key: cord-0905684-1ewhqpwb
authors: Quinti, Isabella; Lougaris, Vassilios; Milito, Cinzia; Cinetto, Francesco; Pecoraro, Antonio; Mezzaroma, Ivano; Mastroianni, Claudio Maria; Turriziani, Ombretta; Bondioni, Maria Pia; Filippini, Matteo; Soresina, Annarosa; Spadaro, Giuseppe; Agostini, Carlo; Carsetti, Rita; Plebani, Alessandro
title: A possible role for B cells in COVID-19?: Lesson from patients with Agammaglobulinemia
date: 2020-04-22
journal: The Journal of allergy and clinical immunology
DOI: 10.1016/j.jaci.2020.04.013
sha: 01b3715fbaee6d09d7884f51647e7f8f9c6dbd47
doc_id: 905684
cord_uid: 1ewhqpwb

Summary COVID-19 had a mild clinical course in patients with Agammaglobulinemia lacking B lymphocytes, whereas it developed aggressively in Common Variable Immune Deficiency. Our data offer mechanisms for possible therapeutic targets.

An epidemic of Coronavirus SARS-CoV-2 has become the focus of scientific attention 1 Agammaglobulinemias, the COVID-19 course was characterized by mild symptoms, short duration, with no need of treatment with the immune-modulating drug blocking IL-6, and had a favorable outcome. In contrast, patients affected with Common Variable Immune Deficiencies presented with a severe form of the disease requiring multiple drug treatment, including antiretrovirals agents and IL-6 blocking drugs, and mechanical ventilation ( Table 1 ). The strikingly different clinical course of COVID-19 in patients with Agammaglobulinemia compared to CVIDs cannot be explained by the level of serum immunoglobulins which were similarly low in all PAD patients at diagnosis, and were maintained at adequate and comparable levels in all patients by immunoglobulin substitutive therapy (On line Repository, Table) . A detailed COVID-19 clinical history, laboratory data, type and dosage of administered treatment, and disease timing, are provided for each patient in On line Repository, Case reports. Lung HRCT of a patient with Common Variable Immune Deficiency at hospital admission for COVID-19 showed extensive ground glass opacities associated with areas of alveolar consolidation in the upper and lower lobes where the alveolar component predominates over the interstitial one. (Fig. 1A) . Upon treatment, lung HRCT showed reduction in extension of ground glass opacities and areas of alveolar consolidation. (Fig. 1B) . Differently, lung HRCTs of a patient with Agammaglobuliniemia performed at the time of COVID-19 was unchanged with respect to lung HRCT performed one year earlier, and showed bronchiectasis and sequelae of right lung pneumonectomy done at the age of 18 (Fig. 1C, and 1D ). All patients with primary antibody deficiencies are equally vulnerable to most bacterial infections since antibodies are important in blocking infectivity and preventing diseases. In addition, antibodies have a role in the immune response to viral infections 3 . Patients with Agammaglobulinemia are susceptible to a limited number of viral infections only, mainly norovirus and enteroviruses such as polioviruses 4 with an increased incidence of post-vaccination poliomyelitis due to the oral attenuated Sabin vaccine 5 . CVIDs patients are susceptible to rhinoviruses, noroviruses, and herpesviruses that on turn play a role in driving an underlying inflammatory condition. Since only Agammaglobulinemia patients had a mild course of COVID-19, we speculate on a possible role of B lymphocytes in the SARS-CoV-2 induced inflammation. We have already shown that children appear to contain better SARS-CoV-2 in the early phase of infection, possibly because their B cells are able to generate natural antibodies timely upon encounter with novel pathogens when compared to B cells from adults 6 . The role of inflammation in aggravating the clinical picture of subjects with COVID-19 has already been described. Treatment with drugs such as IL-6 inhibitors aimed at reducing the Cytokine Storm Syndrome (CSS) and lung inflammation associated with a profound increase of cytokines such as IL-6 and increased ferritin 7 have already been carried out, initially on an individual basis, and currently within clinical trials. Of note, our CVID patients (3 out of 5) that required IL-6 blocking treatment presented increased unchanged with respect to lung HRCT performed one year earlier ( Fig. 1A and 1B . Chest x-ray showed diffuse interstitial alveolar infiltrates. Lung HRCT at admission confirmed extensive infiltrates ( Fig. 2A) . Oropharyngeal swab resulted positive for SARS-CoV-2.

He was started on lopinavir/ritonavir 400/100 mg qd, hydroxychloroquine 200 mg bid, and piperacillin/tazobactam. After admission, his respiratory condition worsened dramatically and he was started on mechanical ventilation. Laboratory tests showed increased ferritin (7200 ug/L; normal values <400), and LDH serum levels (495 U/L; normal values <225). Therapy with tocilizumab (8 mg/kg/die) was started.

After two days of mechanical ventilation, the patient was switched to remdesivir 200 mg iv/qd (first day) followed by remdesivir 100 mg iv qd. The clinical condition, and lung HRCT improved (Fig. 2B) , and 72 hours later he did not require any more mechanical ventilation. He is still hospitalized, with a steady improvement of clinical conditions, and laboratory values. 

Covid-19 -Navigating the Uncharted

ESID Registry Working Party and collaborators The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity