key: cord-257309-sazs5wgh
authors: Ho, Hsi-en; Mathew, Sheryl; Peluso, Michael J.; Cunningham-Rundles, Charlotte
title: Clinical Outcomes and Features of Covid-19 in Patients with Primary Immunodeficiencies in New York City
date: 2020-10-08
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.09.052
sha: 
doc_id: 257309
cord_uid: sazs5wgh

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The clinical impact of Covid-19 in primary immunodeficiency diseases varies from mild illness to death. In our center, humoral immunodeficiency patients with poor outcomes had pre-existing autoimmune/inflammatory complications, lung disease, or additional comorbidities, and exhibited higher pro-inflammatory responses (IL-6, D-dimer).

Main Text: Coronavirus disease 2019 (Covid-19) remains an ongoing pandemic, and data on the clinical impact of SARS-CoV-2 infection in patients with primary immunodeficiency diseases (PIDs) are limited (1) (2) (3) . In Spring of 2020, New York City became the epicenter of the SARS-CoV-2 pandemic. Here, we report the clinical features and outcomes of Covid-19 in patients from a large PID center in New York City during this period.

Between January and July 2020, 16 patients followed at the Mount Sinai Hospital PID clinic tested positive for SARS-CoV-2. Of these, 12 were confirmed to have Covid-19 by nucleic acid amplification from nasopharyngeal/oropharyngeal swab specimens, and 4 by serologic assay (4) . Table 1 summarizes the demographics, PID diagnoses and related comorbidities of patients in the cohort. Five out of 16 patients were female, and the median age was 44.5 years (IQR 28-64).

Nine patients had common variable immunodeficiency (CVID; NFKB1, n=2; STAT3 gain-offunction, n=1) and 3 patients had X-linked agammaglobulinemia (XLA) due to Bruton tyrosine kinase (BTK) mutations. Other PID diagnoses in the cohort included hypogammaglobulinemia, IgA-IgG2 deficiency, interferon gamma receptor 2 (IFNGR2) deficiency, and X-linked hyper-IgM syndrome (XHIGM) (n=1 each). Seven patients had pre-existing PID-associated autoimmune/inflammatory complications. Table 1 shows the clinical parameters and course of COVID-19 in the study cohort. The most commonly recorded symptoms were: cough (16/16), subjective fever (15/16), dyspnea (8/16), J o u r n a l P r e -p r o o f diarrhea (7/16), fatigue/weakness (7/16), and emesis (2/16). One patient presented with altered mental status as the primary complaint. One patient with XHIGM experienced fever, cough, severe oral ulcers, and stomatitis during the associated clinical course. At initial presentation to a healthcare setting, fever (>38°C) was recorded in 7 patients, hypoxia (sPO2<92%) was recorded in 6 patients, and hypotension (systolic blood pressure < 90 mmHg) was recorded in 1 patient.

The median duration of symptoms (time from symptom onset to resolution or death) was 29 days (IQR 18-33). Chest X-ray on presentation was abnormal in 13/14 cases in which data were available. Co-infections identified during the COVID-19 hospitalization included:

Campylobacter enteritis in a patient with hypogammaglobulinemia, Mycobacterium avium complex lung disease in a patient with IFNGR2 deficiency, and oral candidiasis in a patient with XHIGM.

Twelve out of 16 patients required hospitalization, 5 of which involved intensive care unit In all, 4/16 individuals died (CVID, n=2; hypogammaglobulinemia, n=1; IgA-IgG2 deficiency, n=1) and 12/16 individuals recovered from COVID-19. Three of the 4 patients who died had preexisting PID-associated autoimmune/inflammatory complications; 2 of these individuals also had pre-existing PID-associated chronic lung disease (bronchiectasis, n=1; interstitial lung disease, n=1). In addition, one patient was a kidney transplant recipient. The age of those who died ranged from 39-76 years.

Two out of 9 CVID patients required mechanical ventilation. While all 3 XLA patients in this series did not require mechanical ventilation and all recovered, the significance of this observation is difficult to interpret given the limited number of cases, the relatively young age of these individuals, and the utilization of convalescent plasma. Figure 1 and Table E1 show immune parameters and inflammatory profiles of Covid-19 among antibody-deficient individuals. In patients with paired data from prior to and during the Covid-19 presentation, we noted significant declines in total lymphocyte count (median 1150 vs 650 cells/uL, p=0.001, n=12; lymphopenia <1000 cells/ul, n=8) and eosinophil count (median 100 vs 0 cells/uL, p=0.031, n=12, Figure E1 ) during Covid-19. There was a trend toward lower neutrophil count (median 3900 vs 2150 cell/ul, p=0.052, n=12; neutropenia <1000 cells/uL, n=2) during Covid-19 ( Figure E1 ). Lymphopenia in Covid-19 has been associated with disease severity in patients without PIDs (5) . Three out of 4 individuals who died in this cohort had lymphopenia (100, 300, and 700 cells/uL). There was no statistically significant difference in nadir lymphocyte count between those who died and those who recovered (median 500 vs 850 cells/uL, respectively).

In humoral immunodeficiency individuals with available data, systemic inflammatory markers were commonly elevated (10/10 patients had elevated CRP, 8/9 had elevated fibrinogen, 8/10 had elevated D-dimer). Similarly, peak serum IL-6 and IL-8 were commonly elevated (10/10 patients for IL-6, 8/8 patients for IL-8). Serum TNF-a was elevated in 4/8 patients, while IL-1b was not commonly elevated (1/8 patients). Inflammatory markers including IL-6 and D-dimer were significantly higher in those who died compared with those who recovered (p=0.0190, p=0.0095, respectively; Figure E1 ), while no significant differences were observed for CRP and J o u r n a l P r e -p r o o f fibrinogen (insufficient data points were available for meaningful comparison of IL8, TNF-a, and IL-1b).

BTK protein is involved in the signaling of the viral ssRNA-sensing Toll-like receptor pathway (6) . Indeed, increased monocyte BTK activation has been shown during severe Covid-19, with the application of BTK-inhibitors leading to reduced measures of inflammation and protection against pulmonary injury in initial studies (6, 7) . Here, we observed reduced measures of . Absolute eosinophil counts and absolute neutrophil counts of Covid-19 in antibody-deficient subjects with paired data, n=12; P-value calculated utilizing Wilcoxon matched-pairs signed rank test. Comparison of peak IL-6, D-dimer, fibrinogen, CRP between those who died and those who recovered; P-value calculated utilizing Mann-Whitney test. ANC, absolute neutrophil counts; AEC, absolute eosinophil counts; CRP, C-reactive protein. 

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

Rapid recovery of a SARS-CoV-2-infected X-linked agammaglobulinemia patient after infusion of COVID-19 convalescent plasma

Two X-linked agammaglobulinemia patients develop pneumonia as COVID-19 manifestation but recover

A serological assay to detect SARS-CoV-2 seroconversion in humans

Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study

The BTK inhibitor ibrutinib may protect against pulmonary injury in COVID-19-infected patients

Clinical Characteristics of Covid-19 in New York City

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

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