Low IgG trough and lymphocyte subset counts are associated with hospitalization for COVID-19 in patients with primary antibody deficiency

Abstract

Clinical ImplicationsHigher IgG trough in patients with primary antibody deficiency on IgG replacement therapy may reduce the need for hospitalization from coronavirus disease 2019. Monitoring lymphocyte counts in these patients may identify at-risk patients for hospitalization for coronavirus disease 2019.High-dose IgG therapy has been used in coronavirus disease 2019 (COVID-19) to modulate inflammatory responses.1Gharebaghi N. Nejadrahim R. Mousavi S.J. Sadat-Ebrahimi S.R. Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial.BMC Infect Dis. 2020; 20: 786Crossref PubMed Scopus (73) Google Scholar However, studies on the effect of IgG replacement therapy (IgGRT) on COVID-19 with primary antibody deficiency (PAD) are limited. IgGRT has been shown to modulate T-cell immunity and diminish proinflammatory responses of monocytes in common variable immune deficiency (CVID).2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar,3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar A case report on clinical outcomes of a CVID patient with COVID-19 postulated benefit of both high-dose intravenous immunoglobulin treatment and/or compliance with IgGRT in reducing the severity of COVID-19.4Aljaberi R. Wishah K. Positive outcome in a patient with coronavirus disease 2019 and common variable immunodeficiency after intravenous immunoglobulin.Ann Allergy Asthma Immunol. 2020; 125: 349-350Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar A study on cellular and humoral immune responses of 2 patients with CVID on IgGRT who presented with mild to asymptomatic COVID-19 showed robust CD4+ T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but 1 of the patients failed to mount SARS-CoV-2–specific antibody response.5Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41: 1146-1153Crossref PubMed Scopus (28) Google Scholar Well-established risk factors for COVID-19, including age and comorbidities, could also influence the outcome of COVID-19 in these patients.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar However, the function of IgGRT on modulation of cellular immunity and inflammation suggests a possible role for IgGRT in the outcomes of COVID-19 for these patients with PAD.2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar,3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar Here, we investigated the clinical and immunologic characteristics of patients with PAD on IgGRT, in relation to their clinical outcomes of COVID-19, assessed by the hospitalization.We performed a retrospective chart review of patients with COVID-19 from March 2020 to August 2021 at the Yale-New Haven Health System, Yale-affiliated community practices, and University of Virginia (UVA) Allergy and Immunology clinics. We collected demographics, comorbidities, home medications including IgGRT, laboratory data, and clinical outcomes of COVID-19 including hospitalization and mortality. We identified a total of 23 patients with PAD on IgGRT with SARS-CoV-2 infection based on positive nucleic-acid assay result (Yale-New Haven Health System [n = 10], Yale-affiliated community practices [n = 4], and UVA [n = 9]). Two of these patients were planned for, but not yet initiated on, IgGRT. This study was reviewed and approved by the institutional review boards of Yale University and UVA.Of the total 23 PAD patients with COVID-19 identified in this cohort, 26% (n = 6) of patients were hospitalized whereas 74% (n = 17) were treated as outpatients (Table I). None required intensive care unit management, and all patients survived. From this cohort, 56% (n = 13) of patients met the criteria for CVID and 43% (n = 10) of patients met the criteria for other PADs (Table I).7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google Scholar Protective titer pneumococcal polysaccharide vaccine was defined as titer greater than or equal to 1.3 μg/mL in this study (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org).7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google Scholar However, given the lack of consensus on defining protective antibody response, we also included a lower threshold considered protective against invasive pneumococcal disease defined as titer greater than or equal to 0.35 μg/mL (Table E1).8Bonilla F.A. Barlan I. Chapel H. Costa-Carvalho B.T. Cunningham-Rundles C. de la Morena M.T. et al.International Consensus Document (ICON): common variable immunodeficiency disorders.J Allergy Clin Immunol Pract. 2016; 4: 38-59Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar Criteria for diagnoses of CVID and other PADs are described in this article’s Online Repository’s Methods section at www.jaci-inpractice.org.7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google ScholarTable IClinical characteristics, outcome, and treatments of PAD patients with COVID-19PatientAge (y)SexEthnicityDiagnosisHospitalizedCHFAutoimmune disorderLung diseaseLast CT chest (no. of years ago)Malignancy historyIs therapy as outpatient?COVID treatment121MWhiteCVIDNoNoNoNo5NoNoCasirivimab225FWhiteCVIDNoNoNoNo6NoNoNo335FWhiteCVIDNoNoNoAsthmaNANoNoNo464FWhiteCVIDNoNoImmune thrombocytopenic purpuraBronchiectasis6Breast cancerNoNo565FWhiteCVIDNoNoNoNoNANoNoNo665FWhiteCVIDNoNoNoNo5NoNoNo769FWhiteCVIDNoNoNoBronchiectasis2NoNoBamlanivimab871MWhiteCVIDNoNoNoNo7NoNoNo932FWhiteCVID due to NFKB2 mutationNoNoAlopecia areataNo1NoNoBamlanivimab1039MWhiteBruton’s agammaglobulinemiaNoNoNoNo4NoNoCasirivimab/ imdevimab, prednisone1142FWhiteIgG deficiencyNoNoHashimoto’s thyroiditisNo1NoNoNo1265FWhiteIgG deficiencyNoNoNoAsthma<1Cervical cancerNoNo1369MWhiteIgG deficiencyNoNoNoAsthmaNANoNoNo1471MWhiteIgG deficiencyNoNoNoCOPD1Prostate cancerNoBamlanivimab1557FHispanicsAbD, IgG2 deficiencyNoNoNoAsthma, COPD, bronchiectasis<1NoNoNo1642FWhitesAbDNoNoNoNoNANoNoBamlanivimab1772MWhitesAbDNoNoNoCOPD1NoNoNo1858FWhiteCVIDYesNoNoAsthma<1NoNoDexamethasone, remdesivir, convalescent plasma1968MWhiteCVIDYesNoHashimoto’s thyroiditisCOPD, bronchiectasis1NoNoDexamethasone, remdesivir2070MWhiteCVIDYesYesSarcoidosisPulmonary sarcoidosis2NoMethotrexateDexamethasone, remdesivir2177FWhiteCVIDYesYesNoAsthma3NoNoDexamethasone, remdesivir2218FWhiteAgammaglobulinemia due to TCF3 mutationYesNoNoNo1NoNoNo2374FWhiteIgG deficiencyYesYesSLE, connective tissue overlap syndromeAsthma1NoLeuflonimide, prednisoneDexamethasone, remdesivirCOPD, Chronic obstructive pulmonary disorder; F, female; M, male; NA, information not applicable or not available; sAbD, specific antibody deficiency; SLE, systemic lupus erythematous. Open table in a new tab Available laboratory data were compared between patients who were hospitalized and those managed as outpatients. Most recent IgG trough level (791 mg/dL vs 1090 mg/dL; P = .0033) and baseline absolute counts of CD3+ (683 cell/μL vs 1290 cell/μL; P = .0082), CD3+CD4+ (341 cell/μL vs 784 cell/μL; P = .0029), and CD19+ cells (24.3 cell/μL vs 101 cell/μL; P = .0081) were significantly lower in the hospitalized patients compared with the outpatients (Figure 1). There was no significant difference in age, sex, baseline IgG level before IgGRT, IgG monthly dosing, baseline absolute counts of CD3+CD8+ T cells and CD3−CD16+CD56+ natural killer cells, or switched memory B-cell percentages between these 2 groups (Table E1). Within patients with CVID only, hospitalization was associated with IgG trough level (806 mg/dL vs 1112 mg/dL; P = .0028) and baseline absolute CD3+CD4+ T-cell counts (276 cell/μL vs 652 cell/μL; P = .0485) (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org). Patients with CVID compared with all other patients with PAD had significantly higher IgGRT dose and lower levels of baseline IgA and IgM, but there were no significant differences in hospitalization, age, baseline IgG level, IgG trough, and other immune parameters.Next, we compared the well-established comorbidities associated with poor outcome of COVID-19 between hospitalized and nonhospitalized PAD patients with COVID-19.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar Frequencies of lung disease, autoimmune disorder, malignancy, use of immunosuppressive therapy, hypertension, coronary artery disease, diabetes mellitus, obesity, chronic kidney disease, smoking, and congestive heart failure (CHF) were compared.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar Of these, hospitalized patients presented with a significantly higher frequency of CHF than nonhospitalized patients (50% vs 0%; P = .0113; Table I). Although lung disease did not show a significant difference between hospitalized patients and outpatients in all patients with PAD, an increased percentage of lung disease was observed in hospitalized patients with CVID compared with outpatients (100% vs 33%; P = .069; Table I). Many of our patients did not have recent chest imaging (Table I); therefore, assessment of current lung disease was limited.This study showed that hospitalized patients with PAD on IgGRT due to COVID-19 presented with lower IgG trough level and absolute counts of CD3+, CD3+CD4+ T cells, and CD19+ B cells, as well as higher frequency of CHF compared with nonhospitalized patients. Lymphocytopenia and exhaustion of T lymphocytes have been associated with worse COVID-19 outcomes.9Zheng H.Y. Zhang M. Yang C.X. Zhang N. Wang X.C. Yang X.P. et al.Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.Cell Mol Immunol. 2020; 17: 541-543Crossref PubMed Scopus (549) Google Scholar CHF is also one of the well-described comorbidities associated with poor outcome of COVID-19.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar However, to our knowledge, this is the first study demonstrating an association of lower IgG trough level with hospitalization for COVID-19 in patients with PAD receiving IgGRT. High-dose immunoglobulin therapy (1 g/kg) is frequently used as an immune-modulating therapy for autoimmune and inflammatory disorders.1Gharebaghi N. Nejadrahim R. Mousavi S.J. Sadat-Ebrahimi S.R. Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial.BMC Infect Dis. 2020; 20: 786Crossref PubMed Scopus (73) Google Scholar Although IgGRT is typically lower in dose (400-600 mg/kg) in PAD, IgGRT was also shown to modulate T-cell immunity by increasing CD4+ T-cell counts and suppressing CD8+ T-cell activation,2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar and diminishing proinflammatory responses of monocytes.3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar Therefore, it is tempting to speculate that maintaining higher IgG trough levels may positively modulate the cellular immune response and inflammation, leading to favorable outcome of COVID-19.Limitations of the study include the small sample size. Inherent to the retrospective chart review design, some subjects had incomplete clinical and laboratory values available for analysis. Six nonhospitalized subjects were treated with COVID-19 monoclonal antibody therapy as outpatients. Likely, their initial presentation was not severe for hospitalization; however, it is also feasible that this therapy may have later protected them from hospitalization. Further investigations are warranted to better characterize the effect of IgGRT on immune modulation and protection from severe disease outcomes of COVID-19 in patients with PAD. Clinical ImplicationsHigher IgG trough in patients with primary antibody deficiency on IgG replacement therapy may reduce the need for hospitalization from coronavirus disease 2019. Monitoring lymphocyte counts in these patients may identify at-risk patients for hospitalization for coronavirus disease 2019. Higher IgG trough in patients with primary antibody deficiency on IgG replacement therapy may reduce the need for hospitalization from coronavirus disease 2019. Monitoring lymphocyte counts in these patients may identify at-risk patients for hospitalization for coronavirus disease 2019. Higher IgG trough in patients with primary antibody deficiency on IgG replacement therapy may reduce the need for hospitalization from coronavirus disease 2019. Monitoring lymphocyte counts in these patients may identify at-risk patients for hospitalization for coronavirus disease 2019. High-dose IgG therapy has been used in coronavirus disease 2019 (COVID-19) to modulate inflammatory responses.1Gharebaghi N. Nejadrahim R. Mousavi S.J. Sadat-Ebrahimi S.R. Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial.BMC Infect Dis. 2020; 20: 786Crossref PubMed Scopus (73) Google Scholar However, studies on the effect of IgG replacement therapy (IgGRT) on COVID-19 with primary antibody deficiency (PAD) are limited. IgGRT has been shown to modulate T-cell immunity and diminish proinflammatory responses of monocytes in common variable immune deficiency (CVID).2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar,3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar A case report on clinical outcomes of a CVID patient with COVID-19 postulated benefit of both high-dose intravenous immunoglobulin treatment and/or compliance with IgGRT in reducing the severity of COVID-19.4Aljaberi R. Wishah K. Positive outcome in a patient with coronavirus disease 2019 and common variable immunodeficiency after intravenous immunoglobulin.Ann Allergy Asthma Immunol. 2020; 125: 349-350Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar A study on cellular and humoral immune responses of 2 patients with CVID on IgGRT who presented with mild to asymptomatic COVID-19 showed robust CD4+ T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but 1 of the patients failed to mount SARS-CoV-2–specific antibody response.5Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41: 1146-1153Crossref PubMed Scopus (28) Google Scholar Well-established risk factors for COVID-19, including age and comorbidities, could also influence the outcome of COVID-19 in these patients.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar However, the function of IgGRT on modulation of cellular immunity and inflammation suggests a possible role for IgGRT in the outcomes of COVID-19 for these patients with PAD.2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar,3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar Here, we investigated the clinical and immunologic characteristics of patients with PAD on IgGRT, in relation to their clinical outcomes of COVID-19, assessed by the hospitalization. We performed a retrospective chart review of patients with COVID-19 from March 2020 to August 2021 at the Yale-New Haven Health System, Yale-affiliated community practices, and University of Virginia (UVA) Allergy and Immunology clinics. We collected demographics, comorbidities, home medications including IgGRT, laboratory data, and clinical outcomes of COVID-19 including hospitalization and mortality. We identified a total of 23 patients with PAD on IgGRT with SARS-CoV-2 infection based on positive nucleic-acid assay result (Yale-New Haven Health System [n = 10], Yale-affiliated community practices [n = 4], and UVA [n = 9]). Two of these patients were planned for, but not yet initiated on, IgGRT. This study was reviewed and approved by the institutional review boards of Yale University and UVA. Of the total 23 PAD patients with COVID-19 identified in this cohort, 26% (n = 6) of patients were hospitalized whereas 74% (n = 17) were treated as outpatients (Table I). None required intensive care unit management, and all patients survived. From this cohort, 56% (n = 13) of patients met the criteria for CVID and 43% (n = 10) of patients met the criteria for other PADs (Table I).7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google Scholar Protective titer pneumococcal polysaccharide vaccine was defined as titer greater than or equal to 1.3 μg/mL in this study (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org).7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google Scholar However, given the lack of consensus on defining protective antibody response, we also included a lower threshold considered protective against invasive pneumococcal disease defined as titer greater than or equal to 0.35 μg/mL (Table E1).8Bonilla F.A. Barlan I. Chapel H. Costa-Carvalho B.T. Cunningham-Rundles C. de la Morena M.T. et al.International Consensus Document (ICON): common variable immunodeficiency disorders.J Allergy Clin Immunol Pract. 2016; 4: 38-59Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar Criteria for diagnoses of CVID and other PADs are described in this article’s Online Repository’s Methods section at www.jaci-inpractice.org.7Shin J.J. Liauw D. Siddiqui S. Lee J. Chung E.J. Steele R. et al.Immunological and clinical phenotyping in primary antibody deficiencies: a growing disease spectrum.J Clin Immunol. 2020; 40: 592-601Crossref PubMed Scopus (8) Google Scholar COPD, Chronic obstructive pulmonary disorder; F, female; M, male; NA, information not applicable or not available; sAbD, specific antibody deficiency; SLE, systemic lupus erythematous. Available laboratory data were compared between patients who were hospitalized and those managed as outpatients. Most recent IgG trough level (791 mg/dL vs 1090 mg/dL; P = .0033) and baseline absolute counts of CD3+ (683 cell/μL vs 1290 cell/μL; P = .0082), CD3+CD4+ (341 cell/μL vs 784 cell/μL; P = .0029), and CD19+ cells (24.3 cell/μL vs 101 cell/μL; P = .0081) were significantly lower in the hospitalized patients compared with the outpatients (Figure 1). There was no significant difference in age, sex, baseline IgG level before IgGRT, IgG monthly dosing, baseline absolute counts of CD3+CD8+ T cells and CD3−CD16+CD56+ natural killer cells, or switched memory B-cell percentages between these 2 groups (Table E1). Within patients with CVID only, hospitalization was associated with IgG trough level (806 mg/dL vs 1112 mg/dL; P = .0028) and baseline absolute CD3+CD4+ T-cell counts (276 cell/μL vs 652 cell/μL; P = .0485) (see Figure E1 in this article’s Online Repository at www.jaci-inpractice.org). Patients with CVID compared with all other patients with PAD had significantly higher IgGRT dose and lower levels of baseline IgA and IgM, but there were no significant differences in hospitalization, age, baseline IgG level, IgG trough, and other immune parameters. Next, we compared the well-established comorbidities associated with poor outcome of COVID-19 between hospitalized and nonhospitalized PAD patients with COVID-19.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar Frequencies of lung disease, autoimmune disorder, malignancy, use of immunosuppressive therapy, hypertension, coronary artery disease, diabetes mellitus, obesity, chronic kidney disease, smoking, and congestive heart failure (CHF) were compared.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar Of these, hospitalized patients presented with a significantly higher frequency of CHF than nonhospitalized patients (50% vs 0%; P = .0113; Table I). Although lung disease did not show a significant difference between hospitalized patients and outpatients in all patients with PAD, an increased percentage of lung disease was observed in hospitalized patients with CVID compared with outpatients (100% vs 33%; P = .069; Table I). Many of our patients did not have recent chest imaging (Table I); therefore, assessment of current lung disease was limited. This study showed that hospitalized patients with PAD on IgGRT due to COVID-19 presented with lower IgG trough level and absolute counts of CD3+, CD3+CD4+ T cells, and CD19+ B cells, as well as higher frequency of CHF compared with nonhospitalized patients. Lymphocytopenia and exhaustion of T lymphocytes have been associated with worse COVID-19 outcomes.9Zheng H.Y. Zhang M. Yang C.X. Zhang N. Wang X.C. Yang X.P. et al.Elevated exhaustion levels and reduced functional diversity of T cells in peripheral blood may predict severe progression in COVID-19 patients.Cell Mol Immunol. 2020; 17: 541-543Crossref PubMed Scopus (549) Google Scholar CHF is also one of the well-described comorbidities associated with poor outcome of COVID-19.6Suleyman G. Fadel R.A. Malette K.M. Hammond C. Abdulla H. Entz A. et al.Clinical characteristics and morbidity associated with coronavirus disease 2019 in a series of patients in Metropolitan Detroit.JAMA Netw Open. 2020; 3e2012270Crossref PubMed Scopus (345) Google Scholar However, to our knowledge, this is the first study demonstrating an association of lower IgG trough level with hospitalization for COVID-19 in patients with PAD receiving IgGRT. High-dose immunoglobulin therapy (1 g/kg) is frequently used as an immune-modulating therapy for autoimmune and inflammatory disorders.1Gharebaghi N. Nejadrahim R. Mousavi S.J. Sadat-Ebrahimi S.R. Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial.BMC Infect Dis. 2020; 20: 786Crossref PubMed Scopus (73) Google Scholar Although IgGRT is typically lower in dose (400-600 mg/kg) in PAD, IgGRT was also shown to modulate T-cell immunity by increasing CD4+ T-cell counts and suppressing CD8+ T-cell activation,2Paquin-Proulx D. Santos B.A. Carvalho K.I. Toledo-Barros M. Barreto de Oliveira A.K. Kokron C.M. et al.IVIg immune reconstitution treatment alleviates the state of persistent immune activation and suppressed CD4 T cell counts in CVID.PLoS One. 2013; 8e75199PubMed Google Scholar and diminishing proinflammatory responses of monocytes.3Siedlar M. Strach M. Bukowska-Strakova K. Lenart M. Szaflarska A. Weglarczyk K. et al.Preparations of intravenous immunoglobulins diminish the number and proinflammatory response of CD14+CD16++ monocytes in common variable immunodeficiency (CVID) patients.Clin Immunol. 2011; 139: 122-132Crossref PubMed Scopus (47) Google Scholar Therefore, it is tempting to speculate that maintaining higher IgG trough levels may positively modulate the cellular immune response and inflammation, leading to favorable outcome of COVID-19. Limitations of the study include the small sample size. Inherent to the retrospective chart review design, some subjects had incomplete clinical and laboratory values available for analysis. Six nonhospitalized subjects were treated with COVID-19 monoclonal antibody therapy as outpatients. Likely, their initial presentation was not severe for hospitalization; however, it is also feasible that this therapy may have later protected them from hospitalization. Further investigations are warranted to better characterize the effect of IgGRT on immune modulation and protection from severe disease outcomes of COVID-19 in patients with PAD. Special thanks go to Soundari Sureshanand and Richard Hintz from the Joint Data Analytics Team (JDAT) at the Yale Center for Clinical Investigation for their proficient and efficient handling of data extraction and reporting. Data extraction was also supported by the Yale School of Medicine, Department of Internal Medicine, Clinical and Translational Research Accelerator. The content is solely the responsibility of the authors and does not necessarily represent the official views of the members of NIH, JDAT and the Clinical and Translational Research Accelerator. Online RepositoryMethodsDefining diagnoses of PADsCVID was defined with low IgG, IgA, and/or IgM levels (2 SDs below the mean for age) and decreased immune response to a pneumococcal polysaccharide vaccine (PNA) vaccine.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar For PNA vaccine response, we used either 14 or 23 serotype panel that was available for both prevaccination and postvaccination. Protective titer was defined as titer greater than or equal to 1.3 μg/mL, and patients with more than 70% of serotypes with protective titers after vaccination were considered to have protective PNA vaccine response.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG deficiency was assigned if IgG levels were lower than 2 SD below the mean for age without meeting the criteria for CVID.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG subclass deficiency was assigned if IgG subclass 1, 2, 3, or 4 levels were lower than 2 SD below the mean of age, with normal levels of total IgG and other IgG subclasses.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Specific antibody deficiency was assigned if a patient had a low immune response to a PNA vaccine but normal levels of IgG, IgA, and IgM.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Patients were excluded from this study if chart review revealed an alternative cause for hypogammaglobulinemia such as intestinal loss, chronic corticosteroid use, preexisting diagnoses of hematopoietic malignancies before the diagnosis of PADs, or use of B-cell–depleting therapies.Table E1Immunologic characteristics, IgGRT dose, and IgG trough levels of PAD patients with COVID-19PatientAge (y)SexBaseline (mg/dL)Baseline (cells/mm3)Baseline (%)Pneumococcal vaccine responseIgG trough (mg/dL)IgGRT dose (mg/kg/mo)IgGIgAIgMCD3CD4CD8NKCD19smBClinically noted poor response?∗Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.Serotypes with titer≥1.3 μg/mLSerotypes with titer≥0.35 μg/mL121M4900201701707714105270.8NA8 of 2317 of 231096925225F5911432144876659038841Yes8 of 2322 of 231000430335F63805NANANANANANAYes3 of 148 of 141350820464F74067994783192104710.1Yes0 of 141 of 141017960565F4636265727570191220124NAYes8 of 2318 of 23986230665F45352559937412342271225.6NA1 of 14NA1072400769FNA35221562475102515219NANANANA1141515871M43567271218100319326364NAYes5 of 149 of 141132500932FNA0036017018037106NANANANA12114551039MNA017243010107922730NANANANA5262001142FNA2181271235793402233166NAYesNANA11465001265F4541551229756543217111912.8Yes7 of 2313 of 2312074801369M586173631034740262NANANANo17 of 2323 of 23586†Not yet started on IgGRT.1471M31035765174512994672036119.2Yes5 of 1411 of 1410624101557F11094079316231267430796290NAYes6 of 2317 of 2316333501642F8753931421047645399NA206NANA1 of 238 of 2313303801772M692314NA147992255619252NANANANA10374201858F527110269745543581136015.8YesNANA527†Not yet started on IgGRT.1968M19890NANANANANA0.1Yes0 of 140 of 149006002070M486611022014564173124.8Yes9 of 2317 of 238963502177FNA5994524129982061918.3NANANA9015402218F000100060333819715NANANANA9954002374F4542688069927243650168.2Yes2 of 146 of 14528400F, Female; M, male; NA, information not available; NK, natural killer; smB, switched memory B.∗ Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.† Not yet started on IgGRT. Open table in a new tab MethodsDefining diagnoses of PADsCVID was defined with low IgG, IgA, and/or IgM levels (2 SDs below the mean for age) and decreased immune response to a pneumococcal polysaccharide vaccine (PNA) vaccine.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar For PNA vaccine response, we used either 14 or 23 serotype panel that was available for both prevaccination and postvaccination. Protective titer was defined as titer greater than or equal to 1.3 μg/mL, and patients with more than 70% of serotypes with protective titers after vaccination were considered to have protective PNA vaccine response.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG deficiency was assigned if IgG levels were lower than 2 SD below the mean for age without meeting the criteria for CVID.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG subclass deficiency was assigned if IgG subclass 1, 2, 3, or 4 levels were lower than 2 SD below the mean of age, with normal levels of total IgG and other IgG subclasses.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Specific antibody deficiency was assigned if a patient had a low immune response to a PNA vaccine but normal levels of IgG, IgA, and IgM.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Patients were excluded from this study if chart review revealed an alternative cause for hypogammaglobulinemia such as intestinal loss, chronic corticosteroid use, preexisting diagnoses of hematopoietic malignancies before the diagnosis of PADs, or use of B-cell–depleting therapies.Table E1Immunologic characteristics, IgGRT dose, and IgG trough levels of PAD patients with COVID-19PatientAge (y)SexBaseline (mg/dL)Baseline (cells/mm3)Baseline (%)Pneumococcal vaccine responseIgG trough (mg/dL)IgGRT dose (mg/kg/mo)IgGIgAIgMCD3CD4CD8NKCD19smBClinically noted poor response?∗Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.Serotypes with titer≥1.3 μg/mLSerotypes with titer≥0.35 μg/mL121M4900201701707714105270.8NA8 of 2317 of 231096925225F5911432144876659038841Yes8 of 2322 of 231000430335F63805NANANANANANAYes3 of 148 of 141350820464F74067994783192104710.1Yes0 of 141 of 141017960565F4636265727570191220124NAYes8 of 2318 of 23986230665F45352559937412342271225.6NA1 of 14NA1072400769FNA35221562475102515219NANANANA1141515871M43567271218100319326364NAYes5 of 149 of 141132500932FNA0036017018037106NANANANA12114551039MNA017243010107922730NANANANA5262001142FNA2181271235793402233166NAYesNANA11465001265F4541551229756543217111912.8Yes7 of 2313 of 2312074801369M586173631034740262NANANANo17 of 2323 of 23586†Not yet started on IgGRT.1471M31035765174512994672036119.2Yes5 of 1411 of 1410624101557F11094079316231267430796290NAYes6 of 2317 of 2316333501642F8753931421047645399NA206NANA1 of 238 of 2313303801772M692314NA147992255619252NANANANA10374201858F527110269745543581136015.8YesNANA527†Not yet started on IgGRT.1968M19890NANANANANA0.1Yes0 of 140 of 149006002070M486611022014564173124.8Yes9 of 2317 of 238963502177FNA5994524129982061918.3NANANA9015402218F000100060333819715NANANANA9954002374F4542688069927243650168.2Yes2 of 146 of 14528400F, Female; M, male; NA, information not available; NK, natural killer; smB, switched memory B.∗ Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.† Not yet started on IgGRT. Open table in a new tab Defining diagnoses of PADsCVID was defined with low IgG, IgA, and/or IgM levels (2 SDs below the mean for age) and decreased immune response to a pneumococcal polysaccharide vaccine (PNA) vaccine.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar For PNA vaccine response, we used either 14 or 23 serotype panel that was available for both prevaccination and postvaccination. Protective titer was defined as titer greater than or equal to 1.3 μg/mL, and patients with more than 70% of serotypes with protective titers after vaccination were considered to have protective PNA vaccine response.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG deficiency was assigned if IgG levels were lower than 2 SD below the mean for age without meeting the criteria for CVID.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG subclass deficiency was assigned if IgG subclass 1, 2, 3, or 4 levels were lower than 2 SD below the mean of age, with normal levels of total IgG and other IgG subclasses.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Specific antibody deficiency was assigned if a patient had a low immune response to a PNA vaccine but normal levels of IgG, IgA, and IgM.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Patients were excluded from this study if chart review revealed an alternative cause for hypogammaglobulinemia such as intestinal loss, chronic corticosteroid use, preexisting diagnoses of hematopoietic malignancies before the diagnosis of PADs, or use of B-cell–depleting therapies.Table E1Immunologic characteristics, IgGRT dose, and IgG trough levels of PAD patients with COVID-19PatientAge (y)SexBaseline (mg/dL)Baseline (cells/mm3)Baseline (%)Pneumococcal vaccine responseIgG trough (mg/dL)IgGRT dose (mg/kg/mo)IgGIgAIgMCD3CD4CD8NKCD19smBClinically noted poor response?∗Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.Serotypes with titer≥1.3 μg/mLSerotypes with titer≥0.35 μg/mL121M4900201701707714105270.8NA8 of 2317 of 231096925225F5911432144876659038841Yes8 of 2322 of 231000430335F63805NANANANANANAYes3 of 148 of 141350820464F74067994783192104710.1Yes0 of 141 of 141017960565F4636265727570191220124NAYes8 of 2318 of 23986230665F45352559937412342271225.6NA1 of 14NA1072400769FNA35221562475102515219NANANANA1141515871M43567271218100319326364NAYes5 of 149 of 141132500932FNA0036017018037106NANANANA12114551039MNA017243010107922730NANANANA5262001142FNA2181271235793402233166NAYesNANA11465001265F4541551229756543217111912.8Yes7 of 2313 of 2312074801369M586173631034740262NANANANo17 of 2323 of 23586†Not yet started on IgGRT.1471M31035765174512994672036119.2Yes5 of 1411 of 1410624101557F11094079316231267430796290NAYes6 of 2317 of 2316333501642F8753931421047645399NA206NANA1 of 238 of 2313303801772M692314NA147992255619252NANANANA10374201858F527110269745543581136015.8YesNANA527†Not yet started on IgGRT.1968M19890NANANANANA0.1Yes0 of 140 of 149006002070M486611022014564173124.8Yes9 of 2317 of 238963502177FNA5994524129982061918.3NANANA9015402218F000100060333819715NANANANA9954002374F4542688069927243650168.2Yes2 of 146 of 14528400F, Female; M, male; NA, information not available; NK, natural killer; smB, switched memory B.∗ Clinically noted in chart as poor pneumococcal vaccine responder in charting documentation, independent of available laboratory data in our electronic medical system because some patients had outside workup done before establishing care.† Not yet started on IgGRT. Open table in a new tab CVID was defined with low IgG, IgA, and/or IgM levels (2 SDs below the mean for age) and decreased immune response to a pneumococcal polysaccharide vaccine (PNA) vaccine.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar For PNA vaccine response, we used either 14 or 23 serotype panel that was available for both prevaccination and postvaccination. Protective titer was defined as titer greater than or equal to 1.3 μg/mL, and patients with more than 70% of serotypes with protective titers after vaccination were considered to have protective PNA vaccine response.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG deficiency was assigned if IgG levels were lower than 2 SD below the mean for age without meeting the criteria for CVID.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar IgG subclass deficiency was assigned if IgG subclass 1, 2, 3, or 4 levels were lower than 2 SD below the mean of age, with normal levels of total IgG and other IgG subclasses.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Specific antibody deficiency was assigned if a patient had a low immune response to a PNA vaccine but normal levels of IgG, IgA, and IgM.E1Kinoshita H. Durkee-Shock J. Jensen-Wachspress M. Kankate V.V. Lang H. Lazarski C.A. et al.Robust antibody and T cell responses to SARS-CoV-2 in patients with antibody deficiency.J Clin Immunol. 2021; 41 (1146-53)Crossref PubMed Scopus (28) Google Scholar Patients were excluded from this study if chart review revealed an alternative cause for hypogammaglobulinemia such as intestinal loss, chronic corticosteroid use, preexisting diagnoses of hematopoietic malignancies before the diagnosis of PADs, or use of B-cell–depleting therapies. F, Female; M, male; NA, information not available; NK, natural killer; smB, switched memory B.