retrospective case study report

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A How-To Guide for Conducting Retrospective Analyses: Example COVID-19 Study

In the urgent setting of the COVID-19 pandemic, treatment hypotheses abound, each of which requires careful evaluation. A randomized controlled trial generally provides the strongest possible evaluation of a treatment, but the efficiency and effectiveness of the trial depend on the existing evidence supporting the treatment. The researcher must therefore compile a body of evidence justifying the use of time and resources to further investigate a treatment hypothesis in a trial. An observational study can help provide this evidence, but the lack of randomized exposure and the researcher’s inability to control treatment administration and data collection introduce significant challenges for non-experimental studies. A proper analysis of observational health care data thus requires an extensive background in a diverse set of topics ranging from epidemiology and causal analysis to relevant medical specialties and data sources. Here we provide 10 rules that serve as an end-to-end introduction to retrospective analyses of observational health care data. A running example of a COVID-19 study presents a practical implementation of each rule in the context of a specific treatment hypothesis. When carefully designed and properly executed, a retrospective analysis framed around these rules will inform the decisions of whether and how to investigate a treatment hypothesis in a randomized controlled trial.

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Retrospective studies and chart reviews

Affiliation.

1 Respiratory Care, Ellison 401, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA. [email protected]
PMID: 15447798

A retrospective study uses existing data that have been recorded for reasons other than research. A retrospective case series is the description of a group of cases with a new or unusual disease or treatment. With a case-control study, cases with and without the condition of interest are identified, and the degree of exposure to a possible risk factor is then retrospectively compared between the 2 groups. With a matched case-control study, control subjects are selected such that they resemble (match) the cases with regards to certain characteristics (eg, age, comorbidity, severity of disease). Retrospective study designs are generally considered inferior to prospective study designs. Therefore, a retrospective study design should never be used when a prospective design is feasible.

Case-Control Studies
Epidemiologic Studies*
Retrospective Studies

Retrospective Studies and Chart Reviews

Chris nickson.

Nov 3, 2020
Retrospective studies are designed to analyse pre-existing data, and are subject to numerous biases as a result
Retrospective studies may be based on chart reviews (data collection from the medical records of patients)
case series
retrospective cohort studies (current or historical cohorts)
case-control studies

STATISTICAL ANALYSIS USED IN RETROSPECTIVE STUDIES

Compare outcomes between treatment and control group
Used if treatment and control group are selected by a chance mechanism
Divide all patients into subgroups according to a risk factor, then perform comparison within these subgroups
Used if only one key confounding variable exists
Find pairs of patients that have specific characteristics in common, but received different treatments; compares outcome only in these pairs
Used if only a few confounders exist and if the size of one of the comparison groups is much larger than the other
More than one confounder is controlled simultaneously, if a larger number of confounders needs to be adjusted for computer software and statistical advice is necessary
Used if sample size is large
Simple description of data
Used if sample size is low and other options failed

ADVANTAGES OF RETROSPECTIVE STUDIES

quicker, cheaper and easier than prospective cohort studies
can address rare diseases and identify potential risk factors (e.g. case-control studies)
not prone to loss of follow up
may be used as the initial study generating hypotheses to be studied further by larger, more expensive prospective studies

DISADVANTAGES OF RETROSPECTIVE STUDIES

inferior level of evidence compared with prospective studies
controls are often recruited by convenience sampling, and are thus not representative of the general population and prone to selection bias
prone to recall bias or misclassification bias
subject to confounding (other risk factors may be present that were not measured)
cannot determine causation, only association
some key statistics cannot be measured
temporal relationships are often difficult to assess
retrospective cohort studies need large sample sizes if outcomes are rare

SOURCES OF ERROR IN CHART REVIEWS AND THEIR SOLUTIONS

From Kaji et al (2014) and Gilbert et al (1996):

establish whether necessary information is available in the charts
establish if there are sufficient charts to perform the analysis with adequate precision
perform a sample size calculation
Declare any conflict of interest Provide evidence of institutional review board approval
Submit the data collection form, as well as the coding rules and definitions, as an online appendix
Case selection or exclusion using explicit protocols and well described the criteria
Ensure all available charts have an equal chance of selection
Provide a flow diagram showing how the study sample was derive from the source population
define the predictor and outcome variables to be collected a priori
Develop a coding manual and publish as an online appendix
Use standardized abstraction forms to guide data collection
Provide precise definitions of variables
Pilot test the abstraction form
Ensure uniform handling of data that is conflicting, ambiguous, missing, or unknown
Perform a sensitivity analysis if needed
Blind chart reviewers to the etiologic relation being studied or the hypotheses being tested. If groups of patients are to be compared, the abstractor should be blinded to the patient’s group assignment
Describe how blinding was maintained in the article
Train chart abstractors to perform their jobs.
Describe the qualifications and training of the chart abstracters.
Ideally, train abstractors before the study starts, using a set of “practice” medical records.
Ensure uniform training, especially in multi-center studies
Monitor the performance of the chart abstractors
Hold periodic meetings with chart abstractors and study coordinators to resolve disputes and review coding rules.
A second reviewer should re-abstract a sample of charts, blinded to the information obtained by the first correlation reviewer.
Report a kappa-statistic, intraclass coefficient, or other measure of agreement to assess inter-rater reliability of the data
Provide justification for the criteria for each variable

SOURCES OF ERROR FROM THE USE OF ELECTRONIC MEDICAL RECORDS

Potential biases introduced from:

use of boilerplates (a unit of writing that can be reused over and over without change)
items copied and pasted
default tick boxes
delays in time stamps relative to actual care

References and Links

CCC — Case-control studies

Journal articles

Gilbert EH, Lowenstein SR, Koziol-McLain J, Barta DC, Steiner J. Chart reviews in emergency medicine research: Where are the methods? Ann Emerg Med. 1996 Mar;27(3):305-8. PMID: 8599488 .
Kaji AH, Schriger D, Green S. Looking through the retrospectoscope: reducing bias in emergency medicine chart review studies. Ann Emerg Med. 2014 Sep;64(3):292-8. PMID: 24746846 .
Sauerland S, Lefering R, Neugebauer EA. Retrospective clinical studies in surgery: potentials and pitfalls. J Hand Surg Br. 2002 Apr;27(2):117-21. PMID: 12027483 .
Worster A, Bledsoe RD, Cleve P, Fernandes CM, Upadhye S, Eva K. Reassessing the methods of medical record review studies in emergency medicine research. Ann Emerg Med. 2005 Apr;45(4):448-51. PMID: 15795729 .

Critical Care

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also a Clinical Adjunct Associate Professor at Monash University . He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine . He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE . He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com , the RAGE podcast , the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of three amazing children.

On Twitter, he is @precordialthump .

| INTENSIVE | RAGE | Resuscitology | SMACC

Case-control and Cohort studies: A brief overview

Posted on 6th December 2017 by Saul Crandon

Introduction

Case-control and cohort studies are observational studies that lie near the middle of the hierarchy of evidence . These types of studies, along with randomised controlled trials, constitute analytical studies, whereas case reports and case series define descriptive studies (1). Although these studies are not ranked as highly as randomised controlled trials, they can provide strong evidence if designed appropriately.

Case-control studies

Case-control studies are retrospective. They clearly define two groups at the start: one with the outcome/disease and one without the outcome/disease. They look back to assess whether there is a statistically significant difference in the rates of exposure to a defined risk factor between the groups. See Figure 1 for a pictorial representation of a case-control study design. This can suggest associations between the risk factor and development of the disease in question, although no definitive causality can be drawn. The main outcome measure in case-control studies is odds ratio (OR) .

Figure 1. Case-control study design.

Cases should be selected based on objective inclusion and exclusion criteria from a reliable source such as a disease registry. An inherent issue with selecting cases is that a certain proportion of those with the disease would not have a formal diagnosis, may not present for medical care, may be misdiagnosed or may have died before getting a diagnosis. Regardless of how the cases are selected, they should be representative of the broader disease population that you are investigating to ensure generalisability.

Case-control studies should include two groups that are identical EXCEPT for their outcome / disease status.

As such, controls should also be selected carefully. It is possible to match controls to the cases selected on the basis of various factors (e.g. age, sex) to ensure these do not confound the study results. It may even increase statistical power and study precision by choosing up to three or four controls per case (2).

Case-controls can provide fast results and they are cheaper to perform than most other studies. The fact that the analysis is retrospective, allows rare diseases or diseases with long latency periods to be investigated. Furthermore, you can assess multiple exposures to get a better understanding of possible risk factors for the defined outcome / disease.

Nevertheless, as case-controls are retrospective, they are more prone to bias. One of the main examples is recall bias. Often case-control studies require the participants to self-report their exposure to a certain factor. Recall bias is the systematic difference in how the two groups may recall past events e.g. in a study investigating stillbirth, a mother who experienced this may recall the possible contributing factors a lot more vividly than a mother who had a healthy birth.

A summary of the pros and cons of case-control studies are provided in Table 1.

Table 1. Advantages and disadvantages of case-control studies.

Cohort studies

Cohort studies can be retrospective or prospective. Retrospective cohort studies are NOT the same as case-control studies.

In retrospective cohort studies, the exposure and outcomes have already happened. They are usually conducted on data that already exists (from prospective studies) and the exposures are defined before looking at the existing outcome data to see whether exposure to a risk factor is associated with a statistically significant difference in the outcome development rate.

Prospective cohort studies are more common. People are recruited into cohort studies regardless of their exposure or outcome status. This is one of their important strengths. People are often recruited because of their geographical area or occupation, for example, and researchers can then measure and analyse a range of exposures and outcomes.

The study then follows these participants for a defined period to assess the proportion that develop the outcome/disease of interest. See Figure 2 for a pictorial representation of a cohort study design. Therefore, cohort studies are good for assessing prognosis, risk factors and harm. The outcome measure in cohort studies is usually a risk ratio / relative risk (RR).

Figure 2. Cohort study design.

Cohort studies should include two groups that are identical EXCEPT for their exposure status.

As a result, both exposed and unexposed groups should be recruited from the same source population. Another important consideration is attrition. If a significant number of participants are not followed up (lost, death, dropped out) then this may impact the validity of the study. Not only does it decrease the study’s power, but there may be attrition bias – a significant difference between the groups of those that did not complete the study.

Cohort studies can assess a range of outcomes allowing an exposure to be rigorously assessed for its impact in developing disease. Additionally, they are good for rare exposures, e.g. contact with a chemical radiation blast.

Whilst cohort studies are useful, they can be expensive and time-consuming, especially if a long follow-up period is chosen or the disease itself is rare or has a long latency.

A summary of the pros and cons of cohort studies are provided in Table 2.

The Strengthening of Reporting of Observational Studies in Epidemiology Statement (STROBE)

STROBE provides a checklist of important steps for conducting these types of studies, as well as acting as best-practice reporting guidelines (3). Both case-control and cohort studies are observational, with varying advantages and disadvantages. However, the most important factor to the quality of evidence these studies provide, is their methodological quality.

Song, J. and Chung, K. Observational Studies: Cohort and Case-Control Studies .Â Plastic and Reconstructive Surgery. Â 2010 Dec;126(6):2234-2242.
Ury HK. Efficiency of case-control studies with multiple controls per case: Continuous or dichotomous data .Â Biometrics .Â 1975 Sep;31(3):643â€“649.
von Elm E, Altman DG, Egger M, Pocock SJ, GÃ¸tzsche PC, Vandenbroucke JP; STROBE Initiative.Â The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Â Lancet 2007 Oct;370(9596):1453-14577. PMID: 18064739.

Saul Crandon

No Comments on Case-control and Cohort studies: A brief overview

Very well presented, excellent clarifications. Has put me right back into class, literally!

Very clear and informative! Thank you.

very informative article.

Thank you for the easy to understand blog in cohort studies. I want to follow a group of people with and without a disease to see what health outcomes occurs to them in future such as hospitalisations, diagnoses, procedures etc, as I have many health outcomes to consider, my questions is how to make sure these outcomes has not occurred before the “exposure disease”. As, in cohort studies we are looking at incidence (new) cases, so if an outcome have occurred before the exposure, I can leave them out of the analysis. But because I am not looking at a single outcome which can be checked easily and if happened before exposure can be left out. I have EHR data, so all the exposure and outcome have occurred. my aim is to check the rates of different health outcomes between the exposed)dementia) and unexposed(non-dementia) individuals.

Very helpful information

Thanks for making this subject student friendly and easier to understand. A great help.

Thanks a lot. It really helped me to understand the topic. I am taking epidemiology class this winter, and your paper really saved me.

Happy new year.

Wow its amazing n simple way of briefing ,which i was enjoyed to learn this.its very easy n quick to pick ideas .. Thanks n stay connected

Saul you absolute melt! Really good work man

am a student of public health. This information is simple and well presented to the point. Thank you so much.

very helpful information provided here

really thanks for wonderful information because i doing my bachelor degree research by survival model

Quite informative thank you so much for the info please continue posting. An mph student with Africa university Zimbabwe.

Thank you this was so helpful amazing

Apreciated the information provided above.

So clear and perfect. The language is simple and superb.I am recommending this to all budding epidemiology students. Thanks a lot.

Great to hear, thank you AJ!

I have recently completed an investigational study where evidence of phlebitis was determined in a control cohort by data mining from electronic medical records. We then introduced an intervention in an attempt to reduce incidence of phlebitis in a second cohort. Again, results were determined by data mining. This was an expedited study, so there subjects were enrolled in a specific cohort based on date(s) of the drug infused. How do I define this study? Thanks so much.

thanks for the information and knowledge about observational studies. am a masters student in public health/epidemilogy of the faculty of medicines and pharmaceutical sciences , University of Dschang. this information is very explicit and straight to the point

Very much helpful

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Institutional Review Board

Case report publication guidance: irb review and hipaa compliance.

Background:

Many journals now require a letter, or other acknowledgement, from an IRB prior to publication of a case report. Specifically, they wish to know whether IRB approval was obtained or was not required for the described case. The JHM IRBs have adopted a policy to address the following question and answers.

Q: What constitutes a “case report”?

A case report for IRB purposes is a retrospective analysis of one, two, or three clinical cases. If more than three cases are involved in the analytical activity, the activity will constitute “research.”

Please review the JHM Organization Policy on Single Case Reports and Case Series (Policy No. 102.3) .

Q: Do faculty who prepare a case report as an article for submission to a journal require IRB approval prior to preparation?

No. A case report is a medical/educational activity that does not meet the DHHS definition of “research”, which is: "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge." Therefore, the activity does not have to be reviewed by a JHM IRB.

Q: Can I request that the IRB make a formal determination that my case report is not research?

In certain cases, journals may require a formal determination from the IRB that a case report does not constitute research. Researchers seeking an official IRB determination that a case report is not research should submit a not-human subjects research (NHSR) application through the eIRB system.

The following steps should be followed when submitting a request for a formal determination from the IRB:

In Section 1, Item 7, select “NHSR/QA” as the review type
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Prospective vs. Retrospective Studies

Prospective

A prospective study watches for outcomes, such as the development of a disease, during the study period and relates this to other factors such as suspected risk or protection factor(s). The study usually involves taking a cohort of subjects and watching them over a long period. The outcome of interest should be common; otherwise, the number of outcomes observed will be too small to be statistically meaningful (indistinguishable from those that may have arisen by chance). All efforts should be made to avoid sources of bias such as the loss of individuals to follow up during the study. Prospective studies usually have fewer potential sources of bias and confounding than retrospective studies.

Retrospective

A retrospective study looks backwards and examines exposures to suspected risk or protection factors in relation to an outcome that is established at the start of the study. Many valuable case-control studies, such as Lane and Claypon's 1926 investigation of risk factors for breast cancer, were retrospective investigations. Most sources of error due to confounding and bias are more common in retrospective studies than in prospective studies. For this reason, retrospective investigations are often criticised. If the outcome of interest is uncommon, however, the size of prospective investigation required to estimate relative risk is often too large to be feasible. In retrospective studies the odds ratio provides an estimate of relative risk. You should take special care to avoid sources of bias and confounding in retrospective studies.

Prospective investigation is required to make precise estimates of either the incidence of an outcome or the relative risk of an outcome based on exposure.

Case-Control studies

Case-Control studies are usually but not exclusively retrospective, the opposite is true for cohort studies. The following notes relate case-control to cohort studies:

outcome is measured before exposure
controls are selected on the basis of not having the outcome
good for rare outcomes
relatively inexpensive
smaller numbers required
quicker to complete
prone to selection bias
prone to recall/retrospective bias
related methods are risk (retrospective) , chi-square 2 by 2 test , Fisher's exact test , exact confidence interval for odds ratio , odds ratio meta-analysis and conditional logistic regression .

Cohort studies

Cohort studies are usually but not exclusively prospective, the opposite is true for case-control studies. The following notes relate cohort to case-control studies:

outcome is measured after exposure
yields true incidence rates and relative risks
may uncover unanticipated associations with outcome
best for common outcomes
requires large numbers
takes a long time to complete
prone to attrition bias (compensate by using person-time methods)
prone to the bias of change in methods over time
related methods are risk (prospective) , relative risk meta-analysis , risk difference meta-analysis and proportions

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Case Study Types

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Generally completed by a retrospective review of medical records that highlights a unique treatment, case, or outcome
Often clinical in nature
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Prospective Single Subject Case Study Review/Report

Often social/behavioral in nature
In-depth prospective analysis and report involving unique or exceptional observations or experiences about one, or a few, individual human subjects
Is intended to contribute to generalizable knowledge

Neonatal herpes: case series in two obstetric centres over a 10-year period (2013–2023), France

Published: 27 April 2024

Cite this article

Elise Bouthry 1 , 2 ,
Vincent Portet-Sulla 2 , 3 , 4 ,
Melek Manai Bouokazi 3 ,
Claire Périllaud-Dubois 2 , 5 ,
François-Charles Javaugue 3 ,
Laure Jule 6 ,
Claire Boithias 6 ,
Nolwenn Le Saché 6 ,
Mostafa Mokhtari 6 ,
Diane Carrière 6 ,
Louise Sonnier 7 ,
Rafik Benammar 8 ,
Alexandra Letourneau 9 ,
Alexandre J. Vivanti 2 , 9 ,
Anne-Gaël Cordier 10 , 9 nAff2 ,
Emmanuelle Letamendia-Richard 8 &
Christelle Vauloup-Fellous 2 , 3 , 4

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Neonatal herpes simplex virus (HSV) infection (HSV infection in infants less than 6 weeks of age) is rare but mortality and morbidity rates are high after disseminated disease and encephalitis. In France, the epidemiology is poorly described, and two decades ago, incidence was estimated to be 3 per 100,000 live births a year. We describe determinants, epidemiologic and clinical characteristics of neonatal HSV infection in a managed-care population attending in two major obstetric and paediatric centres, Paris, France, over a 10-year period. This retrospective case series study was conducted from 2013 to 2023, in infants less than 42 days of age who had virologically confirmed HSV infection. We report an overall rate of neonatal herpes of 5.5 per 100,000 live births a year and an incidence of symptomatic cases of 1.2 per 100,000 live births a year. HSV-1 was the major serotype involved (84.2%) and post-natal acquisition through the orolabial route reached 63.2%. All neonates who had neonatal HSV PCR screening (owing to clinical signs in parents) and who received prompt acyclovir treatment remained asymptomatic. Symptomatic forms accounted for 21.1% cases of the total and mortality was high (62.5% of symptomatic forms).

Conclusion : This case series confirms that neonates at risk for HSV disease and poor outcome are those born to HSV-seronegative mothers, preterm infants, and those who received acyclovir after onset of symptoms (mainly because mothers did not present evidence of acute HSV infection). Our study confirms the major role of HSV-1 and the frequency of its early post-natal acquisition.

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Trends in the incidence, mortality, and cost of neonatal herpes simplex virus hospitalizations in the United States from 2003 to 2014

Viral Genetic Diversity and Its Potential Contributions to the Development and Progression of Neonatal Herpes Simplex Virus (HSV) Disease

Enteroviral and herpes simplex virus central nervous system infections in infants < 90 days old: a Paediatric Investigators’ Collaborative Network on Infections in Canada (PICNIC) study

Data availability.

All data supporting the findings of this study are available within the paper and its supplementary information.

Abbreviations

Central nervous disease

Cycle threshold

Herpes simplex virus

Initial non-primary infection

Initial primary infection

Polymerase chain reaction

Skin, eyes, mouth

Week of gestation

Looker KJ, Magaret AS, May MT, Turner KME, Vickerman P, Newman L, Gottlieb S (2017) First estimates of the global and regional incidence of neonatal herpes infection. Lancet Glob Health 5:e300–e309. https://doi.org/10.1016/S2214-109X(16)30362-X

Article PubMed PubMed Central Google Scholar

Bernstein DI, Bellamy AR, Hook EW, Levin MJ, Wald A, Ewell MG, Wolff PA, Deal CD, Heineman TC, Dubin G, Belshe RB (2013) Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. Clin Infect Dis 56:344–351. https://doi.org/10.1093/cid/cis891

Article CAS PubMed Google Scholar

Looker KJ, Magaret AS, Turner KME, Vickerman P, Gottlieb S, Newman L (2015) Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS ONE 10. https://doi.org/10.1371/journal.pone.0114989

Article CAS PubMed PubMed Central Google Scholar

Delaney S, Gardella C, Saracino M, Margaret A, Wald A (2014) Seroprevalence of herpes simplex virus type 1 and 2 among pregnant women, 1989–2010. Obstet Gynecol Surv 312:746–748. https://doi.org/10.1001/jama.2014.4359

Article CAS Google Scholar

Looker KJ, Magaret AS, May MT, Turner KME, Vickerman P, Gottlieb S, Newman L (2015) Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS ONE 10. https://doi.org/10.1371/journal.pone.0140765

Picone O (2017) Genital herpes and pregnancy: epidemiology, clinical manifestations, prevention and screening. Guidelines for clinical practice from the French College of Gynecologists and Obstetrician (CNGOF). Gynecol Obstet Fertil Senol 45:642–654

CAS PubMed Google Scholar

Brown ZA, Selke S, Zeh J, Kopelman J, Maslow A, Ashley RL, Watts DH, Berry S, Herd M, Corey L (1997) The acquisition of herpes simplex virus during pregnancy. N Engl J Med 337:509–515. https://doi.org/10.1056/NEJM199708213370801

Gupta R, Warren T, Wald A (2007) Genital herpes Lancet Lond Engl 370:2127–2137. https://doi.org/10.1016/S0140-6736(07)61908-4

Article Google Scholar

Aujard Y (2002) Modalities of treatment local and general, medicamentous or not, controlling neonate suspected to be infected/contaminated by HSV1 or HSV2. Ann Dermatol Venereol 129:655–661

Garland SM, Steben M (2014) Genital herpes. Best Pract Res Clin Obstet Gynaecol 28:1098–1110. https://doi.org/10.1016/j.bpobgyn.2014.07.015

Article PubMed Google Scholar

Brown ZA, Benedetti J, Ashley R, Burchett S, Selke S, Berry S, Vontver LA, Corey L (1991) Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 324:1247–1252. https://doi.org/10.1056/NEJM199105023241804

Whitley R, Arvin A, Prober C, Corey L, Burchett S, Plotkin S, Starr S, Jacobs R, Powell D, Nahmias A et al (1991) Predictors of morbidity and mortality in neonates with herpes simplex virus infections. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. N Engl J Med 14(324):450–454. https://doi.org/10.1056/NEJM199102143240704

Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Frenkel LM, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM et al (2001) Natural history of neonatal herpes simplex virus infections in the acyclovir era. Pediatrics 108:223–229. https://doi.org/10.1542/peds.108.2.223

Caviness AC, Demmler GJ, Selwyn BJ (2008) Clinical and laboratory features of neonatal herpes simplex virus infection: a case-control study. Pediatr Infect Dis J 27:425–430. https://doi.org/10.1097/INF.0b013e3181646d95

Morris SR, Bauer HM, Samuel MC, Gallagher D, Bolan G (2008) Neonatal herpes morbidity and mortality in California, 1995–2003. Sex Transm Dis 35:14–18

Kropp RY, Wong T, Cormier L, Ringrose A, Burton S, Embree JE, Steben M (2006) Neonatal herpes simplex virus infections in Canada: results of a 3-year national prospective study. Pediatrics 117:1955–1962. https://doi.org/10.1542/peds.2005-1778

Jones CA, Raynes-Greenow C, Isaacs D (2014) Population-based surveillance of neonatal herpes simplex virus infection in Australia, 1997–2011. Clin Infect Dis 59:525–531. https://doi.org/10.1093/cid/ciu381

Koren A, Tasher D, Stein M, Yossepowitch O, Somekh E (2013) Neonatal herpes simplex virus infections in Israel. Pediatr Infect Dis J 32:120–123. https://doi.org/10.1097/INF.0b013e3182717f0b

Hemelaar SJAL, Poeran J, Steegers EAP, van der Meijden WI (2015) Neonatal herpes infections in the Netherlands in the period 2006–2011. J Matern Fetal Neonatal Med 28:905–909. https://doi.org/10.3109/14767058.2014.937691

Curfman AL, Glissmeyer EW, Ahmad FA, Korgenski EK, Blaschke AJ, Byington CL, Miller AS (2016) Initial presentation of neonatal herpes simplex virus infection. J Pediatr 172:121-126.e1. https://doi.org/10.1016/j.jpeds.2016.02.015

Lopez-Medina E, Cantey JB, Sánchez PJ (2015) The mortality of neonatal herpes simplex virus infection. J Pediatr 166:1529-1532.e1. https://doi.org/10.1016/j.jpeds.2015.03.004

Kimberlin DW, Whitley RJ, Wan W, Powell DA, Storch G, Ahmed A, Palmer A, Sánchez PJ, Jacobs RF, Bradley JS et al (2011) Oral acyclovir suppression and neurodevelopment after neonatal herpes. N Engl J Med 365:1284–1292. https://doi.org/10.1056/NEJMoa1003509

Shane AL, Sánchez PJ, Stoll BJ (2017) Neonatal sepsis. Lancet 390:1770–1780. https://doi.org/10.1016/S0140-6736(17)31002-4

Gantt S, Muller WJ (2013) The immunologic basis for severe neonatal herpes disease and potential strategies for therapeutic intervention. Clin Dev Immunol 2013. https://doi.org/10.1155/2013/369172

Renesme L (2017) Neonatal herpes: epidemiology, clinical manifestations and management. Guidelines for clinical practice from the French College of Gynecologists and Obstetricians (CNGOF). Gynecol Obstet Fertil Senol 45:691–704. https://doi.org/10.1016/j.gofs.2017.10.005

Kimberlin DW, Baley J (2013) Guidance on management of asymptomatic neonates born to women with active genital herpes lesions. Pediatrics 131:e635-646. https://doi.org/10.1542/peds.2012-3216

Corey L, Wald A (2009) Maternal and neonatal herpes simplex virus infections. N Engl J Med 361:1376–1378. https://doi.org/10.1056/NEJMra0807633

Brown ZA, Wald A, Morrow RA, Selke S, Zeh J, Corey L (2003) Effect of serologic status and cesarean delivery on transmission tates of herpes simplex virus from mother to infant. JAMA 289:203–209. https://doi.org/10.1001/jama.289.2.203

Whitley R, Davis EA, Suppapanya N (2007) Incidence of neonatal herpes simplex virus infections in a managed-care population. Sex Transm Dis 34:704–708. https://doi.org/10.1097/01.olq.0000258432.33412.e2

Batra D, Davies P, Manktelow BN, Smith C (2014) The incidence and presentation of neonatal herpes in a single UK tertiary centre, 2006–2013. Arch Dis Child Educ Pract Ed 99:916–921. https://doi.org/10.1136/archdischild-2013-305335

Pascual A, Moessinger A, Gerber S, Meylan P, Swiss Paediatric Surveillance Unit (SPSU) (2011) l. Neonatal herpes simplex virus infections in Switzerland: results of a 6-year national prospective surveillance study. Clin Microbiol Infect 17:1907–1910. https://doi.org/10.1111/j.1469-0691.2011.03641.x

Flagg EW, Weinstock H (2011) Incidence of neonatal herpes simplex virus infections in the United States, 2006. Pediatrics 127:e1-8. https://doi.org/10.1542/peds.2010-0134

Aymard M, Braig S, Judlin P, F et al (2021) Herpès néonatal : enquête rétrospective française (1998–1999). Arch Pédiatr 8:549

Google Scholar

Cantey JB, Klein AM, Sánchez PJ (2015) Herpes simplex virus DNAemia preceding neonatal disease. J Pediatr 166:1308–1309. https://doi.org/10.1016/j.jpeds.2015.01.042

Kimberlin DW, Lakeman FD, Arvin AM, Prober CG, Corey L, Powell DA, Burchett SK, Jacobs RF, Starr SE, Whitley RJ (1996) Application of the polymerase chain reaction to the diagnosis and management of neonatal herpes simplex virus disease. J Infect Dis 174:1162–1167. https://doi.org/10.1093/infdis/174.6.1162

Cantey JB, Mejías A, Wallihan R, Doern C, Brock E, Salamon D, Marcon M, Sánchez PJ (2012) Use of blood polymerase chain reaction testing for diagnosis of herpes simplex virus infection. J Pediatr 161:357–361. https://doi.org/10.1016/j.jpeds.2012.04.009

Chua C, Arnolds M, Niklas V (2015) Molecular diagnostics and newborns at risk for genital herpes simplex virus. Pediatr Ann 44:e97-102. https://doi.org/10.3928/00904481-20150512-08

Melvin AJ, Mohan KM, Schiffer JT, Drolette LM, Magaret A, Corey L, Wald A (2015) Plasma and cerebrospinal fluid herpes simplex virus levels at diagnosis and outcome of neonatal infection. J Pediatr 166:827–833. https://doi.org/10.1016/j.jpeds.2014.11.011

Brower LH, Wilson PM, Kurowski EM, Haslam D, Courter J, Goyal N, Durling M, Shah SS, Schondelmeyer A (2019) Using quality improvement to implement a standardized approach to neonatal herpes simplex virus. Pediatrics. https://doi.org/10.1542/PEDS.2018-0262

O’Riordan DP, Golden WC, Aucott SW (2006) Herpes simplex virus infections in preterm infants. Pediatrics 118:e1612–e1622. https://doi.org/10.1542/peds.2005-1228

van der Wiel H, Weiland HT, van Doornum GJ, van der Straaten PJ, Berger HM (1985) Disseminated neonatal herpes simplex virus infection acquired from the father. Eur J Pediatr 144:56–57. https://doi.org/10.1007/BF00491927

Yeager AS, Ashley RL, Corey L (1983) Transmission of herpes simplex virus from father to neonate. J Pediatr 103:905–907. https://doi.org/10.1016/s0022-3476(83)80710-0

Bal A, Zandotti C, Nougairede A, Ninove L, Roquelaure B, Charrel RN (2013) Fulminant hepatitis due to father-to-newborn transmission of herpes simplex virus type 1. Open Virol J 7:96–97. https://doi.org/10.2174/1874357901307010096

Ramchandani M, Kong M, Tronstein E, Selke S, Mikhaylova A, Magaret A, Huang ML, Johnston C, Corey L, Wald A (2016) Herpes simplex virus type 1 shedding in tears and nasal and oral mucosa of healthy adults. Sex Transm Dis 43:756–760. https://doi.org/10.1097/OLQ.0000000000000522

Hammerberg O, Watts J, Chernesky M, Luchsinger I, Rawls W (1983) An outbreak of herpes simplex virus type 1 in an intensive care nursery. Pediatr Infect Dis 2:290–294. https://doi.org/10.1097/00006454-198307000-00007

Linnemann CC, Buchman TG, Light IJ, Ballard JL (1978) Transmission of herpes-simplex virus type 1 in a nursery for the newborn. Identification of viral isolates by D.N.A. “fingerprinting.” Lancet 1:964–966. https://doi.org/10.1016/s0140-6736(78)90251-9

Pinninti SG, Kimberlin DW (2013) Maternal and neonatal herpes simplex virus infections. Am J Perinatol 30:113–119. https://doi.org/10.1055/s-0032-1332802

De Guzman MC, Chawla R, Duttchen K (2014) Possible neonatal herpes simplex virus (HSV) acquired postpartum from maternal oral HSV reactivation after neuraxial morphine. A A Case Rep 2:103–105. https://doi.org/10.1213/XAA.0000000000000013

Van Der Wiel H, Weiland HT, Van Doornum GJJ, van der Straaten PJ, H M Berger HM (1985) Disseminated neonatal herpes simplex virus infection acquired from the father. Eur J Pediatr 144:56–57. https://doi.org/10.1007/BF00491927

Bradley H, Markowitz LE, Gibson T, McQuillan GM (2014) Seroprevalence of herpes simplex virus types 1 and 2-United States, 1999–2010. J Infect Dis 209:325–333. https://doi.org/10.1093/infdis/jit458

Mercer CH, Tanton C, Prah P, Erens B, Sonnenberg P, Clifton S, Macdowall W, Lewis R, Field N, Datta J et al (2013) Changes in sexual attitudes and lifestyles in Britain through the life course and over time: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet 382:1781–1794. https://doi.org/10.1016/S0140-6736(13)62035-8

Gnann JW, Whitley RJ (2016) Clinical practice. Genital Herpes N Engl J Med 375:666–674. https://doi.org/10.1056/NEJMcp1603178

Gupta R, Warren T, Wald A (2007) Genital herpes. Lancet 370:2127–2133. https://doi.org/10.1016/S0140-6736(07)61908-4

Langenberg AG, Corey L, Ashley RL, Leong WP, Straus SE (1999) A prospective study of new infections with herpes simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group. N Engl J Med 341:1432–1438. https://doi.org/10.1056/NEJM199911043411904

Kidszun A, Bruns A, Schreiner D, TippmannS WJ, Pokora RM, Urschitz MS, Mildenberger E (2022) Characteristics of neonatal herpes simplex virus infections in Germany: results of a 2-year prospective nationwide surveillance study. Arch Dis Child Fetal Neonatal Ed 107:F188–F192. https://doi.org/10.1136/ARCHDISCHILD-2021-321940

Dungu KHS, Lund S, Malchau Carlsen EL, Hartling UL, Matthesen AT, Franck KT, MK, Ulrik Justesen S, Nielsen HL, Nielsen ALY, et al (2023) Herpes simplex virus infection among neonates suspected of invasive bacterial infection: a population-based cohort study. Arch Dis Child Fetal Neonatal. https://doi.org/10.1136/ARCHDISCHILD-2023-325583

Teutsch SM, Nunez CA, Morris A, Eslick GD, Berkhout A, Novakovic D, Brotherton JML, McGregor S, Khawar L, Khandaker G et al (2022) Australian Paediatric Surveillance Unit (APSU) Annual Surveillance Report 2021. Commun Dis Intell. https://doi.org/10.33321/CDI.2022.46.66

Matthias J, Du Bernard S, Schillinger JA, Hong J, Pearson V, Peterman TA (2021) Estimating neonatal herpes simplex virus incidence and mortality using capture-recapture, Florida. Clin Infect Dis 73:506–512. https://doi.org/10.1093/CID/CIAA727

Kimberlin DW (2014) The scarlet H. J Infect Dis 209:315–317. https://doi.org/10.1093/infdis/jit459

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Author information

Anne-Gaël Cordier

Present address: Groupe de Recherche sur les Infections pendant la grossesse (GRIG), Paris, France

Authors and Affiliations

Department of Virology, Angers University Hospital, 4 rue Larrey, 49933, Angers, France

Elise Bouthry

Groupe de Recherche sur les Infections pendant la grossesse (GRIG), Paris, France

Elise Bouthry, Vincent Portet-Sulla, Claire Périllaud-Dubois, Alexandre J. Vivanti & Christelle Vauloup-Fellous

Division of Virology, WHO Rubella National Reference Laboratory, Dept of Biology and Genetics, Paris Saclay University Hospital, APHP, Paris, France

Vincent Portet-Sulla, Melek Manai Bouokazi, François-Charles Javaugue & Christelle Vauloup-Fellous

Center for Immunology of Viral, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, INSERM U1184, CEA, Auto-Immune, Fontenay-Aux-Roses, France

Vincent Portet-Sulla & Christelle Vauloup-Fellous

Virology Department, Sorbonne University, Saint-Antoine Hospital, AP-HP, Pierre Louis Epidemiology and Public Health Institute (iPLESP), INSERM 1136, Paris, France

Claire Périllaud-Dubois

Division of Paediatric Critical Care and Neonatal Medicine, FAME Department, Paris Saclay University Hospital, “Kremlin-Bicetre” Medical Center-APHP, Paris, France

Laure Jule, Claire Boithias, Nolwenn Le Saché, Mostafa Mokhtari & Diane Carrière

Division of Obstetrics and Gynecology, Centre Hospitalier Simone Veil, 41000, Blois, France

Louise Sonnier

Department of Neonatal Medicine, DMU2 Santé des Femmes et des Nouveau-nés, Paris Saclay University Hospital, “Antoine Béclère” Medical Center-APHP, Paris, France

Rafik Benammar & Emmanuelle Letamendia-Richard

Division of Obstetrics and Gynecology, DMU Santé des Femmes et des Nouveau-Nés, Paris Saclay University Hospital, “Antoine Béclère” Medical Center-APHP, Paris, France

Alexandra Letourneau, Alexandre J. Vivanti & Anne-Gaël Cordier

Department of Obstetrics and Gynecology, AP-HP.Sorbonne Université, “Tenon” Medical Center-APHP, Paris, France

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Contributions

FC.J and C.VF designed and implemented the study. E.B, V.PS, C.PD, FC.J, M.MB, and C.VF performed and interpreted routine virological analysis and, if necessary, complementary analysis. L.J, C.B, N.LS, M.M, D.C, L.S, R.B, A.L, AJ.V, AG.C, and E.L managed the patients and their mothers. E.B, FC.J, M.MB, and C.VF collected the data. FC.J and C.VF analyzed and interpreted the data, and drafted the manuscript. All authors critically reviewed the manuscript for important intellectual content and approved the final version. All authors agree to be accountable for all aspects of this work.

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Bouthry, E., Portet-Sulla, V., Bouokazi, M.M. et al. Neonatal herpes: case series in two obstetric centres over a 10-year period (2013–2023), France. Eur J Pediatr (2024). https://doi.org/10.1007/s00431-024-05581-9

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Received : 20 February 2024

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Published : 27 April 2024

DOI : https://doi.org/10.1007/s00431-024-05581-9

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Guide to retrospective case study data reports

Section 1 – what is being analyzed.

Case Studies Home
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For each case study site, EPA researchers took samples from a variety of sources and tested them for a broad range of substances and chemicals, including components of hydraulic fracturing fluids. Water conditions, such as temperature and dissolved oxygen referred to as “parameters” were also monitored and recorded. These are listed in the first table labeled, “Analytes and Parameters.” (Analytes tab)

Although each case study site has different geology and hydrology, EPA generally uses the same water quality test methods for all the sites to assess conditions in the area.

Section 2 – Understanding the Data

Many of the data have notes and labels that represent important descriptions for understanding what the values listed mean. All of the possible data notes and abbreviations are listed in the following reference tables:

Quality Assurance/Quality Control Definitions, Data Qualifiers and Data Descriptors

Section 3 – Key for Sample ID Numbers

Each sample taken has a unique identification number. The Key explains the numbering system for the samples.

Section 4 – Data Tables

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Published: 07 May 2024

Molecular characterization of influenza virus circulating in Nepal in the year 2019

Rachana Mehta 1 ,
Bimalesh Kumar Jha 1 ,
Balkrishna Awal 1 ,
Ranjit Sah 1 ,
Lilee Shrestha 1 ,
Chhoting Sherpa 1 ,
Smriti Shrestha 1 &
Runa Jha 1

Scientific Reports volume 14 , Article number: 10436 ( 2024 ) Cite this article

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Medical research
Microbiology
Molecular biology

Influenza (sometimes referred to as “flu”) is a contagious viral infection of the airways in the lungs that affects a significant portion of the world's population. Clinical symptoms of influenza virus infections can range widely, from severe pneumonia to moderate or even asymptomatic sickness. If left untreated, influenza can have more severe effects on the heart, brain, and lungs than on the respiratory tract and can necessitate hospitalization. This study was aimed to investigate and characterize all types of influenza cases prevailing in Nepal and to analyze seasonal occurrence of Influenza in Nepal in the year 2019. A cross sectional, retrospective and descriptive study was carried out at National Influenza Center (NIC), National Public Health Laboratory Kathmandu Nepal for the period of one year (Jan–Dec 2019). A total of 3606 throat swab samples from various age groups and sexes were processed at the NIC. The specimens were primarily stored at 4 °C and processed using ABI 7500 RT PCR system for the identification of Influenza virus types and subtypes. Data accessed for research purpose were retrieved from National Influenza Centre (NIC) on 1st Jan 2020. Of the total 3606 patients suspected of having influenza infection, influenza viruses were isolated from 1213 (33.6%) patients with male predominance. The highest number of infection was caused by Influenza A/Pdm09 strain 739 (60.9%) followed by Influenza B 304 (25.1%) and Influenza A/H3 169 (13.9%) and most remarkable finding of this study was the detection of H5N1 in human which is the first ever case of such infection in human from Nepal. Similar to other tropical nations, influenza viruses were detected year-round in various geographical locations of Nepal. The influenza virus type and subtypes that were in circulation in Nepal were comparable to vaccine candidate viruses, which the currently available influenza vaccine may prevent.

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Introduction.

Influenza is an acute viral disease of the respiratory tract which is caused by influenza virus 1 . There are four different serotypes of this virus, which belongs to the Orthomyxoviridae family: influenza A, influenza B, influenza C, and influenza D. Although the influenza A and B viruses are the ones that cause the common seasonal flu outbreaks in people, influenza C infections often cause minor symptoms and are not linked to widespread human flu epidemics. Influenza D viruses affect cattle largely and are not known to be able to infect or sicken humans 2 . Based on the antigenic characteristics of the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA), influenza viruses of type A can be further divided into two major groups, namely low pathogenic seasonal influenza (A/H1N1, A/H1N1 pdm09, A/H3N2) and highly pathogenic influenza virus (H5N1, H5N6, H7N9) 3 , 4 . Eleven NA subtypes (N1-N11) and 18 HA subtypes (H1-H18) have so far been identified 5 .

Seasonal epidemics are generally caused by influenza A viruses, including subtypes H1N1pdm09 and H3N2, and influenza B viruses, specifically lineages B-Yamagata and B-victoria 6 . According to current estimates, seasonal influenza kills between 250,000 and fifty thousand individuals worldwide each year, affecting between 10 and 20% percent of the global population 7 , 8 . The influenza A virus undergoes a minor antigenic change, namely antigenic drift from year to year and may also undergo a major changes, termed an antigenic shift as occurred with the emergence of the swine origin A/H1N1 pdm 09 influenza virus, which was considered a major pandemic threat to human health 9 . Influenza related complications including hospitalization and deaths are often seen in very young, elderly and people with underlying medical conditions 10 .

Similar to the tropical and sub-tropical regions of Southeast Asia, Nepal experiences year-round influenza B, A/H3N2, and A/H1N1 pdm09 circulation, with a peak from July to November. However, the rate of infection transmission reach peak during the post-rain and winter season of Nepal 8 .

As each influenza season is characterized by specific patterns of circulating influenza viruses, the identification and characterization of influenza viruses is essential in order to develop effective vaccines against the influenza strains predicted to circulate in the upcoming season 6 . Therefore, this study is aimed to investigate influenza cases, to characterize influenza types and subtypes and also to analyze the seasonal occurrence of influenza infection in Nepal.

Methods and methodology

Study design and sample collection.

A retrospective, descriptive and cross sectional study was carried out at the National Influenza Center (NIC), National Public Health Laboratory (NPHL), Kathmandu, Nepal for the period of one year (January–December 2019). The data were obtained from the National Influenza centre for the research purpose on 1st Jan 2020. A total of 3606 throat swab specimens were collected from sentinel site of National Influenza Surveillance Network and NPHL. The samples obtained at sentinel sites were transported to NPHL in a cold chain box and preserved in viral transport media within 24 h where they were kept at 4 °C until processing. According to the WHO case criteria for ILI and SARI, patients included in the study either had pneumonia or influenza-like illness (ILI), which includes fever (> 38 °C), cough, running nose, chills, and sore throat within last seven days 11 .

Sample processing and virus identification

All samples in viral transport media were aliquoted into two micro centrifuge tubes. One was kept at − 70 °C while the other was utilized for RNA extraction. Using the QIAamp® Viral RNA Mini Kit (QIAGEN GmbH, Hilden, Germany) and following the manufacturer's instructions, influenza viral RNA was extracted. Applied Bio systems TM 7500 Real-Time PCR System and AgPath-IDTM One-step RT-PCR Kit from Thermo Fisher Scientific, USA, were used to identify the influenza virus. First, influenza A and B viruses were screened for in the retrieved RNA. Further classification into subtypes and lineages was done on the sample that tested positive for influenza A/B. Influenza A positive sample were further tested for Pdm A, Pdm H1, A/H3 while samples exhibiting influenza B positivity were checked for B/Yamagata and B/Victoria lineage. Due to limited supply of PCR kit, only 83 influenza B positive samples were further processed to determine their lineages. The primers and probes used in the reaction mixture for identification of various influenza virus types, subtypes and lineages (H1N1, H3N2, H1N1pdm09, Influenza B, B/Victoria, B/Yamagata) were provided by US Center for Disease Control and Prevention (CDC) through the IRR and the assays were carried out according to manufacturer’s protocols. Cycle threshold (Ct) values greater than 40 were regarded as positive in samples 12 .

In accordance with established guidelines and regulations, all methods employed in this study were conducted after obtaining approval from Nepal Health research council. The research procedures followed ethical standards and adhered to the recommended protocols outline in Helsinki declaration.

Ethical consideration

This study is a Laboratory based retrospective study conducted at National Public Health Laboratory. Ethical approval was obtained from Ethical Review Committee, Nepal Health Research Council (NHRC ref. no. 1966 on 18 March 2020) and no individual consent from participants were taken as data was extracted from ongoing Global Influenza Surveillance Program with the approval of Director of the National Public Health Laboratory. All the samples were anonymized and only code number generated in Global Influenza Surveillance Program (Nepal) were used for analysis.

Therefore, written informed consent is deemed unnecessary for this research as this study was approved by both NHRC and NPHL.

Demographic characteristics of patients

During the year 2019, a total of 3606 throat swab specimens from 1880 males and 1726 females were tested at National Public Health Laboratory for Influenza virus infection, among which 1213 samples tested positive (33.6%). Gender distribution and clinical findings (SARI or ILI) of samples received and positive cases is seen in Table 1 .

Age-wise distribution of influenza suspected cases as well as influenza positive was observed higher in age group 15–45 years (Table 2 ).

National Public Health Laboratory received samples from 73 districts in 2019. However, positive cases for influenza infection were confirmed from 56 districts only. District wise distribution of positive cases is shown in Fig. 1 .

District wise transmission of influenza viruses, 2019 (Map was created independently using ArcGIS Version 10.5, arcgis.com).

Prevalence of influenza virus

Among 1213 influenza positive cases, Influenza type A accounted for 909 (74.9%) cases of infection whereas influenza type B was found in 304 (25.1%) cases. Among Influenza type A, most positive cases 739 (60.9%) were found infected with influenza A/Pdm09 subtype whereas 169 (13.9%) were positive for influenza A/H3 subtype. Among the 304 cases of influenza B infection, only 83 isolates were further differentiated into lineage and this revealed higher number of viruses from B/Victoria lineage 60 (4.95%) in comparison to B/Yamagata lineage 23 (1.89%) (Table 3 ).

Seasonal distribution of influenza viruses

Figure 2 , illustrates the distribution of cases of influenza in different months throughout the year 2019. It can be observed that higher numbers of influenza cases were reported with two peaks in the year 2019, first during the month of January–February and second during the month of August–September. The highest numbers of cases were recorded in the month of January and February. Positivity rate was 53.1% in January, 47.4% in February and 37.3% in the month of September. The least number of influenza positive cases were reported in the months of May, June, July, November and December.

Month wise analysis of influenza cases in year 2019 (N = 3606).

Influenza A/Pdm09 strain was found predominant during the first peak whereas InfA/H3 was predominant during second peak. (Fig. 3 ) A single case of H5N1 was also identified which was first human case of H5N1 reported from Nepal.

Influenza subtypes identified in different moths of the year 2019 (n = 1213).

In Nepal, influenza is one of the major causes of public health problems, yet little is known about its epidemiology. Following an outbreak, the influenza virus has been seen to re-assort with various types of genetic alterations, creating a new strain that may further fuel an epidemic 13 . According to the World Health Organization, the H1N1pdm09 or H3N2 subtype of the influenza A virus has been co-circulating in the European region throughout the 2018–2019 flu season 14 . However, either influenza A(H1N1) pdm09 or A(H3N2) dominated (2014/15–2016/17) of influenza season 15 . Every season, a new strain or genetic variation of the influenza virus reemerges, bringing with it novel antigenic features that may reduce vaccine-induced protection due to strain mismatches between the vaccine and circulating strains. To provide the best protection against influenza infection, it is required to identify and define the novel strain of virus and adjust the vaccine in accordance with the dominant strain. The Early warning response system (EWARS) in Nepal, established by the Epidemiology and Diseases control division (EDCD) in 1997 is a hospital based syndromic surveillance that received weekly reporting of number of cases and deaths of six priority diseases / syndromes including SARI. At present 118 sites are reporting to EWARS. In 2019, 10542 SARI were reported to EWARS from these sites 16 .

During the study period, influenza A/Pdm09 was the most predominant strain (53.1%) circulating in Nepal. A study conducted by Adhikari et.al also reported similar finding according to which pandemic influenza AH1N1 dominated in the year 2009 in Nepal 17 . However, different from previous study by Upadhayay et al. and Jha et al. which showed influenza A/H3 was responsible for 60.1% and 51.0% of the total infection in year 2014 and 2016 in Nepal respectively 8 , 15 . According to a study from tropical Asia, influenza A predominated over influenza B between 2007 and 2013, which is consistent with our study 18 . In this investigation, we found that the B/Victoria lineage of the influenza type B virus predominated over the B/Yamagata lineage, which was different from the study carried out by Jha et.al in the year 2016 in Nepal 15 . Although our research reveals that B/Victoria lineage predominated over B/Yamagata which is similar to study conducted by Northern Hemisphere during the 2016–2017 season 19 . The prevalence rates given in different studies may differ since they were conducted at diverse times and locations.

This study illustrates circulations of influenza infection throughout the year with the first peak in January–February followed by August–September. The study conducted by Jha et al. in the past from the same institution also demonstrated that Nepal observes two peaks of influenza infection round the year; first in the month of January and second in the month of July–August 15 . In our study second peak was observed in the month of August–September rather than July–August which is slightly different from previous study. Similar to our findings, a study from mainland China by Sun et al. showed two influenza activity peaks, one in the winter and the other in the spring of each monitoring year 20 . In contrast, the temperate region of the Japanese mainland only suffers a single surge in influenza activity during the winter months 21 . Numerous research looked at the seasonal patterns of influenza, but the mechanisms by which new virus strains arise and propagate are still not fully known but likely include a combination of climatic conditions, susceptibility of the population and virus characteristics 22 , 23 . From the perspective of public health, knowledge of the seasonality of pathogens is essential to help determine the timing of interventions, especially in a nation with a variety of climatic and economic conditions 24 . In this perspective, for optimizing influenza management tactics and for understanding the epidemiology and seasonality of influenza, a good influenza monitoring and surveillance system is crucial 25 .

One of the most remarkable findings of this study was the detection of H5N1 from human, which was the first ever case of such infection in human from Nepal. NPHL confirmed the Influenza A infection from throat swab sample of 21-year-old male patient admitted in Hospital. However, the patient could not be saved and died following respiratory complications on 29th March 2019. The subtype of the virus was tested negative for Influenza A/Pdm09 and Influenza A/H3, which was later confirmed at NIC of Japan, on 30 April, 2019 a WHO Collaborating Center for Influenza to be Influenza A/H5N1 26 , 27 .

Due to several restrictions on this work, including a lack of funding and resources, we were unable to carry out comprehensive genomic characterizations. However, to comprehend the epidemiology and seasonality of influenza and to optimize control methods, effective and ongoing influenza monitoring and surveillance systems are required.

Conclusion and recommendations

In Nepal, influenza viruses have been found all year long in various regions, just like in other tropical countries ( Supplementary Information ). All forms of influenza viruses are in circulation, with the peak season occurring between January and March. To connect viral genetic changes with antigenic changes, it is required to compare the genetic patterns of the influenza virus throughout time.

Data availability

All necessary data are included in paper. The Datasets analyzed during the Current study are available in Global Influenza Surveillance Network. Remaining data will be provided by corresponding authors on reasonable request.

Upadhyay, B. P., Ghimire, P., Tashiro, M. & Banjara, M. R. Characterization of seasonal influenza virus type and subtypes isolated from influenza like illness cases of 2012. Kathmandu Univ. Med. J. 57 (1), 56–60 (2017).

Google Scholar

Javanian, M. et al. A brief review of influenza virus infection. J. Med. Virol. 93 (8), 4638–4646 (2021).

Article CAS PubMed Google Scholar

de Mattos Silva Oliveira, T. F. et al. Molecular characterization of influenza viruses collected from young children in Uberlandia, Brazil-from 2001 to 2010. BMC Infect. Dis. 15 (1), 1–9 (2015).

Article Google Scholar

Upadhyay, B. P. Influenza: An emerging and re-emerging public health threat in Nepal. Ann. Clin. Chem. Lab. Med. 3 (2), 1–2 (2017).

Phipps, L., Essen, S. C. & Brown, I. H. Genetic subtyping of influenza A viruses using RT-PCR with a single set of primers based on conserved sequences within the HA2 coding region. J. Virol. Methods 122 (1), 119–122 (2004).

Ye, C. et al. Understanding the complex seasonality of seasonal influenza A and B virus transmission: Evidence from six years of surveillance data in Shanghai, China. Int. J. Infect. Dis. 1 (81), 57–65 (2019).

Oshitani, H. Influenza surveillance and control in the Western Pacific Region. Western Pac. Surveill. Response J. WPSAR. 1 (1), 3 (2010).

Article PubMed Google Scholar

Upadhyay, B.P., Ghimire, P., Tashiro, M., & Banjara, M.R. Molecular epidemiology and antigenic characterization of seasonal influenza viruses circulating in Nepal.

Fineberg, H. V. Pandemic preparedness and response—Lessons from the H1N1 influenza of 2009. N. Engl. J. Med. 370 (14), 1335–1342 (2014).

Acharya, B., Upadhyay, B. P., Adhikari, S., Rayamajhi, A. & Thapa, K. Influenza virus types and subtypes among pediatric patients having influenza like illness in summer season. Age. 5 , 5 (2016).

Fitzner, J. et al. Revision of clinical case definitions: Influenza-like illness and severe acute respiratory infection. Bull. World Health Organ. 96 (2), 122 (2018).

Centers for Disease Control and Prevention. CDC protocol of realtime RTPCR for influenza A (H1N1). Centers for Disease Control and Prevention: Atlanta, GA, USA. (2009).

Krammer, F. Emerging influenza viruses and the prospect of a universal influenza virus vaccine. Biotechnol. J. 10 (5), 690–770 (2015).

Sominina, A. et al. Assessing the intense influenza A (H1N1) pdm09 epidemic and vaccine effectiveness in the post-COVID Season in the Russian Federation. Viruses. 15 (8), 1780 (2023).

Article CAS PubMed PubMed Central Google Scholar

Jha, B. K., Pandit, R., Jha, R. & Manandhar, K. D. Overview of seasonal influenza and recommended vaccine during the 2016/2017 season in Nepal. Heliyon. 6 (1), e03304 (2020).

Article PubMed PubMed Central Google Scholar

Dhoubhadel, B. G. et al. A major dengue epidemic in 2022 in Nepal: Need of an efficient early-warning system. Front. Trop. Dis. https://doi.org/10.3389/fitd.2023.1217939 (2023).

Adhikari, B. R. et al. Outbreak of pandemic influenza A/H1N1 2009 in Nepal. Virol. J. 8 , 1–8 (2011).

Caini, S. et al. Epidemiological and virological characteristics of influenza B: Results of the Global Influenza B Study. Influenza Other Respir. Viruses. https://doi.org/10.1111/irv.12319 (2015).

Puzelli, S. et al. Co-circulation of the two influenza B lineages during 13 consecutive influenza surveillance seasons in Italy, 2004–2017. BMC Infect. Dis. 19 (1), 1–1 (2019).

Diamond, C. et al. Regional-based within-year seasonal variations in influenza-related health outcomes across mainland China: A systematic review and spatio-temporal analysis. BMC Med. 20 (1), 58 (2022).

Dave, K. & Lee, P. C. Global geographical and temporal patterns of seasonal influenza and associated climatic factors. Epidemiol. Rev. 41 (1), 51–68 (2019).

Moorthy, M. et al. Deviations in influenza seasonality: Odd coincidence or obscure consequence?. Clin. Microbiol. Infect. 18 (10), 955–962 (2012).

World Health Organization. A manual for estimating disease burden associated with seasonal influenza.

Feng, L. et al. Viral etiologies of hospitalized acute lower respiratory infection patients in China, 2009–2013. PLoS ONE. 9 (6), e99419 (2014).

Article ADS PubMed PubMed Central Google Scholar

Lee, E. C. et al. Deploying digital health data to optimize influenza surveillance at national and local scales. PLoS Comput. Biol. 14 (3), e1006020 (2018).

Thapa, K., Mishra, V. P., Twanabasu, S. & Kusma, S. Bird flu in Nepal. Int. J. Res. Med. Sci. 8 , 1593 (2020).

https://www.who.int/nepal/news/detail/01-05-2019-information-on-avian-influenza-a-(h5n1)-identified-in-human-in-nepal

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Acknowledgements

We express our deep appreciation to CDC IRR for their invaluable support in providing the reagents. Additionally, we are grateful to the director of NPHL for giving us the opportunity to conduct this study.

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Rachana Mehta, Bimalesh Kumar Jha, Balkrishna Awal, Ranjit Sah, Lilee Shrestha, Chhoting Sherpa, Smriti Shrestha & Runa Jha

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A: RJ.: Conceptualization, Data curation, Investigation, B: R.S.: Data curation, Writing review & editing. C: B.K.J.: Data curation, Investigation, writing original draft, Writing review & editing. D: R.M.: Data curation, Investigation, Writing original draft, Writing review & editing. E: B.K.A.: Writing original draft, Writing review & editing. F: L.S.: Writing review & editing. G: C.S.: Data curation. H: S.S.: Data curation.

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Mehta, R., Jha, B.K., Awal, B. et al. Molecular characterization of influenza virus circulating in Nepal in the year 2019. Sci Rep 14 , 10436 (2024). https://doi.org/10.1038/s41598-024-58676-6

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Published: 06 May 2024

Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium

Maximilian Feth 1 ,
Natasha Weaver 2 , 3 ,
Robert B. Fanning 4 , 5 ,
Sung-Min Cho 6 , 7 ,
Matthew J. Griffee 8 , 9 ,
Mauro Panigada 10 ,
Akram M. Zaaqoq 11 ,
Ahmed Labib 12 ,
Glenn J. R. Whitman 6 ,
Rakesh C. Arora 13 , 14 ,
Bo S. Kim 6 ,
Nicole White 2 ,
Jacky Y. Suen 15 , 16 , 19 ,
Gianluigi Li Bassi 15 , 17 , 18 , 19 ,
Giles J. Peek 20 ,
Roberto Lorusso 21 ,
Heidi Dalton 22 ,
John F. Fraser 15 , 16 , 17 , 18 , 19 ,
Jonathon P. Fanning ORCID: orcid.org/0000-0002-1675-0522 15 , 16 , 17 , 23 , 24 on behalf of

the COVID-19 Critical Care Consortium

Journal of Intensive Care volume 12 , Article number: 18 ( 2024 ) Cite this article

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Extracorporeal membrane oxygenation (ECMO) is a rescue therapy in patients with severe acute respiratory distress syndrome (ARDS) secondary to COVID-19. While bleeding and thrombosis complicate ECMO, these events may also occur secondary to COVID-19. Data regarding bleeding and thrombotic events in COVID-19 patients on ECMO are sparse.

Using the COVID-19 Critical Care Consortium database, we conducted a retrospective analysis on adult patients with severe COVID-19 requiring ECMO, including centers globally from 01/2020 to 06/2022, to determine the risk of ICU mortality associated with the occurrence of bleeding and clotting disorders.

Among 1,248 COVID-19 patients receiving ECMO support in the registry, coagulation complications were reported in 469 cases (38%), among whom 252 (54%) experienced hemorrhagic complications, 165 (35%) thrombotic complications, and 52 (11%) both. The hazard ratio (HR) for Intensive Care Unit mortality was higher in those with hemorrhagic-only complications than those with neither complication (adjusted HR = 1.60, 95% CI 1.28–1.99, p < 0.001). Death was reported in 617 of the 1248 (49.4%) with multiorgan failure ( n = 257 of 617 [42%]), followed by respiratory failure ( n = 130 of 617 [21%]) and septic shock [ n = 55 of 617 (8.9%)] the leading causes.

Conclusions

Coagulation disorders are frequent in COVID-19 ARDS patients receiving ECMO. Bleeding events contribute substantially to mortality in this cohort. However, this risk may be lower than previously reported in single-nation studies or early case reports.

Trial registration ACTRN12620000421932 ( https://covid19.cochrane.org/studies/crs-13513201 ).

Clinical Perspective

Coagulation disorders such as thrombotic or hemorrhagic events are frequent in COVID-19 ARDS patients receiving ECMO.

While older age, pre-existing cardiac disease, and diabetes were independently associated with bleeding, prone positioning and a longer time from admission to ECMO were associated with a higher percentage of thrombotic events.

A longer duration of ECMO was linked to an increased rate of combined hemorrhagic and thrombotic events.

Extracorporeal membrane oxygenation (ECMO) is a cardiopulmonary support technique that can be lifesaving in patients suffering from severe respiratory and/or circulatory failure [ 1 , 2 , 3 ]. However, ECMO exposes patients to complications such as bleeding and thrombosis [ 4 , 5 , 6 ]. Coagulation disorders in critically ill patients supported with ECMO result from a complex interplay between the underlying illness and both ECMO-related (e.g., shear stress, artificial circuit surface–blood interaction) and iatrogenic factors (e.g., systemic anticoagulation) [ 7 , 8 , 9 ]. These complications are associated with increased morbidity and mortality [ 5 , 10 ]. However, the mechanisms behind coagulation disorders during ECMO are not yet fully understood, and prevention strategies are lacking.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease-2019 (COVID-19), can result in acute respiratory distress syndrome (ARDS) requiring intensive care unit (ICU) admission and advanced respiratory failure management [ 11 , 12 ]. Despite optimal medical management, including mechanical ventilation and prone positioning, mortality and morbidity rates due to refractory respiratory failure among these patients are high [ 13 , 14 ]. A rescue therapy in these patients is ECMO [ 15 , 16 ]. The mechanisms and clinical implications of thrombotic and hemorrhagic events in COVID-19 patients supported with ECMO are areas of ongoing research. This study aimed to define the global frequency, outcomes of, and risk factors for thrombotic and hemorrhagic disorders in COVID-19 patients with refractory ARDS supported with ECMO.

All data for this study were extracted from the global COVID-19 Critical Care Consortium (CCCC) prospective database, which was established to collect and analyze data on patients admitted to intensive care units for the treatment of severe COVID-19 [ 17 ]. The rationale and design have been previously published (Trial registration ACTRN12620000421932) [ 17 ]. Institutional Review Board (IRB) approval was obtained for each participating institution. A waiver of informed consent was granted for all patients. Additional file 1 : Table S1 summarizes all the recruiting sites, including IRB approvals, contributors, and collaborators.

The CCCC database was examined for patients referred to the ICUs of 229 collaborating institutions spanning 32 countries, from January 1, 2020, through June 30, 2022. Patients who satisfied all the following criteria were entered into the registry: (1) age ≥ 16 years; (2) COVID-19 pneumonia with laboratory confirmation (real-time PCR and/ or next-generation sequencing); and (3) admission to ICU due to severe COVID-19 pneumonia. Patients admitted to critical care for conditions unrelated to COVID-19 were excluded.

Data were collected from ICU admission to either in-hospital death or hospital discharge. Data collection followed guidelines for the International Severe Acute Respiratory IncideNce sTudy of Severe Acute and Emerging Infection Consortium (ISARIC), Short-Period Incidence Study for Severe Acute Respiratory Infection (SPRINT-SARI), and the CCCC. All data obtained were de-identified and stored at a Research Electronic Data Capture (REDCap) database hosted at one of the following institutions: Oxford University, United Kingdom; University College Dublin, Ireland; or Monash University, Australia.

According to the ISARIC and the Extracorporeal Membrane Oxygenation for 2019 novel Coronavirus Acute Respiratory Distress Disease (ECMOCARD study) case report forms (CRF), adverse coagulation events included (1) thrombotic events including ischemic stroke, myocardial ischemia, myocardial infarction, deep vein thrombosis (DVT), and pulmonary embolism (PE); (2) hemorrhagic events were classified according to the bleeding site or the two predominant bleeding sources, in cases involving multiple bleeding sites; and (3) disseminated intravascular coagulation (DIC). Adverse coagulation events were diagnosed by treating physicians. The study focused on the following four patient groups treated with ECMO: (1) patients without hemorrhage or thrombosis (controls); (2) patients with both a hemorrhagic and thrombotic event; (3) patients with a hemorrhagic event only; and (4) patients with a thrombotic event only.

The study's primary outcome was mortality in COVID-19 patients supported with ECMO who suffered thrombotic and bleeding events. Secondary outcomes were the incidence of thrombotic and bleeding complications and the duration of ICU requirement (days). Additionally, we investigated risk factors for hemorrhagic or thrombotic events in COVID-19 patients on ECMO. Laboratory assessments were obtained according to the CRFs. ‘First value’ refers to a specific parameter's first recorded value in the CRFs. Minimum and maximum values are the minimum/maximum level of a parameter from enrolling in the study throughout the follow-up period.

Statistical analysis

The study cohort was limited to patients who were treated with ECMO. Patients without thrombotic or hemorrhagic complications were compared to the following subgroups: patients with a hemorrhagic event only, a thrombotic event only, or a combination of hemorrhagic and thrombotic events. Demographic characteristics, medical history, critical care treatment, and outcomes were described and checked for missing data (Additional file 1 : Table S2). Continuous data were summarized as mean with standard deviation or median with interquartile range. Categorical variables were summarized as frequency count and percentage. Differences between groups were evaluated using Pearson's chi-squared test for categorical variables and the Wilcoxon–Mann–Whitney U test for continuous variables.

Survival analysis was used to estimate the effect of coagulation complications (combined and for thrombotic and hemorrhagic complications separately) on the time between ICU admission and mortality. The survival analysis cohort was limited to patients with non-missing discharge status and a valid ICU discharge date. The effect of coagulation complications on the instantaneous mortality hazard was estimated using Cox regression, assuming patients ‘discharged alive’ (alive, home, palliative care, hospitalized, or transferred to another facility) were censored independently. The proportional hazards assumption was verified with log–log plots and a test of Schoenfeld residuals. Parametric Weibull regression also was performed as a sensitivity analysis. Each survival analysis method was used to produce crude estimates and estimates adjusted a priori for patient age, sex, body mass index (BMI), and country of hospitalization. Due to a large proportion of missing BMI data, all analyses were repeated without adjusting for BMI. Regression results were presented as hazard ratios with 95% confidence intervals and p values.

Analysis was performed in SAS 9.4 (SAS Institute Inc., Cary, NC, USA), apart from survival analyses performed in Stata 15 (StataCorp, College Station, TX, USA).

During the study period, 1,248 patients receiving VV- or VA-ECMO support due to COVID-19-related critical illness were included in the CCCC database. Table 1 summarizes baseline patient characteristics, including pre-existing health and management conditions. A hemorrhagic or thrombotic event was documented in 469 (38%). Among these 469 patients, 52 (11%) experienced at least one hemorrhagic and one thrombotic complication, while 252 (54%) patients experienced a hemorrhagic event only and 165 (35%) a thrombotic event only (Fig. 1 ),

Study Cohort, Flow Chart. CCCC Covid Critical Care Consortium, ECMO extracorporeal membrane oxygenation

Outcomes and causes of death

The adjusted hazard ratio (HR) for ICU mortality was higher among patients who experienced only a hemorrhagic complication than in patients who had neither type of complication (adjusted HR = 1.60, 95% CI 1.28–1.99, p < 0.001, Table 2 ). No statistically significant differences in ICU mortality were observed in patients with both types of complication (adjusted HR = 1.02, 95% CI 0.67–1.57, p = 0.918) or thrombotic events only (adjusted HR 0.79, 95% CI 0.59–1.05, p = 0.103) relative to patients with neither type of complication. Figure 2 depicts the survival of COVID-19 patients supported with ECMO over time in the four study groups.

Kaplan–Meier Curve comparing patients with a thrombotic event, a hemorrhagic event, both events and neither event. NB Log rank test for equality of survivor functions p < 0.0001

The length of stay (days) within the ICU was longer for patients with both types of complication (42.0 days, 27.5–52.5, p = 0.009) and for those with a thrombotic event only (37.0 days, 24.0–57.0, p = 0.010) than in patients with neither type of complication (30.0 days, 17.0–52.0). Hospital length of stay was longer for those with both types of complication (45.0 days, 29.0–72.0, p = 0.017) and those with thrombotic events (44.0 days, 26.0–69.0, p = 0.003), but shorter among those with hemorrhagic events (28.0 days, 14.0–50.0, p = 0.001) compared to patients with neither type of complication (35.0 days, 19.0–59.0).

Overall, 617 of 1248 patients (49.4%) died in the ICU. The leading cause of death was multiorgan failure (257, 42%), followed by respiratory failure (130, 21%) and septic shock (55, 8.9%) (Table 3 ).

Coagulation complications (Table 4 )

Thrombotic complications were documented in 217 (17.4%) of the 1248 patients with pulmonary embolism being the most common ( n = 86 or 39.6%). Hemorrhagic complications occurred in 304 (24%) of all patients with the most common source being gastrointestinal (112, 36.8%). Note that bleeding severity was not part of the case report forms and, therefore, cannot be commented on.

The most common anticoagulation prophylaxis method was unfractionated heparin (UFH), followed by low molecular weight heparin (LMWH). Other anticoagulation strategies were rarely used (Table 5 ). Table 6 summarizes laboratory assessments.

Advanced ARDS management and ECMO

Clinical management of COVID-19 patients supported with ECMO is shown in Table 5 , while Additional file 1 : Table S3 provides ECMO specific data. Prone positioning during mechanical ventilation was more common in patients with thrombotic events than in controls (111, 81% vs. 354, 69%, p = 0.006). Furthermore, in patients with both types of complication (36/52, 71%, p = 0.004) as well as in patients with just a thrombotic event (112/165, 69%, p < 0.001), tracheostomy was more commonly performed than in controls (289/779, 50%).

Most patients received venovenous (864, 93.8%) rather than venoarterial ECMO (57, 6.2%). Time to admission for ECMO was statistically longer for patients with thrombotic events than in controls ( p = 0.043). Duration of ECMO support also was statistically longer among patients with both complication types ( p = 0.015). Maximum and mean daily ECMO blood flow was significantly less in patients with only thrombotic events than in patients with either hemorrhage events only, as well as among those with either, both, or neither type of complication (maximum daily blood flow p = 0.010, mean daily blood flow rate p = 0.015). However, there was no statistically significant difference in mean daily blood flow rates once adjusted for patient body weight. Circuit changes were most frequent in patients with both types of complications (26%), followed by those with hemorrhage complications (22%) and those with neither type of complication (16%). The incidence of any circuit change was the least frequent in patients with a thrombotic event (12%).

When considering venovenous ECMO only, we found a higher adjusted HR for ICU mortality for patients with hemorrhagic complications (adjusted HR 1.42, 95% CI 1.10–1.84, p = 0.008) compared to those without either type of complication. In contrast to the entire cohort, we observed a statistically significant reduction in HR for ICU mortality for venovenous ECMO patients with thrombotic complications only (HR, 0.64, 95% CI 0.46–0.89, p = 0.008) compared to venovenous ECMO patients without either type of complication (Table 2 ).

International comparison

This study involved participants mainly from the United States ( n = 354), Colombia ( n = 215), Spain ( n = 140), Italy ( n = 140), Kuwait ( n = 126) and Australia ( n = 12). Mortality was highest in Italy (64%), lowest in Australia (33%), and comparable (47–56%) among the other countries. However, ICU length of stay was not significantly different between regions. Table 7 summarizes further parameters by the host nation.

In this international registry, we found that coagulation-related complications occurred in 38% of patients with severe COVID-19 requiring ECMO (hemorrhagic 20.2%; thrombotic 13.2%, and both < 5%). Hemorrhagic events were associated with increased mortality, whereas thrombotic events, alone or combined with hemorrhagic events, did not significantly impact mortality. In a recent study by Mansour et al., 66% of 620 critically ill COVID-19 patients receiving ECMO in France experienced coagulation disorders: 29% had bleeding, 16% thrombotic events, and 20% had both. Compared to this French cohort, our global CCCC study observed a lower incidence of bleeding and combined complications, with thrombotic events being comparable (13.2 vs. 16%). Differences in the choice of anticoagulant agent and/or the therapeutic target level might have contributed to the lower rate of bleeding events we observed in CCCC registry patients. Another potential explanation for the difference in the incidence of bleeding events might be how bleeding events were defined and captured. Nevertheless, both our study and that of Mansour et al. identified an association between coagulation disorders and increased mortality.

Within our population, those experiencing only hemorrhagic but not thrombotic event (alone or in combination) experienced a greater hazard of ICU mortality. This might be due to the high rates of mortality associated with certain types of bleeding, such as intracranial hemorrhage and severe bleeding requiring massive transfusion. Our finding of a reduced hazard of ICU mortality for patients experiencing thrombotic events contrasts with the reports of patients requiring ECMO due to non-Covid-19 conditions who undergo thrombosis. This might either be due to the differences of prothrombotic tendencies of different COVID-19 phenotypes or to the already increased risk of thrombosis resulting from prolonged critical care. Unfortunately, due to missing data, we could not adjust our survival analysis for other factors that might have contributed to mortality in this group. Therefore, though hypothesis generating, our mortality findings should be interpreted with caution.

In our cohort, multi-organ as well as respiratory failure and septic shock were the leading causes of death. This mirrors results reported by Peek et al. in 2009, who found that multi-organ failure accounted for 42% of the deaths in patients treated with ECMO [ 18 ]. Death due to hemorrhagic shock or cerebrovascular events was rare, even though bleeding was identified as a risk factor for mortality. Ischemic stroke and cerebrovascular accidents, generally considered frequent causes of permanent impairment after ECMO, occurred in nine patients in our study (4.1% among patients with a thrombotic event and 0.72% of the entire cohort), which is comparable to the incidence of stroke in a non-COVID ECMO group investigated in the EOLIA trial [ 2 ].

Our study identified several factors independently associated with coagulation disorders: older age, pre-existing cardiac disease, and diabetes were associated with bleeding events, while White ethnicity was associated with an increased risk of all coagulation disorders. Extended ECMO duration was associated with an increased incidence of bleeding but not thrombotic events, diverging from past reports in both in COVID and non-COVID patient populations. Longer mechanical ventilation was associated with both thrombotic and combined complications, but not with bleeding events alone. Both prone positioning during mechanical ventilation and longer time from admission to ECMO were associated with a higher incidence of thrombotic events. This aligns with Gebhard et al.’s 2021 study, which found extended prone positioning increased DVT risk in a small cohort [ 19 ]. These findings suggest a need for vigilance and close monitoring for thrombosis in ECMO patients undergoing prone positioning, awaiting further studies to clarify this relationship.

Subcutaneous administration of anticoagulation was associated with thrombotic complications (both combined and individual), suggesting that this route might not be suitable for preventing thrombosis in COVID-19 ECMO patients. This finding contrasts with Wiegele et al.’s single-center study, where ECMO patients treated with subcutaneous enoxaparin experienced fewer thrombotic or major bleeding events than those receiving unfractionated heparin [ 20 ].

Blood product transfusion was frequent in patients with either or both complications. Transfusion of packed red blood cells was independently associated with both forms of complication (alone or combined). However, platelets, fresh frozen plasma, and cryoprecipitate transfusions occurred more in patients with bleeding events, regardless of whether they were combined with thrombotic complications, but not in patients with only thrombotic events.

Strengths and limitations

This study has several limitations, including missing data and the retrospective nature of data extraction. Despite using standardized case report forms to minimize variations in data reporting, data entry depended on the discretion of physicians and research staff at each participating center and consequently, data completeness was heterogeneous. In addition, variability in ECMO and critical care management across centers, coupled with the voluntary nature of site participation, may have skewed representation to those with sufficient resources to enter the data. This variability hinders the precise assessment of potentially outcome-impacting factors such as the anticoagulation practices and ECMO management protocols.

On the other hand, extensive international collaboration offers valuable insights into thrombotic and bleeding events in COVID-19 ECMO patients globally. The pandemic’s evolving nature and the consequent adaptations in patient management strategies across different COVID waves add complexity to our analysis, particularly as our data collection tools could not be updated to reflect these changes, omitting potentially significant factors like immunomodulatory treatments and vaccination impacts on thrombotic and hemorrhagic complications. Additionally, the case report forms did not define bleeding severity, which might have led to heterogeneous reporting of bleeding events.

Notably, our study found no link between thrombotic events and mortality, possibly due to the lack of a detailed thrombosis severity assessment and the inclusion of minor thrombotic events. Future research should aim for clear definitions and severity grading of hemorrhagic and thrombotic events to enhance understanding and management of these complications.

In an international registry for critically ill COVID-19 patients receiving ECMO, the incidence of bleeding and thrombotic complications were high, albeit lower than previously reported. Bleeding significantly elevated mortality risk, with multi-organ failure and sepsis as the primary causes of death. Factors such as older age and White ethnicity were associated with an increased incidence of bleeding. Extended ECMO duration corresponded with higher bleeding rates but did not affect the occurrence of thrombotic events.

Availability of data and materials

The datasets used and/ or analyzed during the current study are available from the corresponding author in reasonable request.

Abbreviations

Acute respiratory distress syndrome

Body mass index

COVID critical care consortium

Disseminated intravascular coagulation

Deep vein thrombosis

Extracorporeal membrane oxygenation

Intensive care unit

International severe acute respiratory and emerging infection consortium

Low molecular weight heparin

Polymerase chain reaction

Pulmonary embolism

Research electronic data capture

Severe acute respiratory syndrome coronavirus 2

Short-period incidence study of severe acute respiratory infection

Unfractionated heparin

Brodie D, Slutsky AS, Combes A. Extracorporeal life support for adults with respiratory failure and related indications: a review. JAMA. 2019;322(6):557–68.

Article PubMed Google Scholar

Combes A, Hajage D, Capellier G, et al. Extracorporeal membrane oxygenation for severe acute respiratory distress syndrome. N Engl J Med. 2018;378(21):1965–75.

Combes A, Price S, Slutsky AS, Brodie D. Temporary circulatory support for cardiogenic shock. Lancet. 2020;396(10245):199–212.

Dalton HJ, Reeder R, Garcia-Filion P, et al. Factors associated with bleeding and thrombosis in children receiving extracorporeal membrane oxygenation. Am J Respir Crit Care Med. 2017;196(6):762–71.

Article CAS PubMed PubMed Central Google Scholar

Nunez JI, Gosling AF, O’Gara B, et al. Bleeding and thrombotic events in adults supported with venovenous extracorporeal membrane oxygenation: an ELSO registry analysis. Intensive Care Med. 2022;48(2):213–24.

Article CAS PubMed Google Scholar

Trudzinski FC, Minko P, Rapp D, et al. Runtime and aPTT predict venous thrombosis and thromboembolism in patients on extracorporeal membrane oxygenation: a retrospective analysis. Ann Intensive Care. 2016;6(1):66.

Article PubMed PubMed Central Google Scholar

Doyle AJ, Hunt BJ. Current understanding of how extracorporeal membrane oxygenators activate haemostasis and other blood components. Front Med. 2018;5:352.

Article Google Scholar

Xu LC, Bauer JW, Siedlecki CA. Proteins, platelets, and blood coagulation at biomaterial interfaces. Colloids Surf B Biointerfaces. 2014;124:49–68.

Seelhammer TG, Bohman JK, Schulte PJ, Hanson AC, Aganga DO. Comparison of bivalirudin versus heparin for maintenance systemic anticoagulation during adult and pediatric extracorporeal membrane oxygenation. Crit Care Med. 2021;49(9):1481–92.

Zangrillo A, Landoni G, Biondi-Zoccai G, et al. A meta-analysis of complications and mortality of extracorporeal membrane oxygenation. Crit Care Resusc. 2013;15(3):172–8.

PubMed Google Scholar

Cui X, Zhao Z, Zhang T, et al. A systematic review and meta-analysis of children with coronavirus disease 2019 (COVID-19). J Med Virol. 2021;93(2):1057–69.

Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan. China JAMA Intern Med. 2020;180(7):934–43.

Lim ZJ, Subramaniam A, Ponnapa Reddy M, et al. Case fatality rates for patients with COVID-19 requiring invasive mechanical ventilation. A meta-analysis. Am J Respir Crit Care Med. 2021;203(1):54–66.

Zaaqoq AM, Barnett AG, Heinsar S, et al. Prone position during venovenous extracorporeal membrane oxygenation: survival analysis needed for a time-dependent intervention. Crit Care. 2022;26(1):39.

Supady A, Combes A, Barbaro RP, et al. Respiratory indications for ECMO: focus on COVID-19. Intensive Care Med. 2022;48(10):1326–37.

Ramanathan K, Shekar K, Ling RR, et al. Extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis. Crit Care. 2021;25(1):211.

Li Bassi G, Suen J, Barnett AG, et al. Design and rationale of the COVID-19 Critical Care Consortium international, multicentre, observational study. BMJ Open. 2020;10(12): e041417.

Peek GJ, Mugford M, Tiruvoipati R, et al. Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial. Lancet. 2009;374(9698):1351–63.

Gebhard CE, Zellweger N, Gebhard C, et al. Prone positioning as a potential risk factor for deep vein thrombosis in COVID-19 patients: a hypothesis generating observation. J Clin Med. 2021;11(1):103.

Wiegele M, Laxar D, Schaden E, et al. Subcutaneous enoxaparin for systemic anticoagulation of COVID-19 patients during extracorporeal life support. Front Med. 2022;9: 879425.

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Acknowledgements

We recognize the crucial importance of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) and Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) networks in developing and expanding the global Coronavirus Disease 2019 Critical Care Consortium (COVID-19– CCC). We thank the generous support we received from the Extracorporeal Life Support Organization and the International Extracorporeal Membrane Oxygenation Network. We owe Li Wenliang, MD from the Wuhan Central Hospital, an eternal debt of gratitude for reminding the world that doctors should never be censored during a pandemic. Finally, we acknowledge all members of the COVID-19–CCC and various collaborators.

Steering Committee

Gianluigi Li Bassi MD 1,3, 4,5, 7, 8 , PhD; Jacky Y. Suen BSc 1, 2 , PhD; Heidi J. Dalton MD, MCCM 9 ; John Laffey, MA, MD 10 ; Daniel Brodie, MD 11 ; Eddy Fan, MD, PhD 12 ; Antoni Torres, MD, PhD, FERS ATS Fellow 4, 13 36 37 ; Davide Chiumello, MD 14 ; Alyaa Elhazmi 15 ; Carol Hodgson, PT, PhD 16,31 ; Shingo Ichiba, MD 17 ; Carlos Luna, MD18; Srinivas Murthy, MD 19 ; Alistair Nichol, MD, PhD 16, 21,31 ; Pauline Yeung Ng, MD 22 ; Mark Ogino, MD 23 ; Eva Marwali, MD, PhD 35 ; Giacomo Grasselli MD 33, 34 , PhD; Robert Bartlett, MD 25 ; Aidan Burrell, MBBS, PhD 26,27 ; Muhammed Elhadi MBBCh 38 ; Anna Motos 39,40 ; Ferran Barbé MD, PhD 41,42 ; Alberto Zanella MD 33 ; and John F. Fraser MBChB, PhD, FRCP(Glas), FFARCSI, FRCA, FCICM 1, 3, 5, 7, 8 on behalf of the COVID-19 Critical Care Consortium.

Affiliations

1. Critical Care Research Group, The Prince Charles Hospital, Brisbane, Australia

2. Faculty of Medicine, The University of Queensland, Brisbane, Australia

3. University of Queensland, Brisbane, Australia

4. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

5. Queensland University of Technology, Brisbane, Australia

6. School of Public Health, Queensland University of Technology, Brisbane, Australia

7. St Andrew’s War Memorial Hospital, UnitingCare Hospitals, Brisbane Australia

8. Wesley Medical Research, Brisbane, Australia

9. INOVA Fairfax Medical Center, Heart and Vascular Institute, Falls Church VA, USA

10. Anaesthesia and Intensive Care Medicine, Galway University Hospitals, and School of Medicine, National University of Ireland, Galway, Ireland

11. Department of Medicine, Columbia University College of Physicians and Surgeons, New York-Presbyterian Hospital, NY, NY, USA

12. Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Canada

13. Servei de Pneumologia. Hospital Clinic de Barcelona, Barcelona, Spain

14. Ospedale San Paolo, Milan, Italy

15. Dr. Sulaiman Alhabib Medical Group—Research Center, Riyadh, Saudi Arabia

16. Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, Melbourne, Australia

17. Department of Clinical Engineering / Department of Intensive Care Medicine, Tokyo Women’s Medical University Hospital, Japan

18. División Neumonología, Hospital de Clínicas, UBA, Buenos Aires, Argentina

19. Department of Pediatrics, Faculty of Medicine, University of British Columbia, Vancouver, Canada

20. Australian and New Zealand Intensive Care Research Centre, Department of Epidemiology and Preventive Medicine, School of Public Health, Monash University, Melbourne, Australia

21. University College Dublin-Clinical Research Centre at St Vincent’s University Hospital, Dublin

22. Division of Respiratory and Critical Care Medicine, The University of Hong Kong, Hong Kong, China

23. Nemours Alfred I duPont Hospital for Children, Wilmington, DE, USA

24. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

25. University of Michigan Medical Center, Ann Arbor, Michigan, USA

26. Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

27. Department of Intensive Care and Hyperbaric Medicine, The Alfred Hospital, Melbourne, VIC, Australia.

28. Australian Centre for Health Services Innovation (AusHSI) and Centre for Healthcare Transformation, School of Public Health & Social Work, Queensland University of Technology (QUT), Brisbane, Queensland, Australia

29. Child Health Research Centre, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

30. ISARIC, Centre for Tropical Medicine and Global Health, University of Oxford, Oxford, UK

31. Department of Physiotherapy, Alfred Hospital, Melbourne, Australia

32. Department of Intensive Care, Alfred Hospital, Melbourne, Australia

33. Department of Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

34. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy

35. National Cardiovascular Center Harapan Kita, Jakarta, Indonesia

36. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

37. Centro de Investigación Biomédica en Red Enfermedades Respiratorias (CIBERES), Madrid, Spain

38. Faculty of Medicine, University of Tripoli, Tripoli, Libya

39. Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES), Barcelona, Spain.

40. Institut d'Investigacions August Pi i Sunyer (IDIBAPS), Barcelona, Universitat de Barcelona, Barcelona, Spain.

41. Translational Research in Respiratory Medicine, Respiratory Dept, Hospital Universitari Aranu de Vilanova and Santa Maria; IRBLleida, Lleida, Spain.

42. Centro de Investigación Biomedica En Red—Enfermedades Respiratorias (CIBERES), Barcelona, Spain

43. School of Medicine, Griffith University, Brisbane, Australia

The Bill & Melinda Gates Foundation, Grant number INV-034765; Queensland Health; The Prince Charles Hospital Foundation; The Wesley Medical Research; Fisher & Paykel Healthcare; The University of Queensland; The Health Research Board of Ireland. Jacky Y Suen is funded by the Advance Queensland fellowship program, Queensland Government, Australia. Gianluigi Li Bassi is a recipient of the BITRECS fellowship; the “BITRECS” project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 754550 and from the “La Caixa” Foundation (ID 100010434), under the agreement LCF/PR/GN18/50310006.

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Department of Anesthesiology, Intensive Care Medicine, Emergency Medicine, and Pain Medicine, German Armed Forces Hospital Ulm, Ulm, Germany

Maximilian Feth

Queensland University of Technology, Brisbane, QLD, Australia

Natasha Weaver & Nicole White

School of Medicine and Public Health, The University of Newcastle, New South Wales, Australia

Natasha Weaver

St. Vincent’s Hospital, Melbourne, VIC, Australia

Robert B. Fanning

Faculty of Medicine, University of Melbourne, Victoria, Australia

Division of Cardiac Surgery, Department of Surgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

Sung-Min Cho, Glenn J. R. Whitman & Bo S. Kim

Division of Neuroscience Critical Care, Department of Neurology and Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA

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Department of Anesthesiology and Perioperative Medicine, Sections of Critical Care and Perioperative Echocardiography, University of Utah, Salt Lake City, UT, USA

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Anesthesiology Service, Veteran Affairs Medical Center, Salt Lake City, UT, USA

Department of Anesthesia, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico Di Milano, Intensive Care and Emergency, Milano, Lombardia, Italy

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Department of Anaesthesiology, Division of Critical Care Medicine, University of Virginia, Charlottesville, VA, USA

Akram M. Zaaqoq

Medical Intensive Care Unit, Department of Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar

Ahmed Labib

Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA

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Case Western Reserve University School of Medicine, Cleveland, OH, USA

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Jacky Y. Suen, Gianluigi Li Bassi, John F. Fraser & Jonathon P. Fanning

Faculty of Medicine, University of Queensland, Brisbane, Australia

Jacky Y. Suen, John F. Fraser & Jonathon P. Fanning

Intensive Care Unit, St Andrew’s War Memorial Hospital, UnitingCare Health, Spring Hill, QLD, Australia

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Congenital Heart Centre, University of Florida, Gainesville, FL, USA

Giles J. Peek

Cardiothoracic Surgery Department, Heart and Vascular Centre, Maastricht University Medical Centre, and Cardiovascular Research Institute Maastricht, Maastricht, Netherlands

Roberto Lorusso

Heart and Vascular Institute, Inova Fairfax Hospital, Falls Church, VA, USA

Heidi Dalton

Nuffield Department of Population Health, University of Oxford, Oxford, UK

Jonathon P. Fanning

The George Institute for Global Health, Sydney, NSW, Australia

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Gianluigi Li Bassi
, Jacky Y. Suen
, Heidi J. Dalton
, John Laffey
, Daniel Brodie
, Antoni Torres
, Davide Chiumello
, Alyaa Elhazmi
, Carol Hodgson
, Shingo Ichiba
, Carlos Luna
, Srinivas Murthy
, Alistair Nichol
, Pauline Yeung Ng
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, Giacomo Grasselli
, Robert Bartlett
, Aidan Burrell
, Muhammed Elhadi
, Anna Motos
, Ferran Barbé
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& John F. Fraser

Contributions

Study concept and design: Jonathon P. Fanning, Maximilian Feth, Gianluigi Li Bassi, Jacky Y. Suen, John F. Fraser, Acquisition, analysis, or interpretation of data: Maximilian Feth, Jonathon P. Fanning, Robert B. Fanning, Natasha Weaver Statistical analysis: Natasha Weaver, Nicole White Tables and figures: Natasha Weaver, Maximilian Feth, Jonathon P. Fanning, First drafting of the manuscript: Maximilian Feth, Jonathon Fanning. Critical revision for important intellectual content and final approval of the manuscript: Maximilian Feth, Jonathon P. Fanning, Natasha Weaver, Robert B. Fanning, Matthew J. Griffee, MD, Sung-Min Cho, Mauro Panigada, Akram M. Zaaqoq, Yew Woon Chia, Bingwen Eugene Fan, Davide Chiumello, Silvia Coppola, Ahmed Labib, Glenn JR Whitman, Rakesh C. Arora, Bo S. Kim, Anna Motos, Nicole White, Jacky Suen, Gianluigi Li Bassi, Roberto Lorusso, John F. Fraser, Giles J. Peek, Heidi Dalton. Guarantors: Maximilian Feth, Jonathon P. Fanning.

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The rationale and design have been previously published (Trial registration ACTRN12620000421932) [ 17 ]. Institutional Review Board (IRB) approval was obtained for each participating institution. A waiver of informed consent was granted for all patients.

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Competing interests

This study was supported by the COVID-19 Critical Care Consortium.

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Feth, M., Weaver, N., Fanning, R.B. et al. Hemorrhage and thrombosis in COVID-19-patients supported with extracorporeal membrane oxygenation: an international study based on the COVID-19 critical care consortium. j intensive care 12 , 18 (2024). https://doi.org/10.1186/s40560-024-00726-2

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Published : 06 May 2024

DOI : https://doi.org/10.1186/s40560-024-00726-2

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Case Report
Open access
Published: 04 May 2024

Intracranial residual lesions following early intensification in a patient with T-cell acute lymphoblastic leukemia: a case report

Yuichi Nagamatsu 1 ,
Takeshi Isoda 1 , 8 ,
Motoki Inaji 2 ,
Jun Oyama 3 ,
Daiki Niizato 1 ,
Dan Tomomasa 1 ,
Noriko Mitsuiki 1 ,
Motoi Yamashita 1 ,
Takahiro Kamiya 4 ,
Kohsuke Imai 5 , 6 ,
Hirokazu Kanegane 7 ,
Tomohiro Morio 1 &
Masatoshi Takagi 5

BMC Pediatrics volume 24 , Article number: 304 ( 2024 ) Cite this article

85 Accesses

Metrics details

T-cell acute lymphoblastic leukemia (T-ALL) tends to involve central nervous system (CNS) infiltration at diagnosis. However, cases of residual CNS lesions detected at the end of induction and post early intensification have not been recorded in patients with T-ALL. Also, the ratio and prognosis of patients with residual intracranial lesions have not been defined.

Case presentation

A 9-year-old boy with T-ALL had multiple intracranial tumors, which were still detected post early intensification. To investigate residual CNS lesions, we used 11 C-methionine (MET)-positron emission tomography. Negative MET uptake in CNS lesions and excellent MRD status in bone marrow allowed continuing therapies without hematopoietic cell transplantation.

Conclusions

In cases with residual lesions on imaging studies, treatment strategies should be considered by the systemic response, direct assessment of spinal fluid, along with further development of noninvasive imaging methods in CNS. Further retrospective or prospective studies are required to determine the prognosis and frequency of cases with residual intracranial lesions after induction therapy.

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Leukemia is the most common cancer in children and the involvement of the central nervous system (CNS) increases the risk of CNS relapse [ 1 ]. Risk factors of CNS leukemia include infant onset, T-cell acute lymphoblastic leukemia (T-ALL), hyperleukocytosis, and chromosomal abnormalities including KMT2A rearrangements, BCR-ABL1 , and TCF3-PBX1 [ 1 , 2 ]. These features as well as a traumatic tap at initial diagnosis also increase the risk of CNS relapse in ALL [ 1 , 2 , 3 ].

CNS status at initial diagnosis is classified as follows: CNS1, no leukemic cells in cerebrospinal fluid; CNS2, white blood cell (WBC) counts < 5/µL with leukemic cells; CNS3, WBC counts ≥ 5/µL with leukemic cells or neurological symptoms with imaging findings by computed tomography (CT) or magnetic resonance imaging (MRI) [ 4 ]. MRI is helpful to diagnose CNS leukemia in patients with neurological symptoms [ 5 , 6 ]. The percentage of CNS3 leukemia with neurological symptoms and imaging findings in newly diagnosed ALL was estimated to be less than a few percent [ 1 , 5 ].

Residual masses present in the CNS after induction or consolidation therapy are considered treatment failure (TF) [ 7 ]. TF affects later therapies, such as the decision to withdraw from protocol therapy and whether patients proceed to allogeneic hematopoietic cell transplantation (HCT) [ 7 , 8 ]. The percentage of pediatric patients with induction failure (IF), defined by leukemic cells in bone marrow (BM) or extramedullary site after induction, was 2.4% (1041/44,017 cases) [ 8 ]. Among the 1041 cases, CNS status was available for 684 cases. Of these, CNS leukemia accounted for 6% (44/684) [ 8 ]. However, the ratio and prognosis of patients with isolated CNS residual masses by imaging have not been defined.

Here, we report a patient with T-ALL who developed multiple intracranial masses at diagnosis and had remaining residual lesions detected by follow-up MRI at the end of early intensification. We decided treatment strategy based on minimal residual disease (MRD) status in BM, assessment of spinal fluid, and whether 11 C-methionine (MET) uptake in these CNS residual lesions.

A 9-year-old boy was introduced to our hospital with somnolence, slurred speech, and petechiae. A complete blood count showed marked hyperleukocytosis (WBC 760 000/μL). Flow cytometric analysis showed positivity for CD1a, CD2, CD4, CD5, CD7, CD8, cytoplasmic CD3, and terminal deoxynucleotidyl transferase. G-banding revealed a normal karyotype and multiplex polymerase chain reaction (PCR) analysis did not detect fusion genes. Taken together, we diagnosed him with T-ALL. MRI revealed multiple intracranial masses with strong signal heterogeneity consisting of hemorrhage and leukemic infiltrations, which were consistent with definition of CNS3 (Fig. 1 A and B).

Multiple central nervous system infiltrations with hemorrhages on magnetic resonance images (MRI). A and B T2-weighted and T2*-weighted image (T2*WI) MRI shows heterogeneous signals with leukemic masses and hemorrhages. Edema is observed around multiple lesions

We started pre-phase therapy consisting of prednisolone (PSL) in accordance with the Japan Leukemia/Lymphoma Study Group T11 protocol (Fig. 2 A) [ 9 ]. The number of lymphoblasts steadily decreased to 26 (< 1000)/μL in peripheral blood on day 8, and he was considered a PSL good responder (PGR) (Fig. 2 A) [ 9 ]. There was no tumor lysis syndrome under the supportive therapy including hydration and rasburicase administration. His initial symptoms including somnolence and slurred speech gradually improved a week after starting corticosteroid. On day 8, we conducted initial intrathecal therapy (IT). Lumbar puncture (LP) showed a WBC count of 2/µL with mild cellular atypia by conventional cytospin. We completed the induction phase without intracranial hemorrhage. However, the patient had grade 3 hyponatremia due to cerebral salt wasting syndrome, and required additional sodium chloride supplementation by infusion for two weeks. On day 29, he also had grade 3 muscle weakness lower limb due to vincristine or corticosteroid myopathy and skipped vincristine once.

Treatment course, serial MRI, and 11C-methionine (MET) positron emission tomography (PET). A The Japan Leukemia/Lymphoma Study Group (JPLSG) T11 high-risk protocol with treatment response and CNS evaluation by imaging studies. B T2-weighted MRI showed residual multiple lesions at the end of induction. C At the end of early intensification, T2-weighted MRI shows two representative residual lesions at the same position as in ( B ). No significant MET uptake was detected. Scale bar indicates the standardized uptake value (SUV). D MRI images were captured two months after maintenance therapy. BL, blast; BMA, bone marrow analysis; CNS, central nervous system; CRT, cranial radiation therapy; HR, high risk; MET-PET, 11 C-methionine positron emission tomography; MRD, minimal residual disease; NEL, nelarabine; IT, intrathecal; PSL, prednisolone

After day 18 of induction therapy, LP showed no evidence of malignant cells by cytospin. We did not perform flow cytometry analysis for spinal fluid in this case. The minimal residual disease (MRD) determined by PCR to monitor BM responses showed a reduction in lymphoblasts below 0.001% after induction therapy (Fig. 2 A). However, MRI revealed multiple CNS masses (Fig. 2 B). PCR-MRD for BM samples was maintained below 0.001%; however, MRI still showed multiple CNS lesions post early intensification (Fig. 2 C).

To avoid invasive approaches, including needle biopsy or surgical resection, which might cause delaying further intensification therapies, we used 11 C-methionine positron emission tomography (MET-PET) to investigate the activity of the residual lesions. MET-PET revealed no significant uptake, suggesting the low possibility of viable leukemic cells in residual regions (Fig. 2 C). Thus, we classified him as belonging to a high-risk group, but not a very high-risk group requiring HCT, and he received continued chemotherapy including intensive IT, nelarabine, and cranial radiation therapy (CRT) in accordance with the T11 protocol [ 9 ]. The follow-up MRI revealed remission immediately after the maintenance therapy (Fig. 2 D). At 18 months from the cessation of maintenance therapy and 46 months from onset, he has maintained a first remission and can attend regular school without neurological sequelae.

Discussion and conclusions

We experienced a patient with T-ALL who showed multiple residual lesions in the CNS at the end of early intensification. PGR, good PCR-MRD status in BM, and no specific uptake of MET in the CNS allowed a continuation of chemotherapy with CRT, and the avoidance of HCT.

A meta-analysis of hematologic tumors, including pediatric to adult cases with intracranial sarcomas, reported 82 cases from 1999 to 2019 [ 10 ]. The report included 66 cases of AML, 10 cases of CML, 5 cases of APL, and 4 cases of ALL. Among them, three patients with ALL were relapsed cases [ 10 ]. Only two reports showed residual intracranial lesions after the start of treatment in primary ALL, both of which were Philadelphia chromosome positive ALL [ 11 , 12 ]. The prognosis and appropriate treatment for cases of isolated residual CNS masses with excellent treatment responses in the non-CNS region have not been established because of the rarity of these cases.

The prognosis of IF in T-ALL was worse than that of B-ALL, with 10-year survival rates of 28 ± 3% and 41 ± 3%, respectively [ 8 ]. Historically, radiation therapy is beneficial for high-risk groups with T-ALL. The omission of prophylactic CRT in the T-ALL and CNS3 groups has not been established. Patients with CNS3 in the T-ALL group were ineligible in the recent AALL0434 study [ 13 ]. Taken together, chemotherapy with CRT was appropriate for our patient, even with negative MET uptake and good responses in the BM.

18 F-fluorodeoxyglucose (FDG) is involved in glucose transport in tumors and noncancerous lesions including infections, inflammation, and the brain, especially the grey matter. Instead, MET has greater specificity for brain tumors using large amino acid transporter 2 [ 14 ]. MET-PET was developed to detect brain tumors including gliomas [ 14 , 15 , 16 ]. Compared with FDG, MET has an equivalent uptake in children with Hodgkin lymphoma and non-Hodgkin lymphoma at diagnosis and follow-up [ 17 ]. Interim PET has been feasible for evaluating T-lymphoblastic lymphoma [ 18 ]. Furthermore, MET-PET has been used to determine treatment responses in CNS lymphoma [ 19 , 20 ]. Seo-Yeon et al. showed three response patterns correlated with prognosis, including low-, intermediate-, and high-risk, based on the interim tumor-to-normal tissue (T/N) ratio by MET uptake [ 19 ]. The interim T/N ratio in our patient was equivalent to the low-risk category, suggesting the low possibility of viable tumors in residual lesions.

However, there were limitations to this study. We could not perform MET-PET at onset due to his poor initial condition. If the lesion is small-scale or has low uptake of MET, it is difficult to distinguish the viability of residual tumor, which should be judged comprehensively in conjunction with other modalities. Thus, other clinical responses should be taken into account when decision-making. Finally, careful follow-up is required for our patient.

In conclusion, we experienced a patient with T-ALL and multiple residual lesions in the CNS at the end of early intensification. Further retrospective or prospective studies are required to determine the frequency of cases with intracranial residual lesions after induction therapy.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Abbreviations

Acute lymphoblastic leukemia

Acute myeloid leukemia

Acute promyelocytic leukemia

Bone marrow

Chronic myelogenous leukemia

Central nervous system

Cranial radiation therapy

Fluorodeoxyglucose

Hematopoietic cell transplantation

Induction failure

Intrathecal

Lumbar puncture

Minimal residual disease

Magnetic resonance imaging

Positron emission tomography

Polymerase chain reaction

Prednisolone good responder

Prednisolone

Treatment failure

White blood cells

Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–68.

Article PubMed Google Scholar

Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360(26):2730–41.

Article CAS PubMed PubMed Central Google Scholar

Bürger B, Zimmermann M, Mann G, Kühl J, Löning L, Riehm H, et al. Diagnostic cerebrospinal fluid examination in children with acute lymphoblastic leukemia: significance of low leukocyte counts with blasts or traumatic lumbar puncture. J Clin Oncol. 2003;21(2):184–8.

Mahmoud HH, Rivera GK, Hancock ML, Krance RA, Kun LE, Behm FG, et al. Low leukocyte counts with blast cells in cerebrospinal fluid of children with newly diagnosed acute lymphoblastic leukemia. N Engl J Med. 1993;329(5):314–9.

Article CAS PubMed Google Scholar

Ranta S, Palomäki M, Levinsen M, Taskinen M, Abrahamsson J, Mellgren K, et al. Role of neuroimaging in children with acute lymphoblastic leukemia and central nervous system involvement at diagnosis. Pediatr Blood Cancer. 2017;64(1):64–70.

Ulu EM, Töre HG, Bayrak A, Güngör D, Coşkun M. MRI of central nervous system abnormalities in childhood leukemia. Diagn Interv Radiol. 2009;15(2):86–92.

PubMed Google Scholar

Buchmann S, Schrappe M, Baruchel A, Biondi A, Borowitz M, Campbell M, et al. Remission, treatment failure, and relapse in pediatric ALL: an international consensus of the Ponte-di-Legno Consortium. Blood. 2022;139(12):1785–93.

Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366(15):1371–81.

Sato A, Hatta Y, Imai C, Oshima K, Okamoto Y, Deguchi T, et al. Nelarabine, intensive L-asparaginase, and protracted intrathecal therapy for newly diagnosed T-cell acute lymphoblastic leukaemia in children and young adults (ALL-T11): a nationwide, multicenter, phase 2 trial including randomisation in the very high-risk group. Lancet Haematol. 2023;10(6):e419–32.

Lee D, Omofoye OA, Nuño MA, Riestenberg RA, Shahlaie K. Treatment outcomes of intracranial myeloid sarcomas: a meta-analysis. World Neurosurg. 2021;148:29–37.

Cuvelier GD, Vitali AM, Ford JC, Dix DB. Multiple intracranial tumors in Philadelphia chromosome positive acute lymphoblastic leukemia: successful treatment following aggressive supportive care, early cranial radiation, high dose chemotherapy and imatinib. Pediatr Blood Cancer. 2008;51(1):135–7.

Hatakeyama N, Hori T, Yamamoto M, Inazawa N, Igarashi K, Tsutsumi H, et al. Multiple intracranial tumors in Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2013;97(4):441–2.

Hayashi RJ, Winter SS, Dunsmore KP, Devidas M, Chen Z, Wood BL, et al. Successful outcomes of newly diagnosed T lymphoblastic lymphoma: results from Children’s Oncology Group AALL0434. J Clin Oncol. 2020;38(26):3062–70.

Article PubMed PubMed Central Google Scholar

Glaudemans AWJM, Enting RH, Heesters MAAM, Dierckx RAJO, van Rheenen RWJ, Walenkamp AME, et al. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur J Nucl Med Mol Imaging. 2013;40(4):615–35.

Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, et al. Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma. J Neurosurg. 2005;103(3):498–507.

Nakano T, Tamura K, Tanaka Y, Inaji M, Hayashi S, Kobayashi D, et al. Usefulness of (11)C-methionine positron emission tomography for monitoring of treatment response and recurrence in a glioblastoma patient on bevacizumab therapy: a case report. Case Rep Oncol. 2018;11(2):442–9.

Kaste SC, Snyder SE, Metzger ML, Sandlund JT, Howard SC, Krasin M, et al. Comparison of (11)C-methionine and (18)F-FDG PET/CT for staging and follow-up of pediatric lymphoma. J Nucl Medicine : official publication, Society of Nuclear Medicine. 2017;58(3):419–24.

Article Google Scholar

Gökbuget N, Wolf A, Stelljes M, Hüttmann A, Buss EC, Viardot A, et al. Favorable outcome in a large cohort of prospectively treated adult patients with T-lymphoblastic lymphoma (T-LBL) despite slowly evolving complete remission assessed by conventional radiography. Blood. 2014;124(21):370.

Ahn SY, Kwon SY, Jung SH, Ahn JS, Yoo SW, Min JJ, et al. Prognostic significance of interim 11C-methionine PET/CT in primary central nervous system lymphoma. Clin Nucl Med. 2018;43(8):e259–64.

Miyakita Y, Ohno M, Takahashi M, Kurihara H, Katai H, Narita Y. Usefulness of carbon-11-labeled methionine positron-emission tomography for assessing the treatment response of primary central nervous system lymphoma. Jpn J Clin Oncol. 2020;50(5):512–8.

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Acknowledgements

We thank the patient and his parents for participating in this study. We also thank the staff at the Department of Pediatrics, Tokyo Medical and Dental University. We thank J. Ludovic Croxford, PhD, from Edanz ( https://jp.edanz.com/ac ) for editing a draft of this manuscript.

This work was supported in part by JSPS KAKENHI Grant Number (21H02878) and Takeda Science Foundation to TI.

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Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan

Yuichi Nagamatsu, Takeshi Isoda, Daiki Niizato, Dan Tomomasa, Noriko Mitsuiki, Motoi Yamashita & Tomohiro Morio

Department of Neurosurgery, Tokyo Medical and Dental University, Tokyo, Japan

Motoki Inaji

Department of Diagnostic Radiology, Tokyo Medical and Dental University, Tokyo, Japan

Department of Clinical Research Center, Tokyo Medical and Dental University, Tokyo, Japan

Takahiro Kamiya

Department of Community Pediatrics, Perinatal and Maternal Medicine, Tokyo Medical and Dental University, Tokyo, Japan

Kohsuke Imai & Masatoshi Takagi

Department of Pediatrics, National Defense Medical College, Tokorozawa, Japan

Kohsuke Imai

Department of Child Health and Development, Tokyo Medical and Dental University, Tokyo, Japan

Hirokazu Kanegane

Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

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Contributions

Conception and design of study: all authors. Acquisition of data: YN, TI, MI, JO, DN, DT, NM, MY, TK. Performing MET-PET: MI. Radiographic reading: JO. Analysis and/or interpretation of data: all authors. Drafting the manuscript: YN, TI, MI, JO, HK. Revising the manuscript critically for important intellectual content: all authors. Approval of the version of the manuscript to be published: all authors.

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The JPLSG T11 protocol was approved by the ethics boards of Tokyo Medical and Dental University.

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Nagamatsu, Y., Isoda, T., Inaji, M. et al. Intracranial residual lesions following early intensification in a patient with T-cell acute lymphoblastic leukemia: a case report. BMC Pediatr 24 , 304 (2024). https://doi.org/10.1186/s12887-024-04790-3

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Received : 17 February 2023

Accepted : 25 April 2024

Published : 04 May 2024

DOI : https://doi.org/10.1186/s12887-024-04790-3

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