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Severity of SARS-CoV-2 infection in children with inborn errors of immunity (primary immunodeficiencies): a systematic review

Abstract

Background

Inborn errors of immunity (IEIs) are considered significant challenges for children with IEIs, their families, and their medical providers. Infections are the most common complication of IEIs and children can acquire coronavirus disease 2019 (COVID-19) even when protective measures are taken.

Objectives

To estimate the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children with IEIs and analyse the demographic parameters, clinical characteristics and treatment outcomes in children with IEIs with COVID-19 illness.

Methods

For this systematic review, we searched ProQuest, Medline, Embase, PubMed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guideline for studies on the development of COVID-19 in children with IEIs, published from December 1, 2019 to February 28, 2023, with English language restriction.

Results

Of the 1095 papers that were identified, 116 articles were included in the systematic review (73 case report, 38 cohort 4 case-series and 1 case–control studies). Studies involving 710 children with IEIs with confirmed COVID-19 were analyzed. Among all 710 IEIs pediatric cases who acquired SARS-CoV-2, some children were documented to be admitted to the intensive care unit (ICU) (n = 119, 16.8%), intubated and placed on mechanical ventilation (n = 87, 12.2%), suffered acute respiratory distress syndrome (n = 98, 13.8%) or died (n = 60, 8.4%). Overall, COVID-19 in children with different IEIs patents resulted in no or low severity of disease in more than 76% of all included cases (COVID-19 severity: asymptomatic = 105, mild = 351, or moderate = 88). The majority of children with IEIs received treatment for COVID-19 (n = 579, 81.5%). Multisystem inflammatory syndrome in children (MIS-C) due to COVID-19 in children with IEIs occurred in 103 (14.5%). Fatality in children with IEIs with COVID-19 was reported in any of the included IEIs categories for cellular and humoral immunodeficiencies (n = 19, 18.6%), immune dysregulatory diseases (n = 17, 17.9%), innate immunodeficiencies (n = 5, 10%), bone marrow failure (n = 1, 14.3%), complement deficiencies (n = 1, 9.1%), combined immunodeficiencies with associated or syndromic features (n = 7, 5.5%), phagocytic diseases (n = 3, 5.5%), autoinflammatory diseases (n = 2, 3%) and predominantly antibody deficiencies (n = 5, 2.5%). Mortality was COVID-19-related in a considerable number of children with IEIs (29/60, 48.3%). The highest ICU admission and fatality rates were observed in cases belonging to cellular and humoral immunodeficiencies (26.5% and 18.6%) and immune dysregulatory diseases (35.8% and 17.9%) groups, especially in children infected with SARS-CoV-2 who suffered severe combined immunodeficiency (28.6% and 23.8%), combined immunodeficiency (25% and 15%), familial hemophagocytic lymphohistiocytosis (40% and 20%), X-linked lymphoproliferative diseases-1 (75% and 75%) and X-linked lymphoproliferative diseases-2 (50% and 50%) compared to the other IEIs cases.

Conclusion

Children with IEIs infected with SARS-CoV-2 may experience higher rates of ICU admission and mortality in comparison with the immunocompetent pediatric populations. Underlying immune defects does seem to be independent risk factors for severe SARS-CoV-2 infection in children with IEIs, a number of children with SCID and CID were reported to have prolonged infections–though the number of patients is small–but especially immune dysregulation diseases (XLP1 and XLP2) and innate immunodeficiencies impairing type I interferon signalling (IFNAR1, IFNAR2 and TBK1).

Background

Since our knowledge on the multiple aspects and complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), such as multisystem inflammatory syndrome in children (MIS-C), has grown gradually during the coronavirus disease 2019 (COVID-19) pandemic, some relevant features of the disease especially in children were not highlighted in early case reports and small series published. Inborn errors of immunity (IEIs), formerly called primary immunodeficiency disorders, are a growing group of hundreds of disorders [1]. IEIs range considerably in severity from mild infections to serious multisystemic disease [2]. A group of nearly 500 IEIs have been described by the expert committee of the International Union of Immunological Societies (IUIS) [1]. While individually rare, IEIs are considered significant challenges for patients with IEIs, their families, and their medical providers; and children with IEIs present clinically as increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergy, bone marrow failure, and/or malignancy [3]. Very few sporadic cases of IEIs in children with SARS-CoV-2 infection have been reported worldwide [4,5,6,7,8,9,10]. Several previous systematic reviews have reported on the association between IEIs and COVID-19; however, these studies included mixed populations of adults and children, and included a smaller number of studies (with most data for adults and very few pediatric patients) [11,12,13,14,15,16,17,18,19], Moreover, only some of these reviews covered the occurrence of COVID-19 in patients with all categories of IEIs as compiled by the IUIS [11,12,13,14, 19]. Few reviews evaluated clinical course of SARS-CoV-2 infection in patients with IEIs with the limitation of focusing on one major category or subcategory of IEIs such as cellular and humoral immunodeficiencies [17], common variable immunodeficiency [16, 18] or DNA repair defects [15]. Due to the lack of comprehensive and updated systematic reviews focusing on the development of those two medical conditions, we aimed to estimate the incidence of SARS-CoV-2 infection in children with IEIs and analyse the demographic parameters, clinical characteristics and treatment outcomes in those IEIs cases with pediatric COVID-19 illness, with larger and better-quality data. We expect our review to provide clinicians with a thorough understanding of the clinical course and outcome of hundreds of children with IEIs infected with SARS-CoV-2 and predisposing factors and immunological mechanisms underlying severe COVID-19.

Methods

Design

We performed this systematic review following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) [20]. We searched for observational studies published from 1 December 2019 until 28 February 2023, in PROQUEST, MEDLINE, EMBASE, PUBMED, CINAHL, WILEY ONLINE LIBRARY, SCOPUS and NATURE, with a restriction to articles published in the English language. Search terms were based on the IUIS classification of human IEIs [1] (see Additional file 1 for complete search strategies and IEIs in each inborn error of immunity class included in Additional file 1: Tables S1, S2). Articles discussing and reporting the development of COVID-19 in children with IEIs were selected based on the title and abstract.

Inclusion–exclusion criteria

The eligible studies were included based on the following inclusion criteria: (1) published case reports, case-series, case–control and cohort studies that focused on development of COVID-19 in IEIs patients that included children as a population of interest; (2) studies of an experimental or observational design reporting the incidence of SARS-CoV-2 infection in pediatric patients with IEIs. The exclusion criteria included: (1) editorials, commentaries, reviews and meta-analyses; (2) studies that reported IEIs in children with negative SARS-CoV-2 polymerase chain reaction (PCR) tests; (3) studies that reported IEIs in adult COVID-19 patients.

Data extraction

The screening of the papers was performed independently by six reviewers (Saad Alhumaid, Zainah Sabr, Ola Alkhars, Muneera Alabdulqader, Fatemah M. ALShakhs, and Rabab Abbas Majzoub) by screening the titles with abstracts using the selection criteria. Disagreements in the study selection after the full-text screening were discussed; if agreement could not be reached, a third reviewer was involved. We categorized articles as case report, case-series, case–control or cohort studies. The following data were extracted from the selected studies: authors; publication year; study location; study design and setting; age; proportion of male patients; patient ethnicity; identified IEIs; main genetic cause of IEIs; other potential modifiers in immunity-related pathways or specific allele change; IEIs mode of inheritance; COVID-19 severity, if patient experienced multisystem inflammatory syndrome in children (MIS-C), and comorbidities; laboratory findings; IEIs treatment at SARS-CoV-2 infection; if patient was admitted to the intensive care unit (ICU), placed on mechanical ventilation and/or suffered acute respiratory distress syndrome (ARDS); assessment of study risk of bias; and final treatment outcome (survived or died); and they are noted in Additional file 2: Table S3 (see Additional file 2 for summary of the characteristics of the included studies with evidence on IEIs and COVID-19 in pediatric patients, n = 116 studies, 2020–2022).

Quality assessment

Two tools were used appropriately to assess the quality of the studies included in this review: (1) Newcastle–Ottawa Scale (NOS) to evaluate cohort and case–control studies (scoring criteria: > 7 scores = high quality, 5–7 scores = moderate quality, and < 5 scores = low quality) [21]; and (2) modified NOS to evaluate case report and case-series studies (scoring criteria: 5 criteria fulfilled = good, 4 criteria fulfilled = moderate, and 3 criteria fulfilled = low) [22]. Quality assessment was conducted by six co-authors (Yousef Hassan Alalawi, Khalid Al Noaim, Abdulrahman A. Alnaim, Mohammed A. Al Ghamdi, Abdulaziz A. Alahmari, and Sawsan Sami Albattat) who separately evaluated the possibility of bias using these two tools.

Data analysis

We examined primarily the proportion of confirmed SARS-CoV-2 infection in patients with IEIs. This proportion was further classified based on 2022 updated classification of IEIs (i.e., identified IEIs cases were categorized into 10 Tables with subtables segregating groups of disorders into overlapping phenotypes), as compiled by the expert committee of the IUIS [1]. Clinical Spectrum of SARS-CoV-2 Infection from the National Institutes of Health was applied to define severity of COVID-19 (asymptomatic, mild, moderate, severe and critical) [23]. MIS-C was defined according to the current United States Centers for Disease Control and Prevention case definition in an individual aged < 21 years [24].

Descriptive statistics were used to describe the data. For continuous variables, mean and standard deviation were used to summarize the data; and for categorical variables, frequencies and percentages were reported. Microsoft Excel 2019 (Microsoft Corp., Redmond, USA) was used for all statistical analyses.

Results

Study characteristics and quality

A total of 3952 publications were identified (Fig. 1). After exclusion of duplicates and articles that did not fulfill the study inclusion criteria, one hundred and sixteen articles were included in the qualitative synthesis of this systematic review [4,5,6,7,8,9,10, 19, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130,131,132]. The reports of seven hundred and ten cases identified from these articles are presented by groups based on 2022 updated classification of IEIs as described by IUIS [1]. The detailed characteristics of the included studies are shown in Additional file 2: Table S3. There were 73 case report [4,5,6, 8, 9, 25,26,27,28,29,30,31,32, 37,38,39, 44, 45, 49, 51, 53,54,55,56,57,58,59,60, 67,68,69, 72, 76,77,78,79, 82,83,84, 86,87,88, 90, 91, 93, 94, 96, 99,100,101,102,103,104,105,106,107, 109,110,111,112,113,114, 116, 119,120,121,122,123, 126, 127, 129,130,131], 38 cohort [7, 10, 19, 33,34,35,36, 40,41,42,43, 46,47,48, 50, 52, 61,62,63,64,65,66, 70, 71, 73, 74, 80, 81, 92, 95, 97, 98, 108, 117, 118, 124, 125, 132], 4 case-series [85, 89, 115, 128], and 1 case–control [75] studies. These studies were conducted in United States (n = 27), Iran (n = 15), India (n = 10), United Kingdom (n = 8), Italy (n = 8), Turkey (n = 8), Germany (n = 6), Brazil (n = 4), Mexico (n = 3), Israel (n = 3), Spain (n = 3), Saudi Arabia (n = 2), Poland (n = 2), Greece (n = 2), Belgium (n = 2), Switzerland (n = 1), Sweden (n = 1), Hong Kong (n = 1), Peru (n = 1), United Arab Emirates (n = 1), Tunisia (n = 1), and France (n = 1). Only six studies were made within multi-countries (n = 6) [10, 33, 35, 51, 95, 132]. The majority of the studies were single centre [4,5,6, 8, 9, 19, 25,26,27,28,29,30,31,32, 34, 37,38,39, 41, 43,44,45,46,47, 49, 50, 52,53,54,55,56,57,58,59,60, 62, 64, 66,67,68,69, 71, 72, 75,76,77,78,79,80, 82,83,84, 86,87,88,89,90, 93, 94, 96, 98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117, 119,120,121,122,123,124,125,126,127,128,129,130,131] and only 23 studies were multi-centre [7, 10, 33, 35, 36, 40, 42, 48, 51, 61, 63, 65, 70, 73, 74, 81, 85, 91, 92, 95, 97, 118, 132]. Among all included studies in our systematic review, only one study reported on the other potential modifiers in immunity-related pathways for all diagnosed IEIs in children who were infected with SARS-CoV-2 (n = 1, 0.9%) [19]. All case reports and case-series studies were assessed for bias using the modified NOS. Sixty-seven studies were deemed to have high methodological quality, 7 moderate methodological quality, and 3 low methodological quality. Among the 116 included studies, 38 cohort studies were assessed using the NOS: 31 studies were found to be moderate-quality studies (i.e., NOS scores between 5 and 7) and 7 study demonstrated a relatively high quality (i.e., NOS scores > 7); Additional file 2: Table S3.

Fig. 1
figure 1

Flow diagram of studies included in the systematic review

Predominantly antibody deficiencies

Predominantly antibody deficiencies were the first most-common IEIs in children who experienced COVID-19 (n = 197, 27.7%) [8, 19, 27, 28, 34, 36, 40, 42, 45, 46, 49, 50, 52, 55, 62,63,64,65,66, 71, 73, 74, 80, 81, 83, 85, 91, 92, 95, 97, 105, 108, 114, 117, 120, 122, 124, 125, 129, 130] (see Additional file 2: Table S3). Among them, 53 have common variable immunodeficiency (CVID, 26.9% of all predominantly antibody deficiencies) [19, 27, 28, 34, 36, 40, 46, 50, 62,63,64,65,66, 73, 74, 80, 95, 97, 114, 122, 124, 125], 45 have X-linked agammaglobulinemia (XLA, 22.8%) [8, 19, 34, 40, 42, 46, 49, 50, 52, 63, 65, 71, 73, 74, 85, 91, 92, 95, 97, 105, 117, 120, 129, 130], 41 have autosomal recessive or autosomal dominant agammaglobulinemia or hypogammaglobulinemia (20.8%) [45, 52, 55, 63, 65, 80, 83, 124], 28 have isolated IgG subclass deficiencies (14.2%) [81, 108], and 12 have selective IgA deficiencies (6.1%) [46, 48, 52, 65, 81, 124]. The remaining 18 patients have other isotype, light chain, or functional deficiencies with generally normal numbers of B cells [including IgG subclass deficiency with IgA and/or IgM deficiency (n = 2) [108], IgG, IgA and IgM deficiencies (n = 2) [108], partial IgA deficiency (n = 1) [124], and low IgM level (n = 1) [124]]; selective IgM deficiencies (n = 3) [81, 108]; specific antibody deficiency with normal immunoglobulin and B cells levels (n = 4) [40, 65], unspecified predominantly antibody deficiency (n = 3) [65, 95]; UNG deficiency (n = 1) [19] and APRIL deficiency (n = 1) [40]. The most frequent main genetic causes of predominantly antibody deficiencies in children infected with SARS-CoV-2 were BTK (n = 41) [8, 19, 34, 40, 46, 49, 50, 52, 63, 65, 71, 73, 74, 85, 91, 92, 95, 97, 105, 117, 120, 129], NFKB2 (n = 4) [27, 36, 95, 122], TNFRSF13B (n = 3) [62, 114, 125], PIK3CD (n = 3) [19, 65, 97], and PIK3R1 (n = 2) [45, 63]. For patients with predominately antibody deficiencies who acquired SARS-CoV-2, the median interquartile range (IQR) age was 120 months [83–175], with a male predominance [n = 94, 47.7%] [8, 19, 27, 28, 34, 40, 42, 45, 46, 49, 50, 52, 55, 62, 63, 65, 66, 71, 73, 74, 80, 85, 91, 92, 95, 105, 108, 117, 120, 125, 129, 130], and majority of the patients belonged to White (Caucasian) (n = 144, 73.1%) [8, 27, 36, 42, 46, 50, 52, 55, 62,63,64, 66, 71, 73, 80, 81, 83, 85, 95, 97, 105, 108, 114, 120, 122, 124, 129], Hispanic (n = 30, 15.2%) [40, 65, 95, 125] and Persian (n = 15, 7.6%) [19, 28, 34, 48, 74, 117] ethnicity. In those predominantly antibody deficiencies patients, few studies reported on specific allele changes (n = 9, 4.6%) [27, 36, 49, 62, 114, 120, 122, 125, 129]. Reported modes of inheritance for the predominantly antibody deficiencies in children were autosomal recessive (n = 62, 31.5%) [19, 28, 34, 40, 46, 50, 63, 73], X-linked (n = 46, 23.3%) [8, 19, 34, 40, 42, 46, 49, 50, 52, 63, 65, 71, 73, 74, 85, 91, 92, 95, 97, 105, 117, 120, 129, 130], or autosomal dominant (n = 15, 7.6%) [19, 27, 36, 45, 52, 62, 63, 65, 83, 95, 97, 114, 122, 125], however, mode of inheritance in these predominantly antibody deficiencies cases was unknown in a high percentage of patients (n = 120, 60.9%) [40, 46, 48, 52, 55, 63,64,65,66, 74, 80, 81, 95, 97, 108, 124]. COVID-19 in children with predominately antibody deficiencies was asymptomatic (32/197 = 16.2%) [50, 63, 65, 73, 81, 92, 95, 97, 108, 124], mild (120/197 = 61%) [28, 34, 40, 42, 46, 48, 49, 52, 55, 63, 65, 66, 71, 73, 74, 80, 81, 83, 85, 91, 92, 95, 97, 108, 120, 124, 130], moderate (21/197 = 10.6%) [40, 46, 52, 64, 74, 81, 85, 91, 95, 117, 122, 124, 129], severe (14/197 = 7.1%) [8, 19, 27, 36, 45, 65, 81, 91, 105, 114] or critical (2/197 = 1%) [19, 65]. Most children with predominately antibody deficiencies did not get MIS-C due to COVID-19 (178/197, 90.3%) [8, 19, 28, 34, 40, 42, 46, 48,49,50, 52, 55, 63,64,65,66, 71, 73, 80, 81, 83, 85, 92, 95, 97, 105, 108, 117, 120, 122, 124, 129, 130], however, few children with predominately antibody deficiencies were reported to experience MIS-C (9/197, 4.6%) [19, 27, 36, 45, 62, 108, 114, 125]. Few of those predominantly antibody deficiencies cases presented with a previous known history of chronic lung disease (n = 5) [40, 46, 64, 74, 95], chronic heart disease (n = 4) [55, 63, 65, 95], arthritis (n = 4) [49, 52, 114, 122], hypertension (n = 3) [55, 124], Down syndrome (n = 3) [55, 65, 108], autoimmune haemolytic anaemia (n = 2) [40, 52], asthma (n = 2) [52, 124], immune thrombocytopenic purpura (n = 2) [46, 124], hypercholesterolemia (n = 2) [63, 95], hereditary spherocytosis (n = 2) [8, 95], Chromosome 18q deletion (n = 2) [64, 66], seizures (n = 2) [40, 114], psoriasis (n = 2) [27, 95], hemophagocytic lymphohistiocytosis (n = 2) [95], celiac disease (n = 2) [46, 80] or obesity (n = 2) [65, 124]. Patients who suffered predominantly antibody deficiencies and experienced COVID-19 were maybe more likely to have low serum immunoglobulin G levels (n = 29) [19, 36, 66, 108], low serum immunoglobulin A levels (n = 10) [19, 28, 36, 49, 66, 80, 85], high C-reactive protein (n = 8) [8, 27, 48, 55, 64, 71, 73, 105], low serum immunoglobulin M levels (n = 5) [19, 28, 66, 85], lymphopenia (n = 5) [27, 45, 64, 73], thrombocytopenia (n = 5) [8, 40, 45, 55], high ESR (n = 4) [8, 45, 48, 105], raised liver enzymes (n = 3) [27, 55, 114], hypogammaglobulinemia (n = 3) [27, 36, 80], and high D-dimer (n = 3) [27, 55, 105]. As expected, most prescribed therapeutic agents in these predominantly antibody deficiencies cases were intravenous immunoglobulin (n = 49, 24.9%) [8, 19, 27, 28, 34, 40, 42, 45, 48, 49, 52, 63, 65, 73, 74, 80, 85, 91, 92, 95, 105, 129], antibiotics (n = 38, 19.3%) [8, 19, 27, 28, 34, 42, 45, 48, 49, 52, 55, 63, 73, 74, 85, 91, 95, 105, 117, 129], oxygen supplementation (n = 14, 7.1%) [8, 19, 27, 28, 45, 52, 55, 64, 71, 95, 108, 117, 122, 124], steroids (n = 16, 8.1%) [19, 27, 34, 40, 45, 52, 55, 64, 95, 114, 117, 122], convalescent plasma (n = 12, 6.1%) [8, 19, 27, 71, 85, 91, 95, 108, 122], and remdesivir (n = 12, 6.1%) [8, 27, 42, 45, 64, 85, 95, 105, 117, 122], however, treatment was not necessary in a high number of these predominantly antibody deficiencies patients (n = 59, 29.9%) [40, 46, 50, 63, 65, 66, 80, 83, 108, 120, 124, 130]. There were predominantly antibody deficiencies patients who were admitted to the intensive care units (n = 16, 8.1%) [19, 27, 36, 40, 45, 55, 64, 65, 95, 114], intubated and placed on mechanical ventilation (n = 9, 4.6%) [19, 27, 36, 40, 45, 65, 114] and suffered acute respiratory distress syndrome (n = 13, 6.6%) [19, 27, 36, 40, 45, 65, 114, 117, 122]. Clinical outcomes of the predominantly antibody deficiencies patients with mortality were documented in 5 (2.5%) [19, 40, 65, 114], while 190 (96.4%) of the predominantly antibody deficiencies cases recovered [8, 19, 27, 28, 34, 36, 40, 42, 45, 46, 48,49,50, 52, 55, 63,64,65,66, 71, 73, 74, 80, 81, 83, 85, 91, 92, 95, 97, 105, 108, 117, 120, 122, 124, 129, 130] and final treatment outcome was not reported in two predominantly antibody deficiencies patients (n = 2, 1%) [62, 125]. Mortality was COVID-19-related in two children with predominately antibody deficiencies (2/197, 1%) [65, 114], however, COVID-19 was not attributable to death in one child with the reported predominately antibody deficiencies (1/197, 0.5%) [40] and one study failed to report if COVID-19 was a leading or an underlying cause of death in two children with predominately antibody deficiencies (2/197, 1%) [19] (see Table 1).

Table 1 Pediatric patients with IEIs affected by COVID-19, stratified by type of immune defect and treatment outcome (n = 116 studies), 2020–2022

Combined immunodeficiencies with associated or syndromic features

Combined immunodeficiencies with associated or syndromic features were the second most-common IEIs in children who experienced COVID-19 (n = 126, 17.7%) [5, 19, 30, 34, 39, 40, 46,47,48, 52, 56, 62,63,64,65, 73, 74, 76, 81, 92, 95, 97, 99, 108, 112, 117, 118, 123,124,125] (see Additional file 2: Table S3). Among them, 40 have DiGeorge syndromes (31.7% of all syndromic combined immunodeficiencies) [46, 56, 63, 65, 81, 92, 95, 97, 108], 25 have immunodeficiency with ataxia-telangiectasia (19.8%) [34, 46, 48, 52, 62,63,64, 73, 74, 81, 97, 108, 117, 118, 124], and 14 have Wiskott-Aldrich syndromes (WAS) (11.1%) [5, 40, 46, 48, 63, 65, 81, 95, 99, 124]. The remaining 47 patients have Nijmegen breakage syndromes (n = 9) [81, 108]; immunodeficiencies with centromeric instability and facial anomalies (n = 6) [19, 34, 48, 73]; ARPC1B deficiency (n = 3) [39, 40, 95]; STIM1 deficiencies (n = 2) [34, 74]; anhidrotic ectodermodysplasia with immunodeficiency caused by hypomorphic mutations in encoding the nuclear factor κB essential modulator (NEMO) protein (n = 2) [30, 73]; hypoparathyroidism-retardation-dysmorphism syndromes (n = 3) [47]; MCM4 deficiencies (n = 2) [62]; Kabuki syndrome (n = 2) [63, 108]; PGM3 deficiency (n = 2) [76, 95]; ORAI-1 deficiency (n = 1) [125]; TBX1 deficiency (n = 1) [19]; Bloom syndrome (n = 1) [46]; Schimke immuno-osseous dysplasia (n = 1) [46]; unspecified hyper IgM syndromes (n = 7) [48, 65, 74, 92, 112, 123] and unspecified hyper IgE syndromes (n = 5) [34, 46]. The most frequent main genetic causes of combined immunodeficiencies with associated or syndromic features in children infected with SARS-CoV-2 were large (3 Mb) deletion of 22q11.2 (n = 40) [46, 56, 63, 65, 81, 92, 95, 97, 108], ATM deficiency (n = 24) [34, 46, 48, 52, 62,63,64, 73, 74, 81, 97, 108, 117, 118, 124], Wiskott-Aldrich syndrome protein deficiency (n = 14) [5, 40, 46, 48, 63, 65, 81, 95, 99, 124], NBS1 (n = 9) [81, 108], DNMT3B (n = 5) [19, 48, 73], ARPC1B (n = 3) [39, 40, 95], STIM1 (n = 2) [34, 74], IKBKG (n = 2) [30, 73], and PGM3 (n = 2) [76, 95]. For patients with combined immunodeficiencies with associated or syndromic features who acquired SARS-CoV-2, the median interquartile range (IQR) age was 90 months [25.7 to 142.5], with a male predominance [n = 61, 48.4%] [34, 46,47,48, 52, 56, 62, 64, 65, 73, 74, 108, 112, 117, 118, 125], and majority of the patients belonged to White (Caucasian) (n = 91, 72.2%) [5, 30, 46, 52, 62,63,64, 73, 76, 81, 95, 97, 108, 118, 123, 124], Persian (n = 18, 14.3%) [19, 34, 48, 74, 112, 117] and Hispanic (n = 11, 8.7%) [39, 40, 56, 65, 95, 125] ethnicity. In those combined immunodeficiencies with associated or syndromic features patients, few studies reported on specific allele changes (n = 5, 4%) [39, 47, 62, 99, 125]. Reported modes of inheritance for the combined immunodeficiencies with associated or syndromic features in children were autosomal recessive (n = 61, 48.4%) [19, 34, 39, 40, 46,47,48, 52, 62,63,64, 73, 74, 76, 81, 95, 97, 108, 117, 118, 124, 125], autosomal dominant (n = 41, 32.5%) [19, 46, 56, 63, 65, 81, 92, 95, 97, 108], or X-linked (n = 18, 14.3%) [5, 30, 40, 46, 48, 63, 65, 73, 81, 95, 99, 108, 124], however, mode of inheritance in these combined immunodeficiencies with associated or syndromic features cases was unknown in a low percentage of patients (n = 6, 4.8%) [65, 74, 92, 112, 123]. COVID-19 in children with combined immunodeficiencies with associated or syndromic features was asymptomatic (20/126 = 15.9%) [34, 56, 63, 65, 81, 92, 95, 97, 123, 124], mild (66/126 = 52.4%) [5, 34, 40, 46, 48, 52, 63,64,65, 73, 74, 76, 81, 92, 95, 97, 99, 108, 117], moderate (14/126 = 11.1%) [34, 40, 46, 48, 63, 74, 81, 112, 124], severe (9/126 = 7.1%) [19, 30, 34, 39, 48, 65, 97] or critical (1/126 = 0.8%) [65]. Most children with combined immunodeficiencies with associated or syndromic features did not get MIS-C due to COVID-19 (105/126, 83.3%) [5, 19, 34, 39, 40, 46, 48, 52, 56, 63,64,65, 73, 76, 81, 92, 95, 97, 99, 108, 112, 117, 123, 124], however, few children with combined immunodeficiencies with associated or syndromic features were reported to experience MIS-C (11/126, 8.7%) [19, 30, 34, 48, 62, 125]. Few of those combined immunodeficiencies with associated or syndromic features cases presented with a previous known history of cardiopathy (n = 7) [46], chronic heart disease (n = 5) [56, 63, 65], chronic lung disease (n = 3) [40, 64, 124], post hematopoietic stem cell transplant (n = 3) [40, 46, 95], inflammatory bowel disease (n = 3) [40, 73], cognitive disability (n = 3) [63, 95], obesity (n = 3) [56, 63, 65], hypoparathyroidism (n = 2) [63], hypothyroidism (n = 2) [63], developmental delay (n = 2) [46, 47, 63], autoimmune haemolytic anaemia (n = 2) [34, 74], vasculitis (n = 2) [63, 74], gastroesophageal reflux disease (n = 2) [46, 52], hypertension (n = 2) [65], myopathy (n = 2) [34, 74], sepsis or septic shock (n = 2) [39, 95] or nephrotic syndrome (n = 2) [34, 74]. Patients who suffered combined immunodeficiencies with associated or syndromic features and experienced COVID-19 were maybe more likely to have high C-reactive protein (n = 9) [30, 48, 73], high erythrocyte sedimentation rate (n = 8) [30, 48, 73, 112], low serum immunoglobulin M level (n = 5) [19, 52, 56], low serum immunoglobulin A level (n = 5) [19, 47, 52, 99], neutropenia (n = 5) [39, 64, 73, 76], low serum immunoglobulin G level (n = 4) [19, 52, 108], low haemoglobin (n = 4) [30, 48, 112], high D-dimer (n = 3) [73], hypogammaglobulinemia (n = 2) [56, 92], lymphopenia (n = 2) [56, 76], anaemia (n = 2) [62, 112], low white blood cells (n = 2) [30, 64, 123], high lactate dehydrogenase (n = 2) [73], and high interleukin-6 (n = 2) [30, 73]. As expected, most prescribed therapeutic agents in these combined immunodeficiencies with associated or syndromic features cases were antibiotics (n = 37, 29.4%) [5, 19, 30, 34, 39, 46,47,48, 52, 63, 73, 74, 92, 95, 112], intravenous immunoglobulin (n = 32, 25.4%) [5, 19, 30, 34, 39, 40, 46, 48, 52, 65, 73, 74, 92, 95, 123], oxygen supplementation (n = 7, 5.5%) [19, 30, 48, 95, 124], and hydroxychloroquine (n = 5, 4%) [5, 30, 48, 117], however, treatment was not necessary in a considerable number of these combined immunodeficiencies with associated or syndromic features patients (n = 18, 14.3%) [46, 56, 63,64,65, 76, 92, 99, 108, 124]. There were combined immunodeficiencies with associated or syndromic features patients who were admitted to the intensive care units (n = 11, 8.7%) [19, 34, 40, 47, 48, 65, 95], intubated and placed on mechanical ventilation (n = 9, 7.1%) [34, 40, 47, 48, 65, 95] and suffered acute respiratory distress syndrome (n = 9, 7.1%) [34, 40, 47, 48, 65, 95]. Clinical outcomes of the combined immunodeficiencies with associated or syndromic features patients with mortality were documented in 7 (5.5%) [34, 40, 47, 48, 65], while 112 (88.9%) of the combined immunodeficiencies with associated or syndromic features cases recovered [5, 19, 30, 34, 39, 40, 46,47,48, 52, 56, 63,64,65, 73, 74, 76, 81, 92, 95, 97, 99, 108, 112, 117, 123, 124], final treatment outcome was not reported in few combined immunodeficiencies with associated or syndromic features patients (n = 6, 4.8%) [62, 125], and one case was still in the intensive care unit (n = 1, 0.8%) [95]. Mortality was COVID-19-related in two cases with combined immunodeficiencies with associated or syndromic features (2/126, 1.6%) [34, 65], however, COVID-19 was not attributable to death in four of the children with reported combined immunodeficiencies with associated or syndromic features (4/126, 3.2%) [34, 40, 47] and one study failed to report if COVID-19 was a leading or an underlying cause of death in one child with combined immunodeficiencies with associated or syndromic features (1/126, 0.8%) [48] (see Table 1).

Cellular and humoral immunodeficiencies

Cellular and humoral immunodeficiencies were the third most-common IEIs in children who experienced COVID-19 (n = 102, 14.4%) [19, 31, 34, 40, 46, 48, 60, 62, 63, 65, 69, 73, 74, 81, 91, 92, 95, 98, 99, 104, 108, 111, 125, 126, 131] (see Additional file 2: Table S3). Among them, 60 have combined immunodeficiency (CID, 58.8% of all cellular and humoral immunodeficiencies) [19, 46, 48, 62, 63, 65, 73, 74, 91, 92, 95, 98, 99, 104, 111, 125], and 42 have severe combined immunodeficiency (SCID) (41.2%) [19, 31,