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Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

Open AccessPublished:September 24, 2020DOI:https://doi.org/10.1016/j.jaci.2020.09.010

      Background

      There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense.

      Objective

      We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2.

      Methods

      An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI.

      Results

      We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

      Conclusions

      This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2.

      Key words

      Abbreviations used:

      AGS (Aicardi-Goutieres syndrome), AIHA (Autoimmune hemolytic anemia), ALPS (Autoimmune lymphoproliferative syndrome), AR (Autosomal-recessive), CGD (Chronic granulomatous disease), CID (Combined immunodeficiency), COVID-19 (Coronavirus disease 2019), CVID (Common variable immune deficiency), HLH (Hemophagocytic lymphohistiocytosis), HSCT (Hematopoietic stem cell transplantation), ICU (Intensive care unit), IEI (Inborn errors of immunity), P (Patient), PID (Primary immunodeficiency), SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2), X-CGD (X-linked chronic granulomatous disease), X-SCID (X-linked severe combined immunodeficiency)
      In December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus, emerged in the Hubei province of China as a novel human pathogen. SARS-CoV-2 causes an infectious disease (coronavirus disease 2019 [COVID-19]) characterized by pneumonia and acute respiratory failure.
      World Health Organization
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      Table IAge distribution and lethality of SARS-CoV-2 infection in patients with IEI
      Patients with inborn errors of immunityGeneral population
      Age group (y)

      (94 cases)
      M:FCOVID-19 cases per age group in our cohort, N (%)Deaths in our cohort,

      N (%)
      ICU admission,

      N (%)
      Age groups general population (y)COVID-19 cases per age group (general population), %Deaths (general population), %ICU admission (general population), %
      0-26:17 (7.4)1 of 7 (14)3 of 7 (43)0-91.5
      Data from the United States, n = 1,320,488 cases.10
      4.2
      Data from the United Kingdom, n = 73,359 cases (https://www.gov.uk/government/publications/demographic-data-for-coronavirus-testing-england-28-may-to-26-august/demographic-data-for-coronavirus-covid-19-testing-england-28-may-to-26-august).
      0.1
      https://ourworldindata.org/covid-deaths; average of data from Spain, Italy, China, and South Korea.
      0
      https://ourworldindata.org/covid-deaths; average of data from Spain, Italy, China, and South Korea.
      0.7
      Data from the United States, n = 1,320,488 cases.10
      3-1212:517 (18)0 of 172 of 17 (12)
      13-184:48 (8.5)1 of 8 (10)4 of 8 (50)10-193.77.80.10.20.4
      19-244:04 (4.2)0 of 40 of 420-2913.820.00.10.20.5
      25-3410:313 (13.8)0 of 130 of 1330-3916.317.80.40.20.9
      35-449:615 (16)2 of 15 (13)3 of 15 (20)40-4916.614.41.00.31.5
      45-548:19 (9.5)0 of 01 of 9 (11)50-5917.912.72.40.82.5
      55-645:510 (10.6)2 of 10 (20)3 of 10 (30)60-6913.67.66.72.74.1
      65-740:55 (5.3)0070-798.05.316.68.05.6
      >752:35 (5.3)3 (60)2 (40)>808.710.028.716.03.6
      All patients65:35 (1.8:1)NA10 (10)20 (20)All5.4 (1-20)2.3
      F, Female; M, male; N, absolute number.
      Data for the general population are all taken from Stokes et al.
      • Stokes E.K.
      • Zambrano L.D.
      • Anderson K.N.
      • Marder E.P.
      • Raz K.M.
      • El Burai Felix S.
      • et al.
      Coronavirus disease 2019 case surveillance—United States, January 22-May 30, 2020.
      Data from the United States, n = 1,320,488 cases.
      • Stokes E.K.
      • Zambrano L.D.
      • Anderson K.N.
      • Marder E.P.
      • Raz K.M.
      • El Burai Felix S.
      • et al.
      Coronavirus disease 2019 case surveillance—United States, January 22-May 30, 2020.
      https://ourworldindata.org/covid-deaths; average of data from Spain, Italy, China, and South Korea.
      Another contributor to interindividual susceptibility to severe COVID-19 and outcome postinfection is genetic heterogeneity.
      • Casanova J.L.
      • Su H.C.
      COVID Human Genetic, Effort, A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection.
      This reflects the discoveries of patients with inborn errors of immunity (IEI) who exhibit increased susceptibility to pathogen infection.
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      Human inborn errors of immunity: 2019 Update of the IUIS Phenotypical Classification.
      Although more than 430 monogenic IEIs have been described,
      • Tangye S.G.
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      • Cunningham-Rundles C.
      • Etzioni A.
      • et al.
      Human inborn errors of immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.
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      the consequences of SARS-CoV-2 infection have been reported for only a few individuals with these conditions.
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      • et al.
      A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.
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      • et al.
      Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
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      • Lugo Reyes S.O.
      A male infant with COVID-19 in the context of ARPC1B deficiency.
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      Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma.
      Thus, the aim of this multicenter, retrospective international study was to assess the impact of SARS-CoV-2 infection on patients with IEIs, thereby providing the first comprehensive description on the susceptibility of an at-risk population of patients to SARS-CoV-2 infection, as well as their COVID-19 clinical course, severity, complications, and outcomes. This extensive global data set represents an important reference for clinicians treating and managing patients with IEIs in the context of the COVID-19 pandemic.

      Methods

      A retrospective study was undertaken by a web-based survey, approved by the University Hospitals Leuven Committee for Medical Ethics. The questionnaire inquired about demographic data, COVID-19 presentation, treatment, and outcomes in patients with IEIs (according to current diagnostic guidelines) and documented SARS-CoV-2 infection. No identifying information was required, while physicians were given the option of providing their contact details. The survey opened on March 16, 2020, and closed on June 30, 2020. An invitation to participate in the survey was shared with members of various societies (European Society for Immunodeficiencies, Clinical Immunology Society, Latin American Society for Immunodeficiencies, African Society for Immunodeficiencies, Asia Pacific Society for Immunodeficiencies, Australasian Society for Clinical Immunology & Allergy), as well as via the International Patient Organization for Primary Immunodeficiencies, the Jeffrey Modell Foundation, and the International Union of Immunological Societies Committee for Inborn Errors of Immunity, with the aid of social media alerts. Fisher exact test of independence and Bayesian analysis of contingency tables were used to calculate the statistical significance of the correlation between categorical variables.

      Results

       Patients

      A total of 94 patients with an underlying primary immunodeficiency (PID)/IEI and infected by SARS-CoV-2, as determined by serology (n = 8) or diagnostic PCR (n = 86), were reported (Tables I and II). Male to female ratio was 1.8 to 1. Thirty-two patients were younger than 18 years and 62 were adults (median age group, 25-34 years). Eleven patients have been reported previously.
      • Quinti I.
      • Lougaris V.
      • Milito C.
      • Cinetto F.
      • Pecoraro A.
      • Mezzaroma I.
      • et al.
      A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.
      • Soresina A.
      • Moratto D.
      • Chiarini M.
      • Paolillo C.
      • Baresi G.
      • Foca E.
      • et al.
      Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
      • Castano-Jaramillo L.M.
      • Yamazaki-Nakashimada M.A.
      • Scheffler Mendoza S.C.
      • Bustamante-Ogando J.C.
      • Espinosa-Padilla S.E.
      • Lugo Reyes S.O.
      A male infant with COVID-19 in the context of ARPC1B deficiency.
      ,
      • Wahlster L.
      • Weichert-Leahey N.
      • Trissal M.
      • Grace R.F.
      • Sankaran V.G.
      COVID-19 presenting with autoimmune hemolytic anemia in the setting of underlying immune dysregulation.
      Table IISummary of patients’ characteristics
      Pt. no.OutcomePIDAge group (y)SexComorbiditiesUsual therapyManifestationsRespiratory insufficiencyInvasive ventilationSeverityComplicationsTherapyCountrySeroconversionEstimated duration of SARS-CoV-2 PCR positivityDuration of infection/ symptoms
      FeverCoughURSGIMyalgiaOther
      1DeceasedAb def.

      Syndromic presentation
      35-44MNeutropenia, dysmorphism, developmental delay, hypertrophic cardiomyopathyIg, G-CSFXXChest painXECMOICU admissionPneumothorax, pulmonary hypertension, heart failureAntibiotics, steroids, IgFrance
      2DeceasedAb def.

      CVID
      35-44FKidney tx, lymphoma and cervical cancer in remissionIg, steroidsHypotension, renal failureHospital admissionRenal failureAntibiotics, chloroquine, enoxaparin, conv. plasmaUSA
      3DeceasedAb def.

      CVID
      55-64FLung disease, heart disease, ITPIg, rituximab, metoprololXXDyspnea, fatigue, hypotension, renal failureXXICU admissionRenal failureAntibiotics, chloroquine, enoxaparinUSA
      4DeceasedAb def. CVID55-64FLung diseaseIgXXXXICU admissionSepsisAntibiotics, steroids, tocilizumab, lopinavir, ritonavirItalyNo17 d (until death)17 d (until death)
      5DeceasedAb def.

      IgG deficiency
      ≥75FLung disease, heart disease, kidney disease, hypertension, diabetesIgXXDyspnea, hypotension, renal failureXXICU admissionRenal failureAntibiotics, chloroquine, enoxaparinUSA
      6DeceasedAb def.

      IgG2 and IgA deficiency
      ≥75MDiabetes, AIHAIgXHypotension, renal failureXXICU admissionRenal failureAntibiotics, chloroquine, enoxaparinUSA
      7DeceasedAb def. CVID≥75FLymphoproliferative disease, GI disease, genital tract neoplasmIgAcute confusional syndromeHospital admissionE faecium sepsis, renal failureAntibiotics, chloroquineSpain
      8DeceasedPhagocyte defects

      CGD (CYBB)
      0-2MXBurkholderia sepsisXECMOICU admissionHLHAntibiotics, steroidsFrance
      9DeceasedImmune dysregulation disorder (XIAP)13-18M4 mo post-HSCT, severe gut GvHDAntibiotics, antifungals, Ig, steroids, cyclosporineXCollapseXXICU admissionSepsis, HLHAntibiotics, IgChile
      10ResolvedAb def. CVID (NFKB2)35-44MIg, antibiotics, antivirals, mAbXXXXXICU admissionBacterial pneumoniaAntibiotics, Ig, hydroxychloroquine, remdesivir, lopinavir, ritonavir, tocilizumabItaly
      11ResolvedAb def. Agammaglobulinemia35-44MLung diseaseIg, steroids, antibiotics, GM-CSFXXXXECMOICU admissionHLHAntibiotics, steroids, chloroquine, GM-CSF, conv. plasmaBelgium60-75 d50 d
      12ResolvedAb def. CVID55-64MAsthmaIg, immunosuppressiveXXXXXICU admissionSepsis (Candida)Antibiotics, chloroquine, remdesivir, lopinavir, ritonavir, mAbItalyNo4 wk
      13ResolvedAb def. CVID (NFKB2)13-18MAlopecia tot., psoriasisXXXXDyspneaXXICU admissionSepsis

      HLH
      Antibiotics, steroids, tocilizumab, remdesivir, conv. plasmaUSAYes8 d
      14ResolvedAb def. CVID45-54MLung diseaseIg, immunosuppressiveXXXXICU admissionSteroids, chloroquine, tocilizumab remdesivir, lopinavir, ritonavirItalyNo9 d
      15ResolvedCID

      Trisomy 21
      3-12MLung disease, heart disease, pulmonary hypertension, mental disabilityAntibiotics, Ig, antivirals, steroidsXXXXXICU admissionHLHAntibiotics, steroids, Ig, remdesivirGermany
      16Still in ICUCID

      Wiskott-Aldrich syndrome
      3-12M3 mo post-HSCT, GI diseaseAntibiotics, Ig, steroidsXXCMV encephalitis, anosmiaXXICU admissionBacterial pneumoniaSteroids, IgMexico
      17Still in ICUCID

      Trisomy 21
      0-2FHeart defect, tracheostomy with chronic ventilationAntibiotics, IgXXICU admissionChile
      18ResolvedAb def. XLA (BTK)3-12MSpherocytosisIgXXXDyspnea, chest painXAdmission with O2/NIVBacterial pneumoniaAntibiotics, remdesivir, enoxaparin, conv. plasmaUSA
      19ResolvedAb def. CVID25-34FIgXXAnosmiaXAdmission with O2/NIVSteroids, chloroquine, tocilizumab, lopinavir, ritonavirItalyNo9-50 d
      20ResolvedAb def. CVID25-34MIgXXXFatigueXAdmission with O2/NIVAntibiotics, steroidsFranceNo
      21ResolvedAb def. CVID45-54MLung diseaseIg, antibioticsXXXAdmission with O2/NIVAntibiotics, IgFrance
      22ResolvedAb def. CVID45-54MLung diseaseIg, antibioticsXXXXAdmission with O2/NIVAntibioticsFranceYes (IgM)2 mo
      23ResolvedAb def.

      Hypogammaglobulinemia
      45-54FDiabetes, heart disease, hypertension, neuropathy, mitochondrial myopathyIg, antibiotics, antifungals, ACE inhibitor, atorvastatin, bisoprolol, eplenerone, metformin, insulinXXNeuropathyXAdmission with O2/NIVAntbioticsUK15 d18 d
      24ResolvedAb def. CVID45-54MLarge granular lymphocyte leukemiaIgXXXAdmission with O2/NIVAntibiotics, chloroquineSpainYes30 d17 d
      25ResolvedCID

      ARPC1B
      0-2MEczema, cow milk protein allergyAntibiotics, IgXCollapseXAdmission with O2/NIVAntibioticsMexico
      26ResolvedCID

      Trisomy 21
      3-12MXXCoinfection with Mycoplasma pneumoniaeXAdmission with O2/NIVNeutropeniaAntibioticsBelgium
      27ResolvedCID

      DiGeorge syndrome
      0-2MLung disease, tracheostomy with chronic ventilationAntibiotics, IgXXAdmission with O2/NIVIgChile
      28ResolvedAutoinflammatory disorder (MEFV)55-64MLung diseaseXXXXDyspneaXAdmission with O2/NIVSteroids, lopinavir, ritonavirFrance
      29ResolvedCID with immune dysregulation and autoinflammation35-44MHyporegenerative anemia, AIHA, intermittent renal insufficiencyStatus post rituximab, steroidsXXDyspnea

      Coinfection with CoV229E
      Hospital admissionAnemia, neutropeniaChloroquine, lopinavir, ritonavir, tocilizumabGermanyYes42 d13 d
      30ResolvedImmune dysregulation disorder (PEPD)25-34MKidney disease, mental disabilitySteroids, antibiotics, antivirals, antifungals, mABXXXAdmission with O2/NIVSepsisAntibiotics, steroidsItaly
      31ResolvedImmune dysregulation disorder (CTLA4)13-18FLung disease, post-HSCT with poor graft functionIg, antibiotics, antivirals, antifungals,DyspneaXHospital admissionChloroquine, remdesivirSpain
      32ResolvedImmune dysregulation disorder (CTLA4)25-34Lung disease, GI disease, chronic JCV cystitisSteroids, Ig, everolimus, abataceptXAnosmia, ageusiaXAdmission with O2/NIVSteroids, aspirin, remdesivirUSA
      33ResolvedAb def. CVID35-44MLung diseaseAntibiotics, antiviralsXXXDyspnea, fatigueHospital admissionBacterial pneumoniaAntibiotics, lopinavir, ritonavirUK
      34ResolvedAb def.

      Isolated IgG subclass def.
      55-64FLung diseaseAntibiotics, Ig, omalizumabDyspneaHospital admissionBacterial pneumoniaAntibiotics, chloroquineSpain
      35ResolvedCID

      Wiskott-Aldrich syndrome
      0-2M5 mo after gene therapyIg, prophylactic antivirals, pentamidine, thrombopoietin agonistAsymptomaticAsymptomaticMild myocarditisChloroquine, lopinavir, ritonavirItalyYes41 d
      36ResolvedImmune dysregulation disorder

      ALPS-like
      13-18MImmune thrombocytopeniaMycophenolate, eltrombopagXXAnemia, jaundiceHospital admissionAIHASteroidsUSA
      37ResolvedCMC and recurrent sepsis0-2MIgXXXHospital admissionBacterial pneumoniaAntibioticsBelgium
      38ResolvedMSMD

      IFNGR2 deficiency
      0-2MXXMiliary Mycobacterium avium coinfection, leukocytosisHospital admissionMultisystemic inflammatory syndromeAntibiotics, steroids, Ig, antimycobacterial antibioticsUSA
      39ResolvedBone marrow failure (DNAJC21)3-12MExocrine pancreas insufficiency, failure to thrive, cytopenias, bone anomalies, mental disabilityAntibiotics, red blood cell transfusionsXIncreased anemia and thrombocytopeniaHospital admissionIncomplete HLHAntibioticsGermanyYes (IgG, IgA)7 d
      40ResolvedAb def.

      Hypogammaglobulinemia
      3-12MUveitisIgAsymptomaticAsymptomaticChile
      41ResolvedAb def.

      Syndromic presentation
      3-12MHeart defect, CD4+ T-cell lymphopenia, mental disability, dysmorphismIgXXHospital admissionChile
      42ResolvedAb def.

      CVID
      13-18MLung diseaseIgXXHospital admissionIg, chloroquineMexico
      43ResolvedAb def. X-SCID after gene therapy, residual B- cell dysfunction (IL2RG)19-24MIgXXXXAnosmia, ageusia, fatigueNot admittedAntibioticsFrance
      44ResolvedAb def. XLA (BTK)19-24MLung diseaseIgXXDyspneaHospital admissionAntibiotics, chloroquine, enoxaparin, conv. plasmaUSA
      45ResolvedAb def. CVID25-34MIBDIgXXXNot admittedAntibiotics, chloroquineUSA
      46ResolvedAb def. CVID25-34MLung diseaseIgXXXXNAAntibiotics, chloroquine, lopinavir, ritonavirSpain
      47ResolvedAb def. CVID25-34FLung disease, AI diseaseIg, antibioticsXXXDyspneaHospital admissionSteroids, chloroquine, enoxaparinBrazilNo16-35 d
      48ResolvedAb def. CVID25-34MIg, antibioticsSore throatNot admittedAntibioticsArgentina41 d
      49ResolvedAb def. CVID25-34MIgAnosmia, ageusiaNot admittedFranceYes2 wk
      50ResolvedAb def. XLA (BTK)25-34MIgXXHospital admissionAntibiotics, steroids, Ig, chloroquineItaly64 d
      51ResolvedAb def.

      APDS (PIK3R1)
      25-34FIgXSore throatNot admittedUSA
      52ResolvedAb def. CVID35-44FAntibioticsXXXNot admittedThe NetherlandsYes35 d
      53ResolvedAb def. CVID (NFKB1)35-44MChronic diarrheaIgXXXDyspnea, fatigueHospital admissionAntibiotics, chloroquine, enoxaparinUSA
      54ResolvedAb def. XLA (BTK)35-44MIgXXHospital admissionAntibiotics, chloroquine, lopinavir, ritonavirItaly6-14 d
      55ResolvedAb def. CVID35-44FLung diseaseIgXNot admittedAntibioticsSpainNo6-38 d14 d
      56ResolvedAb def CVID35-44FLung diseaseIg, antibioticsXXXXDyspnea, chest painHospital admissionSteroids, chloroquineBrazil
      57ResolvedAb def. XLA (BTK)45-54MLung disease, liver disease, chronic skin and eye conditionsIgAsymptomaticAsymptomaticSpain
      58ResolvedAb def. XLA (BTK)45-54MLung disease, liver diseaseAntibiotics, IgXXCampylobacter jejuni coinfectionHospital admissionSpain
      59At homeAb def. CVID45-54MLung disease, kidney disease, GI diseaseIg, steroids, mAbXNot admittedNA
      60ResolvedAb def. CVID (NFKB1)55-64FSevere anemiaIgXXXDyspnea, fatigueHospital admissionAntibiotics, chloroquine, enoxaparinUSA
      61ResolvedAb def.

      CVID
      55-64MLung disease, lymphoproliferative diseaseIgXXXNot admittedChloroquineSpain
      62ResolvedAb def. CVID55-64MLung disease, hypertension, splenomegaly and lymphadenopathyIgXHospital admissionChloroquine, ivermectin, anakinraGermanyYes (IgM)29 d6 wk
      63ResolvedAb def. CVID55-64FLiver diseaseIgXNot admittedGermanyNo58 d2 wk
      64ResolvedAb def. AR agammaglobulinemia55-64MLung diseaseIgAsymptomaticAsymptomaticItalyNo7 d
      65ResolvedAb def Hypogamma-globulinemia65-74FAortic coarctationIgXXXXXNot admittedFrance
      66ResolvedAb def. CVID65-74FDiabetes, hypertension, obesityAntibioticsXXNot admittedAntibioticsFrance
      67ResolvedAb def. CVID65-74FIg, antibioticsXXDyspneaHospital admissionAntibiotics, chloroquine, enoxaparin, conv. plasmaUSA
      68At homeAb def. CVID65-74FXXFatigueNot admittedUSANo>1 mo>1 mo
      69ResolvedAb def. CVID65-74FDiabetes, obesity, hypertensionAntibioticsXXXFatigueNot admittedFranceNo2 d
      70ResolvedAb def. IgG deficiency≥75MIgXXDyspneaNot admittedAntibiotics, chloroquine, enoxaparinUSA
      71ResolvedAb def. Hypogammaglobulinemia≥75FImmune thrombocytopenia, smoker, previous breast cancerIg, antibiotics, ACE inhibitor, simvastatinXXInfected during hospital admission for strokeHospital admissionAntibioticsUK15-24 d15 d
      72ResolvedCID3-12FAntibioticsXXXHospital admissionLopinavir, ritonavirSpainNo6 d
      73ResolvedCID (ZAP70)13-18FLung disease, diffuse large B-cell lymphomaIg, rituximab, brentuximabXXXHospital admissionFranceYes36 d (still pos)3 d
      74ResolvedCID13-18FHeart defectAntibiotics, IgAsymptomaticAsymptomaticChile
      75ResolvedCID35-44FAIHA, thrombocytopenia, neutropenia, alopecia areata, recurrent HSV, splenomegalyIg, antibiotics, antivirals, rituximabAnosmia, ageusiaNot admittedAntibioticsUKYes3 d
      76ResolvedCID (PGM3)3-12MMental disability, neutropenia, eczemaAntibiotics, antifungals, antivirals, G-CSFXXNot admittedUSA
      77ResolvedCID

      Hyper-IgE (STAT3)
      25-34MLung disease, hypertensionAntibiotics, antifungalsXHeadacheNot admittedUSA
      78ResolvedCID

      Hyper-IgE (STAT3)
      35-44MGI and skin diseaseAntibioticsXAnosmiaNot admittedSpainYes
      79ResolvedAutoinflammation (MEFV)35-44FAmyloidosisCanakinumab, colchicineXXXXDyspneaNot admittedSteroids, chloroquineBrazil
      80ResolvedAutoinflammation (MEFV)45-54FAmyloidosisCanakinumab, colchicineXXXNot admittedBrazil
      81ResolvedAutoinflammation

      AGS (RNASEH2B)
      3-12MMental disabilityAsymptomaticAsymptomaticFrance
      82ResolvedAutoinflammation

      AGS (RNASEH2B)
      3-12MMental disabilityAsymptomaticAsymptomaticFrance
      83ResolvedAutoinflammation

      AGS (SAMHD1)
      3-12FMental disability, spastic quadriplegy, epilepsySodium valproate, baclofenRash on cheeks and armsNot admittedAntibiotics, aspirinUKYes15 d
      84ResolvedImmune dysregulation disorder (PRKCD)3-12MAutoimmunity, invasive infectionsIg, sirolimus, antibiotics, hydroxychloroquineXXRhinovirus coinfectionHospital admissionAntibioticsUK
      85ResolvedImmune dysregulation disorder

      Somatic ALPS
      3-12FSirolimusAsymptomaticAsymptomaticFranceYes42 d (still pos.)28 d
      86ResolvedImmune dysregulation disorder (LRBA)19-24MDiabetesAbatacept, Ig, insulinXXXHospital admissionAntibioticsFrance
      87ResolvedImmune dysregulation

      APECED (AIRE)
      19-24MLung diseases, diabetes, adrenal and thyroid insufficiency, heart disease, exocrine pancreatic insufficiency, functional aspleniaAntibiotics, antifungals, insulin, adrenal and thyroid hormonesXXHospital admissionAntibioticsFrance
      88ResolvedPhagocyte defects

      CGD (CYBB)
      3-12MHyporegenerative anemiaCyclosporine, antibioticsXXHospital admissionAntibioticsFrance<1 mo
      89ResolvedPhagocyte defects

      CGD (NCF2)
      3-12FLung diseaseAntibiotics, antifungalAsymptomaticAsymptomaticUK
      90At homePhagocyte defects25-34MLung diseaseXNot admittedUSA
      91Still in hospitalPhagocyte defects35-44MAntibiotics, antifungals, mAbXXFatigueHospital admissionChloroquineSpain
      92ResolvedPhagocyte defects

      CGD (CYBB)
      45-54MLung diseaseAntibioticsAnosmiaNot admittedAntibioticsMexicoYes
      93ResolvedSTAT1 GOF03-12FLung diseaseIgAsymptomaticAsymptomaticChileYes (IgM)21 d
      94ResolvedGATA2 deficiency13-18FLung disease, bone marrow hypoplasia, pancytopeniaIg, steroids, antifungals, G-CSFXXLower limbs edema, skin rash, hypotensionHospital admissionAntibiotics, steroids, IgChile
      Ab def., Antibody deficiency; ACE, angiotensin-converting enzyme; AI, autoimmune; AIHA, autoimmune hemolytic anemia; ALPS, autoimmune lymphoproliferative syndrome; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy; conv., convalescent; def., deficiency; ECMO, extracorporeal membrane oxygenation; F, female; GI, gastrointestinal; GOF, gain of function; GvHD, graft versus host disease; IBD, inflammatory bowel disease; ITP, immune thrombocytopenia; JCV, JC virus; M, male; MSMD, Mendelian susceptibility to mycobacterial disease; NA, not available; NIV, noninvasive ventilation; pos., positive; Pt. no., patient number; Tx, treatment; URS, upper respiratory symptoms; X-SCID, X-linked severe combined immune deficiency; XLA, X-linked agammaglobulinemia.
      Choroquine and hydroxychloroquine are considered a single treatment group.

       Types and causes of IEI

      The distribution of patients according to IEI groups is shown in Fig 1. Most patients had a pre-existing primary antibody deficiency (53 of 94 [56%]), including
      • 6 with X-linked agammaglobulinemia due to BTK variants (patient [P] 18, P44, P50, P54, P57, and P58);
      • 2 patients with heterozygous NFKB1 (P53 and P60) or NFKB2 (P10 and P13) variants;
      • 1 patient with X-linked severe combined immunodeficiency (X-SCID) who underwent gene therapy 19 years earlier that corrected his T cells but not B cells, thereby remaining antibody deficient (P43);
      • 2 cases of autosomal-recessive (AR) agammaglobulinemia (P11 and P64) (Fig 1 and Table II).
      Figure thumbnail gr1
      Fig 1Distribution of patients based on IEI category, comorbidities, and outcome. Shaded colors indicate patients who succumbed to COVID-19 in that IEI group. The numbers of patients (alive and deceased) are indicated for each individual subcategory on the figure. A, Ambulatory; H, hospitalized; NIV/O2, noninvasive ventilation/oxygen; “+,” with comorbidities; “,” no comorbidities.
      There were also 29 patients with common variable immune deficiency (CVID) and 2 patients with syndromic features (P1: cardiomyopathy and neutropenia; P41: ventricular septum defect and CD4+ T-cell lymphopenia; Table II). Forty-six of 53 antibody-deficient patients received immunoglobulin substitution as standard therapy and 6 received immunosuppressive therapy.
      Six patients had phagocyte defects: 4 with X-linked (variants in CYBB [P8, P88, and P92]) or recessive (bialleic variants in NCF2 [P89]) chronic granulomatous disease (CGD); 1 (P88) was treated with cyclosporin (Fig 1 and Table II). Fourteen patients had combined immunodeficiencies (CIDs), including 10 with syndromic features: Di George syndrome (P27); trisomy 21 (Down syndrome [P15, P17, and P26]),
      • Kong X.F.
      • Worley L.
      • Rinchai D.
      • Bondet V.
      • Jithesh P.V.
      • Goulet M.
      • et al.
      Three copies of four interferon receptor genes underlie a mild type I interferonopathy in Down syndrome.
      ,
      • Verstegen R.H.J.
      • Kusters M.A.A.
      Inborn errors of adaptive immunity in Down syndrome.
      Wiskott-Aldrich syndrome (P16: 3 months post–hematopoietic stem cell transplantation [HSCT]; P35: 5 months post–gene therapy), ARPC1B deficiency (P25), hyper-IgE syndrome due to heterozygous dominant negative variants in STAT3 (P77 and P78), or biallelic variants in PGM3 (P76). Other patients had pathogenic biallelic variants in ZAP70 (P73) or IFNGR2 (P38), or heterozygous gain-of-function variant in STAT1 (P93). P7 had chronic mucocutaneous candidiasis and recurrent pyogenic sepsis, suggesting an underlying innate immune defect. Nine patients presented with an immune dysregulation syndrome: autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (due to biallelic AIRE variants [P87]); LRBA deficiency (P86); CTLA4 haploinsufficiency (P31 [post-HSCT, poor graft function] and P32); autoimmune lymphoproliferation due to pathogenic variants in PRKCD (biallelic; P84), or XIAP (P9, 4 months post-HSCT); autoimmune lymphoproliferative syndrome (ALPS)–like disease (P36 and P85); and prolidase deficiency due to biallelic pathogenic variants in PEPD (P30) (Fig 1 and Table II). The LRBA-deficient, PRKCD-deficient, X-linked inhibitor of apoptosis-deficient, ALPS-like, PEPD-deficient and 1 of the CTLA4-deficient patients (P32) received immunosuppressive treatment (abatacept [n = 2], mycophenolate [n = 1], steroids [n = 3], sirolimus [n = 2], everolimus [n = 1]) (Table II).
      Seven additional patients suffered from an autoinflammatory disease (Fig 1 and Table II):
      • Aicardi-Goutieres syndrome (AGS) due to biallelic RNASEH2B variants (P81 and P82), treated with immunoglobulin substitution and JAK inhibitors, or homozygous SAMHD1pathogenic variants (P83);
      • familial Mediterranean fever (MEFV variant [P28, P79, and P80]), treated with anakinra, canakinumab, and/or colchicine; and
      • an autoinflammatory condition with lymphopenia and autoimmune hemolytic anemia (AIHA), treated with steroids (P29).
      One patient suffered from bone marrow failure caused by biallelic DNAJC21 mutations (P36), and 1 had pancytopenia due to a heterozygous GATA2 variant (P94) (Fig 1 and Table II).
      Before infection, all patients were stable on standard of care treatment; 2 were on angiotensin-converting enzyme inhibitor therapy. The most frequent presenting symptoms were fever (69%) and cough (47%), followed by upper respiratory tract symptoms (runny nose, sneezing: 19%) and shortness of breath/dyspnea (13%). Gastrointestinal symptoms (diarrhea, vomiting) and myalgia were reported in 14% and 16% of patients, respectively, while acute respiratory insufficiency was the presenting feature in 11% of patients. Other reported symptoms were fatigue, sore throat, anosmia/ageusia, collapse, pallor, and anemia.

       Clinical features of SARS-CoV-2+ patients with IEI

      Ten (11%) patients were asymptomatic (ALPS–like [P85], AGS [P81 and P82], STAT1 gain-of-function [P93], Wiskott-Aldrich syndrome [P35], ARCGD [P89], XLA [P56], AR agammaglobulinemia [P64], hypogammaglobulinemia [P40], and CID [P74]), including 4 who had pre-existing lung disease (Table II). In these cases, testing for SARS-CoV-2 was performed only to enable travel, elective treatment, or due to positivity of a symptomatic relative/close contact.
      Twenty-four patients had mild disease and were treated as outpatients (Table II). Two were 3-12 years old, 1 was 19-24 years, 6 were 25-34 years, 5 were 35-44 years, 3 were 45-54 years, 2 were 55-64 years, 4 were 65-74 years, and 1 was older than 75 years. These patients included
      • 14 with predominantly antibody deficiency (11 with CVID, of whom 7 had ≥1comorbidity);
      • 1 patient with X-SCID with persistent defective B-cell function after gene therapy;
      • 1 with activated PI3 kinase syndrome (P51, PIK3R1 mutation);
      • 1 with CID with multiple autoimmune features (P75);
      • 3 with hyper-IgE syndrome due to PGM3 deficiency (P76), or STAT3 loss-of function (P77 and P78) including 1 with chronic lung disease; and
      • 2 with MEFV mutations (P79 and P80), 1 with AGS (P83, SAMHD1 mutation), 1 with CGD due to CYBB mutation (P92), and 1 with an unspecified phagocyte defect (P90).
      Fifty-nine patients (63%) required hospitalization. Clinical progression of 29 of these 59 patients evolved into respiratory insufficiency (49% of hospitalized, 31% of all patients). Thirteen patients required noninvasive ventilation/oxygen administration, and 15 (11 males, 4 females; 16% of all patients) were admitted to intensive care units (ICUs) for invasive ventilation, including extracorporeal membrane oxygenation (3 male patients, 2 succumbed, see below). In addition, individual patients were admitted to ICU for severe AIHA (P36), hypotension (P94), or MIS-C and miliary Mycobacterium avium infection (P38; IFNGR2) but no respiratory complications. Among female patients admitted to ICU for respiratory insufficiency, 2 had CVID and were aged 55-64 years (P3 and P4), 1 was older than 75 years (hypogammaglobulinemia; P5), and one was younger than 2 years with trisomy 21 and chronic invasive ventilation via tracheostomy in the context of congenital heart disease (P17). In contrast, the age distribution of the 11 affected males admitted to ICU was broader than for females, and the general population (Tables I and II):
      • 1 aged 0-2 years (P8 [X-linked chronic granulomatous disease, X-CGD]);
      • 2 aged 3-12 years (P15 [trisomy 21] and P16 [Wiskott-Aldrich syndrome]);
      • 2 aged 13-18 years (P13 [NFKB2] and P9 [XIAP]);
      • 3 aged 35-44 years (P10 [NFKB2], P17 [agammaglobulinemia], and P1 [syndromic primary antibody deficiency]);
      • P14, aged 45-54 years, and P12, aged 55-64 years, both with CVID; and
      • 1 patient 75 years or older (P6 [IgG2/IgA deficiency]).
      The three patients with trisomy 21 experienced acute respiratory insufficiency, requiring invasive (P15 and P17) or noninvasive (P26) ventilation. P15 and P17 also had a pre-existing heart condition; P17 required a tracheostomy and chronic ventilation. Overall, 73% (11 of 15) of the patients needing invasive ventilation had pre-existing comorbidities (Fig 1 and Table II).

       Complications and mortality due to SARS-CoV-2 infection

      Reported complications, as defined according to international guidelines
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      or current practice,
      • Toubiana J.
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      Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study.
      ,
      • Feldstein L.R.
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      Multisystem inflammatory syndrome in U.S. children and adolescents.
      were bacterial pneumonia (n = 6), hemophagocytic lymphohistiocytosis (HLH) (n = 6), sepsis (n = 6 [7%]), MIS-C (P38, IFNGR2, 1%), and kidney failure (n = 5 [5%]). Two patients had sepsis and HLH. Furthermore, individual patients developed AIHA, thrombocytopenia, hyporegenerative anemia, neutropenia, myocarditis, and heart failure.
      Nine patients in this cohort (7 adults and 2 children, 10%) died (Fig 1 and Table II): 4 males (0-2 years: n = 1; 13-18 years: n = 1; 35-44 years: n = 1; >75 years: n = 1), 5 females (35-44 years: n = 1; 55-64 years: n = 2 ; ≥75 years: n = 2). The child aged 0-2 years (P8, Table II) had X-CGD, concomitant Burkholderia sepsis, and HLH. The other child (P9, 13-18 years) had severe gut graft versus host disease following HSCT for XIAP deficiency and developed septic shock and HLH. Thus, it is unclear how much SARS-CoV-2 infection contributed to the death in both children. P1 (male, 35-44 years) suffered a syndromic disease with congenital dysmorphisms, mild developmental delay, hypogammaglobulinemia, neutropenia, hypertrophic cardiomyopathy, and bronchopathy. He developed pneumothorax, pulmonary hypertension, and heart failure after SARS-CoV-2 infection and died despite treatment with antibiotics, immunoglobulin infusion, steroids, and extracorporeal membrane oxygenation. The other deceased patients (5 females and 1 male) suffered from antibody deficiencies (CVID [P2, P3, P4, and P7]; isolated IgG deficiency [P5]; IgA and IgG2 deficiency [P6]; Table II). Most patients were treated for potential bacterial coinfection or superinfection with antibiotics and extra immunoglobulin infusion.
      All adult patients with PID who succumbed to SARS-CoV-2 infection had pre-existing comorbidities (Fig 1 and Table II): P1 had cardiomyopathy and developed pulmonary hypertension and heart failure; P2 had chronic kidney disease, underwent kidney transplant, and had several malignancies; all other patients were older than 55 years, and P3 had chronic lung and heart disease; P4 had chronic lung disease and developed sepsis; P5 had chronic lung, heart, and kidney disease, hypertension, and diabetes; P6 had diabetes; P7 had lymphoproliferative disease, gastrointestinal disease, and genital tract neoplasm and developed Enterococcus faecium sepsis. P2, P3, P5, P6, and P7 all developed hypotension and kidney failure during COVID-19. However, exact cause of COVID-19–related deaths for these patients is unknown.

       Treatments of SARS-CoV-2 infection in patients with IEI

      Therapeutic strategies varied greatly and consisted of the following medications, alone or in combination: antibiotics (51%), immunoglobulin replacement (10.6%), hydroxychloroquine/chloroquine (33%), systemic steroids (21%), mAbs (8.5%, tocilizumab [n = 6] and anakinra [n = 1]), antivirals (lopinavir and ritonavir 12.7%, remdesivir 9.6%, favipravir 1%), and enoxaparin (12.7%). Five patients (2 in ICU) received convalescent plasma and other treatments (antibiotics, chloroquine, remdesivir, steroids, enoxaparin, tocilizumab), with 4 surviving. Six patients were treated with tocilizumab, 4 in ICU, 1 of whom died of infection. (Hydroxy)chloroquine was administered to 31 patients (5 succumbed), and remdesivir to 9 patients, 5 of whom required admission to ICU and invasive ventilation, all of whom survived.
      The association between outcome (alive/dead) and the onset of respiratory insufficiency, the presence of comorbidities, or the sex of the patient was not significantly different between patients who survived or patients who succumbed to SARS-CoV-2. Moreover, no correlation could be found between outcome and respiratory insufficiency, age groups, or PID type. Individual patient categories were too small to allow for multivariate analysis.

      Discussion

      Individuals with IEIs, and subsequent immune deficiency or immune dysregulation, are a priori considered an at-risk population for developing severe COVID-19 following SARS-CoV2 infection. Although a few studies have reported outcomes of SARS-CoV-2 infection in small numbers of patients with PID,
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      A possible role for B cells in COVID-19? Lesson from patients with agammaglobulinemia.
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      Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover.
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      • Bustamante-Ogando J.C.
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      A male infant with COVID-19 in the context of ARPC1B deficiency.
      • Mira E.
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      • Fernandez S.
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      Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma.
      the impact of the COVID-19 pandemic on the broader global population of these patients has not been established. Here, we report the occurrence and course of SARS-CoV-2 infection in 94 patients with IEI. Distribution between diagnostic IEI categories reflected that of large patient registries (esidregistry.org; usidnet.org). Thus, patients with antibody deficiencies are the predominant group with COVID, and approximately 20% of patients had CIDs or impaired innate immunity (Fig 1).
      Overall, presentation and risk factors (eg, pre-existing heart, lung, or kidney disease) for severe COVID-19 in patients with IEI seem very similar to those in the general population. Case-fatality rate was approximately 10%, in line with global data from the general population (1%-20%, Table I).
      World Health Organization
      Coronavirus disease (COVID-19) pandemic.
      ,
      • Stokes E.K.
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      Coronavirus disease 2019 case surveillance—United States, January 22-May 30, 2020.
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      • Wang D.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      , The mortality rate may actually be lower, because death of some patients may have resulted from IEI, rather than SARS-CoV-2 infection (eg, Burkholderia infection in P8 [X-CGD]; severe graft versus host disease in P9 [XIAP deficiency, post-HSCT]). Thus, perhaps surprisingly, the inherent immunocompromised state of the patients studied here was generally not a predominant risk factor for severe COVID-19. Similar to some epidemiological analyses,
      • Wang D.
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      Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.
      there was a male predominance among all patients with IEI (1.8:1), as well as those admitted to ICU (2.8:1). The sex ratio among patients with CVID with a more severe course (requiring at least oxygen) was also strongly skewed toward males (M:F, 8:5). However, there are apparent differences in the age distribution of patients with IEI affected by SARS-CoV-2 (median age, 25-34 years) as well as the frequency of ICU admissions (16%) compared with the general population (Table I).
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      Our study suggests that younger male patients with IEI are more likely to endure severe COVID-19 and require ICU admission. This skewing is not explained by the inclusion of X-linked disorders in this cohort (n = 13). Rather, differential levels of inflammatory mediators, T-cell responses, and/or virus-specific antibodies between infected males and females may explain the predominance of males with severe COVID-19.
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      Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions.
      One of the key findings from our study is the identification of both redundancies in the human immune system for host defense against SARS-CoV-2 and putative mediators of immune pathology following viral infection. First, many patients with defects predominantly in the adaptive immune system (eg, defective humoral [XLA, agammaglobulinemia, persisting humoral immunodeficiency in X-SCID after gene therapy] and/or T-cell [ZAP70, PGM3, STAT3, ARPC1B mutations] responses) were either asymptomatic or had only mild disease and promptly recovered (Table II; see references 19-22). Similarly, 11 patients with CVID had mild disease and did not require hospital admission, despite several having comorbidities. Thus, certain components of adaptive immunity do not appear to be essential for controlling SARS-CoV-2 infection. Rather, these adaptive immune deficiencies may even contribute to a milder course by reducing the immune-mediated sequelae. This is consistent with findings that patients with IEIs that specifically affect B- and T-cell development or function do not exhibit increased susceptibility to severe disease caused by influenza infection.
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      Our findings that patients with CVID comprised a large proportion of our cohort (>30%), and that 4 of these patients died (45% of all deaths), may infer that intact humoral immunity is important for host defense against SARS-CoV-2. However, these patients were generally older than the rest of the cohort (median age range, 45-54 years), and many had pre-existing health conditions that predispose to severe COVID-19 in the general population (lung disease in ∼50%, kidney/heart/gut/liver disease in ∼20%; Table II).
      Second, with the exception of the patient with X-CGD with Burkholderia sepsis, the other 3 patients with CGD had relatively mild disease, suggesting a modest contribution of neutrophil function in anti–SARS-CoV-2 immunity.
      Third, mild or asymptomatic disease in SARS-CoV-2+ patients with dominant negative STAT3 variants, despite pre-existing chronic lung disease, suggests that STAT3 signaling contributes to the cytokine storm characteristic of severe COVID-19. Together with findings that serum IL-6 levels are greatly increased during SARS-CoV-2 infection,
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      our data suggest that IL-6/STAT3 contributes to the inflammatory response and subsequent disease severity in COVID-19. Based on this, mild disease in XLA may reflect not only B-cell deficiency but also impaired IL-6 production by BTK-deficient myeloid cells,
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      potentially ameliorating SARS-CoV-2–induced cytokine storm.
      Fourth, all patients with autoinflammatory diseases were asymptomatic or stayed at home. However, most of these patients were young children, and both adults were treated with IL-1 blockade and colchicine.
      Two recent studies provide convincing evidence that disruption of type I IFN signaling is a frequent cause of life-threatening COVID-19.

      Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with severe COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4570.

      ,

      Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffman H-H, Zhang Y, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4585.

      In the first study, 650 patients with life-threatening COVID-19 were studied by whole-exome sequencing under the hypothesis that severe COVID-19 is allelic with severe influenza

      Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with severe COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4570.

      or that genes biologically related to these loci would be involved.
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      ,
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      • Meyts I.
      Recent human genetic errors of innate immunity leading to increased susceptibility to infection.
      Indeed, 3.5% of patients had known (AR IRF7 and IFNAR1 deficiency, autosomal-dominant TLR3, TICAM1, TBK1, and IRF3 deficiency) and new (autosomal-dominant UNC93B1, IRF7, IFNAR1, and IFNAR2 deficiency) genetic defects abolishing induction or amplification of type I IFNs.

      Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with severe COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4570.

      In the second study, neutralizing autoantibodies against type I IFNs were found in 10.2% of 987 patients with life-threatening COVID-19 pneumonia, resulting in low or undetectable serum levels of IFN-α during acute disease; 94% of the patients with autoantibodies were male. The net result of both the anti-IFN autoantibodies and the loss-of-function variants in crucial type I IFN pathway genes is a profound defect in type I IFN immunity, underlying life-threatening COVID-19 pneumonia.
      Intriguingly, we observed mild disease in patients with interferonopathies (AGS) treated with JAK inhibitors, suggesting sufficient residual type I IFN to protect from severe initial infection. It was striking that patients with NFKB1 or NFKB2 mutations required hospitalization, with both NFKB2-deficient individuals being admitted to ICU (Table II). Because the canonical and alternate NFKB pathways are activated in plasmacytoid dendritic cells to produce large amounts of type 1 IFNs,
      • Ito T.
      • Kanzler H.
      • Duramad O.
      • Cao W.
      • Liu Y.J.
      Specialization, kinetics, and repertoire of type 1 interferon responses by human plasmacytoid predendritic cells.
      severe COVID-19 in patients with NFKB1 or NFKB2 loss-of-function variants may be explained by deficient type I IFN responses. Similarly, an absence of type 1 IFN-producing myeloid cells may underlie COVID-19 due to GATA2 haploinsufficiency (Table I).
      • Sologuren I.
      • Martinez-Saavedra M.T.
      • Sole-Violan J.
      • de Borges de Oliveira Jr., E.
      • Betancor E.
      • Casas I.
      • et al.
      Lethal influenza in two related adults with inherited GATA2 deficiency.
      Because autoimmunity is a frequent manifestation of CVID, it can be hypothesized that the presence or absence of anti–type I IFN autoantibodies predisposed patients with CVID to either life-threatening or mild disease after SARS-CoV-2 infection. The finding of neutralizing anti-IFN autoantibodies in some individuals with severe COVID-1940 may also explain why patients with agammaglobulinemia generally did not develop severe COVID-19, and predict that COVID-19 may occur in some AIRE-deficient patients because these patients produce autoantibodies against type 1 IFNs.
      • Meager A.
      • Visvalingam K.
      • Peterson P.
      • Moll K.
      • Murumagi A.
      • Krohn K.
      • et al.
      Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1.
      Moving forward, it will be important to not only study the functionality of immune cells from patients with IEI in the context of innate IFN signaling but also assess these patients for neutralizing anti–type 1 IFN antibodies.
      Several caveats of our study need to be recognized. First, asymptomatic or mildly symptomatic SARS-CoV-2–infected patients with IEI are likely to be underdiagnosed, mainly due to regional testing priorities contributing to an ascertainment bias of such a retrospective study. Second, because we were guided by the most recent update of IEI,
      • Tangye S.G.
      • Al-Herz W.
      • Bousfiha A.
      • Chatila T.
      • Cunningham-Rundles C.
      • Etzioni A.
      • et al.
      Human inborn errors of immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee.
      • Bousfiha A.
      • Jeddane L.
      • Picard C.
      • Al-Herz W.
      • Ailal F.
      • Chatila T.
      • et al.
      Human inborn errors of immunity: 2019 Update of the IUIS Phenotypical Classification.
      • Notarangelo L.D.
      • Bacchetta R.
      • Casanova J.L.
      • Su H.C.
      Human inborn errors of immunity: an expanding universe.
      it is unlikely that all patients with IEI who have been infected with SARS-CoV-2 were captured by our survey. Indeed, the field of IEI continues to grow rapidly, with more than 35 novel genetic defects having been described since the last update by the International Union of Immunological Societies committee. Thus, we have not considered SARS-CoV-2 infection in individuals with these putative novel monogenic causes of immune dysregulation. Third, if our survey accurately reflects the true incidence of COVID-19 in IEI, it suggests that immunodeficient patients have been less frequently infected and are less symptomatic than the general population. This could be explained by patients with IEI being informed early in the pandemic about safety measures by patient and scientific organizations. Moreover, patients with IEI are familiar with frequent sanitation practices, avoiding crowds, physical distancing, self-isolation, and so forth, as recommended during this pandemic. Fourth, our study does not include any patients with known defects of type I IFN pathways. On the basis of findings from studies of severe influenza,
      • Zhang Q.
      Human genetics of life-threatening influenza pneumonitis.
      ,
      • Moens L.
      • Meyts I.
      Recent human genetic errors of innate immunity leading to increased susceptibility to infection.
      and recent investigation of the genetics of life-threatening SARS-CoV-2 infection,

      Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with severe COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4570.

      these patients are even more strongly advised to practice strict hand hygiene, mask wearing, and social distancing than other patients with PID.

       Conclusions

      We report the course of COVID-19 in 94 patients with IEI. The survey revealed that a substantial subgroup of patients with IEI suffer only a mild course of disease. Risk factors predisposing to severe disease and mortality among patients with IEI were comparable to those in the general population. However, younger patients with IEI were more severely affected and more frequently admitted to ICU compared with the general population. These findings warrant recommendation for further stringent personal protective measures for patients affected by IEI. The urgent need to document the impact of SARS-CoV-2 on patients with defined IEIs is currently being met by registries developed by additional organizations (eg, ESID registry, ERN-RITA joint effort, and COPID19), as well as the COVID Human Genetic Effort, which is performing large-scale genetic and functional studies on patients affected by severe COVID-19.
      • Casanova J.L.
      • Su H.C.
      COVID Human Genetic, Effort, A global effort to define the human genetics of protective immunity to SARS-CoV-2 infection.
      ,

      Zhang Q, Bastard P, Liu Z, Le Pen J, Moncada-Velez M, Chen J, et al. Inborn errors of type I IFN immunity in patients with severe COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4570.

      ,

      Bastard P, Rosen LB, Zhang Q, Michailidis E, Hoffman H-H, Zhang Y, et al. Auto-antibodies against type I IFNs in patients with life-threatening COVID-19 [published online ahead of print September 24, 2020]. Science. https://doi.org/10.1126/science.abd4585.

      Ideally, these studies will also include prospective longitudinal analysis to determine the long-term impact of SARS-CoV-2 even in convalescent individuals. These initiatives will further our insight into susceptibility of individual patients with IEI to disease. This will not only reveal necessary and redundant pathways for host defense against SARS-CoV-2 but also identify those that mediate collateral tissue damage in response to viral infection. Collectively, this and future studies have the potential to provide opportunities for immune modulation to treat COVID-19 in patients with IEI as well as the general population.
      Clinical implications
      Risk factors predisposing to severe disease and mortality after SARS-CoV-2 infection in patients with IEI were similar to those in the general population. Notwithstanding inclusion and diagnostic bias, admission rates to ICU tended to be higher and median age of affected patients lower than in the general population.
      We thank all the patients and clinicians involved in the care for these patients. We also thank the European Society for Immunodeficiencies, Clinical Immunology Society, Latin American Society for Immunodeficiencies, African Society for Immunodeficiencies, Asia Pacific Society for Immunodeficiencies, Australasian Society for Clinical Immunology & Allergy, the International Patient Organization for Primary Immunodeficiencies, and the Jeffrey Modell Foundation for distributing and promoting the e-survey to their members.
      Membership of the International Union of Immunological Societies Committee of Inborn Errors of Immunity: Waleed Al-Herz, Aziz Bousfiha, Charlotte Cunningham-Rundles, Jose Luis Franco, Steven M. Holland, Christoph Klein, Isabelle Meyts, Tomohiro Morio, Eric Oksenhendler, Capucine Picard, Anne Puel, Jennifer Puck, Mikko Seppanen, Raz Somech, Helen Su, Kathleen E. Sullivan, Stuart G. Tangye, and Troy R. Torgerson.

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