key: cord-0905940-o52cip0p
authors: Milito, C.; Lougaris, V.; Giardino, G.; Punziano, A.; Vultaggio, A.; Carrabba, M.; Cinetto, F.; Scarpa, R.; Delle Piane, R. M.; Baselli, L.; Ricci, S.; Rivalta, B.; Conti, F.; Marasco, C.; Marzollo, A.; Firinu, D.; Pulvirenti, F.; Lagnese, G.; Vivarelli, E.; Cancrini, C.; Martire, B.; Danieli, M. G.; Pession, A.; Vacca, A.; Azzari, C.; Fabio, G.; Matucci, A.; Soresina, A. R.; Agostini, C.; Spadaro, G.; Badolato, R.; Cicalese, M. P.; Aiuti, A.; Plebani, A.; Pignata, C.; Quinti, I.
title: Clinical outcome, incidence and SARS-CoV-2 infection fatality rates in Italian patients with Inborn Errors of Immunity.
date: 2021-04-21
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2021.04.017
sha: 4e8f1d16f14a7e640ded2661a1544ad2c5479eb0
doc_id: 905940
cord_uid: o52cip0p

nan

Inborn Errors of Immunity. 

All Authors have no relevant affiliations or financial involvement with any organization or entity 58 with a financial interest in or financial conflict with the subject matter or materials discussed in the 59 manuscript. In the one-year study period, 131 cases of SARS-CoV-2 infection were notified among 3263 IEI 88 patients, 33 of them ≤18 years. According to WHO criteria 2020, 4 patients might be stratified 89 in asymptomatic, mild, moderate, and severe COVID-19. The asymptomatic condition, revealed by 90 the screening of patients attending the hospital sites, and of household contacts, was reported 91 in 36.3% of patients ≤18 years, and 24.5% of patients >18 years. Mean age 92 was similar in asymptomatic, mild/moderate or severe COVID-19 patients, and in patients who died 93 for COVID-19, with the exception of asymptomatic adult patients who were younger than severe 94 COVID-19 adult patients (P <0.003). (Table I) (Table II) . Only the incidence in pediatric age 99 was significantly lower in IEI patients (2.36) in comparison to the Italian pediatric population (4.11, 100 P<0.001), a finding possibly due to the continuous patients' education on protection procedures our 101 patients have been following since diagnosis. The highest number of SARS-CoV-2 infected 102 fatality rate was 3.81% in IEIs, compared to 3.28% in the Italian population (P=0.61), and 5.10% in 104 IEI adult patients compared to 3.68% in the adult general population (P=0.5). Nonetheless, the 105 fatality rate among IEI Italian patients is lower than previously reported from other IEI cohorts, 106 ranging from 9.57 1 to 25. 2 IEI patients showed a younger age at death (median age: 52 years, range: 107 30-59, vs 83 years, range: 0-109), and did not have those comorbidities predisposing to a severe 108 COVID-19 in the not-immunocompromised population 5 . Pre-existing comorbidities associated to 109 COVID-19 severity were described in only 6/11 IEI patients with severe COVID-19 (1 110 hypertension, 2 cardiomyopathy, 3 chronic lung diseases) and in only 2/5 IEI patients who died to 111

Distribution of SARS-CoV-2 infected patients by IEI entities and by children and adult populations 113 are shown in Figure E1A ,B,C. Del 22q11 and CVID accounted for the most affected IEI in the 114 pediatric and adult age, respectively. The cumulative incidence, and infection fatality rate by type of 115 IEI and by age are shown in Table II . Given the low numbers among different IEI entities, a higher 116 SARS-CoV-2 incidence was found only by comparing CVID to SIgAD (P=0.04). The fatality rate 117 was high in Good's Syndrome and in Del 22q11, both conditions associated with a T-cell defect. A 118 condition of lymphopenia and CD4 lymphopenia was detected in the pre-SARS-CoV-2 period in 119 about 10% and 20% of IEI, respectively, mainly in Del22q11 and CVID patients. However, this 120 was not a risk factor for the subsequent COVID-19 severity. As reported in non-121 immunocompromised adult patients, 6 Neutrophil/Lymphocyte ratio (NLR) was higher in patients 122 with severe COVID-19 than in asymptomatic patients (7.3 ± 7.4 vs 2.0 ± 0.9, P=0.008), and in 123 mild/moderate disease patients (3.3 ± 3.9, P=0.04).. 124

Since IEI patients might struggle with clearing the infection, we calculated the time from the first 125 SARS-CoV-2 positive PCR to the first SARS-CoV-2 negative PCR. One third of patients with 126 antibody deficiencies were SARS-CoV-2 positive for more than 3 weeks, representing a possible 127 risk factor for viral spreading 7 . A similar length was observed in patients with 128 Agammaglobulinemia (56.4 ± 38.1 days), CVID (47.6 ± 20.9 days), SIgAD (52.5 ± 71.2 days). 129

Shorter times were described in patients with Del 22q11 (29.1 ± 33.9 days, P<0.01) ( Figure E2) . 130

The long time of observation might have helped correct some initial conclusions also from our 131 group 8 , since patients with Agammaglobulinemia and ARA might also show a severe COVID-19, 132 even if none died. Our study has a major limitation of possible underestimation, but less relevant 133 than that described in the general population 9 , as we started our study at the early stages of the 134 pandemic, and we followed our patient rigorously. The purely descriptive data set on IEI patients 135 might be the basis for a comparison over time of the trend of SARS-CoV-2 infection in this 136 population as is for data on the trend of SARS-CoV-2 infection in the general population. 137 138 Acknowledgments 139

We thank our patients and their families. 140 

Coronavirus disease 2019 143 in patients with inborn errors of immunity: An international study

COVID-19 in patients with primary immunodeficiencies in New York City

Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network

Twenty Years of Experience (1999-2019)

Covid-19: risk factors for severe disease and death

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Evolution of SARS-CoV-2 in an Immunocompromised Host

for B cells in COVID-19? Lesson from patients with agammaglobulinemia

Substantial 163 underestimation of SARS-CoV-2 infection in the United States