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Department of Infectious Diseases, Singapore General Hospital, SingaporeDepartment of Infection Prevention and Epidemiology, Singapore General Hospital, Singapore
Good syndrome (GS) is a rare acquired immunodeficiency.
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Relapsing bacterial and viral infections are common in GS.
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Relapsing COVID-19 infection has not been previously reported in GS.
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We report a case of GS manifesting as relapsing COVID-19 infection.
Abstract
Good syndrome (GS) is a rare acquired immunodeficiency disease characterized by the presence of thymoma with combined B and T cell immunodeficiency in adults. Recurrent bacterial infections, particularly sinopulmonary infections caused by encapsulated bacteria, remain the most common infective presentation of GS; however, relapsing viral infections have also been reported, likely due to impaired T cell-mediated immunity. Relapsing COVID-19 infection, however, has not been previously reported as a manifestation of GS. We present two cases of relapsing COVID-19 infection in patients with GS; in one case, relapsing COVID-19 was the first manifestation of newly diagnosed GS.
Good syndrome (GS) is a rare acquired immunodeficiency characterized by the presence of thymoma with combined B and T cell immunodeficiency. Recurrent bacterial infections remain the most common infective presentation of GS [
DEFicit Immunitaire de l'adulte Study Group. Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications.
]. However, relapsing viral infections have also been reported in patients with GS, likely due to delayed viral clearance arising from impaired T cell-mediated immunity [
DEFicit Immunitaire de l'adulte Study Group. Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications.
Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies.
Detection of viable SARS-CoV-2 in deep respiratory specimens despite negative nasopharyngeal SARS-CoV-2 RT-PCR: occult COVID-19 as an unsuspected cause of pulmonary infiltrates in immunocompromised patients.
]. We present two cases of relapsing COVID-19 infection in patients with GS; in one case, relapsing COVID-19 was the first manifestation of newly diagnosed GS.
Methods
Literature review
We conducted a PubMed search using the terms “Good's syndrome”, “COVID-19”, and “SARS-CoV-2” up to August 2022. Clinical information was compiled and cases were scrutinized to determine if they fulfilled the definitions for a relapse of COVID-19 infection.
Definitions
A relapse was defined as a clinical recurrence occurring within 90-days of primary infection, whereas a recurrence was defined as a new clinical episode of symptoms consistent with acute COVID-19, accompanied by repositive/persisting polymerase-chain-reaction (PCR) or rapid-antigen-tests (RATs) in respiratory samples [
Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies.
]. Such symptomatic cases were distinguished from SARS-CoV-2 PCR repositivity, which describes positive PCR after negative tests in an asymptomatic patient within 90-days of primary infection; asymptomatic cases of SARS-CoV-2 PCR repositivity were excluded because these cases are unlikely to reflect persistent viral replication [
]. Weakly positive PCR results (cycle threshold [Ct] values >35) were also excluded because such results probably do not reflect true active infection but rather a nonreplicating virus [
Cepheid Xpert Xpress-SARS-CoV-2 RT-PCR assay (targeting E/N2-SARS-CoV-2-gene targets) was used for respiratory samples from nasopharyngeal (NP) swabs and bronchoalveolar lavage (BAL). A serology test for SARS-CoV-2 immunoglobulin (Ig) G was performed using chemiluminescent microparticle immunoassay on the Architect i2000SR system (Abbott Laboratories). Whole genome sequencing (WGS) was performed according to previously published protocols on a MinION MK1b system (Oxford Nanopore Technologies, Oxford, UK) in accordance with the ARTIC Network protocol v3 [
Patient A was a male aged 65 years with a history of thymoma and thymectomy 2 years previously; hypogammaglobulinemia screening at the time of thymectomy was initially negative. He had received three doses of BNT162b2 messenger RNA vaccine. He first tested positive for COVID-19 on RAT 5 months previously; he symptomatically improved after a week, and routine computed tomography scan (CT scan) of the thorax (post-thymectomy surveillance) 2 months later was unremarkable (Supplementary Figure 1). A total of 3 months later, he had new fever and coryzal symptoms, and repeat RAT for COVID-19 was again positive. He was admitted for further evaluation of a suspected COVID-19 relapse (Figure 1). Initial SARS-CoV-2 PCR (NP) on admission returned positive on both the E/N2-gene targets (Ct value = 24.5). He did not require supplemental oxygen. A repeat CT of the thorax showed bilateral ground-glass opacities consistent with organizing pneumonia (Supplementary Figure 1). SARS-CoV-2 IgG against both spike and nucleocapsid protein were undetectable. He was given one dose of tixagevimab-cilgavimab, as well as intravenous remdesivir for 5 days. Given the unusual relapsing presentation of COVID-19 infection, additional evaluation for immunodeficiency was performed. The results were significant for hypogammaglobulinemia, with an IgG level of 331 mg/dl (normal range 549-1711 mg/dl). Further immunophenotypic lymphocyte analysis revealed a complete absence of B lymphocytes in peripheral blood (clusters of differentiation [CD]19 <0.1%, CD20 <0.1%). T lymphocyte subpopulations were also reduced (T CD4+ 109 cells/µl, normal range 256-1594 cells/µl; T CD8+ 125 cells/µl, normal range 59-1034 cells/µl). Serology for HIV was negative. These immunological findings were compatible with GS. The patient underwent bronchoscopy a week after admission. BAL fluid was negative for other respiratory viruses on multiplex PCR, and the microscopy for Pneumocystis was negative. Cytomegalovirus (CMV) antigen from BAL fluid was negative. SARS-CoV-2 PCR returned positive on both BAL fluid and lung tissue. The histopathology results were consistent with pneumonitis and organizing pneumonia, in keeping with chronic infection (Supplementary Figure 2). After treatment with remdesivir/tixagevimab-cilgavimab, repeat SARS-CoV-2 PCR (NP) was negative at D152. However, on D167, the patient again tested positive on RAT (Figure 1); SARS-CoV-2 PCR (NP) was repeated and, again, returned positive. The patient received 5 days of nirmatrelvir/ritonavir. SARS-CoV-2 PCR (NP) at D182 was negative. Notably, the WGS of respiratory samples collected over the course of illness consistently attributed the patient's SARS-CoV-2 strain to Omicron BA 2.4, which was in keeping with the timing of initial infection 5 months previously in February 2022, during the emergence of Omicron BA2 in Singapore [
Enhanced infection-prevention measures including universal N95 usage and daily testing: the impact on SARS-CoV-2 transmission in cohorted hospital cubicles through successive Delta and Omicron waves.
Patient B was a female aged 69 years with known GS on replacement intravenous immunoglobulin five times weekly and multiple previous infectious complications, including CMV retinitis and colitis. Patient B had received three doses of BNT162b2 messenger RNA vaccine previously. On initial diagnosis of COVID-19 (positive PCR/RAT), the patient received 7 days of remdesivir and sotrovimab, was given undetectable SARS-CoV-2 IgG, and was discharged well. A total of 40 days later, the patient represented with new-onset breathlessness, requiring supplemental oxygen; CT of the thorax (day 42) showed interval progression of bilateral ground-glass changes (Supplementary Figure 1); although, the SARS-CoV-2 PCR on admission (NP) was negative. BAL (day 56) tested positive for SARS-CoV-2, confirming relapse of COVID-19 (Figure 1). After BAL, the patient subsequently deteriorated and required intubation. SARS-CoV-2 viremia was also detected from day 61 to day 68. The patient received an additional 13 days of remdesivir, as well as tixagevimab/cilgavimab. However, although the SARS-CoV-2 viremia cleared, the patient could not be successfully extubated due to persistent ventilatory requirements and repeat CT of the thorax showed progression to extensive bilateral fibrosis. The patient ultimately died at day 98 of the COVID-19 infection. The testing of respiratory samples collected over the course of illness demonstrated identical SARS-CoV-2 strains across the two admissions, providing supporting evidence for SARS-CoV-2 persistence.
Discussion
To date, there have been six case reports of COVID-19 in patients with GS [
]; most were reported early on in the pandemic, when COVID-19 therapeutic options were more limited. In two of the six case reports, although GS was undiagnosed before presentation with COVID-19, one case had other concurrent opportunistic coinfections, including Pneumocystis pneumonia and cytomegalovirus pneumonitis [
], and the other had persistent COVID-19 infection with PCR positivity at high Ct values (≥35) instead of a relapsing-remitting course (Supplementary Table 1) [
]. In both of our cases, an unusual relapsing course of COVID-19 infection was described, despite the extensive treatment with antivirals/monoclonal antibodies and previous vaccination. WGS results supported relapse rather than reinfection with a different SARS-CoV-2 strain. Relapsing viral infections, such as CMV or herpes simplex virus, have been reported in case series of patients with GS consistent with defects in T cell-mediated immunity [
DEFicit Immunitaire de l'adulte Study Group. Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications.
]. Patients with secondary hypogammaglobulinemia after iatrogenic receipt of anti-CD20 treatment (e.g., rituximab) tend to have more severe COVID-19 manifestations and cases of relapsing-remitting infection have been encountered [
Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies.
]. To the best of our knowledge, this is the first description of relapsing COVID-19 infection as an infectious manifestation of GS. Relapsing COVID-19 infection in patients not known to have a previous immunodeficiency and a history of thymoma should prompt clinicians to evaluate for GS, facilitating timely diagnosis and early initiation of therapy. Conversely, in patients with known GS, negative SARS-CoV-2 testing on NP samples in the setting of unexplained ground-glass infiltrates on lung imaging does not rule out SARS-CoV-2 relapse; invasive sampling must be considered.
Declarations of competing interest
The authors have no competing interests to declare.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Ethics approval
Ethics approval was not required for case reports under our institutional review board guidelines. Written informed consent was obtained from patients for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.
Author contributions
LEW conceptualised the research, collated the data and wrote the manuscript. JYT collated data and edited the manuscript. LLEO, AMTP, KKKK assisted with materials and methods. JKSQ, IV and LW provided supervision and edited the manuscript.
DEFicit Immunitaire de l'adulte Study Group. Good syndrome: an adult-onset immunodeficiency remarkable for its high incidence of invasive infections and autoimmune complications.
Incidence, clinical presentation, relapses and outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients treated with anti-CD20 monoclonal antibodies.
Detection of viable SARS-CoV-2 in deep respiratory specimens despite negative nasopharyngeal SARS-CoV-2 RT-PCR: occult COVID-19 as an unsuspected cause of pulmonary infiltrates in immunocompromised patients.
Enhanced infection-prevention measures including universal N95 usage and daily testing: the impact on SARS-CoV-2 transmission in cohorted hospital cubicles through successive Delta and Omicron waves.
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