A fatal case of coronavirus disease 2019 in a patient with common variable immunodeficiency

Common variable immunodeficiency (CVID) is a heterogeneous group of primary immunodeficiency syndromes characterized by hypogammaglobulinemia and impaired vaccine responses. Although immunodeficiency is described as a risk factor for coronavirus disease 2019 (COVID-19), limited data are available regarding CVID. Of note, 3 recent reports describe mostly positive outcomes in patients with CVID who were diagnosed as having COVID-19,1, 2, 3 with only 1 fatality.³ All these patients had adequate immunoglobulin G (IgG) levels at the time of COVID-19 diagnosis.1, 2, 3 We present a case of a patient with a history of CVID and severely low IgG levels owing to a lapse in immunoglobulin replacement therapy, who died of complications related to COVID-19 despite receiving convalescent plasma and high-dose intravenous immunoglobulin (IVIG).

The patient was a 42-year-old man with a longstanding history of asthma, morbid obesity, and CVID characterized by recurrent sinopulmonary infections. He was previously on regular monthly IVIG and was reportedly stable. However, he had not received any IVIG within the previous 6 months because of insurance issues. He experienced COVID-19 symptoms in May 2020 with a positive result of the nasopharyngeal polymerase chain reaction (PCR) swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). He was initially quarantined at home for 4 days. However, he developed fevers with worsening dyspnea and was, thus, admitted to a community hospital. Chest computed tomography revealed multifocal pneumonia. On hospital day 4, he was intubated because of worsening hypoxemia. On hospital day 5, he received convalescent plasma and started remdesivir. On hospital day 6, vancomycin was started for methicillin-resistant Staphylococcus aureus cultured from his sputum. He was subsequently transferred to our facility for a higher level of care.

On transfer, his presentation was consistent with acute respiratory distress syndrome. Notable laboratory results included IgG of 117 mg/dL, IgA of 10 mg/dL, undetectable IgM, erythrocyte sedimentation rate greater than 130 mm/h, and C-reactive protein greater than 300.0 mg/L. He had a white blood cell count of 8.27 × 10³/μL (76% neutrophils, 8% lymphocytes, 5% monocytes, 1% eosinophils, 2% atypical lymphocytes, and 8% bands). Ceftazidime was started for bacterial pneumonia. Furthermore, meropenem was started for sinusitis after the culture of purulent nasal secretions grew extended-spectrum beta-lactamase–producing Escherichia coli and sinus computed tomography revealed sinus mucosal thickening. He completed 10 days of remdesivir.

He received a 40 g (400 mg/kg) dose of IVIG on hospital day 9 with an increase in serum IgG to 442 mg/mL on hospital day 12 but with no considerable changes in his clinical status. On hospital days 14 and 15, he received high-dose IVIG of 1 g/kg divided into 2 equal doses. His serum IgG elevated to 1396 mg/dL on hospital day 17. He had modest clinical improvement in the subsequent days, including a reduction in fevers and slightly decreased oxygen requirement. Repeat IgG serum concentrations were 615 mg/dL on hospital day 22 and 472 mg/dL on hospital day 26.

The results of multiple nasopharyngeal PCR swab tests for SARS-CoV-2 remained positive during the hospitalization. The results of IgM and IgG serologies for SARS-CoV-2 obtained on hospital days 12 and 16 were both negative.

After hospital day 20, he again had fevers, required increased ventilatory support, and developed methicillin-resistant S aureus bacteremia. On hospital day 30, he had a cardiac arrest in the setting of hypoxemia and hypotension and, unfortunately, expired. The autopsy established the final pathologic diagnosis of COVID-19 pneumonia and bacteremia in the setting of CVID.

This case presents several considerations in the care of patients with CVID with COVID-19. The patient's body mass index was 39 kg/m², and obesity is a known risk factor for severe disease.⁴ Furthermore, the patient was not receiving regular immunoglobulin replacement therapy in the months leading up to his COVID-19 diagnosis. Although it is unlikely that IVIG products available during that time would have contained specific antibodies against SARS-CoV-2, they may have contained cross-reactive antibodies for SARS-CoV, Middle East respiratory syndrome coronavirus, or other human coronaviruses that could potentially provide some protection.^{5 , 6} In addition, regular IVIG therapy may have provided additional protection against the sinopulmonary and other bacterial superinfections that complicated the patient's illness.

The IVIG can have immunomodulatory effects that have been postulated to be helpful in the inflammatory milieu of COVID-19.⁷ The initial increase in the patient's IgG levels after high-dose IVIG waned rapidly, likely because of brisk consumption in the setting of infection. Any transient immunomodulatory effect was insufficient to significantly alter his clinical trajectory.

Notably, in the other reports of patients with CVID recovering from COVID-19, all of them had been receiving regular immunoglobulin replacement therapy preceding the COVID-19 diagnosis. The 2 patients who received IVIG did so early in their COVID-19 course,^{1 , 2} suggesting that IVIG is more efficacious if administered early and in the setting of replete IgG levels. The single reported case of fatality was not noted to have received any antibody-containing products.³

This patient had minimal antibody response to SARS-CoV-2, as would be expected given his history of CVID. In contrast, most patients with COVID-19 develop detectable IgG antibody levels for SARS-CoV-2 within 2 weeks of symptom onset.⁸ In addition, critically ill patients have been found to develop high levels of antibodies for SARS-CoV-2.⁸ We hypothesize that a limited antibody response contributed to impaired nasopharyngeal viral clearance, given the multiple positive results of the PCR tests for SARS-CoV-2 during the patient's hospitalization. However, defects in antibody production are unlikely to be the sole or primary reason for this finding, because persistently positive PCR results for SARS-CoV-2 can be found even in mild cases and among immunocompetent hosts.⁹ It is unclear whether additional convalescent plasma would have been helpful once his condition had become critical or whether it is primarily efficacious early in the illness. One study suggests that convalescent plasma did not reduce mortality among critically ill patients with COVID-19.¹⁰ However, patients with a limited antibody response were not specifically examined.

To the best of our knowledge, this is the first report of a fatality from COVID-19 in a patient with CVID who had not been receiving regular infusions of immunoglobulin at the time of his infection. Patients with CVID may be at a unique risk for COVID-19–related morbidity and mortality, particularly those with comorbidities or inadequate immunoglobulin levels. It is important that patients with CVID have close follow-up and continuity of care during this pandemic. Convalescent plasma and IVIG can be considered, although their efficacy has not been defined. Further studies are needed to elucidate the immunologic mechanisms of COVID-19 in CVID and determine the optimal approach to care.