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

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.

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.

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).

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.

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.

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 [4‐10, 19, 25‐132]. 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 [4‐6, 8, 9, 25‐32, 37‐39, 44, 45, 49, 51, 53‐60, 67‐69, 72, 76‐79, 82‐84, 86‐88, 90, 91, 93, 94, 96, 99‐107, 109‐114, 116, 119‐123, 126, 127, 129‐131], 38 cohort [7, 10, 19, 33‐36, 40‐43, 46‐48, 50, 52, 61‐66, 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 [4‐6, 8, 9, 19, 25‐32, 34, 37‐39, 41, 43‐47, 49, 50, 52‐60, 62, 64, 66‐69, 71, 72, 75‐80, 82‐84, 86‐90, 93, 94, 96, 98‐117, 119‐131] 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.

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, 62‐66, 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, 62‐66, 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, 62‐64, 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, 63‐66, 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, 48‐50, 52, 55, 63‐66, 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, 48‐50, 52, 55, 63‐66, 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).

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, 46‐48, 52, 56, 62‐65, 73, 74, 76, 81, 92, 95, 97, 99, 108, 112, 117, 118, 123‐125] (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, 62‐64, 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, 62‐64, 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, 46‐48, 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, 62‐64, 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, 46‐48, 52, 62‐64, 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, 63‐65, 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, 63‐65, 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, 46‐48, 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, 63‐65, 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, 46‐48, 52, 56, 63‐65, 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 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, 34, 40, 46, 48, 60, 63, 65, 69, 73, 74, 81, 98, 108, 125, 126, 131]. The most frequent main genetic causes of cellular and humoral immunodeficiencies in children infected with SARS-CoV-2 were DOCK8 deficiency (n = 6) [62, 125], IL2RG (n = 5) [46, 65, 108, 126], RelB deficiency (n = 3) [91, 92], JAK3 deficiency (n = 3) [31, 46, 131], and IL7Ra deficiency (n = 3) [19, 69, 73]. For patients with cellular and humoral immunodeficiencies who acquired SARS-CoV-2, the median interquartile range (IQR) age was 48 months [13.5 to 122], with a male predominance [n = 61, 59.8%] [19, 31, 40, 46, 48, 62, 63, 65, 73, 74, 92, 95, 98, 99, 108, 125, 126], and majority of the patients belonged to White (Caucasian) (n = 47, 46.1%) [46, 60, 62, 63, 73, 81, 95, 104, 108, 111, 125, 126, 131], Persian (n = 28, 27.4%) [19, 34, 48, 74, 98] and Hispanic (n = 18, 17.6%) [40, 65, 95, 125] ethnicity. In those cellular and humoral immunodeficiencies patients, few studies reported on specific allele changes (n = 8, 7.8%) [31, 60, 62, 69, 99, 111, 125, 126]. Reported modes of inheritance for the cellular and humoral immunodeficiencies in children were autosomal recessive (n = 61, 59.8%) [19, 31, 34, 40, 46, 48, 60, 62, 63, 65, 69, 73, 74, 81, 91, 92, 95, 98, 111, 125, 131], X-linked (n = 8, 7.8%) [19, 46, 65, 92, 99, 108, 126], or autosomal dominant (n = 1, 1%) [19], however, mode of inheritance in these cellular and humoral immunodeficiencies cases was unknown in a high percentage of patients (n = 32, 31.4%) [19, 46, 48, 63, 65, 73, 95, 98, 104]. COVID-19 in children with cellular and humoral immunodeficiencies was asymptomatic (16/102 = 15.7%) [63, 65, 73, 81, 92, 95, 99], mild (45/102 = 44.1%) [46, 60, 63, 65, 69, 73, 74, 81, 91, 92, 95, 98, 108, 111, 131], moderate (20/102 = 20%) [31, 34, 40, 46, 48, 63, 65, 73, 74, 81, 98, 126], severe (6/102 = 5.7%) [19, 48, 74, 104] or critical (6/102 = 5.7%) [19, 48, 73]. Most children with cellular and humoral immunodeficiencies did not get MIS-C due to COVID-19 (69/102, 67.6%) [19, 31, 34, 40, 46, 60, 63, 65, 73, 81, 92, 95, 98, 99, 108, 111, 126, 131], however, some children with cellular and humoral immunodeficiencies were reported to experience MIS-C (21/102, 20.6%) [48, 62, 69, 73, 81, 104, 125]. Few of those cellular and humoral immunodeficiencies cases presented with a previous known history of chronic lung disease (n = 7) [46, 63, 95, 98], chronic heart disease (n = 6) [63, 65, 73, 74, 95], epilepsy or seizures (n = 5) [34, 48, 63, 74, 98, 104], Down syndrome (n = 4) [65, 95], hypothyroidism (n = 4) [46, 48, 63, 104], post haematopoietic stem cell transplantation (n = 4) [46, 73, 95], lymphoma (n = 3) [46, 95], cognitive disability (n = 3) [63, 95], developmental delay (n = 3) [46, 63], hemophagocytic lymphohistiocytosis (n = 3) [95], adenitis due to tuberculosis vaccine (n = 3) [34, 48, 131], obesity (n = 3) [65], atrial or ventricular septal defects (n = 3) [34, 74, 104], neurological disorder (n = 2) [48, 74], hypogammaglobulinemia (n = 2) [92], colitis (n = 2) [63, 74], autoimmune haemolytic anaemia (n = 2) [46, 48], eczema (n = 2) [65, 95], hepatitis (n = 2) [63, 126] or dilated cardiomyopathy (n = 2) [34, 74]. Patients who suffered cellular and humoral immunodeficiencies and experienced COVID-19 were maybe more likely to have lymphopenia (n = 11) [31, 48, 60, 81, 104, 126], high C-reactive protein (n = 8) [48, 73, 98], neutropenia (n = 7) [73, 95, 126], high erythrocyte sedimentation rate (n = 7) [48, 69], high D-dimer (n = 5) [73, 104, 126], low serum immunoglobulin A levels (n = 5) [19, 60, 69, 99], low serum immunoglobulin M levels (n = 4) [19, 69, 99], thrombocytopenia (n = 4) [48, 98], high lactate dehydrogenase (n = 4) [73, 104], low serum immunoglobulin G levels (n = 3) [19, 60, 99], raised liver enzymes (n = 3) [69, 104, 108], low white blood cells (n = 3) [48], hypoalbuminemia (n = 2) [69, 73], high ferritin (n = 2) [104, 126], elevated partial thromboplastin time (n = 2) [104, 126], and high interleukin-10 (n = 2) [104, 126]. As expected, most prescribed therapeutic agents in these cellular and humoral immunodeficiencies cases were antibiotics (n = 50, 49%) [19, 31, 34, 46, 48, 73, 74, 95, 98, 104, 111, 131], intravenous immunoglobulin (n = 47, 46.1%) [19, 31, 34, 40, 46, 48, 63, 65, 69, 73, 74, 92, 95, 98, 99, 126, 131], (n = 11, 10.8%), hydroxychloroquine or chloroquine (n = 9, 8.8%) [48, 74, 95, 104, 131], antifungals (n = 6, 5.9%) [31, 34, 73, 74, 95], and oxygen supplementation (n = 6, 5.9%) [31, 95, 104], however, treatment was not necessary in a considerable number of these cellular and humoral immunodeficiencies patients (n = 21, 20.6%) [46, 60, 63, 65, 73, 95, 108]. There were cellular and humoral immunodeficiencies patients who were admitted to the intensive care units (n = 27, 26.5%) [19, 31, 34, 48, 65, 73, 74, 95, 98, 104], intubated and placed on mechanical ventilation (n = 23, 22.5%) [19, 31, 34, 48, 73, 74, 95, 98, 104] and suffered acute respiratory distress syndrome (n = 23, 22.5%) [19, 31, 34, 48, 73, 74, 95, 98, 104]. Clinical outcomes of the cellular and humoral immunodeficiencies patients with mortality were documented in 19 (18.6%) [19, 34, 48, 73, 74, 98], while 72 (70.6%) of the cellular and humoral immunodeficiencies cases recovered [19, 31, 40, 46, 48, 60, 63, 65, 69, 73, 74, 81, 91, 92, 95, 98, 99, 104, 108, 111, 126, 131], and final treatment outcome was not reported in few cellular and humoral immunodeficiencies patients (n = 9, 8.8%) [62, 125], and two cases were still in the intensive care unit (n = 2, 2%) [95]. Mortality was COVID-19-related in twelve cases with cellular and humoral immunodeficiencies (12/102, 11.8%) [48, 73, 74, 98], however, COVID-19 was not attributable to death in three of the children with reported cellular and humoral immunodeficiencies (3/102, 2.9%) [34, 48, 98] and one study failed to report if COVID-19 was a leading or an underlying cause of death in four children with cellular and humoral immunodeficiencies (4/102, 3.9%) [19] (see Table 1).

Immune dysregulatory diseases were the fourth most-common IEIs in children who experienced COVID-19 (n = 95, 13.4%) [6, 9, 19, 29, 32, 35, 38, 40, 43, 44, 46, 48, 50, 52, 54, 57, 58, 62, 63, 65, 67, 72‐74, 79, 81, 82, 84, 86, 88, 93‐97, 99, 100, 102, 109, 110, 113, 115, 118, 121, 125, 130] (see Additional file 2: Table S3). Among them, 25 have familial hemophagocytic lymphohistiocytosis (26.3% of all immune dysregulatory diseases) [6, 19, 29, 48, 62, 65, 67, 72, 73, 79, 81, 82, 84, 88, 99, 110, 125], 19 have autoimmune polyendocrine syndromes type-1 (APS-1) (20%) [35, 38, 73, 86, 94, 102, 113], 9 have autoimmune lymphoproliferative syndrome (ALPS) (9.5%) [50, 81, 95, 97, 130], 6 have LRBA deficiency (6.3%) [57, 58, 115, 125], 5 have TPP2 deficiency (5.3%) [118, 121, 125], 4 have XLP1 (4.2%) [44, 54, 81, 109], 4 have XLP2 (4.2%) [43, 65, 95, 100], 2 have SOCS1 deficiency (2.1%) [9, 96], 2 have CTLA4 deficiency (2.1%) [32, 95], 2 have IL-10Ra deficiency (2.1%) [74, 125], 2 have BACH2 deficiency (2.1%) [19] and 2 have RLTPR deficiency (2.1%) [73]. The remaining 13 patients have NOTCH1 mutation (n = 1) [19]; ALPS-Caspase10 (n = 1) [19]; CD137 deficiency (n = 1) [73]; interleukin-37 deficiency (n = 1) [19]; IPEX syndrome (n = 1) [93]; prolidase deficiency (n = 1) [62]; PRKCD deficiency (n = 1) [95]; MAGT1 deficiency (n = 1) [99]; and unspecified immune dysregulatory disease (n = 5) [40, 46, 52, 63]. The most frequent main genetic causes of immune dysregulatory diseases in children infected with SARS-CoV-2 were AIRE (n = 19) [35, 38, 73, 86, 94, 102, 113], LRBA deficiency (n = 6) [57, 58, 115, 125], PRF1 (n = 6) [74, 125], TPP2 (n = 5) [118, 121, 125], LYST (n = 4) [65, 84, 99, 125], XIAP deficiency (n = 4) [43, 65, 95, 100], SH2D1A deficiency (n = 4) [44, 54, 81, 109], STXBP2 (n = 3) [19, 73, 125], UNC13D (n = 2) [19, 125], SOCS1 deficiency (n = 2) [9, 96], CTLA4 deficiency (n = 2) [32, 95], and IL10RA deficiency (n = 2) [74, 125]. For patients with immune dysregulatory diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 108 months [60 to 168], with a male predominance [n = 55, 57.9%] [6, 9, 19, 32, 35, 40, 43, 44, 46, 50, 54, 57, 58, 62, 63, 65, 72, 73, 79, 82, 88, 93‐95, 99, 100, 102, 109, 113, 115, 125, 130], and majority of the patients belonged to White (Caucasian) (n = 53, 55.8%) [6, 9, 32, 35, 38, 43, 46, 50, 52, 62, 63, 67, 73, 81, 82, 84, 86, 94, 95, 97, 100, 109, 110, 113, 115, 118], Black (n = 12, 12.6%) [79, 93, 125] and Persian (n = 10, 10.5%) [19, 48, 54, 74, 88] ethnicity. In those immune dysregulatory diseases patients, few studies reported on specific allele changes (n = 15, 15.8%) [32, 35, 38, 58, 62, 84, 86, 94, 96, 99, 100, 109, 113, 121, 125]. Reported modes of inheritance for the immune dysregulatory diseases in children were autosomal recessive (n = 64, 67.4%) [6, 19, 29, 35, 38, 48, 57, 58, 62, 65, 67, 72‐74, 79, 81, 82, 84, 86, 88, 94, 95, 99, 102, 110, 113, 115, 118, 121, 125], X-linked (n = 10, 10.5%) [43, 44, 54, 65, 81, 93, 95, 99, 100, 109], or autosomal dominant (n = 7, 7.4%) [9, 19, 32, 35, 95, 96], however, mode of inheritance in these immune dysregulatory diseases cases was unknown in a high percentage of patients (n = 14, 14.7%) [40, 46, 50, 52, 63, 81, 95, 97, 130]. COVID-19 in children with immune dysregulatory diseases was asymptomatic (11/95 = 11.6%) [32, 38, 58, 63, 65, 73, 74, 81, 95, 99], mild (34/95 = 35.8%) [6, 35, 43, 50, 52, 63, 65, 67, 72, 73, 81, 82, 88, 94‐97, 99, 100, 110, 115, 121, 130], moderate (11/95 = 11.6%) [40, 46, 54, 73, 84, 95, 109, 133], severe (19/95 = 20%) [9, 19, 29, 44, 48, 57, 79, 86, 93, 102, 113, 133] or critical (2/95 = 2.1%) [19, 65]. Most children with immune dysregulatory diseases did not get MIS-C due to COVID-19 (71/95, 74.7%) [6, 9, 19, 32, 35, 38, 40, 43, 44, 46, 50, 52, 54, 57, 58, 63, 65, 67, 72‐74, 79, 81, 82, 84, 86, 88, 93‐97, 99, 100, 102, 109, 110, 113, 121, 130], however, some children with immune dysregulatory diseases were reported to experience MIS-C (23/95, 24.2%) [29, 48, 62, 73, 115, 125]. Few of those immune dysregulatory diseases cases presented with a previous known history of hypoparathyroidism (n = 13) [35, 38, 86, 94, 102], adrenal insufficiency (n = 12) [35, 67, 94, 102], cutaneous mucocutaneous candidiasis (n = 11) [35, 38, 94], inflammatory bowel disease (n = 8) [32, 58, 63, 65, 73, 74, 100, 115], arthritis (n = 6) [32, 58, 96, 109, 115], post hematopoietic stem cell transplants (n = 6) [54, 73, 93, 95, 100], grafts rejection (stem cell, gut or heart) (n = 6) [88, 93, 95, 100], hemophagocytic lymphohistiocytosis (n = 5) [62, 73, 95, 109], coagulopathy (n = 5) [9, 46, 82, 88, 109], sepsis (n = 5) [6, 29, 82, 95, 110], autoimmune haemolytic anaemia (n = 4) [9, 40, 48, 58], hepatitis (n = 4) [35, 102], hypogonadism (n = 4) [35, 38, 94], hypertension (n = 4) [65, 73, 79, 102], diabetes mellitus type 1 (n = 3) [32, 63, 102], hypothyroidism (n = 3) [35, 58, 113], immune thrombocytopenic purpura (n = 3) [9, 58, 121], chronic lung disease (n = 3) [58, 95, 110], asthma (n = 3) [35, 113, 121], vitiligo (n = 3) [35, 38, 86], organ failure (heart, liver and respiratory system) (n = 3) [88, 109, 110], gastrointestinal or rectal bleeding (n = 2) [35, 58], ascites (n = 2) [67, 109] or jaundice (n = 2) [82, 95]. Patients who suffered immune dysregulatory diseases and experienced COVID-19 were maybe more likely to have high C-reactive protein (n = 19) [6, 9, 35, 57, 67, 72, 73, 79, 88, 93, 113, 115], thrombocytopenia (n = 15) [6, 9, 48, 58, 72, 79, 82, 84, 88, 96, 100, 109, 115, 121, 130], high D-dimer (n = 14) [6, 35, 57, 72, 73, 82, 88, 93, 109, 113], high ferritin (n = 14) [6, 29, 35, 67, 72, 73, 79, 82, 84, 88, 93, 109, 115], raised liver enzymes (n = 14) [6, 35, 38, 57, 67, 72, 79, 82, 95, 102, 109, 113], high lactate dehydrogenase (n = 12) [9, 35, 57, 73, 88, 93, 109], low haemoglobin (n = 12) [9, 48, 67, 72, 79, 82, 84, 88, 102, 109, 115, 130], lymphopenia (n = 11) [9, 32, 35, 43, 57, 58, 88, 113], low serum immunoglobulin A level (n = 8) [9, 19, 44, 58], low serum immunoglobulin G level (n = 8) [9, 19, 44, 58], high interleukin-6 (n = 7) [29, 35, 43, 72, 73, 79, 115], leukopenia (n = 7) [9, 48, 72, 73, 130], anaemia (n = 7) [58, 82, 84, 88, 95, 109], high erythrocyte sedimentation rate (n = 6) [67, 73, 88, 109, 115], raised procalcitonin (n = 6) [9, 67, 73, 79, 93], high triglycerides (n = 6) [6, 67, 79, 84, 88, 109], high fibrinogen (n = 5) [6, 57, 72, 73, 79, 82, 84, 109], low serum immunoglobulin M level (n = 5) [19, 44, 58], low natural killer cells (n = 4) [44, 67, 84, 96], and high NT-proBNP (n = 3) [29, 88, 115]. As expected, most prescribed therapeutic agents in these immune dysregulatory diseases cases were steroids (n = 36, 37.9%) [9, 19, 29, 32, 35, 40, 43, 44, 54, 57, 67, 72, 74, 79, 82, 84, 86, 88, 95, 96, 100, 102, 109, 110, 113, 115, 121], antibiotics (n = 33, 34.7%) [6, 19, 29, 35, 44, 48, 54, 57, 58, 67, 72‐74, 79, 82, 88, 95, 102, 109, 110, 113], intravenous immunoglobulin (n = 27, 28.4%) [6, 9, 19, 35, 40, 43, 44, 52, 57, 58, 65, 73, 79, 82, 86, 88, 95, 96, 100, 109, 110, 115, 121], hydroxychloroquine or chloroquine (n = 7, 7.4%) [48, 52, 54, 95, 109], oxygen supplementation (n = 6, 6.3%) [57, 79, 102, 109, 113], total parenteral nutrition (n = 6, 6.3%) [19], convalescent plasma (n = 6, 6.3%) [19, 35, 93, 113], tocilizumab (n = 6, 6.3%) [29, 35, 93, 95, 109], remdesivir (n = 5, 5.3%) [43, 79, 93, 102, 109], heparin (n = 5, 5.3%) [88, 102, 113], rituximab (n = 5, 5.3%) [43, 58, 88, 96, 109], antifungals (n = 5, 5.3%) [35, 54, 57, 73], and anakinra (n = 5, 5.3%) [6, 29, 43, 109, 115], however, treatment was not necessary in a considerable number of these immune dysregulatory diseases patients (n = 12, 12.6%) [38, 50, 63, 65, 94, 99, 130]. There were immune dysregulatory diseases patients who were admitted to the intensive care units (n = 34, 35.8%) [19, 29, 35, 44, 46, 48, 54, 57, 58, 65, 67, 72, 73, 79, 82, 84, 86, 88, 93, 95, 102, 109, 110, 113], intubated and placed on mechanical ventilation (n = 25, 26.3%) [19, 29, 35, 44, 46, 48, 54, 57, 58, 65, 67, 73, 79, 82, 86, 88, 93, 95, 109, 110, 113] and suffered acute respiratory distress syndrome (n = 27, 28.4%) [19, 29, 35, 44, 46, 48, 54, 57, 58, 65, 73, 79, 82, 86, 88, 93, 95, 109, 110, 113]. Clinical outcomes of the immune dysregulatory diseases patients with mortality were documented in 17 (17.9%) [19, 29, 44, 46, 48, 54, 58, 65, 73, 82, 88, 93, 95, 109, 110], while 60 (63.1%) of the immune dysregulatory diseases cases recovered [6, 9, 19, 32, 35, 38, 40, 43, 50, 52, 57, 63, 65, 67, 73, 74, 79, 81, 84, 86, 94‐97, 99, 100, 102, 113, 115, 118, 121, 130] and final treatment outcome was not reported in many immune dysregulatory diseases patients (n = 18, 18.9%) [62, 72, 125]. Mortality was COVID-19-related in six cases with immune dysregulatory diseases (6/95, 6.3%) [29, 44, 48, 65, 73], however, COVID-19 was not attributable to death in ten of the children with reported immune dysregulatory diseases (10/95, 10.5%) [46, 54, 58, 73, 82, 88, 93, 95, 109, 110] and one study failed to report if COVID-19 was a leading or an underlying cause of death in one child with immune dysregulatory diseases (1/95, 1%) [19] (see Table 1).

Autoinflammatory diseases were the fifth most-common IEIs in children who experienced COVID-19 (n = 67, 9.4%) [7, 19, 40, 48, 62, 65, 70, 73, 75, 81, 95, 97, 103, 115, 118, 119, 125, 128] (see Additional file 2: Table S3). Among them, 36 have familial Mediterranean fever (53.7% of all autoinflammatory diseases) [7, 62, 65, 70, 75, 115, 128], 4 have Blau syndrome (6%) [62, 125], 3 have Aicardi-Goutières syndrome (4.5%) [97, 103, 118], 3 have familial cold autoinflammatory syndromes 1 (4.5%) [65, 128], 2 have ADA2 deficiency (3%) [73, 125], 2 have NLRP1 deficiency (3%) [19, 62], 2 have TNF receptor-associated periodic syndrome (%) [81, 125], 2 have hyperpigmentation hypertrichosis, histiocytosis-lymphadenopathy plus syndrome SLC29A3 mutation (3%) [119, 125], and 2 have RNASEH2B deficiency (3%) [95]. The remaining 11 patients have familial cold autoinflammatory syndrome 4 (n = 1) [81]; deficiency of the interleukin 1 receptor antagonist (n = 1) [48]; pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome, hyperzincemia and hypercalprotectinemia (n = 1) [62]; mevalonate kinase deficiency (n = 1) [81]; SAMHD1 deficiency (n = 1) [95]; A20 deficiency (n = 1) [118]; Majeed syndrome (n = 1) [125]; STING-like disease (n = 1) [125]; CARD14 mediated psoriasis (n = 1) [125]; and unspecified autoinflammatory diseases (n = 2) [19, 40]. The most frequent main genetic causes of autoinflammatory diseases in children infected with SARS-CoV-2 were MEFV (n = 36) [7, 62, 65, 70, 75, 115, 128], NOD2 (n = 4) [62, 125], NLRP3 (n = 3) [65, 128], ADA2 deficiency (n = 2) [73, 125], NLRP1 deficiency (n = 2) [19, 62], TNFRSF1A (n = 2) [81, 125], and SLC29A3 (n = 2) [119, 125]. For patients with autoinflammatory diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 108 months [78 to 168], with a male predominance [n = 32, 47.8%] [7, 19, 40, 62, 65, 70, 75, 95, 115, 125, 128], and majority of the patients belonged to White (Caucasian) (n = 50, 74.6%) [7, 62, 70, 73, 75, 81, 95, 97, 115, 118, 128], Hispanic (n = 6, 8.9%) [40, 65, 95, 125] and Black (n = 5, 7.5%) [125] ethnicity. In those autoinflammatory diseases patients, few studies reported on specific allele changes (n = 4, 6%) [62, 103, 125, 128]. Reported modes of inheritance for the autoinflammatory diseases in children were autosomal recessive (n = 50, 74.6%) [7, 19, 48, 62, 65, 70, 73, 75, 81, 95, 103, 115, 119, 125, 128], or autosomal dominant (n = 13, 19.4%) [62, 65, 81, 118, 125, 128], however, mode of inheritance in these autoinflammatory diseases cases was unknown in a few percentage of patients (n = 4, 6%) [19, 40, 97, 118]. COVID-19 in children with autoinflammatory diseases was asymptomatic (12/67 = 17.9%) [7, 65, 70, 75, 95, 103], mild (35/67 = 52.2%) [40, 65, 73, 75, 81, 97, 115, 119, 128], moderate (2/67 = 3%) [81, 115] or severe (3/67 = 4.5%) [19, 48]. Most children with autoinflammatory diseases did not get MIS-C due to COVID-19 (47/67, 70.1%) [7, 19, 40, 65, 70, 75, 81, 95, 97, 103, 119, 128], however, some children with autoinflammatory diseases were reported to experience MIS-C (18/67, 26.9%) [48, 62, 73, 115, 125]. Few of those autoinflammatory diseases cases presented with a previous known history of mental disability (n = 3) [95], epilepsy (n = 3) [75, 95], arthralgia or arthritis (n = 2) [128], cryopyrin-associated periodic syndrome (n = 2) [128] or asthma (n = 2) [75]. Patients who suffered autoinflammatory diseases and experienced COVID-19 were maybe more likely to have leukocytosis (n = 19) [75, 115], high erythrocyte sedimentation rate (n = 17) [48, 75, 115], high C-reactive protein (n = 17) [48, 73, 75, 115, 119, 128], high D-dimer (n = 6) [73, 103, 115, 119], high ferritin (n = 5) [73, 115, 119], low haemoglobin (n = 5) [48, 115, 119], high interleukin-6 (n = 4) [115, 119], thrombocytopenia (n = 2) [115, 119], high NT-proBNP (n = 2) [115], raised liver enzymes (n = 2) [103, 119], high lactate dehydrogenase (n = 2) [73, 103], neutropenia (n = 2) [73, 119], high fibrinogen (n = 2) [73, 119], and anaemia (n = 2) [48, 119]. As expected, most prescribed therapeutic agents in these autoinflammatory diseases cases were favipiravir (n = 12) [73, 75], hydroxychloroquine or chloroquine (n = 5) [7, 48, 75, 95], antibiotics (n = 8) [7, 19, 48, 73, 75, 119], steroids (n = 7) [19, 95, 103, 115, 119], intravenous immunoglobulin (n = 6) [40, 73, 115, 119], anakinra (n = 5) [115, 128], and colchicine (n = 3) [70, 128], however, treatment was not necessary in a few number of these autoinflammatory diseases patients (n = 4, 6%) [65, 95]. There were autoinflammatory diseases patients who were admitted to the intensive care units (n = 3, 4.5%) [19, 48], intubated and placed on mechanical ventilation (n = 2, 3%) [40, 48] and suffered acute respiratory distress syndrome (n = 2, 3%) [40, 48]. Clinical outcomes of the autoinflammatory diseases patients with mortality were documented in 2 (3%) [40, 48], while 52 (77.6%) of the autoinflammatory diseases cases recovered [7, 19, 65, 70, 73, 75, 81, 95, 97, 103, 115, 118, 119, 128] and final treatment outcome was not reported in many autoinflammatory diseases patients (n = 13, 19.4%) [48, 65]. Mortality was COVID-19-related in one case with autoinflammatory diseases (1/67, 1.5%) [48] and one study failed to report if COVID-19 was a leading or an underlying cause of death in one child with autoinflammatory diseases (1/67, 1.5%) [40] (see Table 1).

Phagocytic diseases were the sixth most-common IEIs in children who experienced COVID-19 (n = 54, 7.6%) [19, 40, 43, 46, 48, 52, 53, 61‐63, 65, 74, 77, 81, 90, 92, 95, 98, 101, 107, 117, 124, 127] (see Additional file 2: Table S3). Among them, 26 have chronic granulomatous disease (48.1% of all phagocytic diseases) [40, 43, 46, 48, 53, 62, 65, 74, 81, 90, 92, 95, 98, 124], 8 have Shwachman-Diamond syndromes (14.8%) [61, 95, 101], 6 have HAX1 deficiencies (11.1%) [74, 77, 124], 2 have Glycogen storage diseases type 1b (3.7%) [62], and 2 have Elastase deficiency (3.7%) [81, 127]. The remaining 10 patients have JAGN1 deficiency (n = 1) [117]; poikiloderma with neutropenia (n = 1) [107]; cystic fibrosis (n = 1) [19]; leukocyte adhesion deficiency type 3 (n = 1) [65]; GATA2 deficiency (n = 1) [95]; undefined leukopenia (n = 1) [46]; and unspecified phagocytic diseases (n = 4) [52, 63, 101, 124]. The most frequent main genetic causes of phagocytic diseases in children infected with SARS-CoV-2 were CYBB (n = 9) [40, 43, 46, 90, 92, 95], HAX1 deficiency (n = 6) [74, 77, 124], SDBS deficiency (n = 5) [61, 101], NCF1 (n = 3) [62, 92], ELANE (n = 2) [81, 127], and SLC37A4 (n = 2) [62]. For patients with phagocytic diseases who acquired SARS-CoV-2, the median interquartile range (IQR) age was 96 months [22.5 to 180], with a male predominance [n = 26, 48.1%] [19, 40, 43, 46, 48, 52, 53, 62, 65, 74, 90, 92, 95, 98, 101, 107, 127], and majority of the patients belonged to White (Caucasian) (n = 28, 51.8%) [43, 46, 52, 61‐63, 81, 95, 107, 124], Persian (n = 11, 20.4%) [19, 48, 53, 74, 77, 98, 117] and Hispanic (n = 9, 16.7%) [40, 65, 95] ethnicity. In those phagocytic diseases patients, few studies reported on specific allele changes (n = 5, 9.2%) [62, 77, 107, 124, 127]. Reported modes of inheritance for the phagocytic diseases in children were autosomal recessive (n = 32, 59.2%) [19, 53, 61, 62, 65, 74, 77, 81, 92, 101, 107, 117, 124], X-linked (n = 12, 22.2%) [40, 43, 46, 48, 90, 92, 95] or autosomal dominant (n = 4, 7.4%) [81, 95, 101, 127], however, mode of inheritance in these phagocytic diseases cases was unknown in a few percentage of patients (n = 5, 9.2%) [46, 52, 63, 98, 124]. COVID-19 in children with phagocytic diseases was asymptomatic (7/54 = 13%) [65, 92, 95, 98, 124], mild (29/54 = 53.7%) [40, 43, 46, 48, 52, 61, 63, 65, 74, 77, 81, 90, 92, 95, 101, 107, 124], moderate (10/54 = %) [40, 48, 61, 65, 74, 81, 117, 127], severe (2/54 = 3.7%) [53] or critical (1/54 = 1.8%) [19]. Most children with phagocytic diseases did not get MIS-C due to COVID-19 (45/54, 83.3%) [19, 40, 43, 46, 48, 52, 53, 61, 63, 65, 74, 77, 81, 90, 92, 95, 98, 101, 107, 117, 124, 127], however, few children with phagocytic diseases were reported to experience MIS-C (7/54, 13%) [40, 48, 53, 62]. Few of those phagocytic diseases cases presented with a previous known history of sepsis or septic, cardiogenetic or compensated shock (n = 4) [40, 43, 95, 124], liver abscess or disorder (n = 3) [74, 98, 124], chronic lung disease (n = 3) [74, 95], post haematopoietic stem cell transplantation (n = 3) [90, 101], dermatitis (n = 2) [107, 124], immune thrombocytopenic purpura (n = 2) [92, 124], hypotension (n = 2) [40, 95] and Gaucher disease (n = 2) [74, 77]. Patients who suffered phagocytic diseases and experienced COVID-19 were maybe more likely to have lymphopenia (n = 5) [43, 77, 90, 101], high C-reactive protein (n = 5) [43, 53, 77, 90, 107], neutropenia (n = 4) [77, 101, 107, 127], high erythrocyte sedimentation rate (n = 4) [48, 77, 90], low haemoglobin (n = 3) [48, 53], high lactate dehydrogenase (n = 3) [53, 90], thrombocytopenia (n = 3) [40, 95], neutrophilia (n = 3) [43, 90, 107], anaemia (n = 3) [53, 95], thrombocytosis (n = 2) [48, 53], elevated prothrombin time (n = 2) [53] and high ferritin (n = 2) [53, 107]. As expected, most prescribed therapeutic agents in these phagocytic diseases cases were antibiotics (n = 27) [43, 46, 48, 52, 53, 74, 77, 90, 92, 95, 98, 101, 107, 117, 124, 127], antifungals (n = 9) [46, 53, 74, 92, 101], steroids (n = 7) [40, 43, 53, 61, 74, 95], intravenous immunoglobulin (n = 6) [19, 40, 43, 53, 95], oxygen supplementation (n = 4) [48, 53, 127], acyclovir (n = 4) [98, 101, 124], hydroxychloroquine (n = 3) [48, 77, 117], and granulocyte colony-stimulating factor (n = 3) [52, 77, 127], however, treatment was not necessary in a few number of these phagocytic diseases patients (n = 8, 14.8%) [63, 65, 124]. There were phagocytic diseases patients who were admitted to the intensive care units (n = 4, 7.4%) [19, 40, 90, 95], intubated and placed on mechanical ventilation (n = 3, 5.5%) [19, 40, 95] and suffered acute respiratory distress syndrome (n = 5, 9.2%) [19, 40, 53, 95]. Clinical outcomes of the phagocytic diseases patients with mortality were documented in 3 (5.5%) [19, 40, 95], while 47 (87%) of the autoinflammatory diseases cases recovered [40, 43, 46, 48, 52, 53, 61, 63, 65, 74, 77, 81, 90, 92, 95, 98, 101, 107, 117, 124, 127] and final treatment outcome was not reported in four phagocytic diseases patients (n = 4, 7.4%) [62]. COVID-19 was not attributable to death in two of the children with reported phagocytic diseases (2/54, 3.7%) [40, 95] and one study failed to report if COVID-19 was a leading or an underlying cause of death in one child with phagocytic diseases (1/54, 1.8%) [19] (see Table 1).