This case series examines whether interleukin 7 (IL-7) is associated with restored host protective immunity in patients with severe coronavirus disease 2019 (COVID-19) and immunosuppression

Collienne, Christine

François, Bruno

Hantson, Philippe

Hotchkiss, Richard S

Jeannet, Robin

Laterre, Pierre Francois

Remy, Kenneth E

English

Laterre, Pierre-François

DIAL UCLouvain

Association of Interleukin 7 Immunotherapy With Lymphocyte Counts Among Patients With Severe Coronavirus Disease 2019 (COVID-19).

Digital Commons@Becker

Washington University School of Medicine Digital Commons@Becker Open Access Publications 7-1-2020 Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19) Pierre Francois Laterre Bruno François Christine Collienne Philippe Hantson Robin Jeannet See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Authors Pierre Francois Laterre, Bruno François, Christine Collienne, Philippe Hantson, Robin Jeannet, Kenneth E. Remy, and Richard S. Hotchkiss Research Letter | Infectious DiseasesAssociation of Interleukin 7 Immunotherapy With Lymphocyte CountsAmong Patients With Severe Coronavirus Disease 2019 (COVID-19)Pierre Francois Laterre, MD; Bruno François, MD; Christine Collienne, MD; Philippe Hantson, MD, PhD; Robin Jeannet, PhD;Kenneth E. Remy, MD; Richard S. Hotchkiss, MDIntroductionCytokine storm–mediated organ injury continues to dominate current thinking as the primarymechanism for coronavirus disease 2019 (COVID-19). Although there is an initial hyper-inflammatoryphase, mounting evidence suggests that virus-induced defective host immunity may be the realcause of death in many patients.1,2COVID-19 has been called a serial lymphocyte killer because profound and protractedlymphopenia is a near uniform finding among patients with severe COVID-19 and correlates withmorbidity and mortality.1,3 Autopsies demonstrate a devastating depletion of lymphocytes in thespleen and other organs.2 CD4, CD8, and natural killer cells, which play important antiviral roles, aredepleted and have reduced function, leading to immune collapse.1Clinical and pathological findings in patients with COVID-19 indicate that immunosuppression isa critical determinant of outcomes. Secondary hospital-acquired infections occur in 50% of patientswho die.1 Cell inclusion bodies, consistent with viral persistence, have been found in lungs, kidneys,and other organs.1,2 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specificquantitative polymerase chain reaction has revealed viral load in the lungs of most patients atautopsy, consistent with an inability to eliminate the pathogen.1,2 Collectively, these studies indicatethat impaired immune competence is an important pathogenic mechanism in COVID-19.Interleukin 7 (IL-7) is a pleiotropic cytokine essential for lymphocyte survival and expansion.4,5Administration of IL-7 invariably increases circulating and tissue lymphocytes and has beenadministered to more than 450 patients with an excellent safety profile.4,5 IL-7 is currently in multiplerandomized clinical trials for oncologic and infectious disorders, and a trial in the United Kingdom isevaluating its use among patients with severe COVID-19. Importantly, IL-7 has documented efficacyas an antiviral agent.4,5 IL-7 therapy has been shown to restore lymphocyte counts and functionalactivity, leading to decreased viral load and clinical improvement in several life-threating viralinfections.4,5 It has been shown to increase CD4 and CD8 T-cells 3-fold, to improve T-cell activation,to not increase proinflammatory cytokines, and to be well tolerated in patients with bacterial sepsis.6Thus, a compelling scientific rationale exists for examining whether IL-7 is associated with restoredhost protective immunity in patients with COVID-19 and immunosuppression and improveoutcomes.1MethodsIn this case series, IL-7 was approved by the Ethics Committee of St Luc University Hospital (Brussels,Belgium) for compassionate use in 12 critically ill patients with COVID-19 and severe lymphopeniawho had 2 consecutive absolute lymphocyte counts of less than 700/μL (to convert to ×109 permicroliter, mutliply by 0.001). Patients provided written informed consent. This study followed theAppropriate Use and Reporting of Uncontrolled Case Series in the Medical Literature reporting guidelinefor case series. An initial safety dose of 3 μg/kg was followed by a dose of 10 μg/kg by intramuscularinjection twice a week for 2 weeks. A total of 13 patients with COVID-19 who received standard-of-caretreatment and were matched to severity of illness, comorbidities, and other factors were included asa comparator control cohort to the IL-7 treatment group.Author affiliations and article information arelisted at the end of this article.Open Access. This is an open access article distributed under the terms of the CC-BY License.JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485 (Reprinted) July 22, 2020 1/5Downloaded From: https://jamanetwork.com/ by a Washington University - St Louis User  on 08/31/2020Data were analyzed using a mixed-effects model with repeated measures and theautoregression 1 covariance structure. The logs of the absolute lymphocyte scores were usedbecause they provided a better fit to the model. The associations of group, study day, and the groupby study day interaction were all significant. Statistical analyses were conducted in SAS version 9.4(SAS Institute). Statistical significance was set at P < .05, and all tests were 2-tailed.ResultsThe 12 patients in the IL-7 group had a mean (range) age of 62 (48-76) years, and 11 (92%) were men.The 13 patients in the control group had a mean (range) age of 59 (42-83) years, and 9 (69%) weremen (Table). No observed treatment-associated adverse effects were noted, and IL-7 was welltolerated without inducing changes in temperature, blood pressure, or PaO2:FiO2 ratio (Figure).Plasma proinflammatory cytokines were measured before and at 7 and 24 hours after IL-7administration to determine whether IL-7 induced hyper-cytokinemia. Administration of IL-7 was notassociated with changes in tumor necrosis factor α, IL-1β, and IL-12p70 concentrations, which werebelow the level of detection at all time points in all patients. There was no consistent association ofIL-7 administration with IL-6 concentration. Overall, 3 patients (25%) had decreases in IL-6concentrations and 2 patients (17% ) had increases in IL-6 concentration of approximately 1000 to1500 pg/mL at 7 hours after administration of IL-7, suggesting that these changes in IL-6concentration may have been because of changes in the underlying patient physiologic state ratherthan because of IL-7. At day 30, secondary infections occurred in 7 patients (58%) in the IL-7 groupcompared with 11 (85%) in the control group; 30-day mortality was 42% (5) and 46% (6),respectively (Table). IL-7 was associated with a restored lymphocyte count, with the IL-7 grouphaving levels more than 2-fold greater than the control group (mean [SE], 1734/μL [227/μL] vs885/μL [239/μL]; P = .02) (Figure).DiscussionThe findings of this study suggest that IL-7 can be safely administered to critically ill patients withCOVID-19 without exacerbating inflammation or pulmonary injury. IL-7 was associated withTable. Patient CharacteristicsCharacteristicNo. (%)IL-7 group (n = 12) Control group (n = 13)Age, mean (range), y 62 (48-76) 59 (42-83)SexWomen 1 (8) 4 (31)Men 11 (92) 9 (69)BMI, mean (range) 25.13 (0-33.95) 27.33 (21.42-37.37)ComorbiditiesHypertension 6 (50) 6 (46)Diabetes 2 (17) 2 (15)Cardiopathy 2 (17) 2 (15)Other 6 (50) 8 (62)APACHE II score, mean (range) 14 (9-20) 13 (7-16)SOFA score, mean (range) 5 (4-7) 4 (2-5)Worst PaO2:FiO2 ratio, mean (range) 89 (49-182) 83 (54-180)CRP at admission, mean (range), mg/dL 20.1 (0.74-42.3) 1.98 (0.33-48.0)Time from ICU admission to intubation, mean (range), d 3 (0-8) 3 (0-9)aSecondary infection(s) 7 (58) 11 (85)30-day mortality 5 (42) 6 (46)Abbreviations: APACHE, Acute Physiology and ChronicHealth Evaluation; BMI, body mass index (calculatedas weight in kilograms divided by height in meterssquared); CRP, C-reactive protein; ICU, intensive careunit; SOFA, Sequential Organ Failure Assessment.SI conversion factor: To convert CRP to mg/L, multiplyby 10.a 1 of 13 patients was never intubated.JAMA Network Open | Infectious Diseases Interleukin 7 Immunotherapy and Lymphocyte Counts Among Patients With Severe COVID-19JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485 (Reprinted) July 22, 2020 2/5Downloaded From: https://jamanetwork.com/ by a Washington University - St Louis User  on 08/31/2020Figure. Association of Interleukin 7 (IL-7) With Absolute Lymphocyte Count, Body Temperature,and PaO2:FiO2 Ratio25002000150010005000Lymphocytes, No.Study dayLymphocyte count in patients in IL-7 and control groupsA0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30450035004000300025005001000150020000Lymphocytes, No.Study dayLymphocyte count in survivors vs nonsurvivorsB0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 303938373635Body temperature, °CStudy dayBody temperature in patients in IL-7 and control groupsC0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30250150100200500Pao 2:Fio2 ratioStudy dayPao2:Fio2 ratio in patients in IL-7 and control groupsD0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30IL-7ControlIL-7ControlIL-7ControlIL-7 survivorsIL-7 nonsurvivorsControl survivorsControl nonsurvivorsIL-7 was administered at 3 μg/kg on day 1 and at 10μg/kg at days 2, 5, 8, and 12. Points indicate means,and whiskers indicate SEs.JAMA Network Open | Infectious Diseases Interleukin 7 Immunotherapy and Lymphocyte Counts Among Patients With Severe COVID-19JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485 (Reprinted) July 22, 2020 3/5Downloaded From: https://jamanetwork.com/ by a Washington University - St Louis User  on 08/31/2020lymphocytes returning to a reference level, appearing to reverse a pathologic hallmark of COVID-19.Importantly, previous studies have reported that IL-7–associated restoration of lymphocyte numbersenhanced the activity of antiviral agents.6 A limitation of the current study is that no phenotypic orfunctional studies of immune cells were conducted. Administration of IL-7 alone or in combinationwith other therapies warrants serious consideration for patients with COVID-19 and evidence ofimmunosuppression.ARTICLE INFORMATIONAccepted for Publication: June 30, 2020.Published: July 22, 2020. doi:10.1001/jamanetworkopen.2020.16485Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Laterre PFet al. JAMA Network Open.Corresponding Author: Pierre Francois Laterre, MD, Department of Critical Care Medicine, Saint Luc UniversityHospital, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium (pierre-francois.laterre@uclouvain.be).Author Affiliations: Department of Critical Care Medicine, Saint Luc University Hospital, Université Catholique deLouvain, Brussels, Belgium (Laterre, Collienne, Hantson); Intensive Care Unit Department and Inserm CentreInvestigation Clinique 1435 and Unité Mixte de Recherche 1092, University Hospital of Limoges, Limoges, France(François); Department of Intensive Care Medicine and Anaesthesiology, University Hospital of Limoges, Limoges,France (Jeannet); Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis,Missouri (Remy); Department of Anesthesiology and Critical Care Medicine, Washington University School ofMedicine in St Louis, St Louis, Missouri (Remy, Hotchkiss); Department of Medicine, Washington University Schoolof Medicine in St Louis, St Louis, Missouri (Remy, Hotchkiss); Department of Surgery, Washington UniversitySchool of Medicine in St Louis, St Louis, Missouri (Hotchkiss).Author Contributions: Drs Laterre and Hotchkiss had full access to all of the data in the study and takeresponsibility for the integrity of the data and the accuracy of the data analysis.Concept and design: Laterre, François, Remy, Hotchkiss.Acquisition, analysis, or interpretation of data: Collienne, Hantson, Jeannet, Remy, Hotchkiss.Drafting of the manuscript: Hantson, Remy, Hotchkiss.Critical revision of the manuscript for important intellectual content: Laterre, François, Collienne, Jeannet, Remy,Hotchkiss.Statistical analysis: Remy.Administrative, technical, or material support: Collienne, Jeannet, Remy, Hotchkiss.Supervision: Laterre, Hantson, Remy.Conflict of Interest Disclosures: Dr Hotchkiss reported being an investigator on a sepsis study evaluatinginterleukin 7 and receiving grants from the National Institutes of Health outside the submitted work. No otherdisclosures were reported.Funding/Support: Dr Hotchkiss was supported by grant GM126928 from the National Institute of GeneralMedicine Sciences. RevImmune provided recombinant human interleukin 7 to the investigators.Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.Additional Contributions: Michael Morre, DVM (RevImmune), provided the original inspiration for the use ofinterleukin 7 in the management of coronavirus disease 2019 to treat the lymphopenia, a hallmark of the disorder,and was an invaluable resource for important questions on interleukin 7. Teresa Blood, AB (Department ofAnesthesiology, Washington University School of Medicine), helped perform data analysis. Lyle Moldawer, PhD(Department of Surgery, University of Florida Gainesville), assisted with review of the manuscript. Manu Shankar-Hari PhD, MD (School of Immunology and Microbial Sciences, Kings College), assisted with data analysis andmanuscript review. They were not compensated for their time.REFERENCES1. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. J Exp Med. 2020;217(6):217.doi:10.1084/jem.20200678JAMA Network Open | Infectious Diseases Interleukin 7 Immunotherapy and Lymphocyte Counts Among Patients With Severe COVID-19JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485 (Reprinted) July 22, 2020 4/5Downloaded From: https://jamanetwork.com/ by a Washington University - St Louis User  on 08/31/20202. Menter T, Haslbauer JD, Nienhold R, et al. Post-mortem examination of COVID19 patients reveals diffusealveolar damage with severe capillary congestion and variegated findings of lungs and other organs suggestingvascular dysfunction. Histopathology. Published May 4, 2020. doi:10.1111/his.141343. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061-1069. doi:10.1001/jama.2020.15854. Mackall CL, Fry TJ, Gress RE. Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol. 2011;11(5):330-342. doi:10.1038/nri29705. Barata JT, Durum SK, Seddon B. Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol. 2019;20(12):1584-1593. doi:10.1038/s41590-019-0479-x6. Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomizedclinical trial. JCI Insight. 2018;3(5):3. doi:10.1172/jci.insight.98960JAMA Network Open | Infectious Diseases Interleukin 7 Immunotherapy and Lymphocyte Counts Among Patients With Severe COVID-19JAMA Network Open. 2020;3(7):e2016485. doi:10.1001/jamanetworkopen.2020.16485 (Reprinted) July 22, 2020 5/5Downloaded From: https://jamanetwork.com/ by a Washington University - St Louis User  on 08/31/2020

Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19)

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Association of interleukin 7 immunotherapy with lymphocyte counts among patients with severe coronavirus disease 2019 (COVID-19)

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