SARS-CoV-2 symptomatic reinfection among patients with primary antibody deficiency

Abstract

Clinical ImplicationsOur data show a high rate of symptomatic reinfection with severe acute respiratory syndrome coronavirus 2 in patients with primary antibody deficiency. This highlights the susceptibility of this patient population, supporting the need for continued isolation, prophylactic treatment, and further development of therapeutic options. The severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) pandemic has appeared as a global threat to human health, with more than 280 million confirmed cases and more than 5 million deaths so far.1World Health Organization (WHO)WHO Coronavirus (COVID-19) Dashboard.https://covid19.who.int/Date accessed: December 12, 2021Google Scholar However, true reinfection with pre-omicron strains is rare.2Pilz S. Chakeri A. Ioannidis J.P. Richter L. Theiler-Schwetz V. Trummer C. et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (76) Google Scholar, 3Sheehan M.M. Reddy A.J. Rothberg M.B. Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; 73: 1882-1886Crossref PubMed Scopus (53) Google Scholar, 4Rivelli A. Fitzpatrick V. Blair C. Copeland K. Richards J. Incidence of COVID-19 reinfection among Midwestern healthcare employees.PLoS One. 2022; 17e0262164Crossref PubMed Scopus (2) Google Scholar, 5Tang X. Musa S.S. Zhao S. He D. Reinfection or reactivation of severe acute respiratory syndrome coronavirus 2: a systematic review.Front Public Health. 2021; 9: 663045Crossref PubMed Scopus (18) Google Scholar, 6Grammatikos A. Donati M. Johnston S.L. Gompels M.M. Peripheral B cell deficiency and predisposition to viral infections: the paradigm of immune deficiencies.Front Immunol. 2021; 12: 731643Crossref PubMed Scopus (9) Google Scholar Estimated rates of reinfection of 0.6% to 1% were suggested in international and Israeli studies.2Pilz S. Chakeri A. Ioannidis J.P. Richter L. Theiler-Schwetz V. Trummer C. et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (76) Google Scholar, 3Sheehan M.M. Reddy A.J. Rothberg M.B. Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; 73: 1882-1886Crossref PubMed Scopus (53) Google Scholar, 4Rivelli A. Fitzpatrick V. Blair C. Copeland K. Richards J. Incidence of COVID-19 reinfection among Midwestern healthcare employees.PLoS One. 2022; 17e0262164Crossref PubMed Scopus (2) Google Scholar, 5Tang X. Musa S.S. Zhao S. He D. Reinfection or reactivation of severe acute respiratory syndrome coronavirus 2: a systematic review.Front Public Health. 2021; 9: 663045Crossref PubMed Scopus (18) Google Scholar, 6Grammatikos A. Donati M. Johnston S.L. Gompels M.M. Peripheral B cell deficiency and predisposition to viral infections: the paradigm of immune deficiencies.Front Immunol. 2021; 12: 731643Crossref PubMed Scopus (9) Google Scholar Patients with B-cell abnormalities and lack of antibody production are more susceptible to SARS-CoV-2 infection.7Marcus N. Frizinsky S. Hagin D. Ovadia A. Hanna S. Farkash M. et al.Minor clinical impact of COVID-19 pandemic on patients with primary immunodeficiency in Israel.Front Immunol. 2021; 11: 614086Crossref PubMed Scopus (55) Google Scholar It is therefore presumed that such patients, particularly those with primary antibody deficiency (PAD) who rely on intravenous immunoglobulin replacement therapy (IGRT) for protection against other viruses, would likely be more susceptible to reinfection with SARS-CoV-2. Herein, we describe 5 patients with PAD from 2 immunology services in Israel who reported having a symptomatic SARS-CoV-2 infection in July 2020 and January 2021 with a full clinical recovery. All patients had several negative SARS-CoV-2 polymerase chain reaction (PCR) testing after their initial infection. During the delta variant (B.1.617.2) wave occurring in September 2021 in Israel, all 5 patients suffered from a new distinct SARS-CoV-2 symptomatic reinfection. None of the described 5 patients received the Pfizer-BioNTech COVID-19 vaccine because of apprehension of vaccine-related side effects. Patient 1 diagnosed with X-linked agammaglobulinemia (XLA) presented with SARS-CoV-2 infection in January 21. He developed pneumonia needing prolonged hospitalization and treatment with antiviral medication and convalescent plasma. After complete recovery, he was hospitalized again with a new SARS-CoV-2 infection during the delta wave variant. He again suffered from pneumonia (Figure 1), and a similarly severe course complicated by diabetic ketoacidosis. Patient 2 also diagnosed with XLA had his first infection with SARS-CoV-2 in January 2021. He had 5 days of fever and cough. He was not hospitalized. On September 2021, 8 months after the initial disease, he developed fever and cough with positive SARS-CoV-2 PCR. Symptoms resolved after a few days; however, viral PCR testing was positive at day 25 of illness (CCT 24), necessitating prolonged isolation. Patient 3 with hyper-IgM syndrome presented with SARS-CoV-2 infection with fever and cough and respiratory distress in July 2020, and was isolated for 8 weeks because of prolonged positive PCR. His second infection occurred in September 21 again with fever and cough. Patient 4 diagnosed with RelB deficiency had 2 SARS-Cov-2 infections, the first on September 20 and the second on October 21, presenting with cough, upper respiratory symptoms, and fever. Patient 5 diagnosed with XLA presented with fever and diarrhea and was first diagnosed with SARS-CoV-2 infection on January 2021. During his acute illness, he was hospitalized and treated with fluids and ceftriaxone for 2 days. Symptoms resolved; however, PCR testing remained positive for 5 weeks, necessitating prolonged isolation. On September 2021, he developed his second SAR-CoV-2 infection with high fever, cough, headache, and gastrointestinal symptoms. He was hospitalized for 2 days and was treated with ceftriaxone and fluids. Details of these 5 patients are shown in Table I.Table IDemographic and clinical data of 5 patients with primary antibody deficiency who suffered from SARS-CoV-2 reinfectionPatient no.12345Age/sex17.5 y/M13 y/M31 y/M16 y/F9.5 y/MUnderlying PAD diagnosisXLAXLAHIGMSCD40L-defRelBXLADate of first infectionJanuary 21January 21July 20September 20January 21Last day of +PCR test after infection30 d30 d60 d21 d3 dCourse of first infectionSevere pneumoniaHypoxemiaMildModerateRespiratory distressMildModerateHospitalization days8 dNone3 dNone3 dTreatment of first infectionDexamethasoneRemdesivirEnoxaparinConvalescent plasmaNoneDexamethasoneNoneFluids CeftriaxoneDate of second infectionSeptember 21September 21September 21October 21September 21Last day of +PCR test after infection11 d30 dN/A14 d35 dCourse of second infectionSevere pneumoniaHypoxemiaDKA (IDDM1)ModerateModerateModerateModerateHospitalization days5 dNoneNone3 d3 dTreatment of second infectionCeftriaxoneInsulin/fluidsEnoxaparinConvalescent plasmaNoneNoneMonoclonal anti-SARS-CoV-2 antibodies (Regeneron)Ceftriaxone Fluids IVIG30d+PCR, 30 days of positive SARS-CoV-2 PCR test after initial positive PCR; CD40L-def, CD40 ligand deficiency; DKA, diabetic ketoacidosis; HIGMS, hyper-IgM syndrome; IDDM1, insulin-dependent diabetes mellitus; IVIG, intravenous immunoglobulin; N/A, not applicable; PCR, polymerase chain reaction; RelB, transcription factor RelB deficiency; XLA, X-linked agammaglobulinemia. Open table in a new tab 30d+PCR, 30 days of positive SARS-CoV-2 PCR test after initial positive PCR; CD40L-def, CD40 ligand deficiency; DKA, diabetic ketoacidosis; HIGMS, hyper-IgM syndrome; IDDM1, insulin-dependent diabetes mellitus; IVIG, intravenous immunoglobulin; N/A, not applicable; PCR, polymerase chain reaction; RelB, transcription factor RelB deficiency; XLA, X-linked agammaglobulinemia. In this report, we describe 5 patients aged 9 to 31 years with PAD, adequately treated with IGRT, who suffered a SARS-CoV-2 symptomatic reinfection during the delta variant (B.1.617.2) wave. This description is exceptional because of the low rates of reinfection previously reported among immunocompetent hosts.2Pilz S. Chakeri A. Ioannidis J.P. Richter L. Theiler-Schwetz V. Trummer C. et al.SARS-CoV-2 re-infection risk in Austria.Eur J Clin Invest. 2021; 51e13520Crossref Scopus (76) Google Scholar, 3Sheehan M.M. Reddy A.J. Rothberg M.B. Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; 73: 1882-1886Crossref PubMed Scopus (53) Google Scholar, 4Rivelli A. Fitzpatrick V. Blair C. Copeland K. Richards J. Incidence of COVID-19 reinfection among Midwestern healthcare employees.PLoS One. 2022; 17e0262164Crossref PubMed Scopus (2) Google Scholar, 5Tang X. Musa S.S. Zhao S. He D. Reinfection or reactivation of severe acute respiratory syndrome coronavirus 2: a systematic review.Front Public Health. 2021; 9: 663045Crossref PubMed Scopus (18) Google Scholar, 6Grammatikos A. Donati M. Johnston S.L. Gompels M.M. Peripheral B cell deficiency and predisposition to viral infections: the paradigm of immune deficiencies.Front Immunol. 2021; 12: 731643Crossref PubMed Scopus (9) Google Scholar Our cohort included 65 patients with PAD followed at the Schneider's Children Medical Center of Israel and at the Edith Wolfson Medical Center; 11 of 65 (17%) patients with PAD suffered from SARS-CoV-2 infection and 5 of the 11 (42%) patients infected suffered from reinfection during the delta variant wave. This is despite meticulous immunoglobulin replacement therapy protecting them from other infections. Tang et al5Tang X. Musa S.S. Zhao S. He D. Reinfection or reactivation of severe acute respiratory syndrome coronavirus 2: a systematic review.Front Public Health. 2021; 9: 663045Crossref PubMed Scopus (18) Google Scholar described a low risk for SARS-CoV-2 recurrent infection in the general population. Of a total of 113,715 patients described in different publications around the world, only 1% suffered from SARS-CoV-2 reinfection. Another study that analyzed 9119 COVID-19 recovered patients found that only 0.7% became reinfected.4Rivelli A. Fitzpatrick V. Blair C. Copeland K. Richards J. Incidence of COVID-19 reinfection among Midwestern healthcare employees.PLoS One. 2022; 17e0262164Crossref PubMed Scopus (2) Google Scholar Moreover, a significant reduction of 80% to 100% risk of reinfection with SARS-CoV-2 infection during the delta variant wave was shown in those who were previously infected.4Rivelli A. Fitzpatrick V. Blair C. Copeland K. Richards J. Incidence of COVID-19 reinfection among Midwestern healthcare employees.PLoS One. 2022; 17e0262164Crossref PubMed Scopus (2) Google Scholar Similarly, data from Austria showed low rates of hospitalization (5 of 14,840; 0.03%) and death (1 of 14,840; 0.01%) due to reinfection.3Sheehan M.M. Reddy A.J. Rothberg M.B. Reinfection rates among patients who previously tested positive for COVID-19: a retrospective cohort study.Clin Infect Dis. 2021; 73: 1882-1886Crossref PubMed Scopus (53) Google Scholar Data on SARS-CoV-2 in patients with PAD are limited. In an early report after the first 2 waves of SARS-CoV-2 infection in Israel, Marcus et al7Marcus N. Frizinsky S. Hagin D. Ovadia A. Hanna S. Farkash M. et al.Minor clinical impact of COVID-19 pandemic on patients with primary immunodeficiency in Israel.Front Immunol. 2021; 11: 614086Crossref PubMed Scopus (55) Google Scholar reported a low impact of the SARS-CoV-2 infection in patients with inborn errors of immunity (IEI), likely due to adherence to hygiene measures and social isolation. Although this study included patients with all types of IEI, it also showed that most patients who were infected were patients with PAD.7Marcus N. Frizinsky S. Hagin D. Ovadia A. Hanna S. Farkash M. et al.Minor clinical impact of COVID-19 pandemic on patients with primary immunodeficiency in Israel.Front Immunol. 2021; 11: 614086Crossref PubMed Scopus (55) Google Scholar Our findings support that these patients are truly susceptible to this virus and do not mount a protective immune response after a naturally occurring illness. Interestingly, Hagin et al8Hagin D. Freund T. Navon M. Halperin T. Adir D. Marom R. et al.Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity.J Allergy Clin Immunol. 2021; 148: 739-749Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar described a good cellular response to the Pfizer-BioNTech COVID-19 vaccine among patients with IEI, including some patients with PAD. Whether this confers clinical protection against SARS-CoV-2 infection or reinfection in patients with PAD is yet to be determined. The rate of SARS-CoV-2 reinfection was extremely high among our patients with PAD (42%), despite regular immunoglobulin replacement therapy. Farcet et al9Farcet M.R. Karbiener M. Schwaiger J. Ilk R. Kreil T.R. Rapidly increasing SARS-CoV-2 neutralization by intravenous immunoglobulins produced from plasma collected during the 2020 pandemic.J Infect Dis. Published online March 16, 2021; https://doi.org/10.1093/infdis/jiab142Crossref Scopus (11) Google Scholar showed that neutralizing antibody levels in intravenous immunoglobulin lots released since September 2020 are increasing. They extrapolated that lots released after July 2021 should have protective levels of anti-SARS-CoV-2 antibodies.9Farcet M.R. Karbiener M. Schwaiger J. Ilk R. Kreil T.R. Rapidly increasing SARS-CoV-2 neutralization by intravenous immunoglobulins produced from plasma collected during the 2020 pandemic.J Infect Dis. Published online March 16, 2021; https://doi.org/10.1093/infdis/jiab142Crossref Scopus (11) Google Scholar However, such lots may not be readily available, and their clinical effectiveness is yet to be validated. Therefore, additional treatment options, such as prophylactic monoclonal antibodies, should be considered to prevent reinfection during SARS-CoV-2 high-transmission periods. In conclusion, patients with PAD may be at increased risk for SARS-CoV-2 reinfection and therefore should be guided for stringent infection control measures despite past COVID-19 disease with consideration for other prophylactic pharmacological regimens. Whether or not vaccination with anti-SARS-CoV-2 vaccines or monoclonal antibody prophylactic therapy can protect these patients from reinfection with new emerging SARS-CoV-2 variants and will the newly approved antiviral medications be effective is yet to be determined.