-IMV or high flow oxygen
requirement (0 participants required non-IMV or high flow; 1 study, 398
participants; very low-certainty evidence). We are uncertain whether ivermectin
compared to placebo reduces or increases viral clearance at seven days (RR 3.00,
95% CI 0.13 to 67.06; 1 study, 24 participants; low-certainty evidence).
Ivermectin may have little or no effect compared to placebo or standard of care
on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95%
CI 0.89 to 1.21; 1 study, 398 participants; low-certainty evidence) and adverse
events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422
participants; low-certainty evidence). None of the studies reporting duration of
symptoms were eligible for primary analysis. No study reported hospital
admission or quality of life up to 14 days. Ivermectin compared to no treatment
for prevention of SARS-CoV-2 infection We found one study. Mortality up to 28
days was the only outcome eligible for primary analysis. We are uncertain
whether ivermectin reduces or increases mortality compared to no treatment (0
participants died; 1 study, 304 participants; very low-certainty evidence). The
study reported results for development of COVID-19 symptoms and adverse events
up to 14 days that were included in a secondary analysis due to high risk of
bias. No study reported SARS-CoV-2 infection, hospital admission, and quality of
life up to 14 days.
AUTHORS' CONCLUSIONS: Based on the current very low- to low-certainty evidence,
we are uncertain about the efficacy and safety of ivermectin used to treat or
prevent COVID-19. The completed studies are small and few are considered high
quality. Several studies are underway that may produce clearer answers in review
updates. Overall, the reliable evidence available does not support the use
ivermectin for treatment or prevention of COVID-19 outside of well-designed
randomized trials.
Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published
by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.
DOI: 10.1002/14651858.CD015017.pub2
PMCID: PMC8406455
PMID: 34318930 [Indexed for MEDLINE]
Conflict of interest statement: MP: funded by the Federal Ministry of Education
and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021; part of the
CEOsys project, which was paid to the institution). MS: none. MIM: none. SG:
none. PK: none. PM: none. NS: none. SW: is funded by the Federal Ministry of
Education and Research, Germany (NaFoUniMedCovid19, funding number: 01KX2021;
part of the CEOsys project, which was paid to the institution). |
http://www.ncbi.nlm.nih.gov/pubmed/36411267 | 1. Clin Infect Dis. 2023 Apr 3;76(7):1247-1256. doi: 10.1093/cid/ciac899.
AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic
Coronavirus Disease 2019.
Levin MJ(1), Ustianowski A(2), Thomas S(3), Templeton A(4), Yuan Y(3), Seegobin
S(4), Houlihan CF(5)(6), Menendez-Perez I(7), Pollett S(8)(9), Arends RH(10),
Beavon R(11), Dey K(12), Garbes P(12), Kelly EJ(13), Koh GCKW(11), Ivanov S(14),
Near KA(12), Sharbaugh A(15), Streicher K(13), Pangalos MN(16), Esser MT(17);
COVID-19 Study to Optimally Reduce Morbidity in CareHomes and Sites with
Enhanced Risk (STORMCHASER) Study Group.
Author information:
(1)University of Colorado Denver School of Medicine, Aurora, Colorado, USA.
(2)North Manchester General Hospital, Manchester, United Kingdom.
(3)Biometrics, Vaccines and Immune Therapies, BioPharmaceuticals Research and
Development, AstraZeneca, Gaithersburg, Maryland, USA.
(4)Biometrics, Vaccines and Immune Therapies, BioPharmaceuticals Research and
Development, AstraZeneca, Cambridge, United Kingdom.
(5)Department of Clinical Virology, University College London Hospitals National
Health Service Foundation Trust, London, United Kingdom.
(6)Department of Infection and Immunity, University College London, London,
United Kingdom.
(7)Project 4 Research, Miami, Florida, USA.
(8)Infectious Disease Clinical Research Program, Department of Preventive
Medicine and Biostatistics, Uniformed Services University of the Health
Sciences, Bethesda, Maryland, USA.
(9)Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc,
Bethesda, Maryland, USA.
(10)Clinical Pharmacology and Quantitative Pharmacology, Vaccines and Immune
Therapies, BioPharmaceuticals Research and Development, AstraZeneca,
Gaithersburg, Maryland, USA.
(11)Clinical Development, Vaccines and Immune Therapies, BioPharmaceuticals
Research and Development, AstraZeneca, Cambridge, United Kingdom.
(12)Clinical Development, Vaccines and Immune Therapies, BioPharmaceuticals
Research and Development, AstraZeneca, Gaithersburg, Maryland, USA.
(13)Translational Medicine, Vaccines and Immune Therapies, BioPharmaceuticals
Research and Development, AstraZeneca, Gaithersburg, Maryland, USA.
(14)Clinical Development, Vaccines and Immune Therapies, BioPharmaceuticals
Research and Development, AstraZeneca, Gothenburg, Sweden.
(15)Clinical Development, Vaccines and Immune Therapies, BioPharmaceuticals
Research and Development, AstraZeneca, Durham, North Carolina, USA.
(16)BioPharmaceuticals Research and Development, AstraZeneca, Cambridge, United
Kingdom.
(17)Vaccines and Immune Therapies, BioPharmaceuticals Research and Development,
AstraZeneca, Gaithersburg, Maryland, USA.
Comment in
Clin Infect Dis. 2023 Apr 3;76(7):1257-1259. doi: 10.1093/cid/ciac902.
BACKGROUND: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for
post-exposure prophylaxis against symptomatic coronavirus disease 2019
(COVID-19).
METHODS: Adults without prior severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of
exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single
300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and
cilgavimab) or placebo. Primary end points were safety and first post-dose
SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive
symptomatic COVID-19 event before day 183.
RESULTS: A total of 1121 participants were randomized and dosed (AZD7442, n =
749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113)
days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of
749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo,
respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19
occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated
participants, respectively (relative risk reduction, 33.3%; 95% confidence
interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073
(96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing
an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive
symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo.
CONCLUSIONS: This study did not meet the primary efficacy end point of
post-exposure prevention of symptomatic COVID-19. However, analysis of
participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at
baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical
Trials Registration. NCT04625972.
© The Author(s) 2022. Published by Oxford University Press on behalf of
Infectious Diseases Society of America.
DOI: 10.1093/cid/ciac899
PMCID: PMC10069855
PMID: 36411267 [Indexed for MEDLINE]
Conflict of interest statement: Potential conflicts of interest. M. J. L.
reports research support from GSK, Johnson & Johnson, Moderna, and Novavax;
consultancy for Dynavax, GSK, Merck & Co, Pfizer, and Seqirus; and participation
on a data and safety monitoring board (DSMB)/advisory board for GSK. A. U.
reports honoraria/speaker fees from Sanofi, Merck, Janssen, GSK, Roche, ViiV,
and Gilead; advisory boards for Gilead, Merck, and ViiV/GSK; and participation
on a DSMB for COV-Boost study, Flare study, and for Vicore. S. D. P. reports
that the USU Infectious Diseases Clinical Research Program (IDCRP), a US
Department of Defense institution, and HJF were funded under a cooperative
research and development agreement to help conduct the STORM CHASER study,
sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was also funded
by the Department of Defense Joint Program Executive Office for Chemical,
Biological, Radiological, and Nuclear Defense to augment the conduct of an
unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials
were part of the US government COVID-19 response. M. T. E. reports patents
planned, issued, or pending by AstraZeneca on AZD7442. P. G. reports consulting
fees from Medicago and Takeda Vaccines as senior medical director; a leadership
or fiduciary role as a full member of the Academy of Medicine in Rio de Janeiro,
Brazil; and stock or stock options in Takeda Pharmaceuticals, AstraZeneca. All
authors report medical writing assistance provided by Prime Global. S. T., A.
T., Y. Y., S. S., R. H. A., R. B., K. D., P. G., E. J. K., G. C. K. W. K., S.
I., K. A. N., A. S., K. S., M. N. P., and M. T. E. are employees of and hold or
may hold stock in AstraZeneca. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts
of Interest. Conflicts that the editors consider relevant to the content of the
manuscript have been disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/18706401 | 1. Clin Chim Acta. 2008 Dec;398(1-2):1-4. doi: 10.1016/j.cca.2008.07.020. Epub
2008 Jul 24.
B-type natriuretic peptide in acute pulmonary embolism.
Kaczyńska A(1), Kostrubiec M, Ciurzyński M, Pruszczyk P.
Author information:
(1)Department of Internal Medicine and Cardiology, Medical University of Warsaw,
Poland.
Myocardial stretch leads to the natriuretic peptides release in acute or chronic
left ventricular dysfunction. However, there is an accumulating evidence that
B-type natriuretic peptide (BNP) and its N-terminal fragment (NT-proBNP) may
originate from right ventricle and their concentrations are elevated in patients
with acute pulmonary embolism (APE) especially when resulting in right
ventricular dysfunction (RVD). Recently it is underlined that severity
assessment of APE as well as the risk stratification and therapy selection is
based both on patients' hemodynamic status and markers of myocardial injury and
RVD. BNP and NT-proBNP are helpful in identifying patients with RVD in APE,
emerging as an adjunctive tool to echocardiography. Elevated BNP or NT-proBNP
levels are also significant predictors of death and/or complicated clinical
course in APE.
DOI: 10.1016/j.cca.2008.07.020
PMID: 18706401 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36399336 | 1. J Clin Pharmacol. 2023 Mar;63(3):288-297. doi: 10.1002/jcph.2178. Epub 2022
Dec 10.
Ivermectin's Role in the Prevention of COVID-19: A Systematic Review and
Meta-Analysis.
Hu GY(1), Liang CA(2), Lin PC(3), Lin CY(4).
Author information:
(1)Division of Gastroenterology and Hepatology, Department of Internal Medicine,
Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
(2)Department of Pharmacy, Kaohsiung Veterans General Hospital, Kaohsiung,
Taiwan.
(3)Department of Medical Education and Research, Kaohsiung Veterans General
Hospital, Kaohsiung, Taiwan.
(4)Division of Cardiology, Department of Internal Medicine, Kaohsiung Veterans
General Hospital, Kaohsiung, Taiwan.
This systematic review was performed to determine the population that benefited
from prophylactic ivermectin. Seven databases of health-related studies were
searched for eligible trials without language restrictions. Randomized
controlled trials (RCTs) and cohort studies investigating ivermectin for
coronavirus disease 2019 (COVID-19) prevention were included. Data were pooled
using a random-effects model, and subgroups were analyzed by study type and the
pre- or postexposure population. The certainty of the evidence was determined by
the Grading of Recommendations Assessment, Development, and Evaluation approach.
Furthermore, 4 RCTs and 4 cohort studies with a moderate to high risk of bias
were included in the analysis. The prophylactic use of ivermectin significantly
decreased the overall incidence of COVID-19 (odds ratio [OR], 0.26; 95%
confidence interval [CI], 0.16-0.44). Nevertheless, the positive result was not
supported by the RCT. Ivermectin was associated with a lower risk of COVID-19
(OR, 0.22; 95% CI, 0.12-0.40) in the preexposure population, whereas no
protective effect was observed in the postexposure population (OR, 0.39; 95% CI,
0.09-1.67). In summary, prophylactic ivermectin did not prevent COVID-19 in the
postexposure population. Although the protective effect of ivermectin was shown
in the overall and preexposure populations, the results were unreliable owing to
poor-quality evidence.
© 2022, The American College of Clinical Pharmacology.
DOI: 10.1002/jcph.2178
PMID: 36399336 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33284679 | 1. Ann Intern Med. 2021 Mar;174(3):344-352. doi: 10.7326/M20-6519. Epub 2020 Dec
8.
Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute
Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial.
Barnabas RV(1), Brown ER(1), Bershteyn A(2), Stankiewicz Karita HC(3), Johnston
C(1), Thorpe LE(2), Kottkamp A(2), Neuzil KM(4), Laufer MK(4), Deming M(4),
Paasche-Orlow MK(5), Kissinger PJ(6), Luk A(7), Paolino K(8), Landovitz RJ(9),
Hoffman R(9), Schaafsma TT(3), Krows ML(3), Thomas KK(3), Morrison S(3), Haugen
HS(3), Kidoguchi L(3), Wener M(3), Greninger AL(1), Huang ML(10), Jerome KR(1),
Wald A(1), Celum C(3), Chu HY(3), Baeten JM(3); Hydroxychloroquine COVID-19 PEP
Study Team.
Collaborators: Dull P, Miller S, Pham T, Arroyave L, Berz J, Buitron P, Camuso
M, Cardoso L, Cruz R, Dedier J, Dennaoui H, Goldman A, Greenstein C, Henault L,
Johnson T, Kimball S, Martinez C, Martinez E, Ng C, Paarz W, Ogunneye Q,
Paasche‐Orlow L, Rogers M, Salerno K, Smithline M, Streed C, Verma N, Waite K,
Hosek S, Balthazar C, Jarris A, Greene LA, Buist D, Aldana SI, Alsaloum M,
Anastasiou E, Cardozo RA, Badiei B, Bakirova K, Bakirova Z, Barnes C, Bedi SK,
Beggs DB, Bendik SE, Cao M, Chang M, Chen S, Cheng A, Chong SK, Coates J,
Conderino S, Connery J, Connolly M, Contreras AL, Dreier MS, Duan E, Hidalgo ET,
Fadzan M, Fagan SN, Fried J, Gago J, Gakou N, Gill E, Gujral A, Hao X, Hughes C,
James RT, Kim S, Krieger P, Landon SN, Liang ALJ, Lopez PM, Mamistvalova L,
Schwartz MD, McQuay S, Miao WW, Mohaimin S, Naranjo KG, Nguyen‐Stone K, Peltekci
A, Peña A, Perdomo K, Pompeii ML, Quintana L, Reynolds AJ, Pitts RA, Rodriguez
A, Sasankan P, Sharma SR, Shire A, Sota S, Spoer BR, Springer B, Stadelman J,
Wysota CB, Yang J, Yepez M, Cram D, Eustace S, Mandziuk K, Massaro M, Mullenix
C, Reichard T, Towner T, Abbott M, Asiago‐Reddy E, Baxter K, Caiello K, Endy T,
Geneva I, Greco P, Harausz E, Klick M, Mehlek P, Miller C, Reale M, Ripich K,
Shaw A, Terrillion K, Thomas S, Anibaba M, Atkinson E, Blyth M, Campbell MB,
Carsch L, Ganguly A, Gupta S, Larkin H, Hall J, Huntwork J, Huntwork M,
McConville M, McDougal A, Numbi F, Ntambwe C, Palomares M, Plaxico D, Rady H,
Ribando M, Sauter S, Triggs D, Upadhyay N, Schmidt N, Watson S, Zheng C, Arias
R, Bhimani AJ, Blair C, Cambou C, Cayabyab M, Corona R, Escobedo D, Furukawa D,
Gonzalez A, Karpf H, Kofron R, Largaespada K, Lopez N, Mansky H, Martin‐Blais R,
Petreuse A, Shin C, Tran TT, Weldon A, Were G, Agrawal V, Billington M, Birkhold
M, Boyce C, Cloeren M, Palacios CF, Friedman‐Klabanoff D, Kwon A, LeBuhn H, Liu
E, Lu M, McDiarmid M, Myers M, Pa'ahana‐Brown F, Poley M, Shrestha B, Wilkerson
G, Alidina N, Arnold S, Bauer M, Baugh J, Bayer C, Bole M, Brandstetter E, Braun
A, Brown CE, Brown M, Bulterys M, Castor J, Dematteis M, Doan I, Drummond M,
Feutz E, Galagan S, Hamilton D, Hauge K, Hay E, Hladik F, Hou X, Houston D,
Humphreys M, Hussein A, Ikuma M, Issema R, Johnson R, Kirk M, Knauer J, Kuntz
SR, Lawton S, Letterer R, Lingappa E, Lingappa JR, Liou CH, Lund K, Maddox T,
Mathur A, Metter M, McClellan L, Montoya D, Moreno JC, Morlin GC, Pandey U,
Pepper G, Pettit A, Pholsena T, Popp G, Purcell J, Quame‐Amaglo J, Sampoleo R,
Sanger E, Seymour M, Shercliffe A, Somani S, Stewart JC, Tamakole S, Taub JM,
Thuesmunn Z, Tungara A, Valinetz E, Varon DL, Vazquez V, Vo B, Wanga V, Waters
CD, Wei Y, Welsh M, Wicklander K, Wood BR, Young G, Young Z, Zhao L, Zimmermann
A, Brown DJ, Davenport N, Gambito O.
Author information:
(1)University of Washington and Fred Hutchinson Cancer Research Center, Seattle,
Washington (R.V.B., E.R.B., C.J., A.L.G., K.R.J., A.W.).
(2)New York University Grossman School of Medicine, New York, New York (A.B.,
L.E.T., A.K.).
(3)University of Washington, Seattle, Washington (H.C.S., T.T.S., M.L.K.,
K.K.T., S.M., H.S.H., L.K., M.W., C.C., H.Y.C., J.M.B.).
(4)University of Maryland School of Medicine, Baltimore, Maryland (K.M.N.,
M.K.L., M.D.).
(5)Boston University School of Medicine and Boston Medical Center, Boston,
Massachusetts (M.K.P.).
(6)School of Public Health and Tropical Medicine, Tulane University, New
Orleans, Louisiana (P.J.K.).
(7)School of Medicine, Tulane University, New Orleans, Louisiana (A.L.).
(8)State University of New York Upstate Medical University, Syracuse, New York
(K.P.).
(9)University of California, Los Angeles, California (R.J.L., R.H.).
(10)Fred Hutchinson Cancer Research Center, Seattle, Washington (M.H.).
Erratum in
Ann Intern Med. 2021 Mar;174(3):435. doi: 10.7326/L21-0009.
BACKGROUND: Effective prevention against coronavirus disease 2019 (COVID-19),
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is
currently limited to nonpharmaceutical strategies. Laboratory and observational
data suggested that hydroxychloroquine had biological activity against
SARS-CoV-2, potentially permitting its use for prevention.
OBJECTIVE: To test hydroxychloroquine as postexposure prophylaxis for SARS-CoV-2
infection.
DESIGN: Household-randomized, double-blind, controlled trial of
hydroxychloroquine postexposure prophylaxis. (ClinicalTrials.gov: NCT04328961).
SETTING: National U.S. multicenter study.
PARTICIPANTS: Close contacts recently exposed (<96 hours) to persons with
diagnosed SARS-CoV-2 infection.
INTERVENTION: Hydroxychloroquine (400 mg/d for 3 days followed by 200 mg/d for
11 days) or ascorbic acid (500 mg/d followed by 250 mg/d) as a
placebo-equivalent control.
MEASUREMENTS: Participants self-collected mid-turbinate swabs daily (days 1 to
14) for SARS-CoV-2 polymerase chain reaction (PCR) testing. The primary outcome
was PCR-confirmed incident SARS-CoV-2 infection among persons who were
SARS-CoV-2 negative at enrollment.
RESULTS: Between March and August 2020, 671 households were randomly assigned:
337 (407 participants) to the hydroxychloroquine group and 334 (422
participants) to the control group. Retention at day 14 was 91%, and 10 724 of
11 606 (92%) expected swabs were tested. Among the 689 (89%) participants who
were SARS-CoV-2 negative at baseline, there was no difference between the
hydroxychloroquine and control groups in SARS-CoV-2 acquisition by day 14 (53
versus 45 events; adjusted hazard ratio, 1.10 [95% CI, 0.73 to 1.66]; P > 0.20).
The frequency of participants experiencing adverse events was higher in the
hydroxychloroquine group than the control group (66 [16.2%] versus 46 [10.9%],
respectively; P = 0.026).
LIMITATION: The delay between exposure, and then baseline testing and the first
dose of hydroxychloroquine or ascorbic acid, was a median of 2 days.
CONCLUSION: This rigorous randomized controlled trial among persons with recent
exposure excluded a clinically meaningful effect of hydroxychloroquine as
postexposure prophylaxis to prevent SARS-CoV-2 infection.
PRIMARY FUNDING SOURCE: Bill & Melinda Gates Foundation.
DOI: 10.7326/M20-6519
PMCID: PMC7732017
PMID: 33284679 [Indexed for MEDLINE]
Conflict of interest statement: Disclosures: Disclosures can be viewed at
www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M20-6519. |
http://www.ncbi.nlm.nih.gov/pubmed/34669839 | 1. J Bras Pneumol. 2021 Oct 15;47(5):e20210236. doi:
10.36416/1806-3756/e20210236. eCollection 2021.
Use of hydroxychloroquine to prevent SARS-CoV-2 infection and treat mild
COVID-19: a systematic review and meta-analysis.
Tanni SE(1), Bacha HA(2), Naime A(3), Bernardo WM(4).
Author information:
(1). Disciplina de Pneumologia, Departamento de Clínica Médica, Faculdade de
Medicina de Botucatu, Universidade Estadual Paulista, Botucatu (SP) Brasil.
(2). Hospital Israelita Albert Einstein, São Paulo (SP) Brasil.
(3). Disciplina de Doenças Infecciosas, Faculdade de Medicina de Botucatu,
Universidade Estadual Paulista, Botucatu (SP) Brasil.
(4). Faculdade de Medicina, Universidade de São Paulo, São Paulo (SP) Brasil.
OBJECTIVE: Chloroquine or hydroxychloroquine has demonstrated no effect on the
treatment of hospitalized COVID-19 patients. This study aimed to answer
questions related to the use of hydroxychloroquine for pre-exposure or
post-exposure prophylaxis of SARS-CoV-2 infection and in the treatment of
patients with mild COVID-19 in terms of hospitalization, adverse events, and
mortality.
METHODS: This was a systematic review and meta-analysis of phase 3 randomized
clinical trials, selected from various databases, which compared patients who
received hydroxychloroquine for SARS-CoV-2 prophylaxis or treatment of mild
COVID-19 cases with controls.
RESULTS: A total number of 1,376 studies were retrieved. Of those, 9 met the
eligibility criteria and were included in the study. No statistically
significant differences were found between the hydroxychloroquine and control
groups in terms of pre- or post-exposure prophylaxis of SARS-CoV-2 infection.
The use of hydroxychloroquine increased the risk of adverse events by 12% (95%
CI, 6-18%; p < 0.001), and the number needed to harm was 9. In addition, no
significant differences were found between the hydroxychloroquine and control
groups regarding hospitalization (risk difference [RD] = -0.02; 95% CI, -0.04 to
0.00; p = 0.14) or mortality (RD = 0.00; 95% CI, -0.01 to 0.02; p = 0.98) in the
treatment of mild COVID-19.
CONCLUSIONS: The use of hydroxychloroquine for prophylaxis of SARS-CoV-2
infection or treatment of patients with mild COVID-19 is not recommended.
OBJETIVO: A cloroquina ou hidroxicloroquina não apresentou nenhum efeito no
tratamento de pacientes hospitalizados com COVID-19. O objetivo deste estudo foi
responder a questões a respeito do uso de hidroxicloroquina na profilaxia da
infecção por SARS-CoV-2 pré ou pós-exposição e no tratamento de pacientes com
COVID-19 leve no tocante à hospitalização, eventos adversos e mortalidade.
MÉTODOS: Trata-se de uma revisão sistemática e meta-análise de ensaios clínicos
controlados aleatórios de fase 3 que foram selecionados por meio de buscas em
diversos bancos de dados e que compararam controles e pacientes que receberam
hidroxicloroquina para profilaxia de SARS-CoV-2 ou tratamento de COVID-19 leve.
RESULTADOS: Foram identificados 1.376 estudos. Destes, 9 preencheram os
critérios de elegibilidade e foram incluídos no estudo. Não foram encontradas
diferenças significativas entre os grupos hidroxicloroquina e controle quanto à
profilaxia da infecção por SARS-CoV-2 pré ou pós-exposição. O uso de
hidroxicloroquina aumentou o risco de eventos adversos em 12% (IC95%: 6-18%; p <
0,001), e o número necessário para prejudicar foi 9. Não foram encontradas
diferenças significativas entre os grupos hidroxicloroquina e controle quanto à
hospitalização [diferença de risco (DR) = −0,02; IC95%: −0,04 a 0,00; p = 0,14]
e mortalidade (DR = 0,00; IC95%: −0,01 a 0,02; p = 0,98) no tratamento de
COVID-19 leve.
CONCLUSÕES: Não é recomendado o uso de hidroxicloroquina nem na profilaxia da
infecção por SARS-CoV-2 nem no tratamento de pacientes com COVID-19 leve.
DOI: 10.36416/1806-3756/e20210236
PMCID: PMC9013536
PMID: 34669839 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32492293 | 1. N Engl J Med. 2020 Aug 6;383(6):517-525. doi: 10.1056/NEJMoa2016638. Epub 2020
Jun 3.
A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for
Covid-19.
Boulware DR(1), Pullen MF(1), Bangdiwala AS(1), Pastick KA(1), Lofgren SM(1),
Okafor EC(1), Skipper CP(1), Nascene AA(1), Nicol MR(1), Abassi M(1), Engen
NW(1), Cheng MP(1), LaBar D(1), Lother SA(1), MacKenzie LJ(1), Drobot G(1),
Marten N(1), Zarychanski R(1), Kelly LE(1), Schwartz IS(1), McDonald EG(1),
Rajasingham R(1), Lee TC(1), Hullsiek KH(1).
Author information:
(1)From the University of Minnesota (D.R.B., M.F.P., A.S.B., K.A.P., S.M.L.,
E.C.O., C.P.S., A.A.N., M.R.N., M.A., N.W.E., R.R., K.H.H.) and M Health
Fairview Investigational Drug Service Pharmacy (D.L.), Minneapolis; and the
Research Institute of the McGill University Health Centre and the Clinical
Practice Assessment Unit, Department of Medicine, McGill University, Montreal
(M.P.C., E.G.M., T.C.L.), the Department of Internal Medicine, University of
Manitoba (S.A.L., L.J.M., G.D., N.M., R.Z.), the Research Institute in Oncology
and Hematology, CancerCare Manitoba, University of Manitoba (R.Z.), and the
George and Fay Yee Centre for Healthcare Innovation (L.E.K.), Winnipeg, and the
University of Alberta, Edmonton (I.S.S.) - all in Canada.
Comment in
N Engl J Med. 2020 Aug 6;383(6):585-586. doi: 10.1056/NEJMe2020388.
N Engl J Med. 2020 Sep 10;383(11):1087-1088. doi: 10.1056/NEJMc2023617.
N Engl J Med. 2020 Sep 10;383(11):1088. doi: 10.1056/NEJMc2023617.
N Engl J Med. 2020 Sep 10;383(11):1088-1089. doi: 10.1056/NEJMc2023617.
Ann Intern Med. 2020 Oct 20;173(8):JC41. doi: 10.7326/ACPJ202010200-041.
Intern Emerg Med. 2021 Sep;16(6):1729-1731. doi: 10.1007/s11739-021-02633-y.
Postgrad Med J. 2022 Mar;98(e2):e92-e93. doi:
10.1136/postgradmedj-2020-139561.
BACKGROUND: Coronavirus disease 2019 (Covid-19) occurs after exposure to severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are
exposed, the standard of care is observation and quarantine. Whether
hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure
is unknown.
METHODS: We conducted a randomized, double-blind, placebo-controlled trial
across the United States and parts of Canada testing hydroxychloroquine as
postexposure prophylaxis. We enrolled adults who had household or occupational
exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for
more than 10 minutes while wearing neither a face mask nor an eye shield
(high-risk exposure) or while wearing a face mask but no eye shield
(moderate-risk exposure). Within 4 days after exposure, we randomly assigned
participants to receive either placebo or hydroxychloroquine (800 mg once,
followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days).
The primary outcome was the incidence of either laboratory-confirmed Covid-19 or
illness compatible with Covid-19 within 14 days.
RESULTS: We enrolled 821 asymptomatic participants. Overall, 87.6% of the
participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19
contact. The incidence of new illness compatible with Covid-19 did not differ
significantly between participants receiving hydroxychloroquine (49 of 414
[11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute
difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2;
P = 0.35). Side effects were more common with hydroxychloroquine than with
placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
CONCLUSIONS: After high-risk or moderate-risk exposure to Covid-19,
hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed
infection when used as postexposure prophylaxis within 4 days after exposure.
(Funded by David Baszucki and Jan Ellison Baszucki and others;
ClinicalTrials.gov number, NCT04308668.).
Copyright © 2020 Massachusetts Medical Society.
DOI: 10.1056/NEJMoa2016638
PMCID: PMC7289276
PMID: 32492293 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33166694 | 1. Int J Antimicrob Agents. 2020 Dec;56(6):106224. doi:
10.1016/j.ijantimicag.2020.106224. Epub 2020 Nov 6.
Post-exposure prophylaxis with hydroxychloroquine for the prevention of
COVID-19, a myth or a reality? The PEP-CQ Study.
Dhibar DP(1), Arora N(2), Kakkar A(2), Singla N(2), Mohindra R(2), Suri V(2),
Bhalla A(2), Sharma N(2), Singh MP(3), Prakash A(4), Pvm L(5), Medhi B(4).
Author information:
(1)Department of Internal Medicine, PGIMER, Chandigarh, India. Electronic
address: drdeba_prasad@yahoo.co.in.
(2)Department of Internal Medicine, PGIMER, Chandigarh, India.
(3)Department of Virology, PGIMER, Chandigarh, India.
(4)Department of Pharmacology, PGIMER, Chandigarh, India.
(5)Community Medicine and School of Public Health, PGIMER, Chandigarh, India.
Many drugs have been tried for the treatment/prevention of COVID-19 with limited
success. Direct household contacts of COVID-19 patients are at highest risk for
SARS-CoV-2 infection. Hydroxychloroquine (HCQ) has been tried against COVID-19
owing to its in vitro virucidal action against SARS-CoV-2, but the role of HCQ
as post-exposure prophylaxis (PEP) remains inconclusive. In this open-label,
controlled clinical trial, asymptomatic individuals who had direct contact with
laboratory-confirmed COVID-19 cases or had undertaken international travel in
the last 2 weeks were offered HCQ prophylaxis and assigned to PEP (n = 132) or
control (n = 185) group. The PEP group received HCQ 800 mg on Day 1 followed by
400 mg once weekly for 3 weeks. Both groups undertook home quarantine for 2
weeks along with social distancing and personal hygiene. Over 4-week follow-up,
50/317 participants (15.8%) had new-onset COVID-19. The incidence of COVID-19
was significantly (P = 0.033) lower in the PEP (14/132; 10.6%) compared to the
control (36/185; 19.5%) group (total absolute risk reduction, -8.9% points). The
NNT to prevent the occurrence of 1 COVID-19 case was 12. Overall relative risk
was 0.59 (95% CI 0.33-1.05). Compliance was good. The most common adverse event
was epigastric discomfort with burning sensation (three participants), with no
serious adverse events. PEP with HCQ has the potential for the prevention of
COVID-19 in at-risk individuals. Until definitive therapy is available,
continuing PEP with HCQ may be considered in suitable at-risk individuals.
Further randomised clinical trials with larger samples are required for better
evaluation of HCQ as PEP for COVID-19 prevention.
Copyright © 2020 Elsevier Ltd and International Society of Antimicrobial
Chemotherapy. All rights reserved.
DOI: 10.1016/j.ijantimicag.2020.106224
PMCID: PMC7646370
PMID: 33166694 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34153975 | 1. Nature. 2021 Aug;596(7870):103-108. doi: 10.1038/s41586-021-03720-y. Epub 2021
Jun 21.
In vivo monoclonal antibody efficacy against SARS-CoV-2 variant strains.
Chen RE(#)(1)(2), Winkler ES(#)(1)(2), Case JB(#)(1), Aziati ID(1), Bricker
TL(1), Joshi A(1), Darling TL(1), Ying B(1), Errico JM(2), Shrihari S(1),
VanBlargan LA(1), Xie X(3), Gilchuk P(4), Zost SJ(4), Droit L(5), Liu Z(5),
Stumpf S(5), Wang D(5), Handley SA(2), Stine WB Jr(6), Shi PY(3)(7)(8),
Davis-Gardner ME(9), Suthar MS(9), Knight MG(10), Andino R(10), Chiu CY(11)(12),
Ellebedy AH(2)(13)(14), Fremont DH(2)(5)(15), Whelan SPJ(5), Crowe JE
Jr(4)(16)(17), Purcell L(18), Corti D(19), Boon ACM(1)(2)(5), Diamond
MS(20)(21)(22)(23)(24).
Author information:
(1)Department of Medicine, Washington University School of Medicine, St Louis,
MO, USA.
(2)Department of Pathology and Immunology, Washington University School of
Medicine, St Louis, MO, USA.
(3)Department of Biochemistry and Molecular Biology, University of Texas Medical
Branch, Galveston, TX, USA.
(4)Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville,
TN, USA.
(5)Department of Molecular Microbiology, Washington University School of
Medicine, St Louis, MO, USA.
(6)AbbVie Bioresearch Center, Worcester, MA, USA.
(7)Department of Microbiology and Immunology, University of Texas Medical
Branch, Galveston, TX, USA.
(8)Sealy Institute for Vaccine Sciences, University of Texas Medical Branch,
Galveston, TX, USA.
(9)Center for Childhood Infections and Vaccines of Children's Healthcare of
Atlanta, Department of Pediatrics, Emory Vaccine Center, Emory University School
of Medicine, Atlanta, GA, USA.
(10)Department of Microbiology and Immunology, University of California San
Francisco, San Francisco, CA, USA.
(11)Department of Laboratory Medicine, University of California San Francisco,
San Francisco, CA, USA.
(12)Department of Medicine, University of California San Francisco, San
Francisco, CA, USA.
(13)Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy
Programs, Washington University School of Medicine, St Louis, MO, USA.
(14)Center for Vaccines and Immunity to Microbial Pathogens, Washington
University School of Medicine, St Louis, MO, USA.
(15)Department of Biochemistry and Molecular Biophysics, Washington University
School of Medicine, St Louis, MO, USA.
(16)Department of Pediatrics, Vanderbilt University Medical Center, Nashville,
TN, USA.
(17)Department of Pathology, Microbiology and Immunology, Vanderbilt University
Medical Center, Nashville, TN, USA.
(18)Vir Biotechnology, St Louis, MO, USA.
(19)Humabs BioMed SA, a subsidiary of Vir Biotechnology, Bellinzona,
Switzerland.
(20)Department of Medicine, Washington University School of Medicine, St Louis,
MO, USA. diamond@wusm.wustl.edu.
(21)Department of Pathology and Immunology, Washington University School of
Medicine, St Louis, MO, USA. diamond@wusm.wustl.edu.
(22)Department of Molecular Microbiology, Washington University School of
Medicine, St Louis, MO, USA. diamond@wusm.wustl.edu.
(23)Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy
Programs, Washington University School of Medicine, St Louis, MO, USA.
diamond@wusm.wustl.edu.
(24)Center for Vaccines and Immunity to Microbial Pathogens, Washington
University School of Medicine, St Louis, MO, USA. diamond@wusm.wustl.edu.
(#)Contributed equally
Update of
Res Sq. 2021 Apr 23:rs.3.rs-448370. doi: 10.21203/rs.3.rs-448370/v1.
Rapidly emerging SARS-CoV-2 variants jeopardize antibody-based countermeasures.
Although cell culture experiments have demonstrated a loss of potency of several
anti-spike neutralizing antibodies against variant strains of SARS-CoV-21-3, the
in vivo importance of these results remains uncertain. Here we report the in
vitro and in vivo activity of a panel of monoclonal antibodies (mAbs), which
correspond to many in advanced clinical development by Vir Biotechnology,
AbbVie, AstraZeneca, Regeneron and Lilly, against SARS-CoV-2 variant viruses.
Although some individual mAbs showed reduced or abrogated neutralizing activity
in cell culture against B.1.351, B.1.1.28, B.1.617.1 and B.1.526 viruses with
mutations at residue E484 of the spike protein, low prophylactic doses of mAb
combinations protected against infection by many variants in K18-hACE2
transgenic mice, 129S2 immunocompetent mice and hamsters, without the emergence
of resistance. Exceptions were LY-CoV555 monotherapy and LY-CoV555 and LY-CoV016
combination therapy, both of which lost all protective activity, and the
combination of AbbVie 2B04 and 47D11, which showed a partial loss of activity.
When administered after infection, higher doses of several mAb cocktails
protected in vivo against viruses with a B.1.351 spike gene. Therefore, many-but
not all-of the antibody products with Emergency Use Authorization should retain
substantial efficacy against the prevailing variant strains of SARS-CoV-2.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41586-021-03720-y
PMCID: PMC8349859
PMID: 34153975 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34781981 | 1. Trials. 2021 Nov 15;22(1):808. doi: 10.1186/s13063-021-05758-9.
Pre-exposure prophylaxis with hydroxychloroquine for COVID-19: a double-blind,
placebo-controlled randomized clinical trial.
Grau-Pujol B(#)(1)(2)(3), Camprubí-Ferrer D(#)(4), Marti-Soler H(4),
Fernández-Pardos M(4), Carreras-Abad C(4), Andrés MV(4), Ferrer E(4),
Muelas-Fernandez M(4), Jullien S(4), Barilaro G(4), Ajanovic S(4), Vera I(4),
Moreno L(5), Gonzalez-Redondo E(5), Cortes-Serra N(4), Roldán M(4), Arcos AA(4),
Mur I(6), Domingo P(6), Garcia F(5)(7), Guinovart C(4), Muñoz J(4).
Author information:
(1)Barcelona Institute for Global Health (ISGlobal), Hospital Clínic -
University of Barcelona, Rosselló 132 4rt 1a, 08036, Barcelona, Spain.
berta.grau@isglobal.org.
(2)Centro de Investigação em Saúde de Manhiça (CISM), Maputo, Mozambique.
berta.grau@isglobal.org.
(3)Mundo Sano Foundation, Buenos Aires, Argentina. berta.grau@isglobal.org.
(4)Barcelona Institute for Global Health (ISGlobal), Hospital Clínic -
University of Barcelona, Rosselló 132 4rt 1a, 08036, Barcelona, Spain.
(5)Infectious Diseases Department, Hospital Clínic, IDIBAPS, University of
Barcelona, Barcelona, Spain.
(6)Infectious Diseases Unit, Hospital de la Santa Creu i Sant Pau - Institut
d'Investigació Biomèdica Sant Pau, 08025, Barcelona, Spain.
(7)Retrovirology and Viral Immunopathology, AIDS Research Group, IDIBAPS,
Hospital Clinic, University of Barcelona, Barcelona, Spain.
(#)Contributed equally
BACKGROUND: Pre-exposure prophylaxis (PrEP) is a promising strategy to break
COVID-19 transmission. Although hydroxychloroquine was evaluated for treatment
and post-exposure prophylaxis, it is not evaluated for COVID-19 PrEP yet. The
aim of this study was to evaluate the efficacy and safety of PrEP with
hydroxychloroquine against placebo in healthcare workers at high risk of
SARS-CoV-2 infection during an epidemic period.
METHODS: We conducted a double-blind placebo-controlled randomized clinical
trial in three hospitals in Barcelona, Spain. From 350 adult healthcare workers
screened, we included 269 participants with no active or past SARS-CoV-2
infection (determined by a negative nasopharyngeal SARS-CoV-2 PCR and a negative
serology against SARS-CoV-2). Participants allocated in the intervention arm
(PrEP) received 400 mg of hydroxychloroquine daily for the first four
consecutive days and subsequently, 400 mg weekly during the study period.
Participants in the control group followed the same treatment schedule with
placebo tablets.
RESULTS: 52.8% (142/269) of participants were in the hydroxychloroquine arm and
47.2% (127/269) in the placebo arm. Given the national epidemic incidence decay,
only one participant in each group was diagnosed with COVID-19. The trial was
stopped due to futility and our study design was deemed underpowered to evaluate
any benefit regarding PrEP efficacy. Both groups showed a similar proportion of
participants experiencing at least one adverse event (AE) (p=0.548). No serious
AEs were reported. Almost all AEs (96.4%, 106/110) were mild. Only mild
gastrointestinal symptoms were significantly higher in the hydroxychloroquine
arm compared to the placebo arm (27.4% (39/142) vs 15.7% (20/127), p=0.041).
CONCLUSIONS: Although the efficacy of PrEP with hydroxychloroquine for
preventing COVID-19 could not be evaluated, our study showed that PrEP with
hydroxychloroquine at low doses is safe.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04331834 . Registered on April 2,
2020.
© 2021. The Author(s).
DOI: 10.1186/s13063-021-05758-9
PMCID: PMC8591593
PMID: 34781981 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no competing
interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34485970 | 1. Lancet Reg Health Am. 2021 Oct;2:100062. doi: 10.1016/j.lana.2021.100062. Epub
2021 Aug 29.
Efficacy and safety of hydroxychloroquine as pre-and post-exposure prophylaxis
and treatment of COVID-19: A systematic review and meta-analysis of blinded,
placebo-controlled, randomized clinical trials.
Martins-Filho PR(1)(2), Ferreira LC(2)(3), Heimfarth L(4), Araújo AAS(2)(5),
Quintans-Júnior LJ(2)(4).
Author information:
(1)Investigative Pathology Laboratory, Federal University of Sergipe, Aracaju,
Sergipe, Brazil.
(2)Health Sciences Graduate Program, Federal University of Sergipe, Aracaju,
Sergipe, Brazil.
(3)Department of Medicine, Tiradentes University, Aracaju, Sergipe, Brazil.
(4)Laboratory of Neuroscience and Pharmacological Assays, Department of
Physiology, Federal University of Sergipe, São Cristovão, Sergipe, Brazil.
(5)Laboratory of Pharmaceutical Assays and Toxicity, Department of Pharmacy,
Federal University of Sergipe, São Cristovão, Sergipe, Brazil.
BACKGROUND: Hydroxychloroquine (HCQ) is an anti-malarial and immunomodulatory
drug considered a potential candidate for drug repurposing in COVID-19 due to
their in vitro antiviral activity against SARS-CoV-2. Despite the potential
antiviral effects and anti-inflammatory profile, the results based on clinical
studies are contradictory. Therefore, the quality of the decision-making process
from meta-analyses summarizing the available evidence selecting studies with
different designs and unblinded trials is limited. The aim of this study was to
synthesize the best evidence on the efficacy and safety of HCQ as pre-and
post-exposure prophylaxis and treatment of non-hospitalized and hospitalized
patients with COVID-19.
METHODS: Searches were performed in PubMed, Web of Science, Embase, Lilacs, the
website ClinicalTrials.gov and the preprint server medRxiv from January 1, 2020
to May 17, 2021. The following elements were used to define eligibility
criteria: (1) Population: individuals at high-risk of exposure to SARS-CoV-2
(pre-exposure), individuals who had close contact with a positive or probable
case of COVID-19 (post-exposure), non-hospitalized patients with COVID-19 and
hospitalized patients with COVID-19; (2) Intervention: HCQ; (3) Comparison:
placebo; (4) Outcomes: incidence of SARS-CoV-2 infection, need for
hospitalization, length of hospital stay, need for invasive mechanical
ventilation (MV), death, and adverse events; and (5) Study type: blinded,
placebo-controlled, randomized clinical trials (RCTs). Risk of bias was judged
according to the Cochrane guidelines for RCTs. Treatment effects were reported
as relative risk (RR) for dichotomous variables and mean difference (MD) for
continuous variables with 95% confidence intervals (CI). We used either a fixed
or random-effects model to pool the results of individual studies depending on
the presence of heterogeneity. The GRADE system was used to evaluate the
strength of evidence between use of HCQ and the outcomes of interest.
FINDINGS: Fourteen blinded, placebo-controlled RCTs were included in this
meta-analysis. Four trials (1942 patients: HCQ = 1271; placebo = 671) used HCQ
as a prophylactic medication pre-exposure to COVID-19, two (1650 patients:
HCQ = 821; placebo = 829) as a prophylactic medication post-exposure to
COVID-19, three (1018 patients: HCQ = 497; placebo = 521) as treatment for
non-hospitalized patients, and five (1138 patients: HCQ = 572; placebo = 566) as
treatment for hospitalized patients with COVID-19. We found no decreased risk of
SARS-CoV-2 infection among individuals receiving HCQ as pre-exposure (RR = 0.90;
95% CI 0.46 to 1.77) or post-exposure (RR = 0.96; 95% CI 0.72 to 1.29)
prophylaxis to prevent COVID-19. There was no significant decreased risk of
hospitalization for outpatients with SARS-CoV-2 infection (RR = 0.64; 95% CI
0.33 to 1.23) and no decreased risk of MV (RR = 0.81; 95% CI 0.49 to 1.34) and
death (RR = 1.05; 95% CI 0.62 to 1.78) among hospitalized patients with COVID-19
receiving HCQ. The certainty of the results on the lack of clinical benefit for
HCQ was rated as moderate. Moreover, our results demonstrated an increased risk
for any adverse events and gastrointestinal symptoms among those using HCQ.
INTERPRETATION: Available evidence based on the results of blinded,
placebo-controlled RCTs showed no clinical benefits of HCQ as pre-and
post-exposure prophylaxis and treatment of non-hospitalized and hospitalized
patients with COVID-19.
FUNDING: There was no funding source.
© 2021 The Author(s). Published by Elsevier Ltd.
DOI: 10.1016/j.lana.2021.100062
PMCID: PMC8403035
PMID: 34485970
Conflict of interest statement: The authors declare that there is no conflict of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33971103 | 1. Nanotoxicology. 2021 Aug;15(6):779-797. doi: 10.1080/17435390.2021.1919330.
Epub 2021 May 10.
Stabilization of Nrf2 leading to HO-1 activation protects against zinc oxide
nanoparticles-induced endothelial cell death.
Zhang L(1), Zou L(1), Jiang X(2), Cheng S(3), Zhang J(1), Qin X(4), Qin Z(5),
Chen C(3)(6), Zou Z(1)(6).
Author information:
(1)Institute of Life Sciences, Chongqing Medical University, Chongqing, People's
Republic of China.
(2)Center of Experimental Teaching for Public Health, Experimental Teaching and
Management Center, Chongqing Medical University, Chongqing, People's Republic of
China.
(3)Department of Occupational and Environmental Health, School of Public Health
and Management, Chongqing Medical University, Chongqing, People's Republic of
China.
(4)Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical
University, Chongqing, People's Republic of China.
(5)Institute of Cardiovascular Diseases of PLA, the Second Affiliated Hospital,
Third Military Medical University (Army Medical University), Chongqing, People's
Republic of China.
(6)Dongsheng Lung-Brain Disease Joint Lab, Chongqing Medical University,
Chongqing, People's Republic of China.
With the abundant production and wide application of zinc oxide nanoparticles
(ZnONPs), the potential health risks of ZnONPs have raised serious concerns.
Oxidative stress is recognized as the most important outcome of the toxicity
induced by ZnONPs. The Nrf2-Keap1 system and its downstream antioxidative genes
are the fundamental protective mechanisms for redox hemeostasis. However, the
detailed mechanisms of Nrf2 activation in ZnONPs-treated endothelial cells and
murine blood vessels have yet to be elucidated. Herein, we show that Nrf2 was
activated and played a negative role in cell death induced by ZnONPs. Moreover,
we demonstrate that HO-1 was the most extensively upregulated antioxidative
gene-activated by Nrf2. Forced overexpression of HO-1, pharmacological
activation of HO-1 with the agonists RTA-408 (omaveloxolone, an FDA-approved
drug) and RTA-402 repressed cell death, and treatment with HO-1 antagonist SnPP
exacerbated the cell death. Importantly, loss of HO-1 diminished the
cytoprotective role induced by Nrf2 in ZnONPs-treated HUVEC cells, indicating
that the Nrf2-HO-1 axis was the crucial regulatory mechanism for the
antioxidative response in the context of ZnONPs-induced endothelial damage.
Mechanistically, we demonstrate that the p62-Keap1 axis was not involved in the
activation of Nrf2. Intriguingly, the degradation half-life of Nrf2 in HUVEC
cells was increased from less than 1 h under quiescent conditions to
approximately 6 h under ZnONPs treatment condition; moreover, ZnONPs treatment
induced activation of Nrf2/HO-1 and accumulation of ubiquitin in the aorta
ventralis of mouse, suggesting that the ubiquitin-proteasome system had been
perturbed, which subsequently led to the stabilization of Nrf2 and activation of
HO-1. This study might contribute to a better understanding of ZnONPs-associated
toxicity.
DOI: 10.1080/17435390.2021.1919330
PMID: 33971103 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35778789 | 1. Muscle Nerve. 2022 Oct;66(4):508-512. doi: 10.1002/mus.27674. Epub 2022 Jul
21.
Milestones of progression in myotonic dystrophy type 1 and type 2.
Hamel JI(1), McDermott MP(1)(2), Hilbert JE(1), Martens WB(1), Luebbe E(1),
Tawil R(1), Moxley RT 3rd(1), Thornton CA(1).
Author information:
(1)Department of Neurology, University of Rochester Medical Center, Rochester,
New York.
(2)Department of Biostatistics and Computational Biology, University of
Rochester Medical Center, Rochester, New York.
INTRODUCTION/AIMS: Disease progression in myotonic dystrophy (DM) is marked by
milestone events when functional thresholds are crossed. DM type 2 (DM2) is
considered less severe than DM type 1 (DM1), but it is unknown whether this
applies uniformly to all features. We compared the age-dependent risk for
milestone events in DM1 and DM2 and tested for associations with age of onset
and sex.
METHODS: We studied a large cohort of adult participants in a national registry
of DM1 and DM2. Using annual surveys from participants, we ascertained milestone
events for motor involvement (use of cane, walker, ankle brace, wheelchair, or
ventilatory device), systemic involvement (diabetes, pacemaker, cancer), loss of
employment due to DM, and death.
RESULTS: Mean follow-up of registry participants (929 DM1 and 222 DM2 patients)
was 7 years. Disability and motor milestones occurred at earlier ages in DM1
than in DM2. In contrast, the risk of diabetes was higher and tended to occur
earlier in DM2 (hazard ratio [HR], 0.56; P ≤ .001). In DM1, the milestone events
tended to occur earlier, and life expectancy was reduced, when symptoms began at
younger ages. In DM1, men were at greater risk for disability (HR, 1.34;
P ≤ .01), use of ankle braces (HR, 1.41; P = .02), and diabetes (HR, 2.2;
P ≤ .0001), whereas women were at greater risk for needing walkers (HR, 0.68;
P = .001) or malignancy (HR, 0.66; P ≤ .01).
DISCUSSION: Milestone events recorded through registries can be used to assess
long-term impact of DM in large cohorts. Except for diabetes, the age-related
risk of milestone events is greater in DM1 than in DM2.
© 2022 Wiley Periodicals LLC.
DOI: 10.1002/mus.27674
PMID: 35778789 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21496635 | 1. Handb Clin Neurol. 2011;101:193-237. doi: 10.1016/B978-0-08-045031-5.00015-3.
Myotonic dystrophy types 1 and 2.
Ashizawa T(1), Sarkar PS.
Author information:
(1)Department of Neurology, McKnight Brain Institute, The University of Texas
Medical Branch, Galveston, TX, USA. tetsuo.ashizawa@neurology.ufl.edu
Myotonic dystrophies (dystrophia myotonica, or DM) are inherited disorders
characterized by myotonia and progressive muscle degeneration, which are
variably associated with a multisystemic phenotype. To date, two types of
myotonic dystrophy, type 1 (DM1) and type 2 (DM2), are known to exist; both are
autosomal dominant disorders caused by expansion of an untranslated short tandem
repeat DNA sequence (CTG)(n) and (CCTG)(n), respectively. These expanded repeats
in DM1 and DM2 show different patterns of repeat-size instability. Phenotypes of
DM1 and DM2 are similar but there are some important differences, most
conspicuously in the severity of the disease (including the presence or absence
of the congenital form), muscles primarily affected (distal versus proximal),
involved muscle fiber types (type 1 versus type 2 fibers), and some associated
multisystemic phenotypes. The pathogenic mechanism of DM1 and DM2 is thought to
be mediated by the mutant RNA transcripts containing expanded CUG and CCUG
repeats. Strong evidence supports the hypothesis that sequestration of
muscle-blind like (MBNL) proteins by these expanded repeats leads to
misregulated splicing of many gene transcripts in corroboration with the raised
level of CUG-binding protein 1. However, additional mechanisms, such as changes
in the chromatin structure involving CTCN-binding site and gene expression
dysregulations, are emerging. Although treatment of DM1 and DM2 is currently
limited to supportive therapies, new therapeutic approaches based on pathogenic
mechanisms may become feasible in the near future.
Copyright © 2011 Elsevier B.V. All rights reserved.
DOI: 10.1016/B978-0-08-045031-5.00015-3
PMID: 21496635 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35205411 | 1. Genes (Basel). 2022 Feb 17;13(2):367. doi: 10.3390/genes13020367.
Myotonic Dystrophies: A Genetic Overview.
Soltanzadeh P(1).
Author information:
(1)Department of Neurology, David Geffen School of Medicine at UCLA, Los
Angeles, CA 90095, USA.
Myotonic dystrophies (DM) are the most common muscular dystrophies in adults,
which can affect other non-skeletal muscle organs such as the heart, brain and
gastrointestinal system. There are two genetically distinct types of myotonic
dystrophy: myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2),
both dominantly inherited with significant overlap in clinical manifestations.
DM1 results from CTG repeat expansions in the 3'-untranslated region (3'UTR) of
the DMPK (dystrophia myotonica protein kinase) gene on chromosome 19, while DM2
is caused by CCTG repeat expansions in intron 1 of the CNBP (cellular nucleic
acid-binding protein) gene on chromosome 3. Recent advances in genetics and
molecular biology, especially in the field of RNA biology, have allowed better
understanding of the potential pathomechanisms involved in DM. In this review
article, core clinical features and genetics of DM are presented followed by a
discussion on the current postulated pathomechanisms and therapeutic approaches
used in DM, including the ones currently in human clinical trial phase.
DOI: 10.3390/genes13020367
PMCID: PMC8872148
PMID: 35205411 [Indexed for MEDLINE]
Conflict of interest statement: The author declares no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33953559 | 1. Ther Clin Risk Manag. 2021 Apr 28;17:371-387. doi: 10.2147/TCRM.S301817.
eCollection 2021.
Chloroquine and Hydroxychloroquine for the Prevention and Treatment of COVID-19:
A Fiction, Hope or Hype? An Updated Review.
Saghir SAM(1), AlGabri NA(2)(3), Alagawany MM(4), Attia YA(5)(6), Alyileili
SR(7), Elnesr SS(8), Shafi ME(9), Al-Shargi OYA(10), Al-Balagi N(11), Alwajeeh
AS(12), Alsalahi OSA(13), Patra AK(14), Khafaga AF(15), Negida A(16)(17),
Noreldin A(18), Al-Amarat W(19), Almaiman AA(20), El-Tarabily KA(21)(22), Abd
El-Hack ME(4).
Author information:
(1)Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of
Nursing and Medical Sciences, Al-Hussein Bin Talal University, Ma'an, 71111,
Jordan.
(2)Pathology Department, Faculty of Veterinary Medicine, Thamar University,
Dhamar, Yemen.
(3)Laboratory of Regional Djibouti Livestock Quarantine, Abu Yasar International
Est. 1999, Djibouti, Djibouti.
(4)Department of Poultry, Faculty of Agriculture, Zagazig University, Zagazig,
44511, Egypt.
(5)Department of Agriculture, Faculty of Environmental Sciences, King Abdulaziz
University, Jeddah, 21589, Kingdom of Saudi Arabia.
(6)Department of Animal and Poultry Production, Faculty of Agriculture,
Damanhour University, Damanhour, Egypt.
(7)Department of Integrative Agriculture, College of Food and Agriculture,
United Arab Emirates University, Al-Ain, 15551, United Arab Emirates.
(8)Department of Poultry Production, Faculty of Agriculture, Fayoum University,
Fayoum, 63514, Egypt.
(9)Department of Biological Sciences, Zoology, King Abdulaziz University,
Jeddah, 21589, Kingdom of Saudi Arabia.
(10)Department of Pharmacology, College of Pharmacy, Riyadh Elm University,
Riyadh, Kingdom of Saudi Arabia.
(11)Ministry of Health, Riyadh, Kingdom of Saudi Arabia.
(12)Anti-DopingLab, Doha, Qatar.
(13)Department of Medical Laboratories, Faculty of Medicine and Health Sciences,
Hodeidah University, Al Hodaidah, Yemen.
(14)Department of Animal Nutrition, West Bengal University of Animal and Fishery
Sciences, Belgachia, Kolkata, India.
(15)Department of Pathology, Faculty of Veterinary Medicine, Alexandria
University, Edfina, 22758, Egypt.
(16)School of Pharmacy and Biomedical Sciences, University of Portsmouth,
Portsmouth, UK.
(17)Zagazig University Hospitals, Faculty of Medicine, Zagazig University,
Zagazig, Egypt.
(18)Histology and Cytology Department, Faculty of Veterinary Medicine, Damanhour
University, Damanhour, 22511, Egypt.
(19)Department of Medical Support, Al-Karak University College, Al-Balqa'
Applied University, Salt, Jordan.
(20)Department of Applied Medical Sciences, Community College of Uniazah, Qassim
University, Buraydah, 51431, Kingdom of Saudi Arabia.
(21)Department of Biology, College of Science, United Arab Emirates University,
Al-Ain, 15551, United Arab Emirates.
(22)Biosecurity and One Health Research Centre, Harry Butler Institute, Murdoch
University, Murdoch, Western Australia, 6150, Australia.
In December 2019, the novel coronavirus disease pandemic (COVID-19) that began
in China had infected so far more than 109,217,366 million individuals worldwide
and accounted for more than 2,413,912 fatalities. With the dawn of this novel
coronavirus (SARS-CoV-2), there was a requirement to select potential therapies
that might effectively kill the virus, accelerate the recovery, or decrease the
case fatality rate. Besides the currently available antiviral medications for
human immunodeficiency virus (HIV) and hepatitis C virus (HCV), the
chloroquine/hydroxychloroquine (CQ/HCQ) regimen with or without azithromycin has
been repurposed in China and was recommended by the National Health Commission,
China in mid-February 2020. By this time, the selection of this regimen was
based on its efficacy against the previous SARS-CoV-1 virus and its potential to
inhibit viral replication of the SARS-CoV-2 in vitro. There was a shortage of
robust clinical proof about the effectiveness of this regimen against the novel
SARS-CoV-2. Therefore, extensive research effort has been made by several
researchers worldwide to investigate whether this regimen is safe and effective
for the management of COVID-19. In this review, we provided a comprehensive
overview of the CQ/HCQ regimen, summarizing data from in vitro studies and
clinical trials for the protection against or the treatment of SARS-CoV-2.
Despite the initial promising results from the in vitro studies and the
widespread use of CQ/HCQ in clinical settings during the 1st wave of COVID-19,
current data from well-designed randomized controlled trials showed no evidence
of benefit from CQ/HCQ supplementation for the treatment or prophylaxis against
SARS-CoV-2 infection. Particularly, the two largest randomized controlled trials
to date (RECOVERY and WHO SOLIDARITY trials), both confirmed that CQ/HCQ regimen
does not provide any clinical benefit for COVID-19 patients. Therefore, we do
not recommend the use of this regimen in COVID-19 patients outside the context
of clinical trials.
© 2021 Saghir et al.
DOI: 10.2147/TCRM.S301817
PMCID: PMC8092643
PMID: 33953559
Conflict of interest statement: The authors report no conflicts of interest for
this work and declare that the research was conducted in the absence of any
commercial or financial relationships that could be construed as a potential
conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/25121518 | 1. Curr Opin Neurol. 2014 Oct;27(5):599-606. doi: 10.1097/WCO.0000000000000128.
Myotonic dystrophy: diagnosis, management and new therapies.
Turner C(1), Hilton-Jones D.
Author information:
(1)aMRC Centre for Neuromuscular Disease, National Hospital for Neurology and
Neurosurgery, Queen Square, London bOxford Neuromuscular Centre, West Wing, John
Radcliffe Hospital, Oxford, UK.
PURPOSE OF REVIEW: Myotonic dystrophies type 1 and type 2 are progressive
multisystem genetic disorders with clinical and genetic features in common.
Myotonic dystrophy type 1 is the most prevalent muscular dystrophy in adults and
has a wide phenotypic spectrum. The average age of death in myotonic dystrophy
type 1 is in the fifth decade. In comparison, myotonic dystrophy type 2 tends to
cause a milder phenotype with later onset of symptoms and is less common than
myotonic dystrophy type 1. Historically, patients with myotonic dystrophy type 1
have not received the medical and social input they need to maximize their
quality and quantity of life. This review describes the improved understanding
in the molecular and clinical features of myotonic dystrophy type 1 as well as
the screening of clinical complications and their management. We will also
discuss new potential genetic treatments.
RECENT FINDINGS: An active approach to screening and management of myotonic
dystrophies type 1 and type 2 requires a multidisciplinary medical,
rehabilitative and social team. This process will probably improve morbidity and
mortality for patients. Genetic treatments have been successfully used in
in-vitro and animal models to reverse the physiological, histopathological and
transcriptomic features.
SUMMARY: Molecular therapeutics for myotonic dystrophy will probably bridge the
translational gap between bench and bedside in the near future. There will still
be a requirement for clinical screening of patients with myotonic dystrophy with
proactive and systematic management of complications.
DOI: 10.1097/WCO.0000000000000128
PMID: 25121518 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35243403 | 1. JAAD Int. 2022 Feb 22;7:7-12. doi: 10.1016/j.jdin.2021.09.008. eCollection
2022 Jun.
Cutaneous findings in myotonic dystrophy.
Kong HE(1), Pollack BP(2)(1)(3)(4).
Author information:
(1)Department of Dermatology, Emory University School of Medicine, Atlanta,
Georgia.
(2)Atlanta VA Health System, Decatur, Georgia.
(3)Department of Pathology, Emory University School of Medicine, Atlanta,
Georgia.
(4)Winship Cancer Institute of Emory University School of Medicine, Atlanta,
Georgia.
Myotonic dystrophy types 1 and 2 are a group of complex genetic disorders
resulting from the expansion of (CTG)n nucleotide repeats in the DMPK gene. In
addition to the hallmark manifestations of myotonia and skeletal muscle atrophy,
myotonic dystrophy also affects a myriad of other organs including the heart,
lungs, as well as the skin. The most common cutaneous manifestations of myotonic
dystrophy are early male frontal alopecia and adult-onset pilomatricomas.
Myotonic dystrophy also increases the risk of developing malignant skin diseases
such as basal cell carcinoma and melanoma. To aid in the diagnosis and treatment
of myotonic dystrophy related skin conditions, it is important for the
dermatologist to become cognizant of the common and rare cutaneous
manifestations of this genetic disorder. We performed a PubMed search using the
key terms "myotonic dystrophy" AND "cutaneous" OR "skin" OR "dermatologic" AND
"manifestation" OR "finding." The resulting publications were manually reviewed
for additional relevant publications, and subsequent additional searches were
performed as needed, especially regarding the molecular mechanisms of
pathogenesis. In this review, we aim to provide an overview of myotonic
dystrophy types 1 and 2 and summarize their cutaneous manifestations as well as
potential mechanisms of pathogenesis.
© 2021 Published by Elsevier Inc on behalf of the American Academy of
Dermatology, Inc.
DOI: 10.1016/j.jdin.2021.09.008
PMCID: PMC8867117
PMID: 35243403
Conflict of interest statement: None disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/34840883 | 1. Neurol Clin Pract. 2021 Oct;11(5):e682-e685. doi:
10.1212/CPJ.0000000000001073.
Long-term Safety and Efficacy of Mexiletine in Myotonic Dystrophy Types 1 and 2.
Mousele C(1), Matthews E(1), Pitceathly RDS(1), Hanna MG(1), MacDonald S(1),
Savvatis K(1), Carr A(1), Turner C(1).
Author information:
(1)UCL Queen Square Institute of Neurology and The National Hospital for
Neurology and Neurosurgery (CM); Department of Neuromuscular Diseases, UCL Queen
Square Institute of Neurology and The National Hospital for Neurology and
Neurosurgery (EM, RDSP, MGH, AC, CT); The National Hospital for Neurology and
Neurosurgery (SM), Atkinson-Morley Neuromuscular Centre (EM); and Inherited
Cardiovascular Diseases Unit, Barts Health Centre, Barts Healthcare NHS Trust
(KS), London, United Kingdom.
BACKGROUND AND OBJECTIVE: Myotonic dystrophy types 1 and 2 are progressive
multisystem genetic disorders whose core clinical feature is myotonia.
Mexiletine, an antagonist of voltage-gated sodium channels, is a recommended
antimyotonic agent in the nondystrophic myotonias, but its use in myotonic
dystrophy is limited because of lack of data regarding its long-term efficacy
and safety profile.
METHODS: To address this issue, this study retrospectively evaluated patients
with myotonic dystrophy receiving mexiletine over a mean time period of 32.9
months (range 0.1-216 months).
RESULTS: This study demonstrated that 96% of patients reported some improvement
in myotonia symptoms with mexiletine treatment. No clinically relevant cardiac
adverse events were associated with the long-term use of mexiletine.
CONCLUSIONS: These findings support that mexiletine is both safe and effective
when used long-term in myotonic dystrophy.
CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that
mexiletine is a well-tolerated and effective treatment for myotonic dystrophy
types 1 and 2.
© 2021 American Academy of Neurology.
DOI: 10.1212/CPJ.0000000000001073
PMCID: PMC8610501
PMID: 34840883 |
http://www.ncbi.nlm.nih.gov/pubmed/33458578 | 1. Acta Myol. 2020 Dec 1;39(4):222-234. doi: 10.36185/2532-1900-026. eCollection
2020 Dec.
Myotonic dystrophy type 2: the 2020 update.
Meola G(1)(2).
Author information:
(1)Department of Biomedical Sciences for Health, University of Milan, Italy.
(2)Department of Neurorehabilitation Sciences, Casa di Cura del Policlinico,
Milan, Italy.
The myotonic dystrophies are the commonest cause of adult-onset muscular
dystrophy. Phenotypes of DM1 and DM2 are similar, but there are some important
differences, including the presence or absence of congenital form, muscles
primarily affected (distal vs proximal), involved muscle fiber types (type 1 vs
type 2 fibers), and some associated multisystemic phenotypes. There is currently
no cure for the myotonic dystrophies but effective management significantly
reduces the morbidity and mortality of patients. For the enormous understanding
of the molecular pathogenesis of myotonic dystrophy type 1 and myotonic
dystrophy type 2, these diseases are now called "spliceopathies" and are
mediated by a primary disorder of RNA rather than proteins. Despite clinical and
genetic similarities, myotonic dystrophy type 1 and type 2 are distinct
disorders requiring different diagnostic and management strategies. Gene therapy
for myotonic dystrophy type 1 and myotonic dystrophy type 2 appears to be very
close and the near future is an exciting time for clinicians and patients.
©2020 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.
DOI: 10.36185/2532-1900-026
PMCID: PMC7783423
PMID: 33458578 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest The Author declares no
conflict of interest |
http://www.ncbi.nlm.nih.gov/pubmed/22995693 | 1. Lancet Neurol. 2012 Oct;11(10):891-905. doi: 10.1016/S1474-4422(12)70204-1.
The myotonic dystrophies: molecular, clinical, and therapeutic challenges.
Udd B(1), Krahe R.
Author information:
(1)Neuromuscular Research Unit, Tampere University and University Hospital,
Tampere, Finland. bjarne.udd@netikka.fi
Myotonic dystrophy is the most common type of muscular dystrophy in adults and
is characterised by progressive myopathy, myotonia, and multiorgan involvement.
Two genetically distinct entities have been identified. Myotonic dystrophy type
1 (also known as Steinert's disease) was first described more than 100 years
ago, whereas myotonic dystrophy type 2 was identified only 18 years ago, after
genetic testing for type 1 disease could be applied. Both diseases are caused by
autosomal dominant nucleotide repeat expansions. In patients with myotonic
dystrophy type 1, a (CTG)(n) expansion is present in DMPK, whereas in patients
with type 2 disease, there is a (CCTG)(n) expansion in CNBP. When transcribed
into CUG-containing RNA, mutant transcripts aggregate as nuclear foci that
sequester RNA-binding proteins, resulting in a spliceopathy of downstream
effector genes. The prevailing paradigm therefore is that both disorders are
toxic RNA diseases. However, research indicates several additional pathogenic
effects take place with respect to protein translation and turnover. Despite
clinical and genetic similarities, myotonic dystrophy type 1 and type 2 are
distinct disorders requiring different diagnostic and management strategies.
Copyright © 2012 Elsevier Ltd. All rights reserved.
DOI: 10.1016/S1474-4422(12)70204-1
PMID: 22995693 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/11073357 | 1. Curr Opin Neurol. 2000 Oct;13(5):519-25. doi:
10.1097/00019052-200010000-00003.
Myotonic dystrophies.
Meola G(1).
Author information:
(1)Department of Neurology, University of Milan, Italy. giovanni.meola@unimi.it
This review demonstrates genetic and phenotypic heterogeneity in all of the
multisystemic myotonic disorders collectively called 'myotonic dystrophies'
according to the new nomenclature: myotonic dystrophy type 1, myotonic dystrophy
type 2, proximal myotonic myopathy and proximal myotonic dystrophy. Only two
loci have so far been assigned (19q 13.3 in myotonic dystrophy type 1, and 3q
21.3 in myotonic dystrophy type 2). Although the diagnosis of these disorders
may be suspected clinically, it needs to be confirmed by DNA analysis.
DOI: 10.1097/00019052-200010000-00003
PMID: 11073357 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/32067592 | 1. J Am Heart Assoc. 2020 Feb 18;9(4):e014006. doi: 10.1161/JAHA.119.014006. Epub
2020 Feb 6.
Clinical Care Recommendations for Cardiologists Treating Adults With Myotonic
Dystrophy.
McNally EM(1), Mann DL(2), Pinto Y(3), Bhakta D(4), Tomaselli G(5), Nazarian
S(6), Groh WJ(7), Tamura T(8), Duboc D(9), Itoh H(10), Hellerstein L(11), Mammen
PPA(12).
Author information:
(1)Northwestern University Feinberg School of Medicine Chicago IL.
(2)Washington University in St. Louis MO.
(3)University of Amsterdam Amsterdam The Netherlands.
(4)Indiana University School of Medicine Indianapolis IN.
(5)Albert Einstein College of Medicine Bronx NY.
(6)University of Pennsylvania Philadelphia PA.
(7)Medical University of South Carolina Charleston SC.
(8)National Hospital Organization Higashisaitama National Hospital Saitama
Japan.
(9)Hopital Cochin Universite Paris Descartes Paris France.
(10)Shiga University of Medical Science Shiga Japan.
(11)Myotonic Foundation San Francisco CA.
(12)University of Texas Southwestern Medical Center Dallas TX.
Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle
and the heart. Genetic testing for myotonic dystrophy is diagnostic and
identifies those at risk for cardiac complications. The 2 major genetic forms of
myotonic dystrophy, type 1 and type 2, differ in genetic etiology yet share
clinical features. The cardiac management of myotonic dystrophy should include
surveillance for arrhythmias and left ventricular dysfunction, both of which
occur in progressive manner and contribute to morbidity and mortality. To
promote the development of care guidelines for myotonic dystrophy, the Myotonic
Foundation solicited the input of care experts and organized the drafting of
these recommendations. As a rare disorder, large scale clinical trial data to
guide the management of myotonic dystrophy are largely lacking. The following
recommendations represent expert consensus opinion from those with experience in
the management of myotonic dystrophy, in part supported by literature-based
evidence where available.
DOI: 10.1161/JAHA.119.014006
PMCID: PMC7070199
PMID: 32067592 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/23570879 | 1. Gene. 2013 Jun 15;522(2):226-30. doi: 10.1016/j.gene.2013.03.059. Epub 2013
Apr 6.
Myotonic dystrophy type 1 (DM1): a triplet repeat expansion disorder.
Kumar A, Agarwal S, Agarwal D, Phadke SR.
Myotonic dystrophy is a progressive multisystem genetic disorder affecting about
1 in 8000 people worldwide. The unstable repeat expansions of (CTG)n or (CCTG)n
in the DMPK and ZNF9 genes cause the two known subtypes of myotonic dystrophy:
(i) myotonic dystrophy type 1 (DM1) and (ii) myotonic dystrophy type 2 (DM2)
respectively. There is currently no cure but supportive management helps equally
to reduce the morbidity and mortality and patients need close follow up to pay
attention to their clinical problems. This review will focus on the clinical
features, molecular view and genetics, diagnosis and management of DM1.
Copyright © 2013 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.gene.2013.03.059
PMID: 23570879 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/29770119 | 1. Front Neurol. 2018 May 2;9:303. doi: 10.3389/fneur.2018.00303. eCollection
2018.
Core Clinical Phenotypes in Myotonic Dystrophies.
Wenninger S(1), Montagnese F(1), Schoser B(1).
Author information:
(1)Friedrich-Baur-Institute, Klinikum der Universität München, Munich, Germany.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) represent the most frequent
multisystemic muscular dystrophies in adulthood. They are progressive, autosomal
dominant diseases caused by an abnormal expansion of an unstable nucleotide
repeat located in the non-coding region of their respective genes DMPK for DM1
and CNBP in DM2. Clinically, these multisystemic disorders are characterized by
a high variability of muscular and extramuscular symptoms, often causing a delay
in diagnosis. For both subtypes, many symptoms overlap, but some differences
allow their clinical distinction. This article highlights the clinical core
features of myotonic dystrophies, thus facilitating their early recognition and
diagnosis. Particular attention will be given to signs and symptoms of muscular
involvement, to issues related to respiratory impairment, and to the multiorgan
involvement. This article is part of a Special Issue entitled "Beyond Borders:
Myotonic Dystrophies-A European Perception."
DOI: 10.3389/fneur.2018.00303
PMCID: PMC5941986
PMID: 29770119 |
http://www.ncbi.nlm.nih.gov/pubmed/20514907 | 1. Przegl Lek. 2009;66(12):1065-8.
[Cardiac, respiratory and sleep disorders in patients with myotonic dystrophy].
[Article in Polish]
Banach M(1), Rakowicz M, Antczak J, Rola R, Witkowski G, Waliniowska E.
Author information:
(1)Pracownia EMG, Zakładu Neurofizjologii Klinicznej, Instytutu Psychiatrii i
Neurologii w Warszawie. martabanach@yahoo.com
Myotonic dystrophy (MD) is a genetically determined disease with autosomal
dominant mode of inheritance. Relatively recently, MD has been divided into two
sub-types (MD1 and MD2). Clinical symptoms of MD1 result from the expansion of a
(CTG)n trinucleotide of the gene coding for serine/threonine protein kinase and
clinical symptoms in MD2 are associated with the expansion of (CCTG)n in I
intron of the zinc-finger protein 9 (ZNF9). Myotonic dystrophies MD1 and MD2 are
multisystem diseases with numerous symptoms and high interfamily variability,
resulting from the fact that different organs are affected. Until now the
mechanisms that lead to the damage of the central and peripheral nervous
systems, heart muscle and endocrine system have not been fully understood.
Symptoms that are characteristic of MD1 and MD2 are myotonic symptom, muscular
weakness and muscular atrophy. In MD2, muscular weakness and muscular atrophy
are expressed more significantly in proximal segments, which is a
differentiating factor for patients with MD1 who have muscular weakness and
muscular atrophy in distal segments. Apart from myotonia and symptoms of
skeletal muscle damage, the disease affects smooth muscles, heart muscle and the
central nervous system, causing cataract, endocrine disorders, cognitive
dysfunctions, intellectual and personality disturbances as well as sleep
disordered breathing with nocturnal hypoventilation, obstructive, central and
mixed apneas and hypopneas. The symptoms of sleep disordered breathing is
fatigue, reduced cognitive performance and excessive daytime sleepiness. The
pathophysiology of the breathing disorders includes weakness of the respiratory
muscles and disorder of the respiratory drive. Of some interest are the works in
which authors evaluated the incidence and character of abnormalities in the
peripheral and central nervous systems. It has been shown that the number of
CTG-repeats in the same person with MD1 is not stable over time and may
increase, which leads to disease progression and new clinical symptoms.
Cardiologic disorders associated with myotonic dystrophy are common and are part
of the clinical picture of the disease. The dominant pathology are conduction
disturbances and cardiac arrhythmias. It is estimated that 40 to 80% of patients
with MD1 have abnormalities in ECG, and rapid supra-ventricular and ventricular
cardiac arrhythmias are the second common cause of death in patients with MD1.
Unfortunately, most of these pathologies are asymptomatic until life-threatening
conduction blocks and/or supra-ventricular tachyarrhythmias occur. Sometimes,
prodromal symptoms such as collapsing, fainting or feeling of palpitation occur
and they should always draw attention of the treating doctor of a patient with
muscular dystrophy. This paper is aimed at characterizing some common
cardiologic and sleep related respiratory disorders of patients with myotonic
dystrophy which if not recognized in good time may lead to sudden death.
PMID: 20514907 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20625963 | 1. Neurol Neurochir Pol. 2010 May-Jun;44(3):264-76. doi:
10.1016/s0028-3843(14)60041-4.
[Myotonic dystrophy - a new insight into a well-known disease].
[Article in Polish]
Lusakowska A(1), Sułek-Piatkowska A.
Author information:
(1)Katedra i Klinika Neurologii, Warszawski Uniwersytet Medyczny.
anna.lusakowska@wum.edu.pl
Myotonic dystrophy (DM), the most common dystrophy in adults, is an autosomal
dominant disease characterized by a variety of multisystemic features. Two
genetically distinct forms of DM are identified - type 1 (DM1), the classic form
first described by Steinert, and type 2 (DM2), identified by Ricker. DM1 is
caused by trinucleotide expansion of CTG in the myotonic dystrophy protein
kinase gene, whereas in DM2 the expansion of tetranucleotide repeats (CCTG) in
the zinc finger protein 9 gene was identified. Both mutations are dynamic and
are located in non-coding parts of the genes. Phenotype variability of DM1 and
DM2 is caused by a molecular mechanism due to mutated RNA toxicity. This paper
reviews the clinical features of both types of myotonic dystrophies and
summarizes current views on pathogenesis of myotonic dystrophy.
DOI: 10.1016/s0028-3843(14)60041-4
PMID: 20625963 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/20176601 | 1. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):358-67. doi:
10.1136/jnnp.2008.158261. Epub 2010 Feb 22.
The myotonic dystrophies: diagnosis and management.
Turner C(1), Hilton-Jones D.
Author information:
(1)Department of Neurology, National Hospital for Neurology and Neurosurgery,
Queen Square, London WC1N 3BG, UK. chris.turner@uclh.nhs.uk
There are currently two clinically and molecularly defined forms of myotonic
dystrophy: (1) myotonic dystrophy type 1 (DM1), also known as 'Steinert's
disease'; and (2) myotonic dystrophy type 2 (DM2), also known as proximal
myotonic myopathy. DM1 and DM2 are progressive multisystem genetic disorders
with several clinical and genetic features in common. DM1 is the most common
form of adult onset muscular dystrophy whereas DM2 tends to have a milder
phenotype with later onset of symptoms and is rarer than DM1. This review will
focus on the clinical features, diagnosis and management of DM1 and DM2 and will
briefly discuss the recent advances in the understanding of the molecular
pathogenesis of these diseases with particular reference to new treatments using
gene therapy.
DOI: 10.1136/jnnp.2008.158261
PMID: 20176601 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/21623381 | 1. Nat Med. 2011 Jun;17(6):720-5. doi: 10.1038/nm.2374. Epub 2011 May 29.
Misregulated alternative splicing of BIN1 is associated with T tubule
alterations and muscle weakness in myotonic dystrophy.
Fugier C(1), Klein AF, Hammer C, Vassilopoulos S, Ivarsson Y, Toussaint A, Tosch
V, Vignaud A, Ferry A, Messaddeq N, Kokunai Y, Tsuburaya R, de la Grange P,
Dembele D, Francois V, Precigout G, Boulade-Ladame C, Hummel MC, Lopez de Munain
A, Sergeant N, Laquerrière A, Thibault C, Deryckere F, Auboeuf D, Garcia L,
Zimmermann P, Udd B, Schoser B, Takahashi MP, Nishino I, Bassez G, Laporte J,
Furling D, Charlet-Berguerand N.
Author information:
(1)Institut de Génétique et de Biologie Moléculaire et Cellulaire, Institut
National de la Santé et de la Recherche Médicale U964, Centre National de la
Recherche Scientifique UMR7104, University of Strasbourg, Illkirch, France.
Myotonic dystrophy is the most common muscular dystrophy in adults and the first
recognized example of an RNA-mediated disease. Congenital myotonic dystrophy
(CDM1) and myotonic dystrophy of type 1 (DM1) or of type 2 (DM2) are caused by
the expression of mutant RNAs containing expanded CUG or CCUG repeats,
respectively. These mutant RNAs sequester the splicing regulator
Muscleblind-like-1 (MBNL1), resulting in specific misregulation of the
alternative splicing of other pre-mRNAs. We found that alternative splicing of
the bridging integrator-1 (BIN1) pre-mRNA is altered in skeletal muscle samples
of people with CDM1, DM1 and DM2. BIN1 is involved in tubular invaginations of
membranes and is required for the biogenesis of muscle T tubules, which are
specialized skeletal muscle membrane structures essential for
excitation-contraction coupling. Mutations in the BIN1 gene cause centronuclear
myopathy, which shares some histopathological features with myotonic dystrophy.
We found that MBNL1 binds the BIN1 pre-mRNA and regulates its alternative
splicing. BIN1 missplicing results in expression of an inactive form of BIN1
lacking phosphatidylinositol 5-phosphate-binding and membrane-tubulating
activities. Consistent with a defect of BIN1, muscle T tubules are altered in
people with myotonic dystrophy, and membrane structures are restored upon
expression of the normal splicing form of BIN1 in muscle cells of such
individuals. Finally, reproducing BIN1 splicing alteration in mice is sufficient
to promote T tubule alterations and muscle weakness, a predominant feature of
myotonic dystrophy.
DOI: 10.1038/nm.2374
PMID: 21623381 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19360700 | 1. Curr Protoc Hum Genet. 2009 Apr;Chapter 9:Unit 9.6. doi:
10.1002/0471142905.hg0906s61.
Analysis of repetitive regions in myotonic dystrophy type 1 and 2.
Carson NL(1).
Author information:
(1)Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
Myotonic dystrophy is an autosomal dominant disorder characterized by myotonia,
progressive muscle wasting, and cataracts. There are two forms identified:
myotonic dystrophy type 1 (DM1), caused by an expansion of a CTG repeat in the
3' untranslated region of the myotonin-protein kinase (DMPK) gene on chromosome
19, and myotonic dystrophy type 2 (DM2), caused by an expansion of a CCTG repeat
in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene on
chromosome 3. There is no single method that can identify all ranges of repeats
in both disorders. Protocols in this unit describe the analysis of PCR-amplified
CTG repeats from the DMPK gene and CCTG repeats from the CNBP gene,
respectively, using a fluorescent-labeled primer followed by capillary
electrophoresis. An additional protocol describes the analysis of genomic DNA by
Southern blot and hybridization for DM1, while yet another describes a similar
technique to analyze the repeat in DM2 using field-inversion gel
electrophoresis. Both techniques identify 100% of cases of these two disorders.
Copyright 2009 by John Wiley & Sons, Inc.
DOI: 10.1002/0471142905.hg0906s61
PMID: 19360700 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/27727437 | 1. Curr Protoc Hum Genet. 2016 Oct 11;91:9.29.1-9.29.19. doi: 10.1002/cphg.22.
Molecular Diagnosis of Myotonic Dystrophy.
Chakraborty S(1), Vatta M(1), Bachinski LL(2), Krahe R(2), Dlouhy S(1), Bai
S(1).
Author information:
(1)Department of Medical and Molecular Genetics, Indiana University School of
Medicine, Indianapolis, Indiana.
(2)Department of Genetics, University of Texas MD Anderson Cancer Center,
Houston, Texas.
Myotonic dystrophy types 1 (DM1) and 2 (DM2) are autosomal dominant,
microsatellite repeat expansion disorders that affect muscle function. Myotonic
dystrophy type 1 is caused by CTG repeat expansion in the 3' UTR region of the
DMPK gene. Patients with DM2 have expansion of CCTG repeats in intron 1 of the
CNBP gene. In this unit, we review and discuss the clinical phenotypes, genetic
mutations causing the diseases, and the molecular diagnostic approaches and
tools that are used to determine repeat sizes in DM1/2. In summary, the goal of
this chapter is to provide the reader with a basic understanding of the
clinical, genetic and diagnostic aspects of these disorders. © 2016 by John
Wiley & Sons, Inc.
Copyright © 2016 John Wiley & Sons, Inc.
DOI: 10.1002/cphg.22
PMID: 27727437 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/19632331 | 1. Neurobiol Dis. 2009 Oct;36(1):181-90. doi: 10.1016/j.nbd.2009.07.009. Epub
2009 Jul 24.
Absence of a differentiation defect in muscle satellite cells from DM2 patients.
Pelletier R(1), Hamel F, Beaulieu D, Patry L, Haineault C, Tarnopolsky M,
Schoser B, Puymirat J.
Author information:
(1)Human Genetics Research Unit, Laval University, CHUQ, Pavillon CHUL, Ste-Foy,
Quebec, Canada, G1V 4G2. richard.pelletier@crchul.ulaval.ca
Myotonic dystrophy type 1 (DM1) and type II (DM2) are dominantly inherited
multisystemic disorders. DM1 is triggered by the pathological expansion of a
(CTG)(n) triplet repeat in the DMPK gene, whereas a (CCTG)(n) tetranucleotide
repeat expansion in the ZNF9 gene causes DM2. Both forms of the disease share
several features, even though the causative mutations and the loci involved
differ. Important distinctions exist, such as the lack of a congenital form of
DM2. The reason for these disparities is unknown. In this study, we
characterized skeletal muscle satellite cells from adult DM2 patients to provide
an in vitro model for the disease. We used muscle cells from DM1 biopsies as a
comparison tool. Our main finding is that DM2 satellite cells differentiate
normally in vitro. Myotube formation was similar to unaffected controls. In
contrast, fetal DM1 cells were deficient in that ability. Consistent with this
observation, the myogenic program in DM2 was intact but is compromised in fetal
DM1 cells. Although expression of the ZNF9 gene was enhanced in DM2 during
differentiation, the levels of the ZNF9 protein were substantially reduced. This
suggests that the presence of a large CCTG tract impairs the translation of the
ZNF9 mRNA. Additionally, DM2 muscle biopsies displayed the altered splicing of
the insulin receptor mRNA, correlating with insulin resistance in the patients.
Finally, CUGBP1 steady-state protein levels were unchanged in DM2 cultured
muscle cells and in DM2 muscle biopsies relative to controls, whereas they are
increased in DM1 muscle cells. Our findings suggest that the myogenic program
throughout muscle development and tissue regeneration is intact in DM2.
DOI: 10.1016/j.nbd.2009.07.009
PMID: 19632331 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/24435591 | 1. Curr Neurol Neurosci Rep. 2014 Feb;14(2):429. doi: 10.1007/s11910-013-0429-1.
Recent advances in myotonic dystrophy type 2.
Ulane CM(1), Teed S, Sampson J.
Author information:
(1)Department of Neurology, The Neurological Institute, Columbia University
Medical Center, 710 West 168 St., New York, NY, 10032, USA,
cu2119@mail.cumc.columbia.edu.
Myotonic dystrophy is the commonest adult muscular dystrophy. Myotonic dystrophy
type 1 (DM1) and myotonic dystrophy type 2 (DM2) are often discussed jointly,
and although they share many clinical and molecular features, differences do
exist. Historically, more is known about DM1 than about DM2. The literature in
the field of myotonic dystrophy is broad, with advances in our understanding of
DM2. This article reviews recent developments in DM2 with respect to diagnosis,
systemic features, and molecular mechanisms of the disease.
DOI: 10.1007/s11910-013-0429-1
PMID: 24435591 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35543970 | 1. Drugs. 2022 Jun;82(8):925-931. doi: 10.1007/s40265-022-01723-1.
Nivolumab Plus Relatlimab: First Approval.
Paik J(1).
Author information:
(1)Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New
Zealand. dru@adis.com.
Nivolumab plus relatlimab (nivolumab and relatlimab-rmbw; Opdualag™) is a
fixed-dose, combination immunotherapy treatment being developed by Bristol Myers
Squibb for the treatment of multiple types of advanced cancers. Both drugs are
immunoglobulin G4 (IgG4) monoclonal antibodies developed to target immune
checkpoints, with nivolumab targeting the programmed cell death protein 1 (PD-1)
receptor and relatlimab being a newly developed, first-in-class drug targeting
the lymphocyte-activation gene 3 (LAG-3) protein. In March 2022, nivolumab plus
relatlimab received its first approval in the USA for the treatment of
unresectable or metastatic melanoma in adult patients and paediatric patients
aged ≥ 12 years who weigh ≥ 40 kg. This article summarizes the milestones in the
development of this combination therapy leading to this first approval for
unresectable or metastatic melanoma.
© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland
AG.
DOI: 10.1007/s40265-022-01723-1
PMID: 35543970 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36268952 | 1. Ann Pharmacother. 2023 Jun;57(6):738-745. doi: 10.1177/10600280221131396. Epub
2022 Oct 21.
Nivolumab/Relatlimab: A Novel Addition to Immune Checkpoint Inhibitor Therapy in
Unresectable or Metastatic Melanoma.
Phillips AL(1), Reeves DJ(1)(2).
Author information:
(1)College of Pharmacy and Health Sciences, Butler University, Indianapolis, IN,
USA.
(2)Franciscan Health Indianapolis, Indianapolis, IN, USA.
OBJECTIVE: The aim of this article is to assess available data regarding use of
nivolumab/relatlimab for adult and pediatric patients 12 years of age and older
with unresectable or metastatic melanoma.
DATA SOURCES: A search of PubMed conducted from August 2019 to August 2022 with
the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in
14 publications.
STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials written in English
language were analyzed.
DATA SYNTHESIS: Nivolumab/relatlimab was approved by the Food and Drug
Administration following results of a phase 1/2 trial and phase 2/3
RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression
free survival (PFS) of 10.1 months in the first-line setting without new safety
signals. The PFS benefits appear greatest in those with programmed cell
death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse
effects commonly experienced were immune related in nature and require early
identification and prompt management. Grade 3 or 4 adverse effects occurred in
18.9% of patients.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For patients 12 years of age
and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers
a new first-line treatment option. Evaluation of PD-L1 expression along with
concomitant use of medications with potential interactions should be evaluated
when deciding if nivolumab/relatlimab is the most appropriate treatment option.
CONCLUSIONS: Nivolumab/relatlimab adds an additional first-line treatment option
demonstrating promising improved PFS for patients with unresectable or
metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%.
Additional uses of nivolumab/relatlimab may be on the horizon as further
clinical trials are ongoing.
DOI: 10.1177/10600280221131396
PMID: 36268952 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33488009 | 1. Middle East Afr J Ophthalmol. 2020 Oct 30;27(3):145-149. doi:
10.4103/meajo.MEAJO_317_20. eCollection 2020 Jul-Sep.
Surgical Outcomes of Microcatheter-assisted Trabeculotomy as a Secondary
Procedure in Patients with Primary Congenital Glaucoma.
Al Habash A(1), Otaif W(2), Edward DP(3)(4), Al Jadaan I(4).
Author information:
(1)Department of Ophthalmology, College of Medicine, Imam Abdulrahman Bin Faisal
University, Dammam, Saudi Arabia.
(2)Department of Ophthalmology, King Khalid University, Abha, Saudi Arabia.
(3)Department of Ophthalmology and Visual Sciences, University of Illinois at
Chicago, Chicago, Illinois, USA.
(4)Division of Glaucoma, King Khaled Eye Specialist Hospital, Riyadh, Saudi
Arabia.
PURPOSE: To investigate the efficacy and safety of illuminated
microcatheter-assisted trabeculotomy as a secondary procedure in patients with
primary congenital glaucoma (PCG).
METHODS: This retrospective case series included patients with PCG who underwent
trabeculotomy using an illuminated microcatheter with the intent of
catheterizing the full circumference of Schlemm's canal in a single procedure.
Success was defined as intraocular pressure (IOP) ≤21 mmHg, with or without the
use of glaucoma medications. Clinical examination data were collected for up to
36 months postoperatively.
RESULTS: Surgery was performed on 16 eyes of 16 patients. The mean patient age
was 75.1 ± 69.4 months (range: 4.0-216.0 months). Complete catheterization was
achieved in 11 of the 16 eyes (69%), whereas partial catheterization was
achieved in five of the 16 eyes (31%). All eyes had previously undergone surgery
for PCG. The mean follow-up duration was 20.3 ± 9.0 months (range, 12.0-36.0
months). IOP was reduced from a mean of 31.8 ± 6.6 mmHg preoperatively to 15.6 ±
3.7 mmHg at the final follow-up (P < 0.001). The mean preoperative number of
glaucoma medications was 3.9 ± 0.5, which was reduced to 1.1 ± 1.6 at the final
follow-up (P = 0.001). Ten (62.5%) of the 16 eyes did not require glaucoma
medication by the final follow-up. Early transient postoperative hyphema
occurred in six eyes (37.5%). No other complications were noted. All corneas
were clear at the final follow-up.
CONCLUSION: Ab externo circumferential trabeculotomy using an illuminated
microcatheter may be safe and effective as a secondary surgical option for
children with PCG after unsuccessful glaucoma surgery.
Copyright: © 2020 Middle East African Journal of Ophthalmology.
DOI: 10.4103/meajo.MEAJO_317_20
PMCID: PMC7813142
PMID: 33488009 [Indexed for MEDLINE]
Conflict of interest statement: There are no conflicts of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/32672594 | 1. Ophthalmol Glaucoma. 2020 Mar-Apr;3(2):114-121. doi:
10.1016/j.ogla.2019.11.013. Epub 2019 Dec 6.
Outflow Facility Effects of 3 Schlemm's Canal Microinvasive Glaucoma Surgery
Devices.
Toris CB(1), Pattabiraman PP(2), Tye G(3), Samuelson TW(4), Rhee DJ(3).
Author information:
(1)Department of Ophthalmology and Visual Sciences, Case Western Reserve
University, Cleveland, Ohio; Department of Ophthalmology and Visual Sciences,
University of Nebraska Medical Center, Omaha, Nebraska. Electronic address:
ctoris@unmc.edu.
(2)Department of Ophthalmology, Indiana University School of Medicine,
Indianapolis, Indiana.
(3)Department of Ophthalmology and Visual Sciences, Case Western Reserve
University, Cleveland, Ohio.
(4)Minnesota Eye Consultants, Minneapolis, Minnesota; Department of
Ophthalmology, University of Minnesota, Minneapolis, Minnesota.
PURPOSE: To study the effect of 3 Schlemm's canal (SC) microinvasive glaucoma
surgery (MIGS) devices on outflow facility.
DESIGN: Paired comparisons, randomized design, baseline-controlled study.
PARTICIPANTS: Thirty-six pairs of dissected anterior segments from donated human
eye bank eyes without glaucoma were studied. A baseline measurement was
collected from each eye to serve as its control.
METHODS: Using a constant pressure perfusion method, outflow facility was
measured in paired eyes from human donors. Measurements were made at perfusion
pressures of 10 mmHg, 20 mmHg, 30 mmHg, and 40 mmHg. Outflow facility was
measured before (baseline control) and after the implantation of an SC glaucoma
drainage device or sham procedure. Three sets of experiments were carried out
comparing 1 and 2 iStent Trabecular Micro-Bypass Stents and 2 iStent Inject
implants with the Hydrus Microstent.
MAIN OUTCOME MEASURES: Change in outflow facility from baseline or contralateral
eye.
RESULTS: After Hydrus placement, the outflow facility increased from 0.23±0.03
μl/minute per millimeter of mercury at baseline to 0.38±0.03 μl/minute per
millimeter of mercury (P < 0.001). The percent increase in outflow facility was
79±21% for the Hydrus and 11±16% for the 2 iStent Inject devices, a difference
that was significant (P = 0.018). Outflow facility with 1 iStent (0.38±0.07
μl/minute per millimeter of mercury) was greater than baseline (0.28±0.03
μl/minute per millimeter of mercury; P = 0.031). The 1 iStent showed a greater
increase in outflow facility from baseline (0.10±0.04 μl/minute per millimeter
of mercury) compared with the sham procedure (-0.08±0.05 μl/minute per
millimeter of mercury; P = 0.042). No other significant differences were found.
CONCLUSIONS: The longer the MIGS device, and thus the more SC that it dilates,
the greater the outflow facility.
Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc.
All rights reserved.
DOI: 10.1016/j.ogla.2019.11.013
PMID: 32672594 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33613251 | 1. Case Rep Ophthalmol. 2021 Jan 13;12(1):57-61. doi: 10.1159/000510931.
eCollection 2021 Jan-Apr.
Delayed-Onset, Recurrent Hyphema after Microhook ab interno Trabeculotomy.
Tanito M(1).
Author information:
(1)Department of Ophthalmology, Shimane University Faculty of Medicine, Izumo,
Japan.
Trabeculotomy (LOT) and related goniotomy surgeries can be divided into two
classes based on the excision or incision of the trabecular meshwork.
Previously, blood reflux from Schlemm's canal (SC) after long-standing glaucoma
surgery was reported in eyes treated with excisional LOT. The current case is
one of delayed-onset hyphema after incisional LOT. An 87-year-old woman with
bilateral normal-tension glaucoma had undergone microhook ab interno LOT (μLOT)
combined with small incisional cataract surgery in both eyes 4 years previously.
At the scheduled 4-year follow-up visit, numerous red blood cells floating in
the anterior chamber, angle hyphema, and opening of the LOT cleft were observed
in the right eye. No possible cause of hyphema such as rubeosis, Swan syndrome,
or uveitis-glaucoma-hyphema syndrome was identified. This case suggests that SC
can remain open for an extended time even after incisional LOT such as μLOT.
Copyright © 2021 by S. Karger AG, Basel.
DOI: 10.1159/000510931
PMCID: PMC7879268
PMID: 33613251
Conflict of interest statement: The microhooks used were co-developed by Masaki
Tanito, MD, PhD and Inami & Co., Ltd., and provided by Inami & Co., Ltd. Dr.
Tanito receives royalties from Inami & Co., Ltd. |
http://www.ncbi.nlm.nih.gov/pubmed/35954196 | 1. Cells. 2022 Jul 30;11(15):2351. doi: 10.3390/cells11152351.
Cutting-Edge: Preclinical and Clinical Development of the First Approved Lag-3
Inhibitor.
Chocarro L(1), Bocanegra A(1), Blanco E(1)(2), Fernández-Rubio L(1), Arasanz
H(1)(3), Echaide M(1), Garnica M(1), Ramos P(1), Piñeiro-Hermida S(1), Vera
R(3), Escors D(1), Kochan G(1).
Author information:
(1)Oncoimmunology Research Unit, Navarrabiomed-Fundación Miguel Servet,
Universidad Pública de Navarra (UPNA), Hospital Universitario de Navarra (HUN),
Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31001 Pamplona, Spain.
(2)Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad
de Navarra, Instituto de Investigación Sanitaria de Navarra (IdISNA), 31001
Pamplona, Spain.
(3)Medical Oncology Unit, Hospital Universitario de Navarra (HUN), Instituto de
Investigación Sanitaria de Navarra (IdiSNA), 31001 Pamplona, Spain.
Immune checkpoint inhibitors (ICIs) have revolutionized medical practice in
oncology since the FDA approval of the first ICI 11 years ago. In light of this,
Lymphocyte-Activation Gene 3 (LAG-3) is one of the most important
next-generation immune checkpoint molecules, playing a similar role as
Programmed cell Death protein 1 (PD-1) and Cytotoxic T-Lymphocyte Antigen 4
(CTLA-4). 19 LAG-3 targeting molecules are being evaluated at 108 clinical
trials which are demonstrating positive results, including promising bispecific
molecules targeting LAG-3 simultaneously with other ICIs. Recently, a new dual
anti-PD-1 (Nivolumab) and anti-LAG-3 (Relatimab) treatment developed by Bristol
Myers Squibb (Opdualag), was approved by the Food and Drug Administration (FDA)
as the first LAG-3 blocking antibody combination for unresectable or metastatic
melanoma. This novel immunotherapy combination more than doubled median
progression-free survival (PFS) when compared to nivolumab monotherapy (10.1
months versus 4.6 months). Here, we analyze the large clinical trial responsible
for this historical approval (RELATIVITY-047), and discuss the preclinical and
clinical developments that led to its jump into clinical practice. We will also
summarize results achieved by other LAG-3 targeting molecules with promising
anti-tumor activities currently under clinical development in phases I, I/II,
II, and III. Opdualag will boost the entry of more LAG-3 targeting molecules
into clinical practice, supporting the accumulating evidence highlighting the
pivotal role of LAG-3 in cancer.
DOI: 10.3390/cells11152351
PMCID: PMC9367598
PMID: 35954196 [Indexed for MEDLINE]
Conflict of interest statement: D.E. declares authorship in the invention
‘Therapeutic molecules that bind to LAG3 and PD1’ by Crescendo Biologics
(GB201802573D0). H.A. declares to be on the advisory board for AstraZeneca. |
http://www.ncbi.nlm.nih.gov/pubmed/28291197 | 1. Vestn Oftalmol. 2017;133(1):32-36. doi: 10.17116/oftalma2017133132-36.
[Long-term results of combined surgery for open-angle glaucoma].
[Article in Russian; Abstract available in Russian from the publisher]
Baranov IY(1), Shiryaev IV(1), Mitrofanova NV(2), Molodkina NA(1), Balashevich
LI(1).
Author information:
(1)Saint-Petersburg branch of the Academician S.N. Fyodorov IRTC 'Eye
Microsurgery', 21 Yaroslava Gasheka St., Saint-Petersburg, Russian Federation,
192283.
(2)North-Western State Medical University named after I.I. Mechnikov, 1/82
Zanevskiy prospekt, Saint-Petersburg, Russian Federation, 195196.
AIM: to comparatively evaluate the hypotensive effect of minimally invasive
(type 1) and basic (type 2) subscleral removing of the external wall of
Schlemm's canal with subsequent laser trabeculopuncture in patients with
open-angle glaucoma (POAG).
MATERIAL AND METHODS: The main group included 60 patients (64 eyes) treated with
the minimally invasive technique. The control group included 105 patients (105
eyes), who underwent the type 2 surgery.
RESULTS: After sinusotomy, intraocular pressure (IOP) decreased by 25% of its
preoperative values in most patients (in 90.6% of patients from the main group
and 81.9% of the controls, p<0.05). After laser trabeculopuncture, IOP further
decreased down to 15.6±0.4 mmHg in the main group and 17.4±0.3 mmHg in the
control group (p<0.05). Twelve months after the combined treatment, the
hypotensive effect was still present in 81.2% of patients from the main group
and 90.5% of the controls. None of the patients required additional hypotensive
therapy.
CONCLUSION: In POAG patients, the effect of minimally invasive subscleral
removal of the external wall of Schlemm's canal (microfistulazing procedure)
followed by laser trabeculopuncture is no weaker than that of basic technique.
Publisher: Цель — провести сравнительный анализ гипотензивного эффекта операций
субсклерального удаления наружной стенки синуса с последующей лазерной
трабекулопунктурой в микрофистулизирующем (1-й тип) и базовом (2-й тип)
вариантах. Материал и методы. В основную группу вошли 60 пациентов (64 глаза),
которым проведено лазерно-хирургическое лечение 1-го типа. Контрольную группу
составили 105 пациентов (105 глаз), которым было выполнено вмешательство 2-го
типа. Результаты. После хирургического этапа у 90,6% пациентов основной и 81,9%
контрольной групп внутриглазное давление (ВГД) снизилось на 25% от исходного
(p<0,05). После лазерной трабекулопунктуры ВГД снизилось до 15,6±0,4 мм рт.ст. в
основной и до 17,4±0,3 мм рт.ст. в контрольной группах (p<0,05). Через 12 мес
после комбинированного лазерно-хирургического лечения гипотензивный эффект без
дополнительной гипотензивной терапии сохранился у 81,2% пациентов основной и
90,5% — контрольной группы (p<0,05). Заключение. Субсклеральное удаление
наружной стенки синуса в микрофистулизирующем варианте с последующей лазерной
трабекулопунктурой не менее эффективно по сравнению с базовым вариантом операции
снижает ВГД у пациентов с ПОУГ.
DOI: 10.17116/oftalma2017133132-36
PMID: 28291197 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25061877 | 1. J Clin Invest. 2014 Sep;124(9):3960-74. doi: 10.1172/JCI75392. Epub 2014 Jul
25.
Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity.
Park DY, Lee J, Park I, Choi D, Lee S, Song S, Hwang Y, Hong KY, Nakaoka Y,
Makinen T, Kim P, Alitalo K, Hong YK, Koh GY.
Comment in
J Clin Invest. 124:3701.
Schlemm's canal (SC) is a specialized vascular structure in the eye that
functions to drain aqueous humor from the intraocular chamber into systemic
circulation. Dysfunction of SC has been proposed to underlie increased aqueous
humor outflow (AHO) resistance, which leads to elevated ocular pressure, a
factor for glaucoma development in humans. Here, using lymphatic and blood
vasculature reporter mice, we determined that SC, which originates from blood
vessels during the postnatal period, acquires lymphatic identity through
upregulation of prospero homeobox protein 1 (PROX1), the master regulator of
lymphatic development. SC expressed lymphatic valve markers FOXC2 and integrin
α9 and exhibited continuous vascular endothelial-cadherin (VE-cadherin)
junctions and basement membrane, similar to collecting lymphatics. SC notably
lacked luminal valves and expression of the lymphatic endothelial cell markers
podoplanin and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1).
Using an ocular puncture model, we determined that reduced AHO altered the fate
of SC both during development and under pathologic conditions; however,
alteration of VEGF-C/VEGFR3 signaling did not modulate SC integrity and
identity. Intriguingly, PROX1 expression levels linearly correlated with SC
functionality. For example, PROX1 expression was reduced or undetectable under
pathogenic conditions and in deteriorated SCs. Collectively, our data indicate
that PROX1 is an accurate and reliable biosensor of SC integrity and identity.
DOI: 10.1172/JCI75392
PMCID: PMC4153702
PMID: 25061877 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/25061871 | 1. J Clin Invest. 2014 Sep;124(9):3701-3. doi: 10.1172/JCI77507. Epub 2014 Jul
25.
Schlemm's canal: more than meets the eye, lymphatics in disguise.
Karpinich NO, Caron KM.
Comment on
J Clin Invest. 124:3960.
J Clin Invest. 124:3975.
Schlemm's canal (SC) is a unique vascular structure that functions to maintain
fluid homeostasis by draining aqueous humor from the eye into the systemic
circulation. The endothelium lining the inner wall of SC has both blood and
lymphatic vascular characteristics, thus prompting exploration of the
development and regulation of this unique channel. In this issue of the JCI,
back-to-back papers by Aspelund et al. and Park et al. detail the mechanisms of
SC development, which includes a lymphatic reprogramming that is necessary to
maintain proper function. Furthermore, both groups exploit the lymph-like
qualities of this canal: they identify VEGF-C as a potential therapeutic for
glaucoma and suggest that expression of PROX1, a marker of lymphatic fate, could
also serve as a biosensor for monitoring SC integrity. These studies provide
substantial insight into the molecular and cellular pathways that govern SC
development and reveal that ocular pathology is associated with deregulation of
the lymph-like characteristics of SC.
DOI: 10.1172/JCI77507
PMCID: PMC4151199
PMID: 25061871 |
http://www.ncbi.nlm.nih.gov/pubmed/30242758 | 1. Methods Mol Biol. 2018;1846:153-160. doi: 10.1007/978-1-4939-8712-2_10.
Morphological Analysis of Schlemm's Canal in Mice.
Thomson BR(1)(2), Quaggin SE(3)(4).
Author information:
(1)Feinberg Cardiovascular and Renal Research Institute, Northwestern
University, Chicago, IL, USA. benjamin.thomson@northwestern.edu.
(2)The Division of Nephrology/Hypertension, Northwestern University Feinberg
School of Medicine, Chicago, IL, USA. benjamin.thomson@northwestern.edu.
(3)Feinberg Cardiovascular and Renal Research Institute, Northwestern
University, Chicago, IL, USA.
(4)The Division of Nephrology/Hypertension, Northwestern University Feinberg
School of Medicine, Chicago, IL, USA.
Immunofluorescent confocal microscopy is a powerful tool for analysis of the
morphology and development of vascular and lymphatic tissues. Schlemm's canal
(SC) is a large, lymphatic-like vessel in the anterior chamber of the eye, which
is essential for aqueous humor drainage required to maintain intraocular
pressure and is sensitive to defects in blood and lymphatic vascular signaling
pathways. Here, we describe a method to stain and quantify SC area and
morphology in enucleated mouse eyes, providing a tool for understanding its
development and function in small animal genetic or disease models.
DOI: 10.1007/978-1-4939-8712-2_10
PMCID: PMC6499067
PMID: 30242758 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/1426078 | 1. Exp Eye Res. 1992 Sep;55(3):479-88. doi: 10.1016/0014-4835(92)90121-8.
Aspects of the development of Schlemm's canal.
Hamanaka T(1), Bill A, Ichinohasama R, Ishida T.
Author information:
(1)Department of Ophthalmology, Japanese Red Cross Medical Center, Tokyo.
We have tried to answer the question of whether the endothelium of Schlemm's
canal is derived from and retains properties of blood vessels by studying: (1)
the development of Schlemm's canal in human fetal eyes; (2) the existence of
Weibel-Palade bodies in human neonatal, adult human and adult monkey eyes; and
(3) the presence of blood coagulation Factor VIII-related antigen in adult human
and monkey eyes. (1) We observed that the intrascleral plexus of the limbal
region extended deep into the sclera forming a deep scleral plexus by the 17th
week of gestation. After 17 weeks gestation, extensions from the deep scleral
plexus had reached the region of the future corneoscleral meshwork where the
trabecular cells appeared oriented circumferentially. The blind endings of these
extensions appeared to grow circumferentially in the supposed region of
Schlemm's canal and at 27 weeks gestation they formed an incomplete Schlemm's
canal. A complete Schlemm's canal was observed in some sections of the limbal
region at 28 weeks gestation and at approximately 40 weeks gestation the canal
was complete in most sections. (2) Weibel-Palade bodies were found in the
endothelium of aqueous veins and in the inner and outer wall endothelium of
Schlemm's canal. (3) Blood coagulation Factor VIII-related antigen was detected
in the endothelium of the collector channels and Schlemm's canal, as well as in
the blood vessels of the other parts of the eye. Our results indicate that the
endothelium of Schlemm's canal is derived from a vascular origin and that even
in the adult eye it retains some of the properties of a blood vessel.
DOI: 10.1016/0014-4835(92)90121-8
PMID: 1426078 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/10581564 | 1. Morfologiia. 1999;116(5):23-6.
[The macro-microscopic anatomy and topography of the area of the ciliary body in
different segments of the eyeball].
[Article in Russian]
Tulupov SB(1).
Author information:
(1)Department of Operative Surgery and Clinical Anatomy, Medical Academy,
Orenburg.
Differences in parameters of ciliary body and Schlemm's canal in different
meridians of the eyeball has been described using histotopographic methods on 20
eyeballs of human corpses. Circular stripe of sclera with the width to 2.1 mm
from limb was a point of projection of Schlemm's canal, iridocorneal and
iridociliary angles on the sclera surface. The projection of denticulate line
was variable in limits of 1.6 mm to 5.5 mm from limb.
PMID: 10581564 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/729457 | 1. Doc Ophthalmol. 1978 Oct 16;46(1):171-83. doi: 10.1007/BF00174106.
[Indications for the location of trabeculotomy in simple glaucoma. II. The
demonstration of aqueous outflow with fluorescein].
[Article in German]
Grote P.
Iontophoresis is less apt to prove the existence of outflow channels of aqueous
humour, but it is appropriate in demonstrating filtering blebs. After injecting
fluorescein directly into the anterior chamber, the outflow channels are clearly
marked in enucleated non-glaucomatous eyes, as well as in eyes containing a
tumor, prior to enucleation. Regularly, one is able to observe sectors in which
the aqueous veins are filled slowly or not filled at all. Injecting fluorescein
directly in Schlemm's canal proves that in cadaver eyes without glaucoma the
lumen is open all around. Sectorial filling defects of vessels leading out of
Schlemm's canal are often seen. In three patients with simple glaucoma blocking
of dye was noticed during passage through Schlemm's canal without reappearance.
Our experiments give the impression that segmental division of Schlemm's canal
is more marked in eyes with glaucoma than in normal eyes. If local occlusions
within Schlemm's canal are of importance for the range of lowering of
intraocular pressure, one must differentiate between the trabecular and the
intrascleral part of the resistance of outflow in the operation field, in order
to choose the best operating procedure. Such a differentiation seems, in
principle, possible using fluorescein--primarily injected into the anterior
chamber directly, and secondarily into a given part of Schlemm's canal.
DOI: 10.1007/BF00174106
PMID: 729457 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34043841 | 1. Rev Med Virol. 2022 Jan;32(1):e2260. doi: 10.1002/rmv.2260. Epub 2021 May 27.
Quantifying the risk of SARS-CoV-2 reinfection over time.
O Murchu E(1)(2), Byrne P(1), Carty PG(1), De Gascun C(3), Keogan M(4), O'Neill
M(1), Harrington P(1), Ryan M(1)(5).
Author information:
(1)Health Information and Quality Authority, George's Court, Dublin, Ireland.
(2)Trinity College Dublin, Dublin, Ireland.
(3)UCD National Virus Reference Laboratory, Dublin, Ireland.
(4)Beaumont Hospital, Dublin, Ireland.
(5)Department of Pharmacology & Therapeutics, Trinity College Dublin, Trinity
Health Sciences, Dublin, Ireland.
Despite over 140 million SARS-CoV-2 infections worldwide since the beginning of
the pandemic, relatively few confirmed cases of SARS-CoV-2 reinfection have been
reported. While immunity from SARS-CoV-2 infection is probable, at least in the
short term, few studies have quantified the reinfection risk. To our knowledge,
this is the first systematic review to synthesise the evidence on the risk of
SARS-CoV-2 reinfection over time. A standardised protocol was employed, based on
Cochrane methodology. Electronic databases and preprint servers were searched
from 1 January 2020 to 19 February 2021. Eleven large cohort studies were
identified that estimated the risk of SARS-CoV-2 reinfection over time,
including three that enrolled healthcare workers and two that enrolled residents
and staff of elderly care homes. Across studies, the total number of
PCR-positive or antibody-positive participants at baseline was 615,777, and the
maximum duration of follow-up was more than 10 months in three studies.
Reinfection was an uncommon event (absolute rate 0%-1.1%), with no study
reporting an increase in the risk of reinfection over time. Only one study
estimated the population-level risk of reinfection based on whole genome
sequencing in a subset of patients; the estimated risk was low (0.1% [95% CI:
0.08-0.11%]) with no evidence of waning immunity for up to 7 months following
primary infection. These data suggest that naturally acquired SARS-CoV-2
immunity does not wane for at least 10 months post-infection. However, the
applicability of these studies to new variants or to vaccine-induced immunity
remains uncertain.
© 2021 John Wiley & Sons Ltd.
DOI: 10.1002/rmv.2260
PMCID: PMC8209951
PMID: 34043841 [Indexed for MEDLINE]
Conflict of interest statement: No conflict of interest declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35904405 | 1. Eur J Clin Invest. 2022 Oct;52(10):e13845. doi: 10.1111/eci.13845. Epub 2022
Aug 8.
Risk of reinfection and disease after SARS-CoV-2 primary infection:
Meta-analysis.
Flacco ME(1), Acuti Martellucci C(1), Baccolini V(2), De Vito C(2), Renzi E(2),
Villari P(2), Manzoli L(3).
Author information:
(1)Department of Environmental and Preventive Sciences, University of Ferrara,
Ferrara, Italy.
(2)Department of Public Health and Infectious Diseases, Sapienza University,
Rome, Italy.
(3)Department of Medical and Surgical Sciences, University of Bologna, Bologna,
Italy.
INTRODUCTION: A precise estimate of the frequency and severity of SARS-CoV-2
reinfections would be critical to optimize restriction and vaccination policies
for the hundreds of millions previously infected subjects. We performed a
meta-analysis to evaluate the risk of reinfection and COVID-19 following primary
infection.
METHODS: We searched MedLine, Scopus and preprint repositories for cohort
studies evaluating the onset of new infections among baseline
SARS-CoV-2-positive subjects. Random-effect meta-analyses of proportions were
stratified by gender, exposure risk, vaccination status, viral strain, time
between episodes, and reinfection definition.
RESULTS: Ninety-one studies, enrolling 15,034,624 subjects, were included.
Overall, 158,478 reinfections were recorded, corresponding to a pooled rate of
0.97% (95% CI: 0.71%-1.27%), with no substantial differences by definition
criteria, exposure risk or gender. Reinfection rates were still 0.66% after
≥12 months from first infection, and the risk was substantially lower among
vaccinated subjects (0.32% vs. 0.74% for unvaccinated individuals). During the
first 3 months of Omicron wave, the reinfection rates reached 3.31%. Overall
rates of severe/lethal COVID-19 were very low (2-7 per 10,000 subjects according
to definition criteria) and were not affected by strain predominance.
CONCLUSIONS: A strong natural immunity follows the primary infection and may
last for more than one year, suggesting that the risk and health care needs of
recovered subjects might be limited. Although the reinfection rates considerably
increased during the Omicron wave, the risk of a secondary severe or lethal
disease remained very low. The risk-benefit profile of multiple vaccine doses
for this subset of population needs to be carefully evaluated.
© 2022 The Authors. European Journal of Clinical Investigation published by John
Wiley & Sons Ltd on behalf of Stichting European Society for Clinical
Investigation Journal Foundation.
DOI: 10.1111/eci.13845
PMCID: PMC9353414
PMID: 35904405 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35593164 | 1. Euro Surveill. 2022 May;27(20):2200372. doi:
10.2807/1560-7917.ES.2022.27.20.2200372.
Risk and protective factors for SARS-CoV-2 reinfections, surveillance data,
Italy, August 2021 to March 2022.
Sacco C(1), Petrone D(1), Del Manso M(1), Mateo-Urdiales A(1), Fabiani M(1),
Bressi M(1), Bella A(1), Pezzotti P(1), Rota MC(1), Riccardo F(1); Italian
Integrated Surveillance of COVID-19 study group(2).
Author information:
(1)Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
(2)The members of the Italian Integrated Surveillance of COVID-19 study group
are acknowledged at the end of the article.
We explored the risk factors associated with SARS-CoV-2 reinfections in Italy
between August 2021 and March 2022. Regardless of the prevalent virus variant,
being unvaccinated was the most relevant risk factor for reinfection. The risk
of reinfection increased almost 18-fold following emergence of the Omicron
variant compared with Delta. A severe first SARS-CoV-2 infection and age over 60
years were significant risk factors for severe reinfection.
DOI: 10.2807/1560-7917.ES.2022.27.20.2200372
PMCID: PMC9121659
PMID: 35593164 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None declared. |
http://www.ncbi.nlm.nih.gov/pubmed/35233580 | 1. medRxiv [Preprint]. 2022 Feb 26:2022.02.25.22271515. doi:
10.1101/2022.02.25.22271515.
Duration of Protection Against SARS-CoV-2 Reinfection and Associated Risk of
Reinfection Assessed with Real-World Data.
Reynolds SL, Kaufman HW, Meyer WA, Bush C, Cohen O, Cronin K, Kabelac C, Leonard
S, Anderson S, Petkov V, Lowy D, Sharpless N, Penberthy L.
Update in
PLoS One. 2023 Mar 21;18(3):e0280584. doi: 10.1371/journal.pone.0280584.
IMPORTANCE: Better understanding of the protective duration of prior SARS-CoV-2
infection against reinfection is needed.
OBJECTIVE: Primary: To assess the durability of immunity to SARS-CoV-2
reinfection among initially unvaccinated individuals with previous SARS-CoV-2
infection. Secondary: Evaluate the crude SARS-CoV-2 reinfection rate and
associated characteristics.
DESIGN AND SETTING: Retrospective observational study of HealthVerity data among
144,678,382 individuals, during the pandemic era through April 2021.
PARTICIPANTS: Individuals studied had SARS-CoV-2 molecular diagnostic or
antibody index test results from February 29 through December 9, 2020, with
≥365 days of pre-index continuous closed medical enrollment, claims, or
electronic health record activity.
MAIN OUTCOMES AND MEASURES: Rates of reinfection among index-positive
individuals were compared to rates of infection among index-negative
individuals. Factors associated with reinfection were evaluated using
multivariable logistic regression. For both objectives, the outcome was a
subsequent positive molecular diagnostic test result.
RESULTS: Among 22,786,982 individuals with index SARS-CoV-2 laboratory test data
(2,023,341 index positive), the crude rate of reinfection during follow-up was
significantly lower (9.89/1,000-person years) than that of primary infection
(78.39/1,000 person years). Consistent with prior findings, the risk of
reinfection among index-positive individuals was 87% lower than the risk of
infection among index-negative individuals (hazard ratio, 0.13; 95% CI, 0.13,
0.13). The cumulative incidence of reinfection among index-positive individuals
and infection among index-negative individuals was 0.85% (95% CI: 0.82%, 0.88%)
and 6.2% (95% CI: 6.1%, 6.3%), respectively, over follow-up of 375 days. The
duration of protection against reinfection was stable over the median 5 months
and up to 1-year follow-up interval. Factors associated with an increased
reinfection risk included older age, comorbid immunologic conditions, and living
in congregate care settings; healthcare workers had a decreased reinfection
risk.
CONCLUSIONS AND RELEVANCE: This large US population-based study demonstrates
that SARS-CoV-2 reinfection is uncommon among individuals with laboratory
evidence of a previous infection. Protection from SARS-CoV-2 reinfection is
stable up to one year. Reinfection risk was primarily associated with age 85+
years, comorbid immunologic conditions and living in congregate care settings;
healthcare workers demonstrated a decreased reinfection risk. These findings
suggest that infection induced immunity is durable for variants circulating
prior to Delta.
KEY POINTS: Question: How long does prior SARS-CoV-2 infection provide
protection against SARS-CoV-2 reinfection?Finding: Among >22 million individuals
tested February 2020 through April 2021, the relative risk of reinfection among
those with prior infection was 87% lower than the risk of infection among
individuals without prior infection. This protection was durable for up to a
year. Factors associated with increased likelihood of reinfection included older
age (85+ years), comorbid immunologic conditions, and living in congregate care
settings; healthcare workers had lower risk.Meaning: Prior SARS-CoV-2 infection
provides a durable, high relative degree of protection against reinfection.
DOI: 10.1101/2022.02.25.22271515
PMCID: PMC8887071
PMID: 35233580 |
http://www.ncbi.nlm.nih.gov/pubmed/36275814 | 1. Front Med (Lausanne). 2022 Oct 6;9:962653. doi: 10.3389/fmed.2022.962653.
eCollection 2022.
Milder outcomes of SARS-CoV-2 genetically confirmed reinfections compared to
primary infections with the delta variant: A retrospective case-control study.
Suljič A(1), Sočan M(2), Mrzel M(2), Lunar MM(1), Korva M(1), Štorman A(3),
Prosenc K(3), Janežič S(3), Žohar-Čretnik T(3), Zupanič T(2), Poljak M(1),
Avšič-Županc T(1).
Author information:
(1)Faculty of Medicine, Institute of Microbiology and Immunology, University of
Ljubljana, Ljubljana, Slovenia.
(2)National Institute of Public Health, Ljubljana, Slovenia.
(3)National Laboratory of Health, Environment, and Food, Maribor, Slovenia.
BACKGROUND: SARS-CoV-2 infection does not confer long immunity. However, studies
suggest that prior infection is associated with lower risk of reinfection and
milder outcomes of recurrent infections. The aims of this retrospective
observational case-control study were to describe the clinical and molecular
characteristics of genetically confirmed Delta reinfection cases and to assess
the potential protective role of preceding infection on the severity of
reinfection.
METHODS: We used next generation sequencing (NGS) to explore if cases with two
positive real time RT-PCR tests > 90 days apart were infected with a different
SARS-CoV-2 variant. Cases with confirmed reinfection between August 1st and
October 31st, 2021 (the Delta wave) in Slovenia were matched 1:4 by age, sex and
timeframe (week of positive test) with individuals with primary infection.
Sociodemographic and epidemiologic data, vaccination status, and data on
hospitalization and outcome of infection were retrieved from several centralized
and standardized national databases. Additional epidemiologic surveys were
performed on a limited number of cases and controls.
RESULTS: We identified 628 cases of genetically confirmed reinfection during the
study period and matched them with 2,512 control subjects with Delta primary
infection. Primary infections in individuals with reinfection were mainly caused
by B.1.258.17 (51.1%), followed by B.1.1.7 (15.1%) and reinfection was detected
on average 271 days after primary infection (range 101-477 days). Our results
show a substantially lower probability of hospitalization in cases with
reinfection compared with controls (OR: 0.21, p = 0.017), but no significant
difference was observed in intensive care unit admission and deaths. We observed
a significantly lower proportion of vaccinated individuals among cases compared
to controls (4.5% vs. 28.2%), suggesting that hybrid immunity leads to lower
probability of reinfection. Detailed analysis of the temporal distribution of
variants, responsible for reinfections, showed no significant differences in
reinfection potential.
CONCLUSION: Reinfection with the SARS-CoV-2 Delta variant resulted in fewer
hospitalizations compared to the primary Delta infection, suggesting that
primary infection may, to some extent, produce at least short lasting protective
immunity. This study provides additional insight into the reinfection dynamics
that may allow appropriate public health measures to be taken in subsequent
waves of the COVID-19 pandemic.
Copyright © 2022 Suljič, Sočan, Mrzel, Lunar, Korva, Štorman, Prosenc, Janežič,
Žohar-Čretnik, Zupanič, Poljak and Avšič-Županc.
DOI: 10.3389/fmed.2022.962653
PMCID: PMC9582599
PMID: 36275814
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/36298593 | 1. Vaccines (Basel). 2022 Oct 16;10(10):1728. doi: 10.3390/vaccines10101728.
Antibody Response after SARS-CoV-2 Infection with the Delta and Omicron Variant.
Błaszczuk A(1), Michalski A(2), Sikora D(1), Malm M(3), Drop B(3), Polz-Dacewicz
M(1).
Author information:
(1)Department of Virology with SARS Laboratory, Medical University of Lublin,
20-093 Lublin, Poland.
(2)1st Clinical Military Hospital with Outpatient Clinic in Lublin, 20-049
Lublin, Poland.
(3)Department of Computer Science and Medical Statistics with the e-Health
Laboratory, 20-090 Lublin, Poland.
The SARS-CoV-2 virus caused a worldwide COVID-19 pandemic. So far, 6,120,834
confirmed cases of COVID-19 with 116,773 deaths have been reported in Poland.
According to WHO, a total of 54,662,485 vaccine doses have been administered.
New variants emerge that become dominant. The aim of this study was a comparison
of antibody level after infection caused by Delta and Omicron variants. The
study included 203 persons who underwent mild COVID-19 despite two doses of
vaccine. The obtained results indicate that a significantly lower titer was
observed in patients with the Omicron variant infection. Therefore, these
patients may be at risk of reinfection with new strains of the Omicron variant.
Due to the possibility of reinfection, booster vaccinations are necessary.
Further epidemiological and clinical studies are necessary to develop new
prevention strategies.
DOI: 10.3390/vaccines10101728
PMCID: PMC9612121
PMID: 36298593
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35262003 | 1. J Clin Virol Plus. 2021 Jun;1(1):100015. doi: 10.1016/j.jcvp.2021.100015. Epub
2021 May 4.
Comparative genomic analysis demonstrates that true reinfection following
SARS-CoV-2 infection is possible.
O Murchu E(1)(2), O'Neill S(1), Byrne P(1), De Gascun C(3), O'Neill M(1), Ryan
M(1)(4), Harrington P(1).
Author information:
(1)Health Information and Quality Authority, George's Court, George's Lane,
Dublin 7, Ireland.
(2)Trinity College Dublin, Institute of Population Health, Tallaght, Dublin 24,
Ireland.
(3)UCD National Virus Reference Laboratory, Dublin, Ireland.
(4)Department of Pharmacology & Therapeutics, Trinity College Dublin, Trinity
Health Sciences, Dublin 8, Ireland.
BACKGROUND: In recent months, multiple cases of confirmed SARS-CoV-2 reinfection
have been reported. However, accurate epidemiological and virological data,
including genomic analysis where possible, are required to differentiate cases
of prolonged viral RNA shedding (i.e. intermittent detection) from true
reinfection. The objective of this review was to systematically identify and
summarise all cases of SARS-CoV-2 reinfection confirmed by comparative genomic
analysis.
METHODS: A protocol based on Cochrane rapid review methodology was employed.
Databases and pre-print servers were searched until 9/11/2020.
RESULTS: Ten studies, representing 17 patients, were identified (mean age=40;
71% male). The time interval between primary infection and reinfection ranged
from 13 to 142 days (median: 60).Comparative whole genome sequencing confirmed
reinfection in 14 patients (the primary and secondary infections were caused by
different viruses). A further three cases had strong, but not confirmed evidence
of reinfection, as only partial genomes were retrieved on primary
infection.Across 12 studies that reported the number of single nucleotide
polymorphisms (SNPs) comparing the first and second genomes, between 8 and 24
SNPs were discovered. With an average SARS-CoV-2 mutation acquisition rate of
1-2 per month, in all cases it is likely that the secondary infection was caused
by a different SARS-CoV-2 virus, rather than prolonged shedding of viral RNA
from the primary infection.In five reinfection cases, the primary and secondary
infections were caused by different SARS-CoV-2 lineages/clades, strongly
indicating that infections were caused by different viruses.
CONCLUSION: Comparative genomic analyses from 14 patients confirm that
SARS-CoV-2 reinfection can occur.
© 2021 The Authors.
DOI: 10.1016/j.jcvp.2021.100015
PMCID: PMC8093002
PMID: 35262003
Conflict of interest statement: The authors declare that they have no known
competing financial interests or personal relationships that could have appeared
to influence the work reported in this paper. |
http://www.ncbi.nlm.nih.gov/pubmed/34755830 | 1. Clin Infect Dis. 2022 Aug 24;75(1):e208-e215. doi: 10.1093/cid/ciab940.
Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection Associates With
Unstable Housing and Occurs in the Presence of Antibodies.
Bean DJ(1), Monroe J(2), Turcinovic J(1), Moreau Y(2), Connor JH(1), Sagar
M(1)(2).
Author information:
(1)Department of Microbiology, Boston University School of Medicine, Boston,
Massachusetts, USA.
(2)Department of Medicine, Boston University School of Medicine, Boston,
Massachusetts, USA.
BACKGROUND: The factors associated with severe acute respiratory coronavirus 2
(SARS-CoV-2) reinfection remain poorly defined.
METHODS: We identified patients with SARS-CoV-2 infection and at least 1 repeat
reverse transcription polymerase chain reaction result a minimum of 90 days
after the initial positive test and before 21 January 2021. Those with a repeat
positive test were deemed to have reinfection (n = 75), and those with only
negative tests were classified as convalescents (n = 1594). Demographics,
coronavirus disease 2019 (COVID-19) severity, and treatment histories were
obtained from the Boston Medical Center electronic medical record. Humoral
responses were analyzed using SARS-CoV-2-specific enzyme-linked immunosorbent
assays and pseudovirus neutralizations in a subset of reinfection (n = 16) and
convalescent samples (n = 32). Univariate, multivariate, and time to event
analyses were used to identify associations.
RESULTS: Individuals with reinfection had more frequent testing at shorter
intervals compared with the convalescents. Unstable housing was associated with
more than 2-fold greater chance of reinfection. Preexisting comorbidities and
COVID-19 severity after the initial infection were not associated with
reinfection. SARS-CoV-2 immunoglobulin G levels and pseudovirus neutralization
were not different within the early weeks after primary infection and at a
timepoint at least 90 days later in the 2 groups. In the convalescents, but not
in those with reinfection, the late as compared with early humoral responses
were significantly higher.
CONCLUSIONS: Reinfection associates with unstable housing, which is likely a
marker for virus exposure, and reinfection occurs in the presence of SARS-CoV-2
antibodies.
© The Author(s) 2021. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/ciab940
PMCID: PMC8689949
PMID: 34755830 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33338197 | 1. Clin Infect Dis. 2021 Dec 6;73(11):e4223-e4228. doi: 10.1093/cid/ciaa1866.
Reinfection With SARS-CoV-2: Implications for Vaccines.
Cohen JI(1), Burbelo PD(2).
Author information:
(1)Laboratory of Infectious Diseases, National Institutes of Health, Bethesda,
Maryland, USA.
(2)National Institute of Dental and Craniofacial Research, National Institutes
of Health, Bethesda, Maryland,USA.
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has
become pandemic and the duration of protective immunity to the virus is unknown.
Cases of persons reinfected with the virus are being reported with increasing
frequency. At present it is unclear how common reinfection with SARS-CoV-2 is
and how long serum antibodies and virus-specific T cells persist after
infection. For many other respiratory virus infections, including influenza and
the seasonal coronaviruses that cause colds, serum antibodies persist for only
months to a few years and reinfections are very common. Here we review what is
known about the duration of immunity and reinfection with coronaviruses,
including SARS-CoV-2, as well as the duration of immunity to other viruses and
virus vaccines. These findings have implications for the need of continued
protective measures and for vaccines for persons previously infected with
SARS-CoV-2.
Published by Oxford University Press for the Infectious Diseases Society of
America 2020.
DOI: 10.1093/cid/ciaa1866
PMCID: PMC7799323
PMID: 33338197 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33361342 | 1. J Clin Microbiol. 2021 Mar 19;59(4):e02769-20. doi: 10.1128/JCM.02769-20.
Print 2021 Mar 19.
The Importance and Challenges of Identifying SARS-CoV-2 Reinfections.
Babiker A(1)(2), Marvil CE(2), Waggoner JJ(3), Collins MH(3), Piantadosi
A(1)(2).
Author information:
(1)Division of Infectious Diseases, Department of Medicine, Emory University
School of Medicine, Atlanta, Georgia, USA ahmed.babiker@emory.edu
anne.piantadosi@emory.edu.
(2)Department of Pathology and Laboratory Medicine, Emory University School of
Medicine, Atlanta, Georgia, USA.
(3)Division of Infectious Diseases, Department of Medicine, Emory University
School of Medicine, Atlanta, Georgia, USA.
Reports of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
reinfection have raised important questions about the strength and durability of
the immune response to primary infection, which are key factors in predicting
the course of the pandemic. Identifying reinfection requires detecting the virus
at two different time points and using viral genomic data to distinguish
reinfection from persistent viral carriage. This process is hindered by
challenges of logistics and capacity, such as banking samples from primary
infection and performing viral genome sequencing. These challenges may help to
explain why very few cases have been described to date. In addition, reinfection
may be a rare phenomenon, but detailed prospective studies are needed to
rigorously assess its frequency. To provide context for future investigations of
SARS-CoV-2 reinfection, we review 16 cases that have been published to date or
are available in preprint. Reinfection occurred across demographic spectra and
in patients whose initial infections were both asymptomatic/mild and
moderate/severe. For cases in which severity could be compared between episodes,
half of reinfections were less severe, raising the possibility of partial immune
protection. Although many patients had a positive total immunoglobulin or IgG
result at the time of reinfection, very little examination of their immune
response was performed. Further work is needed to elucidate the frequency,
determinants, and consequences of SARS-CoV-2 reinfection. Establishing the
necessary frameworks for surveillance and investigation will rely heavily on
clinical laboratories and clinical investigators, and we propose several
considerations to guide the medical community in identifying and characterizing
SARS-CoV-2 reinfections.
Copyright © 2021 American Society for Microbiology.
DOI: 10.1128/JCM.02769-20
PMCID: PMC8092746
PMID: 33361342 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33315061 | 1. Clin Infect Dis. 2021 Oct 5;73(7):e1830-e1840. doi: 10.1093/cid/ciaa1846.
Assessment of the Risk of Severe Acute Respiratory Syndrome Coronavirus 2
(SARS-CoV-2) Reinfection in an Intense Reexposure Setting.
Abu-Raddad LJ(1)(2)(3), Chemaitelly H(1)(2), Malek JA(4)(5), Ahmed AA(4),
Mohamoud YA(4), Younuskunju S(4), Ayoub HH(6), Al Kanaani Z(7), Al Khal A(7), Al
Kuwari E(7), Butt AA(7), Coyle P(7), Jeremijenko A(7), Kaleeckal AH(7), Latif
AN(7), Shaik RM(7), Abdul Rahim HF(8), Yassine HM(9)(10), Al Kuwari MG(11), Al
Romaihi HE(12), Al-Thani MH(12), Bertollini R(12).
Author information:
(1)Infectious Disease Epidemiology Group, Weill Cornell Medicine-Qatar, Cornell
University, Doha, Qatar.
(2)World Health Organization Collaborating Centre for Disease Epidemiology
Analytics on HIV/AIDS, Sexually Transmitted Infections, and Viral Hepatitis,
Weill Cornell Medicine-Qatar, Cornell University, Qatar Foundation, Education
City, Doha, Qatar.
(3)Department of Population Health Sciences, Weill Cornell Medicine, Cornell
University, New York, New York, USA.
(4)Genomics Laboratory, Weill Cornell Medicine-Qatar, Cornell University, Doha,
Qatar.
(5)Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Cornell
University, Doha, Qatar.
(6)Department of Mathematics, Statistics, and Physics, Qatar University, Doha,
Qatar.
(7)Hamad Medical Corporation, Doha, Qatar.
(8)College of Health Sciences, QU Health, Qatar University, Doha, Qatar.
(9)Biomedical Research Center, Qatar University, Doha, Qatar.
(10)Department of Biomedical Science, College of Health Sciences, Member of QU
Health, Qatar University, Doha, Qatar.
(11)Primary Health Care Corporation, Doha, Qatar.
(12)Ministry of Public Health, Doha, Qatar.
BACKGROUND: Risk of reinfection with severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) is unknown. We assessed the risk and incidence rate
of documented SARS-CoV-2 reinfection in a cohort of laboratory-confirmed cases
in Qatar.
METHODS: All SARS-CoV-2 laboratory-confirmed cases with at least 1 polymerase
chain reaction-positive swab that was ≥45 days after a first positive swab were
individually investigated for evidence of reinfection. Viral genome sequencing
of the paired first positive and reinfection viral specimens was conducted to
confirm reinfection.
RESULTS: Out of 133 266 laboratory-confirmed SARS-CoV-2 cases, 243 persons
(0.18%) had at least 1 subsequent positive swab ≥45 days after the first
positive swab. Of these, 54 cases (22.2%) had strong or good evidence for
reinfection. Median time between the first swab and reinfection swab was 64.5
days (range, 45-129). Twenty-three of the 54 cases (42.6%) were diagnosed at a
health facility, suggesting presence of symptoms, while 31 (57.4%) were
identified incidentally through random testing campaigns/surveys or contact
tracing. Only 1 person was hospitalized at the time of reinfection but was
discharged the next day. No deaths were recorded. Viral genome sequencing
confirmed 4 reinfections of 12 cases with available genetic evidence.
Reinfection risk was estimated at 0.02% (95% confidence interval [CI],
.01%-.02%), and reinfection incidence rate was 0.36 (95% CI, .28-.47) per 10 000
person-weeks.
CONCLUSIONS: SARS-CoV-2 reinfection can occur but is a rare phenomenon
suggestive of protective immunity against reinfection that lasts for at least a
few months post primary infection.
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America.
DOI: 10.1093/cid/ciaa1846
PMCID: PMC7799253
PMID: 33315061 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/34459525 | 1. J Intern Med. 2022 Jan;291(1):72-80. doi: 10.1111/joim.13387. Epub 2021 Sep
27.
Robust humoral and cellular immune responses and low risk for reinfection at
least 8 months following asymptomatic to mild COVID-19.
Havervall S(1), Ng H(1)(2), Jernbom Falk A(3), Greilert-Norin N(1), Månberg
A(3), Marking U(1), Laurén I(4), Gabrielsson L(1), Salomonsson AC(1), Aguilera
K(1), Kihlgren M(1), Månsson M(1), Rosell A(1), Hellström C(3), Andersson E(3),
Olofsson J(3), Skoglund L(3), Yousef J(3), Pin E(3), Lord M(4), Åberg M(5),
Hedhammar M(3), Tegel H(3), Dönnes P(6), Phillipson M(2), Nilsson P(3),
Klingström J(7), Mangsbo S(4), Hober S(3), Thålin C(1).
Author information:
(1)Department of Clinical Sciences, Karolinska Institutet Danderyd Hospital,
Stockholm, Sweden.
(2)Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
(3)Department of Protein Science, SciLifeLab, KTH Royal Institute of Technology,
Stockholm, Sweden.
(4)Department of Pharmacy, Uppsala University, Uppsala, Sweden.
(5)Department of Medical Sciences, Clinical Chemistry and Science for Life
Laboratory, Uppsala University, Uppsala, Sweden.
(6)SciCross AB, Skövde, Sweden.
(7)Centre for Infectious Medicine, Department of Medicine Huddinge, Karolinska
Institutet, Stockholm, Sweden.
BACKGROUND: Emerging data support detectable immune responses for months after
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and
vaccination, but it is not yet established to what degree and for how long
protection against reinfection lasts.
METHODS: We investigated SARS-CoV-2-specific humoral and cellular immune
responses more than 8 months post-asymptomatic, mild and severe infection in a
cohort of 1884 healthcare workers (HCW) and 51 hospitalized COVID-19 patients.
Possible protection against SARS-CoV-2 reinfection was analyzed by a weekly
3-month polymerase chain reaction (PCR) screening of 252 HCW that had
seroconverted 7 months prior to start of screening and 48 HCW that had remained
seronegative at multiple time points.
RESULTS: All COVID-19 patients and 96% (355/370) of HCW who were anti-spike IgG
positive at inclusion remained anti-spike IgG positive at the 8-month follow-up.
Circulating SARS-CoV-2-specific memory T cell responses were detected in 88%
(45/51) of COVID-19 patients and in 63% (233/370) of seropositive HCW. The
cumulative incidence of PCR-confirmed SARS-CoV-2 infection was 1% (3/252) among
anti-spike IgG positive HCW (0.13 cases per 100 weeks at risk) compared to 23%
(11/48) among anti-spike IgG negative HCW (2.78 cases per 100 weeks at risk),
resulting in a protective effect of 95.2% (95% CI 81.9%-99.1%).
CONCLUSIONS: The vast majority of anti-spike IgG positive individuals remain
anti-spike IgG positive for at least 8 months regardless of initial COVID-19
disease severity. The presence of anti-spike IgG antibodies is associated with a
substantially reduced risk of reinfection up to 9 months following asymptomatic
to mild COVID-19.
© 2021 The Authors. Journal of Internal Medicine published by John Wiley & Sons
Ltd on behalf of Association for Publication of The Journal of Internal
Medicine.
DOI: 10.1111/joim.13387
PMCID: PMC8661920
PMID: 34459525 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/34632431 | 1. Lancet Microbe. 2021 Dec;2(12):e666-e675. doi: 10.1016/S2666-5247(21)00219-6.
Epub 2021 Oct 1.
The durability of immunity against reinfection by SARS-CoV-2: a comparative
evolutionary study.
Townsend JP(1)(2)(3)(4), Hassler HB(1), Wang Z(1), Miura S(5), Singh J(6), Kumar
S(5), Ruddle NH(7), Galvani AP(7)(8)(2), Dornburg A(9).
Author information:
(1)Department of Biostatistics, Yale School of Public Health, New Haven, CT,
USA.
(2)Department of Ecology and Evolutionary Biology, Yale University, New Haven,
CT, USA.
(3)Program in Computational Biology and Bioinformatics, Yale University, New
Haven, CT, USA.
(4)Program in Microbiology, Yale University, New Haven, CT, USA.
(5)Institute for Genomics and Evolutionary Medicine, and Department of Biology,
Temple University, Philadelphia, PA, USA.
(6)Yale College, Yale University, New Haven, CT, USA.
(7)Department of Epidemiology of Microbial Diseases, Yale School of Public
Health, New Haven, CT, USA.
(8)Center for Infectious Disease Modeling and Analysis, Yale School of Public
Health, New Haven, CT, USA.
(9)Department of Bioinformatics and Genomics, University of North Carolina,
Charlotte, NC, USA.
BACKGROUND: Among the most consequential unknowns of the devastating COVID-19
pandemic are the durability of immunity and time to likely reinfection. There
are limited direct data on SARS-CoV-2 long-term immune responses and
reinfection. The aim of this study is to use data on the durability of immunity
among evolutionarily close coronavirus relatives of SARS-CoV-2 to estimate times
to reinfection by a comparative evolutionary analysis of related viruses
SARS-CoV, MERS-CoV, human coronavirus (HCoV)-229E, HCoV-OC43, and HCoV-NL63.
METHODS: We conducted phylogenetic analyses of the S, M, and ORF1b genes to
reconstruct a maximum-likelihood molecular phylogeny of human-infecting
coronaviruses. This phylogeny enabled comparative analyses of peak-normalised
nucleocapsid protein, spike protein, and whole-virus lysate IgG antibody optical
density levels, in conjunction with reinfection data on endemic human-infecting
coronaviruses. We performed ancestral and descendent states analyses to estimate
the expected declines in antibody levels over time, the probabilities of
reinfection based on antibody level, and the anticipated times to reinfection
after recovery under conditions of endemic transmission for SARS-CoV-2, as well
as the other human-infecting coronaviruses.
FINDINGS: We obtained antibody optical density data for six human-infecting
coronaviruses, extending from 128 days to 28 years after infection between 1984
and 2020. These data provided a means to estimate profiles of the typical
antibody decline and probabilities of reinfection over time under endemic
conditions. Reinfection by SARS-CoV-2 under endemic conditions would likely
occur between 3 months and 5·1 years after peak antibody response, with a median
of 16 months. This protection is less than half the duration revealed for the
endemic coronaviruses circulating among humans (5-95% quantiles 15 months to 10
years for HCoV-OC43, 31 months to 12 years for HCoV-NL63, and 16 months to 12
years for HCoV-229E). For SARS-CoV, the 5-95% quantiles were 4 months to 6
years, whereas the 95% quantiles for MERS-CoV were inconsistent by dataset.
INTERPRETATION: The timeframe for reinfection is fundamental to numerous aspects
of public health decision making. As the COVID-19 pandemic continues,
reinfection is likely to become increasingly common. Maintaining public health
measures that curb transmission-including among individuals who were previously
infected with SARS-CoV-2-coupled with persistent efforts to accelerate
vaccination worldwide is critical to the prevention of COVID-19 morbidity and
mortality.
FUNDING: US National Science Foundation.
© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article
under the CC BY-NC-ND 4.0 license.
DOI: 10.1016/S2666-5247(21)00219-6
PMCID: PMC8486316
PMID: 34632431 [Indexed for MEDLINE]
Conflict of interest statement: We declare no competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/36164552 | 1. Front Cell Infect Microbiol. 2022 Sep 9;12:951383. doi:
10.3389/fcimb.2022.951383. eCollection 2022.
Occurrence of SARS-CoV-2 reinfections at regular intervals in Ecuador.
Guevara R(1), Prado-Vivar B(1), Márquez S(1), Muñoz EB(1), Carvajal M(1),
Guadalupe JJ(2), Becerra-Wong M(1), Proaño S(1), Bayas-Rea R(1), Coloma J(3),
Grunauer M(4), Trueba G(1), Rojas-Silva P(1), Barragán V(1), Cárdenas P(1).
Author information:
(1)Instituto de Microbiología, Universidad San Francisco de Quito USFQ, Quito,
Ecuador.
(2)Laboratorio de Biotecnología Vegetal, Universidad San Francisco de Quito
USFQ, Quito, Ecuador.
(3)Division of Infectious Diseases and Vaccinology, School of Public Health,
University of California Berkeley, Berkeley, CA, United States.
(4)Escuela de Medicina, Universidad San Francisco de Quito USFQ, Quito, Ecuador.
SARS-CoV-2 reinfection is defined as a new infection with a different virus
variant in an individual who has already recovered from a previous episode of
COVID-19. The first case of reinfection in the world was described in August
2020, since then, reinfections have increased over time and their incidence has
fluctuated with specific SARS-CoV-2 variant waves. Initially, reinfections were
estimated to represent less than 1% of total COVID-19 infections. With the
advent of the Omicron variant, reinfections became more frequent, representing
up to 10% of cases (based on data from developed countries). The frequency of
reinfections in Latin America has been scarcely reported. The current study
shows that in Ecuador, the frequency of reinfections has increased 10-fold
following the introduction of Omicron, after 22 months of surveillance in a
single center of COVID-19 diagnostics. Suspected reinfections were identified
retrospectively from a database of RT-qPCR-positive patients. Cases were
confirmed by sequencing viral genomes from the first and second infections using
the ONT MinION platform. Monthly surveillance showed that the main incidence
peaks of reinfections were reached within four to five months, coinciding with
the increase of COVID-19 cases in the country, suggesting that the emergence of
reinfections is related to higher exposure to the virus during outbreaks. This
study performed the longest monitoring of SARS-CoV-2 reinfections, showing an
occurrence at regular intervals of 4-5 months and confirming a greater
propensity of Omicron to cause reinfections.
Copyright © 2022 Guevara, Prado-Vivar, Márquez, Muñoz, Carvajal, Guadalupe,
Becerra-Wong, Proaño, Bayas-Rea, Coloma, Grunauer, Trueba, Rojas-Silva, Barragán
and Cárdenas.
DOI: 10.3389/fcimb.2022.951383
PMCID: PMC9507970
PMID: 36164552 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33257644 | 1. Am J Case Rep. 2020 Dec 1;21:e927154. doi: 10.12659/AJCR.927154.
A Patient with Asymptomatic SARS-CoV-2 Infection Who Presented 86 Days Later
with COVID-19 Pneumonia Possibly Due to Reinfection with SARS-CoV-2.
Sharma R(1), Sardar S(1), Mohammad Arshad A(1), Ata F(1), Zara S(1), Munir W(2).
Author information:
(1)Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatar.
(2)Department of Infectious Diseases, Hamad Medical Corporation, Doha, Qatar.
BACKGROUND Coronavirus disease 2019 (COVID-19) has radically changed the world,
and promising vaccine trials are currently underway. The immune responses in
asymptomatic and symptomatic individuals infected with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) are still under investigation, and data are
evolving. While it is known that humoral and cell-mediated immune responses
against SARS-CoV-2 are elicited, it is uncertain whether these responses protect
against reinfection or that they provide definitive evidence of viral clearance.
Very few cases have been reported in the literature regarding reinfection with
SARS-CoV-2. CASE REPORT We present a case of a middle-aged man with asymptomatic
SARS-CoV-2 infection who later developed mild symptomatic COVID-19 after a
period of 3 months. The source of reinfection was likely from the community,
which had a soaring burden of infection with the highest number of COVID-19
cases per million in the world at that time. The patient had 2 negative COVID-19
polymerase chain reaction (PCR) tests 2 weeks after the initial infection.
During the second infection, a nasopharyngeal reverse-transcription PCR test and
tests for the presence of COVID-19 immunoglobulin (Ig)M and IgG antibodies were
all positive. CONCLUSIONS Reinfection with SARS-CoV-2 is a strong possibility.
This case raises concerns that asymptomatic infections may not provide long-term
protective immunity to all patients, which could make them susceptible to
reinfection. Possible explanations for reinfection include an interval decrease
in protective antibodies titers after SARS-CoV-2 infection that may be more
prevalent in patients who had an asymptomatic infection. Other possibilities
include viral reactivation after a prolonged carriage of the virus or delayed
immune response.
DOI: 10.12659/AJCR.927154
PMCID: PMC7718490
PMID: 33257644 [Indexed for MEDLINE]
Conflict of interest statement: Conflict of interest: None declared Conflicts of
Interest None. |
http://www.ncbi.nlm.nih.gov/pubmed/33315049 | 1. Clin Infect Dis. 2021 Nov 2;73(9):e2985-e2991. doi: 10.1093/cid/ciaa1850.
Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection of a
Healthcare Worker in a Belgian Nosocomial Outbreak Despite Primary Neutralizing
Antibody Response.
Selhorst P(1)(2), van Ierssel SH(3), Michiels J(1), Mariën J(2)(4),
Bartholomeeusen K(1), Dirinck E(5), Vandamme S(6), Jansens H(6)(7), Ariën
KK(1)(8).
Author information:
(1)Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp,
Belgium.
(2)Outbreak Research Team, Institute of Tropical Medicine, Antwerp, Belgium.
(3)Department of General Internal Medicine, Infectious Diseases and Tropical
Medicine, Antwerp University Hospital, Edegem, Belgium.
(4)Department of Clinical Sciences, Institute of Tropical Medicine, Antwerp,
Belgium.
(5)Department of Endocrinology, Diabetology and Metabolic Disease, Antwerp
University Hospital, Edegem, Belgium.
(6)Department of Microbiology, Antwerp University Hospital, Edegem, Belgium.
(7)Department of Infection Prevention, Antwerp University Hospital, Edegem,
Belgium.
(8)University of Antwerp, Antwerp, Belgium.
Comment on
Clin Infect Dis. 2021 Nov 2;73(9):e2992-e2994. doi: 10.1093/cid/ciaa1936.
BACKGROUND: It is currently unclear whether severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) reinfection will remain a rare event, only occurring
in individuals who fail to mount an effective immune response, or whether it
will occur more frequently when humoral immunity wanes following primary
infection.
METHODS: A case of reinfection was observed in a Belgian nosocomial outbreak
involving 3 patients and 2 healthcare workers. To distinguish reinfection from
persistent infection and detect potential transmission clusters, whole genome
sequencing was performed on nasopharyngeal swabs of all individuals including
the reinfection case's first episode. Immunoglobulin A, immunoglobulin M, and
immunoglobulin G (IgG) and neutralizing antibody responses were quantified in
serum of all individuals, and viral infectiousness was measured in the swabs of
the reinfection case.
RESULTS: Reinfection was confirmed in a young, immunocompetent healthcare worker
as viral genomes derived from the first and second episode belonged to different
SARS-CoV-2 clades. The symptomatic reinfection occurred after an interval of 185
days, despite the development of an effective humoral immune response following
symptomatic primary infection. The second episode, however, was milder and
characterized by a fast rise in serum IgG and neutralizing antibodies. Although
contact tracing and viral culture remained inconclusive, the healthcare worker
formed a transmission cluster with 3 patients and showed evidence of virus
replication but not of neutralizing antibodies in her nasopharyngeal swabs.
CONCLUSIONS: If this case is representative of most patients with coronavirus
disease 2019, long-lived protective immunity against SARS-CoV-2 after primary
infection might not be likely.
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/ciaa1850
PMCID: PMC7799230
PMID: 33315049 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35263638 | 1. Cell Rep. 2022 Mar 15;38(11):110515. doi: 10.1016/j.celrep.2022.110515. Epub
2022 Feb 22.
SARS-CoV-2 reinfection prevents acute respiratory disease in Syrian hamsters but
not replication in the upper respiratory tract.
Hansen F(1), Meade-White K(1), Clancy C(2), Rosenke R(2), Okumura A(1), Hawman
DW(1), Feldmann F(2), Kaza B(1), Jarvis MA(3), Rosenke K(4), Feldmann H(5).
Author information:
(1)Laboratory of Virology, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Rocky Mountain Laboratories, 903 S
4(th) Street, Hamilton, MT 59840, USA.
(2)Rocky Mountain Veterinary Branch, Division of Intramural Research, National
Institute of Allergy and Infectious Diseases, National Institutes of Health,
Hamilton, MT, USA.
(3)Laboratory of Virology, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Rocky Mountain Laboratories, 903 S
4(th) Street, Hamilton, MT 59840, USA; University of Plymouth, Plymouth, Devon,
UK; The Vaccine Group Ltd, Plymouth, Devon, UK.
(4)Laboratory of Virology, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Rocky Mountain Laboratories, 903 S
4(th) Street, Hamilton, MT 59840, USA. Electronic address: kyle.rosenke@nih.gov.
(5)Laboratory of Virology, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Rocky Mountain Laboratories, 903 S
4(th) Street, Hamilton, MT 59840, USA. Electronic address:
feldmannh@niaid.nih.gov.
Human cases of SARS-CoV-2 reinfection have been documented throughout the
pandemic, but are likely under-reported. In the current study, we use the Syrian
hamster SARS-CoV-2 model to assess reinfection with homologous WA1 and
heterologous B.1.1.7 (Alpha) and B.1.351 (Beta) SARS-CoV-2 variants over time.
Upon primary infection with SARS-CoV-2 WA1, hamsters rapidly develop a strong
and long-lasting humoral immune response. After reinfection with homologous and
heterologous SARS-CoV-2 variants, this immune response protects hamsters from
clinical disease, virus replication in the lower respiratory tract, and acute
lung pathology. However, reinfection leads to SARS-CoV-2 replication in the
upper respiratory tract with the potential for virus shedding. Our findings
indicate that reinfection results in restricted SARS-CoV-2 replication despite
substantial levels of humoral immunity, denoting the potential for transmission
through reinfected asymptomatic individuals.
Published by Elsevier Inc.
DOI: 10.1016/j.celrep.2022.110515
PMCID: PMC8860630
PMID: 35263638 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of interests The authors declare no
competing interests. |
http://www.ncbi.nlm.nih.gov/pubmed/33930542 | 1. Int J Infect Dis. 2021 Jul;108:53-56. doi: 10.1016/j.ijid.2021.04.073. Epub
2021 Apr 27.
Evidence of SARS-CoV-2 reinfection within the same clade in Ecuador: A case
study.
Sevillano G(1), Ortega-Paredes D(2), Loaiza K(3), Zurita-Salinas C(1), Zurita
J(4).
Author information:
(1)Unidad de Investigaciones en Biomedicina, Zurita and Zurita Laboratorios,
Quito, Ecuador.
(2)Unidad de Investigación en Enfermedades Transmitidas por Alimentos y
Resistencia a los Antimicrobianos (UNIETAR), Facultad de Veterinaria,
Universidad Central del Ecuador, Quito, Ecuador.
(3)Research Unit, Life Science Initiative, Quito, Ecuador.
(4)Unidad de Investigaciones en Biomedicina, Zurita and Zurita Laboratorios,
Quito, Ecuador; Facultad de Medicina, Pontificia Universidad Católica del
Ecuador, Quito, Ecuador. Electronic address: jzurita@zuritalaboratorios.com.
OBJECTIVES: To date, reported SARS-CoV-2 reinfection cases are mainly from
strains belonging to different clades. As the pandemic advances, a few lineages
have become dominant in certain areas leading to reinfections by similar
strains. Here, we report a reinfection case within the same clade of the initial
infection in a symptomatic 28-year-old-male in Quito-Ecuador.
METHODS: Infection was detected by reverse transcription-polymerase chain
reaction, and immune response evaluated by antibody testing. Whole-genome
sequencing was performed and phylogenetic analysis conducted to determine
relatedness.
RESULTS: Both the infection and the reinfection strains were assigned as
Nextstrain 20B, Pangolin lineage B.1.1 and GISAID clade O. Our analysis
indicated 4-6 fold more nucleotide changes than are expected for reactivation or
persistence compared with the natural rate of SARS-CoV-2 mutation (∼2-3
nucleotide changes per month), thus supporting reinfection. Furthermore,
approximately 3 months after the second infection, COVID-19 antibodies were not
detectable in the patient, suggesting potential vulnerability to a third
infection.
CONCLUSIONS: Our results showed evidence of SARS-CoV-2 reinfection within the
same clade in Ecuador, indicating that previous exposure to SARS-CoV-2 does not
guarantee immunity in all cases.
Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2021.04.073
PMCID: PMC8078048
PMID: 33930542 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36176508 | 1. Future Virol. 2022 Sep:10.2217/fvl-2021-0212. doi: 10.2217/fvl-2021-0212. Epub
2022 Sep 26.
Reinfection and reactivation of SARS-CoV-2.
Dowran R(1)(2), Damavandi AR(2), Azad TM(1).
Author information:
(1)Department of Virology, School of Public Health, Tehran University of Medical
Sciences, Tehran, Iran.
(2)Student Scientific Association of Virology, Student Scientific Research
Center, Tehran University of Medical Sciences, Tehran, Iran.
As the cases of SARS-CoV-2 infection escalates, the essence of in-depth
knowledge around acquired immunity and emergence of reinfection and reactivation
have to be captured. While being a rare phenomenon, reinfection occurs as the
result of diminishing protection conferred by antibodies, especially IgG.
Reactivation is more concerned with the role of various elements including
shedding lingering viral RNA for a prolonged time and incomplete resolution of
infection along with the insight of dormant viral exosomes' role. The concept of
testing positive after two consecutive negative results requires proper
discrimination of reinfection from reactivation. In this review, we summarized
the current evidence for possible mechanisms leading to viral reactivation or
test re-positivity. We also pointed out risk factors associated with both
reinfection and reactivation.
© 2022 Future Medicine Ltd.
DOI: 10.2217/fvl-2021-0212
PMCID: PMC9514089
PMID: 36176508 |
http://www.ncbi.nlm.nih.gov/pubmed/34908003 | 1. Chin Med J (Engl). 2022 Jan 20;135(2):145-152. doi:
10.1097/CM9.0000000000001892.
Reinfection rates among patients previously infected by SARS-CoV-2: systematic
review and meta-analysis.
Mao Y(1), Wang W(2), Ma J(3), Wu S(4), Sun F(5).
Author information:
(1)Department of Pharmacy, First Affiliated Hospital of Fujian Medical
University, Fuzhou, Fujian 350005, China.
(2)National Clinical Research Center for Mental Disorders and Beijing Key
Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical
University, Beijing 100088, China.
(3)Institute of Basic Medical Sciences, Peking University Health Science Center,
Beijing 100191, China.
(4)Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical
University, National Clinical Research Center for Digestive Disease, Beijing
Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of
Digestive Disease, Beijing, 100050, China.
(5)Department of Epidemiology and Biostatistics, School of Public Health, Peking
University Health Science Centre, Beijing 100191, China.
BACKGROUND: Asymptomatic or symptomatic infection with severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) can be followed by reinfection. The
protection conferred by prior infection among coronavirus disease 2019
(COVID-19) patients is unclear. We assessed the incidence of SARS-CoV-2
reinfection and the protection effect of previous infection against reinfection.
METHODS: We searched PubMed, EMBASE, Cochrane, Scopus, Web of Science, and
ClinicalTrials.gov for publications up until the end date of May 1, 2021. The
reinfection rate of recovered patients and the protection against reinfection
were analyzed using meta-analysis.
RESULTS: Overall, 19 studies of 1096 reinfection patients were included. The
pooled reinfection rate was 0.65% (95% confidence interval [CI] 0.39-0.98%). The
symptomatic reinfection rate was a bit lower (0.37% [95% CI 0.11-0.78%],
I2 = 99%). The reinfection rate was much higher in high-risk populations (1.59%
[95% CI 0.30-3.88%], I2 = 90%). The protection against reinfection and
symptomatic reinfection was similar (87.02% [95% CI 83.22-89.96%] and 87.17%
[95% CI 83.09-90.26%], respectively).
CONCLUSIONS: The rate of reinfection with SARS-CoV-2 is relatively low. The
protection against SARS-CoV-2 after natural infection is comparable to that
estimated for vaccine efficacy. These data may help guide public health measures
and vaccination strategies in response to the COVID-19 pandemic. High-quality
clinical studies are needed to establish the relevant risk factors in recovered
patients.
Copyright © 2022 The Chinese Medical Association, produced by Wolters Kluwer,
Inc. under the CC-BY-NC-ND license.
DOI: 10.1097/CM9.0000000000001892
PMCID: PMC8769121
PMID: 34908003 [Indexed for MEDLINE]
Conflict of interest statement: None. |
http://www.ncbi.nlm.nih.gov/pubmed/34492110 | 1. J Public Health (Oxf). 2022 Dec 1;44(4):e475-e478. doi:
10.1093/pubmed/fdab346.
Rate of reinfections after SARS-CoV-2 primary infection in the population of an
Italian province: a cohort study.
Flacco ME(1), Acuti Martellucci C(1), Soldato G(2), Carota R(3), Fazii P(4),
Caponetti A(5), Manzoli L(1).
Author information:
(1)Department of Medical Sciences, University of Ferrara, Ferrara, 44121, Italy.
(2)Department of Preventive Medicine, Public Health Section, Local Health Unit
of Pescara, Pescara, 65100, Italy.
(3)Division of Legal Affairs, Public Health Data Center, Local Health Unit of
Pescara, Pescara, 65100, Italy.
(4)Pescara Hospital, Microbiology Unit, Local Health Unit of Pescara, Pescara,
65100, Italy.
(5)Hospital Directorate, Local Health Unit of Pescara, Pescara, 65100, Italy.
BACKGROUND: Current data suggest that severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) reinfections are rare, but no information are
available on minors and after 12 months of follow-up.
METHODS: This retrospective cohort study included all the population of an
Italian Province, diagnosed with a SARS-CoV-2 infection from March 2020 to May
2021. The primary outcome was the incidence of a reinfection, defined as a new
positive polymerase chain reaction (PCR) test occurring ≥90 days after complete
resolution of the first infection, and data were retrieved from the official
datasets (coronavirus disease 2019 [COVID-19], demographic, hospital and co-pay
exemption) of the Local Health Unit (LHU) of Pescara.
RESULTS: After an average of 201 days of follow-up (max. 414), we recorded 24
reinfections ≥90 days after the resolution of the first 7173 infections (0.33%).
Four reinfections required hospitalization, one was lethal. Most of the
reinfections (n = 13) occurred 6-9 months after the resolution of the first
infection; no new infection was detected 12 or more months later and among the
832 minors.
CONCLUSIONS: This study confirms previous findings on a low risk of SARS-CoV-2
reinfection. If confirmed, these findings suggest that more targeted restriction
policies can be applied to the subjects that recovered after a first infection.
© The Author(s) 2021. Published by Oxford University Press on behalf of Faculty
of Public Health. All rights reserved. For permissions, please e-mail:
journals.permissions@oup.com.
DOI: 10.1093/pubmed/fdab346
PMCID: PMC8522392
PMID: 34492110 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/33219681 | 1. Clin Infect Dis. 2021 Nov 2;73(9):e3002-e3008. doi: 10.1093/cid/ciaa1421.
Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection After
Recovery from Mild Coronavirus Disease 2019.
Lee JS(1), Kim SY(2), Kim TS(1), Hong KH(3), Ryoo NH(4), Lee J(5), Park JH(1),
Cho SI(1), Kim MJ(1), Kim YG(1), Kim B(1), Shin HS(1), Oh HS(1), Seo MS(1), Gwon
TR(1), Kim Y(6), Park JS(7), Chin BS(6), Park WB(8), Park SS(1), Seong MW(1).
Author information:
(1)Department of Laboratory Medicine, Seoul National University Hospital, Seoul
National University College of Medicine, Seoul, South Korea.
(2)Department of Laboratory Medicine, National Medical Center, Seoul, South
Korea.
(3)Department of Laboratory Medicine, Seoul Medical Center, Seoul, South Korea.
(4)Department of Laboratory Medicine, Keimyung University Dongsan Medical
Center, Daegu, South Korea.
(5)Department of Laboratory Medicine, Jeonbuk National University Medical School
and Hospital, Jeonju, South Korea.
(6)Department of Infectious Disease, National Medical Center, Seoul, South
Korea.
(7)Research Institute of Public Health, National Medical Center, Seoul, South
Korea.
(8)Department of Internal Medicine, Seoul National University Hospital, Seoul
National University College of Medicine, Seoul, South Korea.
Comment in
Clin Infect Dis. 2021 Nov 2;73(9):e3009-e3012. doi: 10.1093/cid/ciaa1541.
BACKGROUND: Positive results from real-time reverse-transcription polymerase
chain reaction (rRT-PCR) in recovered patients raise concern that patients who
recover from coronavirus disease 2019 (COVID-19) may be at risk of reinfection.
Currently, however, evidence that supports reinfection with severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been reported.
METHODS: We conducted whole-genome sequencing of the viral RNA from clinical
specimens at the initial infection and at the positive retest from 6 patients
who recovered from COVID-19 and retested positive for SARS-CoV-2 via rRT-PCR
after recovery. A total of 13 viral RNAs from the patients' respiratory
specimens were consecutively obtained, which enabled us to characterize the
difference in viral genomes between initial infection and positive retest.
RESULTS: At the time of the positive retest, we were able to acquire a complete
genome sequence from patient 1, a 21-year-old previously healthy woman. In this
patient, through the phylogenetic analysis, we confirmed that the viral RNA of
positive retest was clustered into a subgroup distinct from that of the initial
infection, suggesting that there was a reinfection of SARS-CoV-2 with a subtype
that was different from that of the primary strain. The spike protein D614G
substitution that defines the clade "G" emerged in reinfection, while mutations
that characterize the clade "V" (ie, nsp6 L37F and ORF3a G251V) were present at
initial infection.
CONCLUSIONS: Reinfection with a genetically distinct SARS-CoV-2 strain may occur
in an immunocompetent patient shortly after recovery from mild COVID-19.
SARS-CoV-2 infection may not confer immunity against a different SARS-CoV-2
strain.
© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.
DOI: 10.1093/cid/ciaa1421
PMCID: PMC7890673
PMID: 33219681 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35935779 | 1. Front Med (Lausanne). 2022 Jul 22;9:906469. doi: 10.3389/fmed.2022.906469.
eCollection 2022.
Mild reinfection with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) Delta variant: First case report from Indonesia.
Isnaini N(1), Mardian Y(2), Lokida D(1)(2), Budiono F(1), Butar-Butar DP(2),
Arlinda D(2)(3), Salim G(2), Kosasih H(2), Wulan WN(2), Perodin J(4), Neal A(5),
Lane HC(5), Karyana M(2)(3).
Author information:
(1)Tangerang District Hospital, Tangerang, Indonesia.
(2)Indonesia Research Partnership on Infectious Disease, Jakarta, Indonesia.
(3)National Institute of Health Research and Development, Ministry of Health,
Jakarta, Indonesia.
(4)Leidos Biomedical Research, Frederick, MD, United States.
(5)National Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD, United States.
BACKGROUND: Reinfection with SARS-CoV-2 has been well documented, yet little is
known about the degree of protection a previous infection provides against
reinfection, especially against Variants of Concern (VOC).
CASE PRESENTATION: Here we describe a case of an unvaccinated 49-year-old man
who experienced two sequential SARS-CoV-2 infections with two different
variants, as evidenced by genomic sequencing. The first episode was caused by
the Pango lineage B.1.466.2 and resulted in severe COVID-19 with 5 days in an
intensive care unit (ICU). The second episode occurred approximately 6 months
later, during the Delta surge in Indonesia. Genomic analysis showed that the
second infection was caused by the Delta variant (Pango lineage B.1.617.2) and
resulted in mild disease that did not require hospitalization. No SARS-CoV-2
nucleic acid was detected between the two episodes, but both binding and
neutralizing antibodies to SARS-CoV-2 were detected prior to the reinfection,
with the second infection leading to an increase in the levels of antibody.
CONCLUSION: We confirmed that the patient experienced a reinfection instead of
persistent viral shedding from the first infection based on epidemiological,
clinical, serological, and genomic analyses. Our case supports the hypothesis
that SARS-CoV-2 reinfection may occur once antibody titers decrease or following
the emergence of a new variant. The milder presentation in the patient's second
infection deserves further investigation to provide a clear picture of the role
of post-infection immunity in altering the course of subsequent disease.
Copyright © 2022 Isnaini, Mardian, Lokida, Budiono, Butar-butar, Arlinda, Salim,
Kosasih, Wulan, Perodin, Neal, Lane and Karyana.
DOI: 10.3389/fmed.2022.906469
PMCID: PMC9355687
PMID: 35935779
Conflict of interest statement: JP was employed by Leidos Biomedical Research,
Inc. The remaining authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as
a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34873592 | 1. Lancet Healthy Longev. 2021 Dec;2(12):e811-e819. doi:
10.1016/S2666-7568(21)00253-1. Epub 2021 Dec 1.
Reinfection with new variants of SARS-CoV-2 after natural infection: a
prospective observational cohort in 13 care homes in England.
Jeffery-Smith A(1)(2), Rowland TAJ(1), Patel M(1), Whitaker H(3), Iyanger N(4),
Williams SV(4), Giddings R(4), Thompson L(4), Zavala M(5), Aiano F(5), Ellis
J(5), Lackenby A(1), Höschler K(1), Brown K(5), Ramsay ME(5), Gopal R(1), Chow
JY(4), Ladhani SN(5)(6), Zambon M(1).
Author information:
(1)Virus Reference Department, Public Health England, London, UK.
(2)Blizard Institute, Queen Mary University of London, London, UK.
(3)Data and Analytical Sciences, Public Health England, London, UK.
(4)London Coronavirus Response Cell, National Infection Service, Public Health
England, London, UK.
(5)Immunisation and Countermeasures Division, Public Health England, London, UK.
(6)Paediatric Infectious Diseases Research Group, St. George's University of
London, London, UK.
Comment in
Lancet Healthy Longev. 2021 Dec;2(12):e776-e777. doi:
10.1016/S2666-7568(21)00276-2.
BACKGROUND: Understanding the duration of protection and risk of reinfection
after natural infection is crucial to planning COVID-19 vaccination for at-risk
groups, including care home residents, particularly with the emergence of more
transmissible variants. We report on the duration, neutralising activity, and
protection against the alpha variant of previous SARS-CoV-2 infection in care
home residents and staff infected more than 6 months previously.
METHODS: We did this prospective observational cohort surveillance in 13 care
homes in Greater London, England. All staff and residents were included. Staff
and residents had regular nose and throat screening for SARS-CoV-2 by RT-PCR
according to national guidelines, with ad hoc testing of symptomatic
individuals. From January, 2021, antigen lateral flow devices were also used,
but positive tests still required RT-PCR confirmation. Staff members took the
swab samples for themselves and the residents. The primary outcome was
SARS-CoV-2 RT-PCR positive primary infection or reinfection in previously
infected individuals, as determined by previous serological testing and
screening or diagnostic RT-PCR results. Poisson regression and Cox proportional
hazards models were used to estimate protective effectiveness of previous
exposure. SARS-CoV-2 spike, nucleoprotein, and neutralising antibodies were
assessed at multiple timepoints as part of the longitudinal follow-up.
FINDINGS: Between April 10 and Aug 3, 2020, we recruited and tested 1625
individuals (933 staff and 692 residents). 248 participants were lost to
follow-up (123 staff and 125 residents) and 1377 participants were included in
the follow-up period to Jan 31, 2021 (810 staff and 567 residents). There were
23 reinfections (ten confirmed, eight probable, five possible) in 656 previously
infected individuals (366 staff and 290 residents), compared with 165 primary
infections in 721 susceptible individuals (444 staff and 277 residents). Those
with confirmed reinfections had no or low neutralising antibody concentration
before reinfection, with boosting of titres after reinfection. Kinetics of
binding and neutralising antibodies were similar in older residents and younger
staff.
INTERPRETATION: SARS-CoV-2 reinfections were rare in older residents and younger
staff. Protection from SARS-CoV-2 was sustained for longer than 9 months,
including against the alpha variant. Reinfection was associated with no or low
neutralising antibody before reinfection, but significant boosting occurred on
reinfection.
FUNDING: Public Health England.
© 2021 Published by Elsevier Ltd. This is an Open Access article under the CC
BY-NC-ND 4.0 license.
DOI: 10.1016/S2666-7568(21)00253-1
PMCID: PMC8635459
PMID: 34873592 [Indexed for MEDLINE]
Conflict of interest statement: We declare no competing interests. The authors
are all employed by Public Health England, which is a public body and an
executive agency of the Department of Health and Social Care. |
http://www.ncbi.nlm.nih.gov/pubmed/33791729 | 1. medRxiv [Preprint]. 2021 Mar 26:2021.03.24.21253992. doi:
10.1101/2021.03.24.21253992.
Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid
organ transplant recipient.
Klein J, Brito AF, Trubin P, Lu P, Wong P, Alpert T, Peña-Hernández MA, Haynes
W, Kamath K, Liu F, Vogels CBF, Fauver JR, Lucas C, Oh J, Mao T, Silva J, Wyllie
AL, Muenker MC, Casanovas-Massana A, Moore AJ, Petrone ME, Kalinich CC; Yale
IMPACT Research Team; Cruz CD, Farhadian S, Ring A, Shon J, Ko AI, Grubaugh ND,
Israelow B, Iwasaki A, Azar MM.
Update in
J Infect Dis. 2022 Feb 1;225(3):374-384. doi: 10.1093/infdis/jiab553.
Prior to the emergence of antigenically distinct SARS-CoV-2 variants,
reinfections were reported infrequently - presumably due to the generation of
durable and protective immune responses. However, case reports also suggested
that rare, repeated infections may occur as soon as 48 days following initial
disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2
reinfections are currently unknown. Here we describe a renal transplant
recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed
by whole virus genome sequencing - 7 months after primary infection. To
elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection,
we performed longitudinal profiling of cellular and humoral responses during
both primary and recurrent SARS-CoV-2 infection. We found that the patient
responded to the primary infection with transient, poor-quality adaptive immune
responses. The patient's immune system was further compromised by intervening
treatment for acute rejection of the renal allograft prior to reinfection.
Importantly, we also identified the development of neutralizing antibodies and
the formation of humoral memory responses prior to SARS-CoV-2 reinfection.
However, these neutralizing antibodies failed to confer protection against
reinfection, suggesting that additional factors are required for efficient
prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting
viral evasion of primary adaptive immune responses, suggesting that
susceptibility to reinfection may be determined by host factors rather than
pathogen adaptation in this patient. In summary, our study suggests that a low
neutralizing antibody presence alone is not sufficient to confer resistance
against reinfection. Thus, patients with solid organ transplantation, or
patients who are otherwise immunosuppressed, who recover from infection with
SARS-CoV-2 may not develop sufficient protective immunity and are at risk of
reinfection.
DOI: 10.1101/2021.03.24.21253992
PMCID: PMC8010761
PMID: 33791729 |
http://www.ncbi.nlm.nih.gov/pubmed/33849385 | 1. Infect Dis (Lond). 2021 Jul;53(7):479-485. doi: 10.1080/23744235.2021.1905174.
Epub 2021 Apr 13.
Reinfection of SARS-CoV-2 - analysis of 23 cases from the literature.
Roberts AT(1), Piani F(1), Longo B(2), Andreini R(2), Meini S(2).
Author information:
(1)Internal Medicine Unit, Santa Maria Annunziata Hospital, Azienda USL Toscana
Centro, Florence, Italy.
(2)Internal Medicine Unit, Felice Lotti Hospital, Pontedera, Azienda USL Toscana
Nord-Ovest, Pisa, Italy.
Comment in
Infect Dis (Lond). 2021 Jul;53(7):486-487. doi:
10.1080/23744235.2021.1910339.
INTRODUCTION: The duration of immunity after infection from SARS-CoV-2
conferring protection from subsequent COVID-19 episodes is not yet fully
understood. We reviewed the literature for cases of documented reinfection.
MATERIALS AND METHODS: A comprehensive computerized search in PubMed, through 15
December 2020, using the following terms in combination: COVID-19, SARS-CoV-2,
reinfection, reactivation, recurrence. To exclude cases due to prolonged viral
shedding or protracted infection, only cases occurring at least 12 weeks apart
or confirmed as being sustained by genetically different viruses by viral genome
analysis were included.
RESULTS: We identified 23 cases globally, for which viral genome analysis was
performed in 10 cases and serology in 19 cases. The mean interval between the
two episodes was 15 weeks. Mean age of cases was 44.5 years, and 10 (43.5%) were
women. In 17/23 cases, no comorbidity was observed. In 10 cases, the first
episode was more severe than the ensuing episode, whereas in seven cases the
ensuing episode was more severe. In four cases, there was no difference in
severity and in two cases both episodes were asymptomatic.
CONCLUSIONS: From this sample of 23 cases, a clear pattern of the second episode
being less or more severe did not emerge. A better understanding of immunity to
SARS-CoV-2, necessary to assess the probability of a second infection and the
durability of protection conferred by vaccination, is warranted.
DOI: 10.1080/23744235.2021.1905174
PMCID: PMC8054490
PMID: 33849385 [Indexed for MEDLINE]
Conflict of interest statement: The authors report no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/33630817 | 1. MMWR Morb Mortal Wkly Rep. 2021 Feb 26;70(8):273-277. doi:
10.15585/mmwr.mm7008a3.
Suspected Recurrent SARS-CoV-2 Infections Among Residents of a Skilled Nursing
Facility During a Second COVID-19 Outbreak - Kentucky, July-November 2020.
Cavanaugh AM, Thoroughman D, Miranda H, Spicer K.
Reinfection with SARS-CoV-2, the virus that causes coronavirus disease 2019
(COVID-19), is believed to be rare (1). Some level of immunity after SARS-CoV-2
infection is expected; however, the evidence regarding duration and level of
protection is still emerging (2). The Kentucky Department for Public Health
(KDPH) and a local health department conducted an investigation at a skilled
nursing facility (SNF) that experienced a second COVID-19 outbreak in October
2020, 3 months after a first outbreak in July. Five residents received positive
SARS-CoV-2 reverse transcription-polymerase chain reaction (RT-PCR) test results
during both outbreaks. During the first outbreak, three of the five patients
were asymptomatic and two had mild symptoms that resolved before the second
outbreak. Disease severity in the five residents during the second outbreak was
worse than that during the first outbreak and included one death. Because test
samples were not retained, phylogenetic strain comparison was not possible.
However, interim period symptom resolution in the two symptomatic patients, at
least four consecutive negative RT-PCR tests for all five patients before
receiving a positive test result during the second outbreak, and the 3-month
interval between the first and the second outbreaks, suggest the possibility
that reinfection occurred. Maintaining physical distance, wearing face coverings
or masks, and frequent hand hygiene are critical mitigation strategies necessary
to prevent transmission of SARS-CoV-2 to SNF residents, a particularly
vulnerable population at risk for poor COVID-19-associated outcomes.* Testing,
containment strategies (isolation and quarantine), and vaccination of residents
and health care personnel (HCP) are also essential components to protecting
vulnerable residents. The findings of this study highlight the importance of
maintaining public health mitigation and protection strategies that reduce
transmission risk, even among persons with a history of COVID-19 infection.
DOI: 10.15585/mmwr.mm7008a3
PMCID: PMC8344982
PMID: 33630817 [Indexed for MEDLINE]
Conflict of interest statement: All authors have completed and submitted the
International Committee of Medical Journal Editors form for disclosure of
potential conflicts of interest. No potential conflicts of interest were
disclosed. |
http://www.ncbi.nlm.nih.gov/pubmed/36413551 | 1. PLoS Med. 2022 Nov 22;19(11):e1004037. doi: 10.1371/journal.pmed.1004037.
eCollection 2022 Nov.
Vaccine effectiveness against SARS-CoV-2 reinfection during periods of Alpha,
Delta, or Omicron dominance: A Danish nationwide study.
Nielsen KF(1), Moustsen-Helms IR(1), Schelde AB(1), Gram MA(1), Emborg HD(1),
Nielsen J(1), Hansen CH(1), Andersen MA(2), Meaidi M(2), Wohlfahrt J(3),
Valentiner-Branth P(1).
Author information:
(1)Department of Infectious Disease Epidemiology and Prevention, Statens Serum
Institut, Copenhagen, Denmark.
(2)Department of Data Integration and Analysis, Statens Serum Institut,
Copenhagen, Denmark.
(3)Department of Epidemiology Research, Statens Serum Institut, Copenhagen,
Denmark.
BACKGROUND: Individuals with a prior Severe Acute Respiratory Syndrome
Coronavirus 2 (SARS-CoV-2) infection have a moderate to high degree of
protection against reinfection, though seemingly less so when the Omicron
variant of SARS-CoV-2 started to circulate. The aim of this study was to
evaluate the vaccine effectiveness (VE) against SARS-CoV-2 reinfection,
Coronavirus Disease 2019 (COVID-19)-related hospitalization, and
COVID-19-related death, in individuals with prior SARS-CoV-2 infection, and to
assess the effect of time since vaccination during periods with different
dominant SARS-CoV-2 variants.
METHODS AND FINDINGS: This study used a nationwide cohort design including all
individuals with a confirmed SARS-CoV-2 infection, who were alive, and residing
in Denmark between 1 January 2020 and 31 January 2022. Using Danish nationwide
registries, we obtained information on SARS-CoV-2 infections, COVID-19
vaccination, age, sex, comorbidity, staying at hospital, and country of origin.
The study population included were individuals with prior SARS-CoV-2 infection.
Estimates of VE against SARS-CoV-2 reinfection with 95% confidence intervals
(CIs) were calculated using a Poisson regression model and adjusted for age,
sex, country of origin, comorbidity, staying at hospital, calendar time, and
test incidence using a Cox regression model. The VE estimates were calculated
separately for three periods with different dominant SARS-CoV-2 variants (Alpha
(B.1.1.7), Delta (B.1.617.2), or Omicron (B.1.1.529)) and by time since
vaccination using unvaccinated as the reference. In total, 148,527 person-years
and 44,192 SARS-CoV-2 infections were included for the analysis regarding
reinfections. The study population comprised of 209,814 individuals infected
before or during the Alpha period, 292,978 before or during the Delta period,
and 245,530 before or during the Omicron period. Of these, 40,281 individuals
had completed their primary vaccination series during the Alpha period (19.2%),
190,026 during the Delta period (64.9%), and 158,563 during the Omicron period
(64.6%). VE against reinfection following any COVID-19 vaccine type administered
in Denmark, peaked at 71% (95% CI: -Inf to 100%) at 104 days or more after
vaccination during the Alpha period, 94% (95% CI: 92% to 96%) 14 to 43 days
after vaccination during the Delta period, and 60% (95% CI: 58% to 62%) 14 to 43
days after vaccination during the Omicron period. Waning immunity following
vaccination was observed and was most pronounced during the Omicron period. Due
to too few events, it was not possible to estimate VE for hospitalization and
death. Study limitations include potentially undetected reinfections,
differences in health-seeking behavior, or risk behavior between the compared
groups.
CONCLUSIONS: This study shows that in previously infected individuals,
completing a primary vaccination series was associated with a significant
protection against SARS-CoV-2 reinfection compared with no vaccination. Even
though vaccination seems to protect to a lesser degree against reinfection with
the Omicron variant, these findings are of public health relevance as they show
that previously infected individuals still benefit from COVID-19 vaccination in
all three variant periods.
Copyright: © 2022 Nielsen et al. This is an open access article distributed
under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original author and source are credited.
DOI: 10.1371/journal.pmed.1004037
PMCID: PMC9681105
PMID: 36413551 [Indexed for MEDLINE]
Conflict of interest statement: The authors have declared that no competing
interests exist. |
http://www.ncbi.nlm.nih.gov/pubmed/34447364 | 1. Front Microbiol. 2021 Aug 10;12:722178. doi: 10.3389/fmicb.2021.722178.
eCollection 2021.
Impact of Prior Infection on Severe Acute Respiratory Syndrome Coronavirus 2
Transmission in Syrian Hamsters.
Zhang C(1)(2), Guo Z(1), Li N(1), Cui H(1)(3), Meng K(1), Liu L(1), Zhao L(1),
Zhang S(1), Qin C(4), Liu J(2), Gao Y(1), Zhang C(1).
Author information:
(1)Changchun Veterinary Research Institute, Chinese Academy of Agricultural
Sciences, Changchun, China.
(2)College of Veterinary Medicine, Hebei Agricultural University, Baoding,
China.
(3)College of Veterinary Medicine, Jilin University, Changchun, China.
(4)Beijing Institute of Microbiology and Epidemiology, Beijing, China.
Prior infection with severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) provides protective immunity against reinfection. However, whether
prior infection blocks SARS-CoV-2 transmission is not yet clear. Here, we
evaluated the impact of prior infection on SARS-CoV-2 transmission in Syrian
hamsters. Our results showed that prior infection significantly reduced
SARS-CoV-2 replication in Syrian hamsters, but sterilizing immunity was not
achieved. Prior infection blocked the airborne transmission of SARS-CoV-2 from
previously infected Syrian hamsters to naïve Syrian hamsters and previously
infected Syrian hamsters. Moreover, prior infection substantially reduced the
efficiency of direct contact transmission between previously infected Syrian
hamsters. However, prior infection had limited impact on SARS-CoV-2 transmission
from previously infected Syrian hamsters to naïve Syrian hamsters via direct
contact in the early course of infection. Human reinfection and SARS-CoV-2
transmission between a previously infected population and a healthy population
would be likely, and a higher vaccination coverage rate was needed to reach herd
immunity. Our work will aid the implementation of appropriate public health and
social measures to control coronavirus infectious disease 2019 (COVID-19)
pandemic.
Copyright © 2021 Zhang, Guo, Li, Cui, Meng, Liu, Zhao, Zhang, Qin, Liu, Gao and
Zhang.
DOI: 10.3389/fmicb.2021.722178
PMCID: PMC8383181
PMID: 34447364
Conflict of interest statement: The authors declare that the research was
conducted in the absence of any commercial or financial relationships that could
be construed as a potential conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34367645 | 1. New Microbes New Infect. 2021 Sep;43:100926. doi: 10.1016/j.nmni.2021.100926.
Epub 2021 Aug 2.
SARS-CoV-2 reinfection in patients negative for immunoglobulin G following
recovery from COVID-19.
Ali AM(1)(2), Ali KM(3), Fatah MH(3), Tawfeeq HM(3), Rostam HM(4)(5).
Author information:
(1)Department of Chemistry, College of Science, University of Garmian, Kalar,
Kurdistan Region, Iraq.
(2)COVID-19 Laboratory, Qala Hospital, Garmian General Directorate of Health,
Ministry of Health, Kalar, Kurdistan Region, Iraq.
(3)Medical Lab Technology Department, Kalar Technical College, Sulaimani
Polytechnic University, Kalar, Kurdistan Region, Iraq.
(4)Immunology & Immuno-bioengineering Group, School of Life Sciences, Faculty of
Medicine & Health Sciences, University of Nottingham, Nottingham, NG7 2RD, UK.
(5)College of Medicine, University of Garmian, Kalar, Kurdistan Region, Iraq.
While many patients infected by severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2) eventually produce neutralising antibodies, the degree of
susceptibility of previously infected individuals to reinfection by SARS-CoV-2
is currently unknown. To better understand the impact of the immunoglobulin
(IgG) level on reinfection in recovered coronavirus disease 2019 (COVID-19)
patients, anti-nucleocapsid IgG levels against SARS-CoV-2 were measured in 829
patients with a previously confirmed infection just after their recovery.
Notably, 87 of these patients had no detectable IgG concentration. While there
was just one case of asymptomatic reinfection 4.5 months after the initial
recovery amongst patients with detectable anti-nucleocapsid IgG levels, 25 of
the 87 patients negative for anti-nucleocapsid IgG were reinfected within one to
three months after their first infection. Therefore, patients who recover from
COVID-19 with no detectable anti-nucleocapsid IgG concentration appear to remain
more susceptible to reinfection by SARS-CoV-2, with no apparent immunity. Also,
although our results suggest the chance is lower, the possibility for recovered
patients with positive anti-nucleocapsid IgG findings to be reinfected similarly
exists.
© 2021 The Author(s).
DOI: 10.1016/j.nmni.2021.100926
PMCID: PMC8327640
PMID: 34367645 |
http://www.ncbi.nlm.nih.gov/pubmed/34468184 | 1. Microbiol Spectr. 2021 Oct 31;9(2):e0008721. doi: 10.1128/Spectrum.00087-21.
Epub 2021 Sep 1.
Mild SARS-CoV-2 Illness Is Not Associated with Reinfections and Provides
Persistent Spike, Nucleocapsid, and Virus-Neutralizing Antibodies.
Schuler CF 4th(1)(2), Gherasim C(3), O'Shea K(1)(2), Manthei DM(3), Chen
J(1)(4), Zettel C(1), Troost JP(5), Kennedy AA(6), Tai AW(6)(7), Giacherio
DA(3), Valdez R(3), Baldwin JL(1)(2), Baker JR Jr(1)(2)(4).
Author information:
(1)Division of Allergy and Clinical Immunology, Department of Internal Medicine,
University of Michigan, Ann Arbor, Michigan, USA.
(2)Mary H. Weiser Food Allergy Center, University of Michigan, Ann Arbor,
Michigan, USA.
(3)Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
(4)Michigan Nanotechnology Institute for Medicine and Biological Sciences,
University of Michigan, Ann Arbor, Michigan, USA.
(5)Michigan Institute for Clinical and Health Research, University of Michigan,
Ann Arbor, Michigan, USA.
(6)Division of Gastroenterology, Department of Internal Medicine, University of
Michigan, Ann Arbor, Michigan, USA.
(7)Department of Microbiology and Immunology, University of Michigan, Ann Arbor,
Michigan, USA.
Uncertainty exists whether mild COVID-19 confers immunity to reinfection.
Questions also remain regarding the persistence of antibodies against SARS-CoV-2
after mild infection. We prospectively followed at-risk individuals with and
without SARS-CoV-2 for reinfection and monitored the spike and nucleocapsid
antibodies. This prospective cohort study was conducted over two visits, 3 to
6 months apart, between May 2020 and February 2021. Adults with and without
COVID-19, verified by FDA EUA-approved SARS-CoV-2 RT-PCR assays, were screened
for spike and nucleocapsid antibody responses using FDA EUA-approved
immunoassays and for pseudoviral neutralization activity. The subjects were
monitored for symptoms, exposure to COVID-19, COVID-19 testing, seroconversion,
reinfection, and vaccination. A total of 653 subjects enrolled; 129 (20%) had a
history of COVID-19 verified by RT-PCR at enrollment. Most had mild disease,
with only three requiring hospitalization. No initially seropositive subjects
experienced a subsequent COVID-19 infection during the follow-up versus 15
infections among initially seronegative subjects (infection rates of 0.00 versus
2.05 per 10,000 days at risk [P = 0.0485]). In all, 90% of SARS-CoV-2-positive
subjects produced spike and nucleocapsid responses, and all but one of these had
persistent antibody levels at follow-up. Pseudoviral neutralization activity was
widespread among participants, did not decrease over time, and correlated with
clinical antibody assays. Reinfection with SARS-CoV-2 was not observed among
individuals with mild clinical COVID-19, while infections continued in a group
without known prior infection. Spike and nucleocapsid COVID-19 antibodies were
associated with almost all infections and persisted at stable levels for the
study duration. IMPORTANCE This article demonstrates that people who have mild
COVID-19 illnesses and produce antibodies are protected from reinfection for up
to 6 months afterward. The antibodies that people produce in this situation are
stable for up to 6 months as well. Clinical antibody assays correlate well with
evidence of antibody-related viral neutralization activity.
DOI: 10.1128/Spectrum.00087-21
PMCID: PMC8557889
PMID: 34468184 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/35743421 | 1. J Clin Med. 2022 Jun 10;11(12):3352. doi: 10.3390/jcm11123352.
Risk of SARS-CoV-2 Reinfections in a Prospective Inception Cohort Study: Impact
of COVID-19 Vaccination.
Casado JL(1), Haemmerle J(2), Vizcarra P(1), Ramirez-Alonso G(2), Salazar-Tosco
A(2), Romero-Hernandez B(3), Blasco M(2), Rodriguez-Dominguez M(3), Mirabella
IG(2), Vallejo A(1)(4), Fernandez-Escribano M(2).
Author information:
(1)Department of Infectious Diseases, IRYCIS (Instituto Ramon y Cajal para la
Investigación Sanitaria), Hospital Universitario Ramón y Cajal, Ctra Colmenar Km
9, 28034 Madrid, Spain.
(2)Department of Occupational Safety and Health, University Hospital Ramón y
Cajal, 28034 Madrid, Spain.
(3)Department of Microbiology, Centro de Investigación Biomédica en Red en
Epidemiologia y Salud Pública, CIBERESP, Hospital Universitario Ramon y Cajal,
28034 Madrid, Spain.
(4)Laboratory of Immunovirology, Department of Infectious Diseases, IRYCIS
(Instituto Ramon y Cajal para la Investigación Sanitaria), Hospital
Universitario Ramón y Cajal, 28034 Madrid, Spain.
The risk of reinfection could be related to the initial SARS-CoV-2 clinical
presentation, but there are no data about the risk change after SARS-CoV-2
vaccination. We evaluated the rate of reinfection in an inception cohort study
of 4943 health care workers (HCWs) according to symptoms and serologic results
during March−May 2020. Incidence rates (IR) and IR ratios (IRR) before and after
SARS-CoV-2 vaccination were determined by adjusting Poisson models. Overall,
1005 HCWs (20.3%) referred COVID-19 suggestive symptoms during the first surge
of disease, and 33.5% and 55% presented a positive PCR or serology result,
respectively. Meanwhile, 13% of asymptomatic HCWs had specific antibodies.
During a follow up of 3422.2 person-years before vaccination, the rate of
reinfection among seropositive individuals was 81% lower for those who were
symptomatic compared with those who were asymptomatic (IRR of 0.19; 95% CI,
0.05−0.67; p = 0.003). During the 3100 person-years period after vaccination, an
overall 74% decrease in the rate of infection was observed (IRR of 0.26; 95% CI,
0.21−0.32; p < 0.001), with a significant 83% and 70% decrease in seropositive
and seronegative HCWs, respectively. In conclusion, the risk of SARS-CoV-2
reinfections is closely related to the clinical and serological presentation of
COVID-19. COVID-19 vaccination further decreases the risk of reinfection more
markedly among seropositive.
DOI: 10.3390/jcm11123352
PMCID: PMC9225121
PMID: 35743421
Conflict of interest statement: The authors declare no conflict of interest. |
http://www.ncbi.nlm.nih.gov/pubmed/34521025 | 1. Int Immunopharmacol. 2021 Nov;100:108108. doi: 10.1016/j.intimp.2021.108108.
Epub 2021 Sep 8.
Immune response variables and viral mutations impact on COVID-19 reinfection and
relapse.
Sanaie S(1), Golipour E(2), Shamekh A(3), Sadaie MR(4), Mahmoodpoor A(5),
Yousefi M(6).
Author information:
(1)Neurosciences Research Center, Aging Research Institute, Tabriz University of
Medical Sciences, Tabriz, Iran.
(2)Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran.
(3)Student Research Committee, Tabriz University of Medical Sciences, Tabriz,
Iran.
(4)NovoMed Consulting, Germantown, MD, USA.
(5)Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine,
Tabriz University of Medical Sciences, Tabriz, Iran.
(6)Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz,
Iran; Department of Immunology, Faculty of Medicine, Tabriz University of
Medical Sciences, Tabriz, Iran. Electronic address: Yousefime@tbzmed.ac.ir.
The possibility of human reinfection with SARS-CoV-2, the coronavirus
responsible for COVID-19, has not previously been thoroughly investigated.
Although it is generally believed that virus-specific antibodies protect against
COVID-19 pathogenesis, their duration of function and temporal activity remain
unknown. Contrary to media reports that people retain protective antibody
responses for a few months, science does not exclude reinfection and disease
relapse shortly after initiating all immune responses during the primary onset
of COVID-19. Despite production of antiviral antibodies, activated CD4+/CD8+
lymphocytes, and long-lived memory B cells, susceptibility to reinfection in
humans for extended periods cannot be precluded due to repeated exposures to
coronavirus or potential reactivation of the virus due to incomplete virus
clearance. However, the mechanism of reinfection remains unknown. The biological
characteristics of SARS-CoV-2, such as emergence of multiple mutations in the
virus RNA molecules, transmissibility, rates of infection, reactivation and
reinfection, can all affect the trajectory of the virus spread. Innate and
adaptive immune response variables, differences in underlying diseases, and
comorbidities, particularly in high risk individuals, can influence the dynamics
of the virus infection. In this article, immune parameters and viral mutations
pertaining to reinfection and disease relapse are reviewed and scientific gaps
are discussed.
Copyright © 2021 Elsevier B.V. All rights reserved.
DOI: 10.1016/j.intimp.2021.108108
PMCID: PMC8423905
PMID: 34521025 [Indexed for MEDLINE]
Conflict of interest statement: The authors declare that they have no known
competing financial interests or personal relationships that could have appeared
to influence the work reported in this paper. |
http://www.ncbi.nlm.nih.gov/pubmed/34961403 | 1. Int Rev Immunol. 2022;41(4):367-392. doi: 10.1080/08830185.2021.2019727. Epub
2021 Dec 28.
An update on host immunity correlates and prospects of re-infection in COVID-19.
Negi N(1)(2), Maurya SP(3), Singh R(3), Das BK(3).
Author information:
(1)Department of Chemical Sciences, University of Limerick, Limerick, Ireland.
(2)Bernal Institute, University of Limerick,Limerick, Ireland.
(3)Department of Microbiology, All India Institute of Medical Sciences, New
Delhi, India.
Reinfection with SARS-CoV-2 is not frequent yet the incidence rate of it is
increasing globally owing to the slow emergence of drift variants that pose a
perpetual threat to vaccination strategies and have a greater propensity for
disease reoccurrence. Long-term protection against SARS-CoV-2 reinfection relies
on the induction of the innate as well as the adaptive immune response endowed
with immune memory. However, a multitude of factors including the selection
pressure, the waning immunity against SARS-CoV-2 over the first year after
infection possibly favors evolution of more infectious immune escape variants,
amplifying the risk of reinfection. Additionally, the correlates of immune
protection, the novel SARS-CoV-2 variants of concern (VOC), the durability of
the adaptive and mucosal immunity remain major challenges for the development of
therapeutic and prophylactic interventions. Interestingly, a recent body of
evidence indicated that the gastrointestinal (GI) tract is another important
target organ for SARS-CoV-2 besides the respiratory system, potentially
increasing the likelihood of reinfection by impacting the microbiome and the
immune response via the gut-lung axis. In this review, we summarized the latest
development in SARS-CoV-2 reinfection, and explored the untapped potential of
trained immunity. We also highlighted the immune memory kinetics of the humoral
and cell-mediated immune response, genetic drift of the emerging viral variants,
and discussed the current challenges in vaccine development. Understanding the
dynamics and the quality of immune response by unlocking the power of the
innate, humoral and cell-mediated immunity during SARS-CoV-2 reinfection would
open newer avenues for drug discovery and vaccine designs.
DOI: 10.1080/08830185.2021.2019727
PMCID: PMC8787841
PMID: 34961403 [Indexed for MEDLINE]
Conflict of interest statement: Authors declared no potential conflicts of
interest. |
http://www.ncbi.nlm.nih.gov/pubmed/35931371 | 1. Int J Infect Dis. 2022 Oct;123:9-16. doi: 10.1016/j.ijid.2022.07.075. Epub
2022 Aug 2.
Epidemiological assessment of SARS-CoV-2 reinfection.
Almadhi M(1), Alsayyad AS(2), Conroy R(3), Atkin S(4), Awadhi AA(5), Al-Tawfiq
JA(6), AlQahtani M(7).
Author information:
(1)National Taskforce for Combating the Coronavirus (COVID-19), Supreme health
council, Manama, Bahrain; University of Manchester, Manchester, UK.
(2)Department of Family and Community Medicine, Arabian Gulf University, Manama,
Bahrain.
(3)Royal College of Surgeons in Ireland, Dublin, Ireland.
(4)Royal College of Surgeons in Ireland, Busaiteen, Bahrain.
(5)National Taskforce for Combating the Coronavirus (COVID-19), Supreme health
council, Manama, Bahrain; Bahrain Defence Force Hospital, Riffa, Bahrain.
(6)Infectious Disease Unit, Specialty Internal Medicine, Johns Hopkins Aramco
Healthcare, Dhahran, Saudi Arabia; Division of Infectious Diseases, Indiana
University School of Medicine, Indianapolis, Indiana, USA; Division of
Infectious Diseases, Johns Hopkins University, Baltimore, Maryland, USA.
(7)National Taskforce for Combating the Coronavirus (COVID-19), Supreme health
council, Manama, Bahrain; Royal College of Surgeons in Ireland, Busaiteen,
Bahrain; Bahrain Defence Force Hospital, Riffa, Bahrain. Electronic address:
mqahtani@rcsi-mub.com.
OBJECTIVES: SARS-CoV-2 vaccination has been shown to reduce infection severity;
however, the reinfection frequency among unvaccinated, partially vaccinated, and
fully vaccinated individuals remains unclear. This study aims to elucidate the
rates of and factors associated with such occurrences.
METHODS: This retrospective epidemiological report included 1362 COVID-19
reinfection cases in Bahrain between April 2020 and July 2021. We analyzed
differences in disease severity and reinfection characteristics among various
vaccination statuses: fully vaccinated, interrupted vaccination, one-dose
vaccination, postreinfection vaccination, and unvaccinated.
RESULTS: Reinfection cases increased from zero per month in April-June 2020 to a
sharp peak of 579 in May 2021. A significantly larger proportion of reinfected
individuals were male (60.3%, P <0.0001). Reinfection episodes were highest
among those 30-39 years of age (29.7%). The fewest reinfection episodes occurred
at 3-6 months after the first infection (20.6%) and most occurred ≥9 months
after the initial infection (46.4%). Most individuals were asymptomatic during
both episodes (35.7%). Reinfection disease severity was mild, with vaccinated
patients less likely to have symptomatic reinfection (odds ratio 0.71,
P = 0.004). Only 6.6% of reinfected patients required hospitalization. One death
was recorded; the patient belonged to the unvaccinated group.
CONCLUSION: Vaccine-induced immunity and previous infection with or without
vaccination were effective in reducing reinfection disease severity.
Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.
DOI: 10.1016/j.ijid.2022.07.075
PMCID: PMC9345650
PMID: 35931371 [Indexed for MEDLINE]
Conflict of interest statement: Declaration of Competing Interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper. |
http://www.ncbi.nlm.nih.gov/pubmed/33853339 | 1. Epidemiol Mikrobiol Imunol. 2021 Spring;70(1):62-67.
COVID-19 reinfections.
[Article in English]
Fabiánová K, Kynčl J, Vlčková I, Jiřincová H, Košťálová J, Liptáková M, Orlíková
H, Šebestová H, Limberková R, Macková B, Malý M.
Reports of SARS-CoV-2 reinfections are on the rise. This study focused on
reinfections in patients with confirmed COVID-19 in the Czech Republic. Between
1 March 2020 and 9 November 2020, 362 084 cases with the onset of symptoms
before 31 October 2020 were reported. Overall, 28 cases of symptomatic
SARS-CoV-2 reinfections were identified, 11 in males and 17 in females, age
range 25-80 years, median age 46 years. The interval between the first and
second episodes of the disease ranged from 101 to 231 days, and the median
interval was 201.5 days. During both symptomatic episodes, all patients have
been tested by RT-PCR. Altogether 26 patients (92.9%) have been tested negative
after recovery from the first episode of COVID-19. Symptomatic reinfections
occurred in nearly 0.2% of all patients at risk. Most patients with reinfection
had mild symptoms in both episodes, and only three episodes were moderate to
severe. Thus, reinfections may have been underdiagnosed. In summary, COVID-19
reinfections are possible and not exceptional.
PMID: 33853339 [Indexed for MEDLINE] |
http://www.ncbi.nlm.nih.gov/pubmed/36301607 | 1. J Med Microbiol. 2022 Oct;71(10). doi: 10.1099/jmm.0.001599.
A retrospective cross-sectional observational study of SARS-CoV-2 reinfection in
La Ribera Health Department, Valencia, Spain.
Belloch García SL(1)(2).
Author information:
(1)Internal Medicine Department, La Ribera University Hospital, Alzira,
Valencia, Spain.
(2)Servicio de Medicina Interna, Hospital Universitario de La Ribera, Alzira,
Valencia, Spain.
Introduction. The possibility of reinfection by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) is a widely proven fact and may have
clinical implications.Hypothesis /Gap Statement. It is not known whether there
have been cases of reinfection by SARS-CoV-2 in La Ribera Health Department.Aim.
To determine whether there have been cases of reinfection by SARS-CoV-2 in La
Ribera Health Department and to identify their characteristics.Methodology.
Retrospective cross-sectional observational study of cases of reinfection by
SARS-CoV-2 in the population of La Ribera Department between March 2020 and
February 2021. The positive baseline cohort includes all cases positive by
RT-PCR for SARS-CoV-2, with reinfection cases being those that, after resolution
of the first episode according to the World Health Organization (WHO) criteria,
presented a new positive RT-PCR result.Results. Out of a total of 15 687 cases
with positive RT-PCR, 40 were considered to be reinfections, which meant a
cumulative incidence of 0.255 % and an incidence density of 5.05 cases per
100 000 person-days. Most of the cases occurred during the highest incidence
peaks of the pandemic in the department. Seventy-five per cent of the patients
in these cases were older than 40 years, 42.5 % were healthcare professionals or
nursing home residents and 12.5 % had an immunosuppressive comorbidity. There
were no severe, critical or death cases. In the reinfection episodes, with
respect to the first episode, there was a tendency to be milder, they required
fewer days of hospitalization, their RT-PCR became negative earlier, they
developed a greater humoral response and the sick leave period was shorter. The
median period between the RT-PCR in the first episode and the RT-PCR in the
second episode was 127.5 days (range: 48-301; IQR: 89.5-256.25)Conclusions.
SARS-CoV-2 reinfection cases are rare, tend to be mild and can occur within a
median period of 127.5 days.
DOI: 10.1099/jmm.0.001599
PMID: 36301607 [Indexed for MEDLINE] |