Primary Immunodeficiency Diseases in COVID-19 Pandemic: A Predisposing or Protective Factor?

Dear Editor

The novel coronavirus disease 19 (COVID-19) is an acute infectious respiratory disorder that emerged from Wuhan, China in the late 2019. , Due to its rapid distribution, the disease spread globally in a period of three months to the point that as of March 12, 2020 the World Health Organization (WHO) declared COVID-19 a pandemic. According to the latest data, up to mid-July 2020, the number of confirmed cases worldwide passed 13 million; of which about 600 thousand cases had died. Clinical manifestations of affected individuals vary, ranging from asymptomatic to severe alveolar damage resulting in acute respiratory distress syndrome (ARDS). , Most critical cases are likely to be among elders and men; also, several comorbidities have been identified as risk factors for this viral infection such as diabetes, hypertension, chronic respiratory disease, cancer and cardiovascular disease. These conditions render both the innate and adaptive immune system imperfect in the long-term, making it fail to mount proper immune responses against various pathogens.

In the same context, increasing number of patients with primary immunodeficiency diseases (PIDs) who develop COVID-19 are expected to be seen. Since most PID cases have major defect in at least one component of humoral or cellular immunity, predisposition to viral and bacterial infections is expected. Conversely, the number of reported COVID-19 cases with underlying PID is scarce. To date, only three separate studies have reported PID cases who developed COVID-19: One was a small case series from Italy describing clinical characteristics of 7 cases of primary antibody deficiency (PAD) with COVID-19, the other reported a boy with specific antibody deficiency (SAD) affected with COVID-19 infection; and the third reported 2 cases of X-linked agammaglobulinemia (XLA) who showed pneumonia as COVID-19 manifestations.9, 10, 11 Interestingly, it seems that the severity of PAD negatively correlates with the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. According to Quinti et al., patients with agammaglobulinemia who lack B lymphocytes showed milder course of disease and did not require intensive care or mechanical ventilation, as compared to patients with common variable immunodeficiency (CVID) who are characterized by dysfunctional B cells. Similarly, the two XLA cases reported by Soresina et al. recovered from SARS-CoV-2 infection despite developing pneumonia in the setting of B cell deficiency.

These observations, along with other reports, either suggest that T cell response is probably more important in immunity against the virus or highlight the role of B cells in SARS-CoV-2-induced inflammation. Little is known about the exact pathogenesis of this virus; however, it is well-described that hyper-inflammation, as seen in cytokine storm, aggravates the clinical profile of individuals with COVID-19 and is associated with fatality of COVID-19. , Hence, in these PID cases the intrinsic lack of B cells is considered as an advantage by preventing the development of inflammation. As seen in children who appear to better contain disease due to their immature anti-inflammatory response, it could be postulated that PID patients are surprisingly less likely to develop or experience severe phases of the infection as a result of immune system defect.

Some PID cases with antibody deficiency receive monthly immunoglobulin replacement therapy to compensate for the lack of proper antibody production. Despite limited evidence of efficacy, infusion of polyclonal immunoglobulins that were derived from plasma of healthy donors is used as one of the treatment modalities in COVID-19 patients. Speculation is that the pool of immunoglobulin might possess antibodies with the ability of cross-reacting with SARS-CoV-2 proteins as well as modulatory function on monocytes and macrophages that have a central role in the known cytokine storm. , , Therefore, it could be suggested that PID subjects who receive routine immunoglobulin replacement therapy are provided with these antibodies prior to infection.

In the absence of larger and/or thorough data, it remains unclear whether PID is a predisposing or, paradoxically, a protective factor for SARS-CoV-2 infection. Therefore, broader surveys of patients with PID in national and international levels are required to draw more compelling clinical conclusions.