Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense. Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2. Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI. Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died.

Common Variable Immunodeficiency belongs to the group of rare diseases encompassing antibody deficiency syndromes of highly variable clinical presentation and outcome. The multicenter prospective study on a cohort of 224 patients with Common Variable Immunodeficiency provides an updated view of the spectrum of illnesses which occurred at the clinical onset and over a long period of follow-up (mean time: 11 years) and information on the effects of long-term immunoglobulin treatment. The mean age at the time of diagnosis was 26.6 years. Seventy-five patients were younger than 14 years of age. The mean age at the onset of symptoms was 16.9 years. This implicates with a mean diagnostic delay of 8.9 years. Respiratory tract infections were the most prominent clinical problem observed at diagnosis and during the follow-up. Intravenous immunoglobulin administration induced a significant reduction in the incidence of acute infections, mainly acute pneumonia and acute otitis. However, a progressive increase in the prevalence of patients with chronic diseases, mainly sinusitis and lung disease, was observed in all age groups, including the pediatric population. The morbidity of Common Variable Immunodeficiency due to all associated clinical conditions increased over time despite an adequate replacement with intravenous immunoglobulins. Our data stressed the need to develop international guidelines for the prevention and therapy of chronic lung disease, chronic sinusitis, chronic diarrhoea, and chronic granulomatosis in patients with humoral immunodeficiencies.

Patient registries are instrumental for clinical research in rare diseases. They help to achieve a sufficient sample size for epidemiological and clinical research and to assess the feasibility of clinical trials. The European Society for Immunodeficiencies (ESID) registry currently comprises information on >25,000 patients with inborn errors of immunity (IEI). The prerequisite of a patient to be included into the ESID registry is an IEI either defined by a defect in a gene included in the disease classification of the international union of immunological societies (IUIS), or verified by applying clinical criteria. Because a relevant number of patients, including those with common variable immunodeficiency (CVID), representing the largest group of patients in the registry, remains without a genetic diagnosis, consensus on classification of these patients is mandatory. Here, we present clinical criteria for a large number of IEI that were designed in expert panels with external review. They were implemented for novel entries and verification of existing datasets from 2014, yielding a substantial refinement. For instance, 8% of adults and 27% of children with CVID (176 out of 1704 patients) were reclassified to 22 different immunodeficiencies, illustrating progress in genetics, but also the previous lack of standardized disease definitions. Importantly, apart from registry purposes, the clinical criteria are also helpful to support treatment decisions in the absence of a genetic diagnosis or in patients with variants of unknown significance.

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Background:The recent SARS-CoV-2 pandemic, which has recently affected Italy since February 21, constitutes a threat to normal subjects, as the coronavirus disease-19 can manifest with a broad spectrum of clinical phenotypes ranging from asymptomatic cases to pneumonia or even death. There is evidence that older age and several comorbidities can affect the risk to develop severe pneumonia and possibly the need of mechanic ventilation in subjects infected with SARS-CoV-2.Therefore, we evaluated the outcome of SARS-CoV-2 infection in patients with inborn errors of immunity (IEI) such as X-linked agammaglobulinemia (XLA). Methods:When the SARS-CoV-2 epidemic has reached Italy, we have activated a surveillance protocol of patients with IEI, to perform SARS-CoV-2 search by nasopharyngeal swab in patients presenting with symptoms that could be a manifestation of COVID-19, such as fever, cough, diarrhea, or vomiting. Results:We describe two patients with X-linked agammaglobulinemia (XLA) aged 34 and 26 years with complete absence of B cells from peripheral blood who developed COVID-19, as diagnosed by SARS-CoV-2 detection by nasopharyngeal swab, while receiving immunoglobulin infusions. Both patients developed interstitial pneumonia characterized by fever, cough, and anorexia and associated with elevation of CRP and ferritin, but have never required oxygen ventilation or intensive care. Conclusion:Our report suggests that XLA patients might present with high risk to develop pneumonia after SARS-CoV-2 infection, but can recover from infection, suggesting that B-cell response might be important, but is not strictly required to overcome the disease. However, there is a need for larger observational studies to extend these conclusions to other patients with similar genetic immune defects. K E Y W O R D S BTK, immunoglobulins, SARS-CoV-2, X linked agammaglobulinemia How to cite this article: Soresina A, Moratto D, Chiarini M, et al. Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover. Pediatr Allergy Immunol. 2020;00:1-5. https://doi.

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