Clinical characteristics of COVID-19 in children and young adolescents with inborn errors of immunity.

CONFLICT OF INTEREST

Authors indicate no such interest.

AUTHOR CONTRIBUTIONS

Ozge Yilmaz Topal: Data curation (equal); Formal analysis (equal); Methodology (equal); Resources (equal); Supervision (equal); Visualization (equal); Writing‐original draft (equal); Writing‐review & editing (equal). Ayşe Metin: Data curation (equal); Methodology (equal); Supervision (equal);Writing‐review&editing (equal). ilknur kulhas celik: Data curation (equal); Formal analysis (equal); Methodology (equal); Supervision (equal); Visualization (equal); Writing‐review & editing (equal). Azize Pınar Metbulut: Data curation (equal); Formal analysis (equal); Methodology (equal); Supervision (equal); Visualization (equal). Selma Alim Aydin: Data curation (equal); Formal analysis (equal); Methodology (equal); Resources (equal). Aslinur Ozkaya Parlakay: Data curation (equal); Formal analysis (equal); Methodology (equal); Supervision (equal).

To the Editor,

The novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has rapidly spread across the globe, and the World Health Organization (WHO) declared coronavirus disease 2019 (COVID‐19) a pandemic in mid‐March of 2020.

In the pediatric age group, symptomatic COVID‐19 has been mostly reported in children with inborn errors of immunity (IEI), chronic lung disease, and heart disease. Patients with IEI can be expected to have more severe illness. Moreover, due to weak cellular immunity and viral control, more severe disease is expected in patients with combined immunodeficiencies than in those with humoral defects. However, other authors have proposed that the opposite may be expected in immunocompromised patients. In children with IEI, the lack of the pro‐inflammatory cytokine storm implicated in the pathogenesis of severe COVID‐19 may protect these patients from multiple organ failure. Therefore, we aimed to determine the incidence and clinical severity of COVID‐19 in IEI patients under follow‐up in our hospital.

Patients who were followed up or newly diagnosed with IEI in our clinic between September 1, 2019, and October 1, 2020, were included in the study. The patients' parents were called and asked whether the patient had COVID‐19 or had contact with anyone with COVID‐19. The patients' results from viral tests including reverse transcription‐polymerase chain reaction (RT‐PCR) of a nasopharyngeal sample and IgM/IgG antibody testing for SARS‐CoV‐2 were recorded. Indications for hospitalization and treatment were determined based on the pediatric patient management and treatment guide from the Turkish Ministry of Health.

Statistical analyses were performed using IBM SPSS Statistics for Windows version 22.0 statistical software package (IBM Corp.). Numbers and percentages were reported for discrete variables; continuous variables were expressed as mean and standard deviation for data with normal distribution and as median and interquartile range (IQR) for non‐normally distributed data.

The study included 371 IEI patients with a median age of 88 months (IQR: 36–156 months). Of these, 368 patients were under regular follow‐up due to IEI and 3 patients were newly diagnosed with predominantly antibody deficiency after COVID‐19 infection.

Of the 368 patients who were already under follow‐up for IEI, 261 patients had predominantly antibody deficiency, 41 had combined immunodeficiencies with associated or syndromic features, 40 had congenital defects of phagocyte number or function, 8 had immunodeficiencies affecting cellular and humoral immunity, 7 had diseases of immune dysregulation, 7 had defects of intrinsic and innate immunity, 2 had autoinflammatory disorders, 1 patient had both predominantly antibody deficiency and complement deficiency, and 1 patient had phenocopies of IEI.

According to parent/caregiver reports, none of the patients had stopped taking prophylactic treatment and all patients had adhered to strict isolation, mask use, and social distancing measures during the pandemic.

The characteristics of the previously followed IEI patients who had COVID‐19 infection are given in Table 1. Contact status and test results of the patients are presented in Figure 1.

TABLE 1

Characterization of pediatric COVID‐19 patients with previously diagnosed IEI

Patient	IEI	Age (year)	Clinical manifestations of IEI	Routine prophylaxis	Contact with patient with COVID−19	Symptoms	PCR/ antibodies	Hospitalization	Treatment
Predominantly antibody deficiencies
1	CVID	15	Recurrent otitis and mastoiditis	‐	Family	No	PCR (+)	No	No
2	CVID	18	Fanconi aplastic anemia, short stature, microcephaly, pituitary microadenoma, mental retardation	‐	Family	Fever	PCR (+)	No	No
3	CVID	7	Dental abscess, recurrent pneumonia	TMP‐SMX	Family	Nausea	PCR (+)	No	No
4	CVID	7	Recurrent pneumonia, recurrent urinary tract infection	TMP‐SMX	Family	Fever	PCR (+)	No	No
5	CVID	14	Recurrent upper respiratory tract infections, recurrent pneumonia	‐	Family	Nasal flow	PCR (+)	No	No
6	CVID	17	Immune thrombocytopenic purpura, bronchiectasis, recurrent pneumonia	IVIG	Family	Headache, arthralgia	PCR (+)	No	No
7	CVID (the next‐generation sequencing identified a germline heterozygous pathogenic variant in the exon 17 of the NF‐κB2 gene, c.1832G<A p. [Arg853Ter])	9	Microcephaly, hepatosplenomegaly, chronic anemia, macrothrombocytopenia, hypothyroidism, joint hyperlaxity, short stature, recurrent pneumonia, recurrent urinary tract infections, inflammatory bowel disease	IVIG, TMP‐SMX, Fluconazole	Family	Fever	PCR not performed Ab (+)	No	No
8	CVID	19	Asthma, food allergy	‐	Family	Fever, sore throat	PCR (+)	No	Favipiravir, hydroxychloroquine
9	CVID	14	Asthma, recurrent upper respiratory tract infections, previous adenotonsillectomy, recurrent gingivitis, obesity, hypertension, factor deficiency	‐	Family	Fever, headache, cough, dyspnea	PCR (+)	Yes	Oxygen
10	Selective IgA deficiency	6	Recurrent upper respiratory tract infections	‐	Family	Fever, stomachache, vomiting	PCR (+)	No	No
11	Selective IgA deficiency	10	G6PD deficiency, nasal polyposis, recurrent suppurative otitis, hearing loss, hypertelorism, micrognathia, recurrent pneumonia	‐	Family	Asymptomatic	PCR (+)	No	No
12	Selective IgA deficiency	20	Asthma, allergic rhinitis, recurrent infections of gastrointestinal tract	‐	Unknown	Fever, headache, myalgia	PCR (+)	No	No
13	Selective IgA deficiency	8	Recurrent upper respiratory tract infections, recurrent pneumonia	‐	Unknown	Fever, headache, malaise, loss of appetite, and anosmia	PCR (+)	No	No
14	Transient hypogammaglobulinemia of infancy	3	Recurrent bronchiolitis, antibiotic allergy	‐	Family	Fever	PCR (+)	No	No
15	Transient hypogammaglobulinemia of infancy	4	Recurrent upper respiratory tract infections, recurrent pneumonia	‐	Unknown	Fever, vomiting, cough, diarrhea	PCR (+)	YES	Hydroxychloroquine
16	Partial IgA deficiency	6	Recurrent upper respiratory tract infections, recurrent pneumonia	‐	Family	Conjunctivitis	PCR (+)	No	No
17	Decrease of IgM level	14	Recurrent bronchiolitis, allergic rhinitis	‐	Family	Fever, headache, myalgia, arthralgia	PCR (+)	No	No
Combined immunodeficiencies
Syndromic combined immunodeficiencies
18	Wiskott‐Aldrich syndrome (treated with gene therapy)	11	FMF, recurrent pneumonia, recurrent infections of gastrointestinal tract, persistent microthrombocytopenia, and recurrent suppurative infections despite gene therapy	‐	Family	Asymptomatic	PCR not performed Ab (+)	No	No
19	Ataxia‐telangiectasia	12	Previous non‐Hodgkin lymphoma, recurrent pneumonia, chronic lung disease	IVIG	Unknown	Fever, cough, dyspnea	PCR (+)	Yes	Oxygen
Congenital defects of phagocyte number or function
20	Kostmann disease (HAX−1 c.130‐131insA., pW44X homozygous mutation)	2	Recurrent gingivitis, recurrent lower respiratory tract infections	TMP_SMX	Unknown	Fever, herpetic stomatitis, diarrhea	PCR (‐) Ab (+)	Yes	Cefotaxime, acyclovir
21	Kostmann disease (HAX−1 c.130‐131insA., pW44X homozygous mutation)	14	Recurrent cellulitis, recurrent lower respiratory tract infections, recurrent oral aphthous ulcers	GCSF	Family	Asymptomatic	PCR not performed Ab (+)	No	No
22	Kostmann disease (HAX−1 c.130‐131insA., pW44X homozygous mutation)	20	Recurrent cellulitis, recurrent lower respiratory tract infections, recurrent oral aphthous ulcers	GCSF	Family	Cough	PCR (+)	Yes	Oxygen
23	Kostmann disease (HAX−1 c.130‐131insA., pW44X homozygous mutation)	17	Recurrent cellulitis, recurrent lower respiratory tract infections, recurrent oral aphthous ulcers	GCSF	Family	Cough	PCR (+)	No	Favipiravir
24	Congenital neutropenia	7 months	Food allergy, atopic dermatitis, previous infantile sepsis, pyoderma	GCSF	Family	Fever	PCR (+)	Yes	Ceftriaxone
25	Chronic granulomatous disease	16	Chronic ITP, recurrent infections of gastrointestinal tract, recurrent actinomyces, and staphylococcal lymphadenitis	Itraconazole, TMP‐SMX	Unknown	Fever, sore throat	PCR (‐) Ab (+)	No	No
26	Chronic granulomatous disease	3	Multiple liver abscess, necrotizing Aspergillus pneumonia, staphylococcal pneumonia	‐	Unknown	Asymptomatic	PCR (‐) Ab (+)	No	No
Defects in intrinsic and innate immunity
27	Predisposition to severe viral infection	13	Kawasaki after MMR vaccination at 1 year old, recurrent viral interstitial pneumonia	‐	Family	Fever, cough, dyspnea, loss of appetite, bilateral conjunctivitis, erythema nodosum, hypotension, autoimmune hemolytic anemia	PCR (+)	Yes	Favipiravir, interferon alpha, oxygen, enoxaparin sodium, dexamethasone, teicoplanin, ceftriaxone, azithromycin
28	IL−21R deficiency	21	Asthma Food‐induced anaphylaxis, multiple food allergy, drug allergy	IVIG, TMP‐SMX	Family	Asthma attack	PCR (+)	Yes	Favipiravir, methylprednisolone, salbutamol
Phenocopies of inborn errors of immunity
29	RAS‐associated autoimmune leukoproliferative disease (SPRED1(NM_152594) C.684+50A>T homozygous)	10	Flattened nose, ptosis, hypertelorism, downslanting palpebral fissures and epicanthal folds, low hairline, long philtrum, aplastic anemia, secondary HLH	‐	Family	Fever, vomiting	PCR (+)	Yes	No

Abbreviations: Ab, antibodies; CVID, common variable immunodeficiency; FMF, familial Mediterranean fever; G6PD, glucose‐6‐phosphate dehydrogenase; GCSF, granulocyte‐colony stimulating factor; HLH, hemophagocytic lymphohistiocytosis; IEI, inborn errors of immunity; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; TMP‐SMX, trimethoprim‐sulfamethoxazole.

FIGURE 1

Contact status and test results of the patients

CVID (the next‐generation sequencing identified a germline heterozygous pathogenic variant in the exon 17 of the NF‐κB2 gene, c.1832G

PCR not performed

Ab (+)

Fever, sore throat

Fever, vomiting, cough, diarrhea

PCR not performed

Ab (+)

Fever, cough, dyspnea

Kostmann disease

(HAX−1 c.130‐131insA., pW44X homozygous mutation)

Fever, herpetic stomatitis, diarrhea

PCR (‐)

Ab (+)

Kostmann disease

(HAX−1 c.130‐131insA., pW44X homozygous mutation)

PCR not performed

Ab (+)

Kostmann disease

(HAX−1 c.130‐131insA., pW44X homozygous mutation)

Kostmann disease

(HAX−1 c.130‐131insA., pW44X homozygous mutation)

PCR (‐)

Ab (+)

Asthma

Food‐induced anaphylaxis, multiple food allergy, drug allergy

RAS‐associated autoimmune leukoproliferative disease

(SPRED1(NM_152594) C.684+50A>T homozygous)

Abbreviations: Ab, antibodies; CVID, common variable immunodeficiency; FMF, familial Mediterranean fever; G6PD, glucose‐6‐phosphate dehydrogenase; GCSF, granulocyte‐colony stimulating factor; HLH, hemophagocytic lymphohistiocytosis; IEI, inborn errors of immunity; IVIG, intravenous immunoglobulin; PCR, polymerase chain reaction; TMP‐SMX, trimethoprim‐sulfamethoxazole.

Contact status and test results of the patients

The median age of the 32 patients (32/371; 8.6%) who were diagnosed with COVID‐19 was 127 months (IQR: 71.25–183 months). Nine of the 29 previously known IEI patients diagnosed with COVID‐19 required hospitalization, and 1 patient diagnosed with IEI after COVID‐19 was hospitalized due to multisystem inflammatory syndrome in children (MIS‐C). Therefore, a total of 10 (31.25%) of the 32 patients with confirmed SARS‐CoV‐2 infection were hospitalized. Among the hospitalized patients, 3 (30%) had predominantly antibody deficiency, 3 (30%) had congenital defects of phagocyte number or function, 2 (20%) had defects in intrinsic and innate immunity, 1 (10%) had combined immunodeficiencies with associated or syndromic features, and 1 patient (10%) had phenocopies of IEI. None of the patients died.

It has been reported in the literature that the incidence of COVID‐19 in children is lower than in adults. Wu et al. reported that only 2% of 44672 COVID‐19 confirmed cases were under 19 years of age. Therefore, the low confirmation rate in this study (7.88% [29/368] of patients who were already under follow‐up for IEI) may also be attributed to the patients being in the pediatric age group.

High‐risk contact was reported in only 59 (16.03%) of the 368 patients who were reached by phone, and of those, SARS‐CoV‐2 test results were negative in 5 patients and positive in 22 patients, and the other 32 patients had not been tested. The low rates of risky contact and COVID‐19 in this patient group may be partly explained by the fact that families carefully followed strict isolation measures due to their experience with severe infections. However, PCR and serology tests were not performed for 32 (54.24%) of the 59 patients with risky contact because they had no symptoms. These patients either were not infected with SARS‐CoV‐2 or had asymptomatic infection. The absence of test results for these patients is a limitation of our study.

A study from Turkey showed that children with COVID‐19 tend to be asymptomatic or have mild symptoms. Only 1.5% of 1156 confirmed pediatric COVID‐19 cases had severe disease, 56% had an underlying condition, and 2 patients died. In our study, there was no mortality. Of the 32 patients with confirmed COVID‐19 in this study, 65.6% recovered with no treatment, and 11 (34.38%) received treatment for COVID‐19 (Table 1). Ten of 32 patients were followed in hospital, while the other 68.75% of the patients did not require hospitalization due to COVID‐19. All of the patients survived with no infection‐related sequelae. In the literature, it has been reported that patients with IEI can either be expected to have more severe illness due to weak cellular immunity, or less severe disease due to the absence of a pro‐inflammatory cytokine storm. , Therefore, it is unclear whether IEI is a protective or predisposing factor for COVID‐19. In our study, the lack of mortality may be attributed to ACE receptor levels and the absence of cytokine storm. This may support the theory that IEI patients may be less likely to develop severe manifestations of COVID‐19 due to their immune system defect.

Some articles in the literature have included COVID‐19 outcomes in IEI patients. A study from the United Kingdom reported that IEI patients with COVID‐19 had a median age of 42 years and that older age was associated with mortality. In a study from Italy, 131 cases of SARS‐CoV‐2 infection occurred in patients with IEI, 33 of whom were aged 18 years or younger. The mean age of the patients who died was 48.5 ± 13.0 years. A high fatality rate was reported in Good's syndrome and in Del 22q11, both conditions associated with a T‐cell defect. Marcus et al. reported the clinical findings of COVID‐19 in 20 patients with IEI. Their age ranged from 4 months to 60 years and 16 patients (80%) had humoral immunodeficiency. None of the patients suffered from hypoxemia, and none required hospital admission. In an international study, 94 COVID‐19 patients with IEI (32 patients were <18 years old) were reported and 9 of them died. Two of the patients were in the pediatric age group; one had a phagocyte defect and another had immune dysregulation disorder. These studies suggest that there is significant heterogeneity in disease severity among these patients. However, it seems that older age is consistently associated with poorer prognosis. The literature also includes a few articles reporting COVID‐19 outcomes in patients followed up due to antibody deficiency. , , Most of the patients with COVID‐19 in our study were diagnosed with predominant antibody deficiency. In the literature, mortality was low in pediatric patients with IEI, similar to the other data related to children in our study.

In conclusion, mortality was not observed in any of the 32 patients (most with predominantly antibody deficiencies) diagnosed with COVID‐19 in our study. All of the patients fully recovered with no infection‐related sequelae. More information is needed about COVID‐19 outcomes in patients with various IEI.