Jocelyn R. Farmer,Alison Galbraith,Mei-Sing Ong
Association of inborn errors of immunity with severe COVID-19 and post-acute sequelae of COVID-19
Association of inborn errors of immunity with severe COVID-19 and post-acute sequelae of COVID-19

Clinical Implications Our study demonstrates an increased risk for severe SARS-CoV-2 and subsequent development of post-acute sequelae of SARS-CoV-2 in patients with inborn errors of immunity, independent of preexisting lung disease, which highlights the need for further research to understand the underlying drivers.  Patients with inborn errors of immunity (IEI) are considered to be an at-risk population for severe SARS-CoV-2 infection, which may be driven by baseline immune dysfunction, increased predisposition to chronic pulmonary disease, and/or a lack of response to protective vaccines. To date, the full impact of SARS-CoV-2 infection on IEI patients remains poorly understood. Two systematic reviews reported a nonsignificant elevated risk for severe SARS-CoV-2 infection among immunocompromised patients, but most existing studies are limited by a small sample size. , Furthermore, whether IEI patients are also more likely to experience post-acute sequelae of SARS-CoV-2 (PASC), also known as long COVID, remains understudied. Here, we leveraged a large claims data set from Harvard Pilgrim Health Care to examine the association of IEI disorders with the severity of SARS-CoV-2 infection and subsequent development of PASC. Harvard Pilgrim Health Care is a nonprofit health plan serving the New England area across four states (Massachusetts, Maine, Connecticut, and New Hampshire). This work was approved by the Harvard Pilgrim Health Care Institutional Review Board. The study cohort was composed of patients aged less than 65 years who received the diagnosis of SARS-CoV-2 between February 2020 and December 2021. We defined the index date as the date of the first occurrence of SARS-CoV-2 diagnosis. All patients were continuously enrolled in the health plan for 90 days or more before the index date. The analysis of PASC included patients who were continuously enrolled for at least 30 days after infection. Diagnosed cases of SARS-CoV-2, PASC, and IEI were identified by International Classification of Diseases, 10th Revision codes (see Table E1 in this article’s Online Repository at www.jaci-inpractice.org). We applied inverse probability weighting (IPW) to estimate the risks for SARS-CoV-2 hospitalization (model 1) and PASC (model 2) in IEI patients, compared with non-IEI patients. We considered SARS-CoV-2 hospitalizations occurring any time after the index date. Inverse probability weights were assigned based on patients’ age, sex, socioeconomic status, preexisting chronic pulmonary disease, and number of hospitalizations and intensive care unit (ICU) admissions 30 to 90 days before SARS-CoV-2 infection. We used the Centers for Disease Control and Prevention’s Social Vulnerability Index, derived from patients’ place of residence at the census tract level, as a contextual measure of socioeconomic disadvantage. Preexisting chronic pulmonary disease diagnosed any time before SARS-CoV-2 infection was considered a confounder, because it is a common comorbidity among patients with IEI and a known risk factor for severe SARS-CoV-2. We included SARS-CoV-2 hospitalization (cumulative hospitalized days) in model 2 to adjust for the potential impact of SARS-CoV-2 severity on the development of PASC. A total of 47,405 unique patients received the diagnosis of SARS-CoV-2 in this cohort, 229 of whom had IEI. Among IEI patients, 20 were hospitalized (8.7%), eight required ICU admission (3.5%), and 126 had a preexisting chronic pulmonary disease (55.0%) (Table I ). After adjusting for potential confounders in the IPW model, IEI was associated with an elevated risk for requiring hospitalization for treatment of SARS-CoV-2 (odds ratio = 1.96; 95% CI, 1.12-3.18). A total of 38,970 patients (including 179 IEI patients) were observed more than 30 days after SARS-CoV-2 infection. Among those with IEI, eight (4.5%) received the diagnosis of PASC, two of whom were admitted to the ICU (1.1%) and five of whom had a preexisting chronic pulmonary disease (2.8%). After adjusting for potential confounders in the IPW model, patients with IEI had a greater odds of developing PASC, compared with patients without IEI (odds ratio = 3.20; 95% CI, 1.46-6.04). This study demonstrated a significant risk for severe illness among IEI patients with SARS-CoV-2 infection, confirming small-sample studies that were underpowered to establish statistical significance. Most patients (n = 187; 82%) in this cohort had predominantly antibody defects (PAD) (see Table E2 in this article’s Online Repository at www.jaci-inpractice.org). Nine percent of those patients developed severe infection, consistent with prior studies documenting severe SARS-CoV-2 in about 10% of common variable immune deficiency patients. Effective immune response against SARS-CoV-2 involves both the innate and adaptive immune systems. Delayed production of neutralizing antibodies has been associated with worse SARS-CoV-2 outcomes. Moreover, patients with PAD, particularly common variable immune deficiency, are at risk for mounting less effective humoral immune responses after SARS-CoV-2 immunization compared with health controls. Poor humoral immunity may contribute to worse SARS-CoV-2 outcomes in PAD patients directly or indirectly, through the failed support of T cells. Given the time frame of this study, we did not evaluate the impact of full SARS-CoV-2 immunization (including bivalent booster vaccine) and antiviral rescue therapy (eg, Paxlovid). Predominantly antibody defects patients mount some protective response to SARS-CoV-2 immunization. A dedicated follow-up study will be necessary to address the impact of emerging anti-COVID management strategies, and a larger IEI cohort is needed to delineate risk further among specific IEI diagnoses. This analysis further identified IEI as a significant risk factor for PASC, independent of disease severity and preexisting chronic pulmonary disease. Research into pathomechanisms of PASC remains limited and inciting triggers may be diverse. However, unique immune signatures have been described in PASC patients, including dysregulation of the memory T-cell response. Because IEI patients are frequently defined by dysregulated lymphocyte function and memory, these patients may yield an important understanding of immune mechanisms contributing to PASC. Important future questions include those regarding IEI subtypes and specific immunophenotypes with increased risk for PASC, as well as the impact of concomitant immunomodulator therapies. This cohort included only patients with a diagnosis of SARS-CoV-2 or PASC. We were unable to identify those with undiagnosed SARS-CoV-2 or PASC. This may have explained the lower prevalence of PASC in this cohort, compared with published data. Our study data set was also confined to the period before Omicron became the dominant variant in the United States and before readily available oral antiviral drug therapy was approved for use in the United States. As treatment strategies for SARS-CoV-2 continue to improve and new variants of the virus emerge, it is likely that downstream sequelae may also change over time. The limited granularity of International Classification of Diseases, 10th Revision codes further precluded in-depth evaluation of severe COVID-19 and PASC risk by genetic diagnoses of IEI. Finally, because of limitations of the data set, we were unable to assess mortality risk and the cause of prolonged hospitalization among IEI patients. Nonetheless, our analyses provide important insights into the risk for severe COVID-19 and PASC in patients with IEI.