We collected data from 121 patients diagnosed with IEI and infected by SARS-CoV-2 between March and December 2020. The diagnosis of SARS-CoV-2 infection was confirmed by RT-PCR from nasopharyngeal or nasal swab in 82 patients (67.8%); by RT-PCR and serology, in three patients (2.5%); only by serology in 22 patients (18.2%); and only by point-of-care test, in three patients (2.5%), totaling 110 (90.9%) patients. The other 11 patients (9.1%) were included since they presented typical clinical manifestations of SARS-CoV-2 infection and/or typical imaging tests and history of contact with confirmed cases. No reinfections were reported during the study period.
Patients’ ages ranged from six months to 74 yo (median age of 25.1 years). Age distribution was: ≤ 18 yo, 57 patients (47.1%); 19 - 59 yo, 60 patients (49.6%) and ≥ 60 yo, four (3.3%) patients. Sixty-seven patients were female (55.4%). Four out of 121 patients were previously included in Meyts et al. , 13 patients with hereditary angioedema were included in Grumach et al.  and one common variable immunodeficiency (CVID) patient was previously reported .
Most patients were diagnosed as predominantly antibody deficiencies (n=53/43.8%) and complement deficiencies (n=25/20.7%). The distribution of cases according to the IEI classification group is shown in Figure 1A.
Before SARS-CoV-2 infection, 49/121 (40.5%) patients were under regular human immunoglobulin (IG) replacement, either intravenously (89.8%) or subcutaneously (10.2%). Chemoprophylaxis was used by 31/121 (25.6%) patients, and 11/121 (9.1%) were using azithromycin. The use of immunosuppressors was reported in 11.6% (n=14), one of them for hemophagocytic syndrome, other for lymphoma and the rest for autoimmune disorders. Other drugs included androgens in 8.3% (n=10) and “immunomodulators” (colchicine or hydroxychloroquine) in 6.8% (n=8).
Comorbidities were absent in 70 patients (57.8%); at least one comorbidity was observed in 37 patients (30.5%); two comorbidities in 10 patients (8.3%) and three or more comorbidities in four (3.3%). Lung diseases were the most frequent comorbidities (n=34): 15.7% presented bronchiectasis (n=19); 7.4%, asthma (n=9); and 5%, other lung diseases (n=6). Systemic arterial hypertension affected 11.6% (n=14); obesity, 8.3% (n=10); overweight, 1.7% (n=2); gastrointestinal disorders, 5.7% (n=8); surgically corrected congenital heart diseases, 2.5% (n=3); Down Syndrome, 2.5% (n=3); type II diabetes mellitus, 3.3% (n=4); type I diabetes mellitus, 1.7% (n=2). One patient was pregnant.
A hundred and twenty IEI patients presented acute SARS-CoV-2 infection where 21 were classified as asymptomatic and 99 were symptomatic (i.e., had COVID-19) (Figure 1B). One patient presented MIS-C. From 100 symptomatic patients (99 diagnosed with COVID-19 and one patient with MIS-C), 35 patients were hospitalized and 94 recovered. The 21 asymptomatic patients underwent SARS-CoV-2 RT-PCR test either because of hospitalization for another reason than COVID-19 or due to a history of contact with a positive case.
There was no correlation between sex and severity of the infection, neither in general (Kendall's tau-b 0.095, p=0.265 Fisher's test) nor in the group of children/adolescents (Kendall’s tau-b 0.052, p=0.693 Fisher’s test) or the group of adults (Kendall’s tau-b 0.032, p=0.794 Fisher’s test).
A significant difference in the median age among the five levels of severity of SARS-CoV-2 infection was identified (Kruskal-Wallis test p=0.004). The asymptomatic group median age was lower than the other levels of severity. However, a significant difference was detected between asymptomatic and mild cases and also severe cases but not between asymptomatic and critical or moderate cases (age standard deviation for critical and moderate cases was higher). No significant difference was identified between mild, moderate, severe and critical cases median ages (Figure 2).
A clear correlation between IEI group and the severity of infection was not identified (Gamma 0.001, p=0.992; Kendall’s tau-b 0.001, p=0.992 Monte Carlo method). Complement deficiencies were the second most common IEI and no report of severe cases was observed. On the other hand, in the phenocopy group, the only patient reported died. The distribution of SARS-CoV-2 infections severity in the different types of IEI is described in figure 3.
There was a weak correlation between the use of immunoglobulin and higher severity of SARS-CoV-2 infection (Cramer's V 0.345, p= 0.005 per Fisher's test) and between the use of immunosuppressors and lower severity of SARs-CoV-2 infection (Cramer's V 0.304, p=0.029 per Fisher's test). Six/14 patients who were in use of immunosuppressors were asymptomatic, 4/14 had mild COVID-19, and one presented with a critical disease.
A difference in the number of comorbidities in relation to the severity of SARS-CoV-2 infection was observed (Kruskal-Wallis test p<0.001) but there was a difference only between asymptomatic + mild + moderate cases and severe + critical cases. In addition, there was a difference between the number of comorbidities and the age group of patients (Kruskal-Wallis test p=0.008), but only between ≤18 yo + 19-59yo groups and ≥60 yo, but not between ≤18 yo and 19-59 yo groups.
The correlation between types of comorbidities presented by the patients and the severity of SARS-CoV-2 infection showed a weak correlation between the presence of bronchiectasis (Cramer's V 0.365, p=0.004 by Fisher's test) and cardiopathy (Cramer’s V 0.302, p= 0.047 Fisher’s test) and higher severity. The pregnant patient, who had an autoinflammatory disease (CAPS-NLRP12 mutation) presented as mild COVID-19.
Fever was the most common symptom, reported in 66/99 (66.7%) patients with COVID-19. Other frequent symptoms were cough in 56.6% (n=56), upper airway symptoms (sore throat, nasal congestion, coryza) in 53.3% (n=53), hypo or anosmia in 38.4% (n=380, headache in 32.2% (n=32), dyspnea in 29.3% (n=29), dys or ageusia in 29.3% (n=29), diarrhea in 23.2% (n=23), fatigue in 8.1% (n=8), chest pain in 6.1% (n=6), abdominal pain in 5.1% (n=5), vomiting in 4% (n=4) and pericarditis in 2% (n=2). Other clinical manifestations have been described in only one case each: conjunctivitis, ocular and nasal burning, parotitis, cholestasis and oral ulcers. Five patients with hereditary angioedema (35.7% of the 24 patients) presented edema attacks: four with subcutaneous edema (one also with abdominal crisis) and one with laryngeal edema. Five patients presented cutaneous rash and one of them had a previous diagnosis of CAPS-NLRP3 and presented a diffuse cutaneous maculopapular rash that on skin biopsy demonstrated lymphocytic vasculitis, probably related to the viral infection. Bacterial pneumonia was a secondary diagnosis in 11 cases and sepsis in two, but with no identification of an infectious agent.
A six-year-old girl with a possible IRAK4/MyD88 defect (genetic testing in progress) presented fever, skin rash, pleural and pericardial effusion, ascites and nonspecific pulmonary infiltrate with dragged evolution. SARS-CoV-2 RT-PCR by swab was three times negative, and serology (IgG > 100 AU/mL) was positive also three times. In addition, cytokine dosage showed a significant increase of IL-10 and a lower increase in IL-6, diagnosed as a systemic inflammatory condition after Infection by SARS-CoV-2 (MIS-C).
The correlation between clinical manifestations and severity of COVID-19 in patients ≤ 18 years showed a moderate correlation between rash (Cramer's V 0.598, p=0.024 Fisher's test), and vomiting (Cramer's V 0.598, p=0.024 Fisher's test) with higher severity. These symptoms were identified only in the ≤ 18 yo group. Clinical manifestations and severity of COVID-19 in patients ≥ 19 yo, showed a correlation between cough (weak - Cramer's V 0.337, p=0.027 Fisher's test) and dyspnea (moderate- Cramer's V 0.456, p=0.003 Fisher's test) both associated with higher severity.
Ten patients with SCID (n=7), LAD type III (n=1), WAS (n=1) and XIAP mutation (n=1) had SARS-CoV-2 infection after hematopoietic stem cell transplant (HSCT). The majority (n=7) were detected after 100 days of transplantation, and of these, four were asymptomatic and three had mild COVID-19. Among the three patients with SARS-CoV-2 infection within the first 100 days of HSCT, two were asymptomatic. A third one was a patient with XIAP mutation presenting mild COVID-19 symptoms (fever and rash with positive RT-PCR) on the sixth day after a haploidentical HSCT. He developed multiple complications related to poor graft function and veno-oclusive disease and died due to a fungal infection four months after being hospitalized most of the time.
Patients classified as critical COVID-19 died. All of them presented severe pulmonary manifestation with sepsis and/or multiple organ failure. Four of them were male, ranging from two to 74 years, a median age of 20.2 years. Two patients were diagnosed with X-linked agammaglobulinemia, one with common variable immunodeficiency, one with hyper IgM syndrome (CD40L defect) and one with Good Syndrome.
The patient with hyper IgM syndrome was a 15-year-old-boy with no comorbidities and a severe inflammatory manifestation of COVID-19. One of the deceased patients with a diagnosis of X-linked agammaglobulinemia was an obese child. The other patient with X-linked agammaglobulinemia was a young adult with bronchiectasis, asthma, hypertension, and overweight. A year younger, this patient's brother, also diagnosed with X-linked agammaglobulinemia, obese, and no other comorbidities, evolved with COVID-19 classified as moderate and recovered well. The deceased patient with common variable immunodeficiency presented bronchiectasis and arterial hypertension. The patient with Good Syndrome (74 yo) who had myasthenia gravis went through adrenalectomy and pulmonary lobectomy previously.
Case Fatality Ratio and inpatient mortality were 5% and 17.1%, respectively, among all 121 patients. CFR and inpatient mortality according to IEI classification were respectively: antibody deficiencies (n=53) 6.38% and 17.6%; non severe combined T/B cells deficiency (n=5) 20% and 50%, immune dysregulation (n=3) 50% and 50%; and phenocopies (n=1) 100% and 100%. CFR in ≤ 18 yo group (n=57) was 3.5%; in 19-59 yo (n=60), 5% and in ≥ 60 yo (n=4), 25%.
Data from the 121 patients of the study are detailed in supplemental file 1.