Expert Review of Clinical Immunology

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20

Autoimmunity in Common Variable

Immunodeficiency: A Systematic Review and Meta-
Analysis

Fatema Sadaat Rizvi , Hamed Zainaldain , Hosein Rafiemanesh , Mahnaz

Jamee , Nikoo Hossein-Khannazer , Haleh Hamedifar , Araz Sabzevari , Reza
Yazdani , Hassan Abolhassani , Asghar Aghamohammadi & Gholamreza Azizi

To cite this article: Fatema Sadaat Rizvi , Hamed Zainaldain , Hosein Rafiemanesh , Mahnaz
Jamee , Nikoo Hossein-Khannazer , Haleh Hamedifar , Araz Sabzevari , Reza Yazdani , Hassan
Abolhassani , Asghar Aghamohammadi & Gholamreza Azizi (2020): Autoimmunity in Common
Variable Immunodeficiency: A Systematic Review and Meta-Analysis, Expert Review of Clinical
Immunology, DOI: 10.1080/1744666X.2021.1850272

To link to this article: https://doi.org/10.1080/1744666X.2021.1850272

Accepted author version posted online: 18

Nov 2020.

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 Publisher: Taylor & Francis & Informa UK Limited, trading as Taylor & Francis Group

Journal: Expert Review of Clinical Immunology

DOI: 10.1080/1744666X.2021.1850272
Autoimmunity in Common Variable Immunodeficiency: A
Systematic Review and Meta-Analysis

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Fatema Sadaat Rizvi1, Hamed Zainaldain1, Hosein Rafiemanesh2, Mahnaz Jamee3,4, Nikoo

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Hossein-Khannazer5, Haleh Hamedifar6,7, Araz Sabzevari6,8*, Reza Yazdani1, Hassan
Abolhassani9, Asghar Aghamohammadi1, Gholamreza Azizi4*

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1- Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences,
Tehran, Iran

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2- Student Research Committee, Department of Epidemiology, School of Public Health and Safety, Shahid Beheshti
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University of Medical Sciences, Tehran, Iran

3- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran

4- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
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5- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver
Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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6- CinnaGen Medical Biotechnology Research Center, Alborz University of medical sciences, Karaj, Iran
7- CinnaGen Research and production Co., Alborz, Iran
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8- Orchid pharmed company, Tehran, Iran

9- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska

University Hospital Huddinge, Stockholm, Sweden
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*Correspondence to:
CinnaGen Medical Biotechnology Research Center, Alborz University of Medical Sciences, Karaj, Iran, E-mail:
sabzvari.a@orchidpharmed.com and Non-communicable Diseases Research Center, Vice Chancellor for Research,
Alborz University of Medical Sciences, Karaj, Iran; E-mail: azizi@abzums.ac.ir
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Autoimmunity in Common Variable Immunodeficiency: A Systematic Review and Meta-Analysis

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Fatema Sadaat Rizvi1, Hamed Zainaldain1, Hosein Rafiemanesh2, Mahnaz Jamee3,4, Nikoo Hossein-
5 6,7 6,8* 1 9
Khannazer , Haleh Hamedifar , Araz Sabzevari , Reza Yazdani , Hassan Abolhassani , Asghar
Aghamohammadi1, Gholamreza Azizi4*

1
Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical
Sciences, Tehran, Iran

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 2
Student Research Committee, Department of Epidemiology, School of Public Health and Safety, Shahid
Beheshti University of Medical Sciences, Tehran, Iran
3
Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran
4
Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
5
Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and
Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
6
CinnaGen Medical Biotechnology Research Center, Alborz University of medical sciences, Karaj, Iran
7
CinnaGen Research and production Co., Alborz, Iran

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8

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Orchid pharmed company, Tehran, Iran
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Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska

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University Hospital Huddinge, Stockholm, Sweden

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*Corresponding authors:
Araz Sabzevari, CinnaGen Medical Biotechnology Research Center, Alborz University of Medical
Sciences, Karaj, Iran
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E-mail: sabzvari.a@orchidpharmed.com
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Gholamreza Azizi, Non-communicable Diseases Research Center, Vice Chancellor for Research, Alborz
University of Medical Sciences, Karaj, Iran
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E-mail: azizi@abzums.ac.ir
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Abstract
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Objectives: Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of
immunity characterized by variable clinical manifestations including infections, autoimmunity, chronic lung
disease, polyclonal lymphocytic infiltration, enteropathy, and malignancy. This study aimed to evaluate
the prevalence of autoimmunity in CVID patients. In this study, the authors aimed to assess the
prevalence of various types of autoimmune manifestations in CVID patients and evaluate the probable
associations between autoimmunity and other clinical and immunological features in these patients.
Methods: Web of Science, Scopus, and PubMed databases were searched systemically to find eligible
studies from the earliest available date to February 2020 with standard keywords. Pooled estimates of the

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 autoimmunity prevalence and the corresponding 95% confidence intervals (CI) were calculated using
random-effects models.
Results: The overall prevalence of autoimmunity was 29.8% (95% CI: 26.4-33.3; I2=82.8%). The
prevalences of hematologic autoimmune diseases, autoimmune gastrointestinal disorders, autoimmune
rheumatologic disorders, autoimmune skin disorders and autoimmune endocrinopathy in CVID patients
were 18.9% (95% CI: 15.4-22.5; I2=87.0%), 11.5% (95% CI: 8.7-14.4; I2=84.1%), 6.4% (95% CI: 3.8-9.0;
I2=88.3%), 5.9% (95% CI: 3.9-7.8; I2=86.5%) and 2.5% (95% CI: 1.7-3.3; I2=38.9%), respectively. There
were significantly higher lymphocyte, CD3+ T cell, and CD4+ T cell count among CVID patients without

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autoimmunity (p<0.05). Furthermore, failure to thrive, organomegaly, enteropathy, and meningitis was
significantly higher in CVID patients with autoimmunity compared to patients without autoimmunity

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(p<0.05).
Conclusions: Many CVID patients could present with autoimmunity as part of the disease or even as the

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first or only clinical manifestation of the disease. Care providers may need to pay particular attention to

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the possible association of these two disorders since the co-occurrence of CVID and autoimmunity could
be a misleading clue.

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Keywords: Common variable immunodeficiency, Hypogammaglobulinemia, Autoimmunity, Autoimmune
cytopenia, Primary antibody deficiency
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1. Introduction
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Common variable immunodeficiency (CVID) is the most common symptomatic inborn error of immunity
characterized by highly heterogeneous clinical features including infections, autoimmunity, chronic lung
disease, polyclonal lymphocytic infiltration, enteropathy, and malignancy [1,2]. CVID is diagnosed based
on the reduction of at least two immunoglobulin isotypes, IgG with IgA and/or IgM, as well as impaired
specific antibody response to protein and polysaccharide antigens [3,4]. In addition to impaired
differentiation of B cells to plasma and memory B cells [5,6], T-cell defects are also observed in
approximately one-third of reported CVID patients, providing inconstant clinical manifestations of the
disease suchlike the development of opportunistic or uncommon infections [3,7-9].

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 In several studies, the association of CVID and autoimmunity is effectually explained [10,11]. It is
suggested that 15-54% of patients with CVID have autoimmune complications that are poorly recognized
and managed in several cases [5,12]. The most common autoimmune manifestation observed in CVID
patients is autoimmune cytopenia that encompassing idiopathic thrombocytopenic purpura (ITP),
autoimmune hemolytic anemia (AIHA), neutropenia, and pernicious anemia. Furthermore, autoimmune
endocrinological, gastrointestinal, dermatological, and rheumatological disorders have also been reported
[9,10,13-15]. CVID patients with autoimmunity show defects in the frequency and function of B and T cell
subsets, especially a decrease in regulatory T cells (Tregs) and an increase in CD21low B cells [16,17].

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In this study, the authors aimed to assess the prevalence of various types of autoimmune manifestations
in CVID patients and evaluate the probable associations between autoimmunity and other clinical and

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immunological features in these patients.

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2. Materials and methods
2.1- Search strategy
Our search strategy is composed of three main components: (1) comprehensive searching of

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international and national electronic databases for published documents, (2) hand-searching of the
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reference section of the retrieved scientific documents, and (3) contacting experts in the field in order to
assess unavailable papers.
2.2- Databases searched
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A comprehensive search was made, using the Web of Science, Scopus, and PubMed databases to
gather English articles published up to February 2020. Search strategy and MeSH terms were
categorized in two groups and combined: 1) “CVID”, “common variable immunodeficiency”,
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“hypogammaglobulinemia”, or “primary antibody deficiency”, 2) “ITP”, “AIHA”, “neutropenia”, “pernicious

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anemia”, “diabetes”, “autoimmune thyroiditis”, “graves”, “Hashimoto”, “hepatitis”, “enteropathy”, “IBD”,

“ulcerative colitis”, “Crohn”, “celiac disease”, “atrophic gastritis”, “psoriasis”, “lichen planus”, “atopic
dermatitis”, “vitiligo”, “alopecia”, “SLE”, “RA”, “JRA”, “JIA”, “Sjogren’s syndrome”, “vasculitis”, or “Behcet’s
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disease”.
2.3- Screening process
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The selection process of the obtained documents was performed in two steps: (1) the preliminary
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screening of all relevant studies based on the titles and abstracts; (2) detailed assessments of available
full-texts for eligibility criteria. In addition, references from original articles, previous reviews, and
conference papers were further scanned manually for additional studies of interest. The studies qualified
for the inclusion criteria: i) were written in English, ii) designed as prospective or retrospective cohort,
cross-sectional, case series or case-control studies, iii) conducted on human subjects with CVID
diagnosis based on the PAGID (Pan-American Group for Immunodeficiency) and ESID (European
Society for Immunodeficiencies) diagnostic criteria, iv) evaluated epidemiological, clinical and
immunological features of patients, and v) reported their main or alternative outcome of interest as

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 autoimmunity incidence or prevalence.

Furthermore, to gain further insight into the characteristics of CVID patients with autoimmunity,
demographic, clinical, and immunological data were obtained from all studies which described in detail
the characterization of CVID patients with or without autoimmunity For studies with overlapping data,
those with a larger cohort of samples and more detailed information were included. Both steps of study
selection were taken independently by two reviewers and any disagreement was resolved via consensus
with a third reviewer.

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2.4- Data extraction

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Data were extracted from all included studies into a standardized Microsoft Excel spreadsheet. The

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following data were collected: name of the first author, published year, the original country of the study,
study design, and the study population characteristics including demographic, clinical, and immunologic

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data. The medical records of all papers were gathered if a case was reported in more than one study.

2.5- Statistical analysis

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Available data of respective studies were extracted to form an aggregated set and then data analysis was
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conducted with simple pooled data to provide an overall summary of subgroup data. Data were combined
without being weighted and the analysis was performed as if the data were derived from a single sample.
Descriptive statistics such as frequency and percentage were used to demonstrate the characteristics of
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the included study. Moreover, to provide frequencies and percentages for categorical variables, mean
with standard deviation (SD), and median with interquartile range (IQR) were reported as appropriate
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based on the normality. The Shapiro-Wilk test and graphical approaches were used to check for normality
assumption. A comparison was performed among CVID patients with and without autoimmunity for
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demographic, immunological, and clinical features. The meta-analysis was performed using the random
effects model to assess pooled prevalence of autoimmunity in CVID patients. A graphical display of the
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reported autoimmunity prevalence in the included studies was presented in the forest plot. The
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heterogeneity was tested using the I square (I ) statistic [18], which describes the percentage of variation
between studies that is due to heterogeneity rather than chance. Analytical analyses were performed by
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Stata v.14 (StataCorp, College Station, TX) using Mann-Whitney U, Chi-square, and Fisher exact tests. A
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P-value of less than 0.05 was considered statistically significant.

3. Results

3.1- Study selection and studies’ characteristics

The results of the literature search and selection process based on the preferred reporting items for
systematic reviews and meta-analyses (PRISMA) flow chart are shown in Figure S1. A total of 5023

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 articles were retrieved from the initial search in different databases, of which 1385 were duplicated
studies. After screening of 3638 studies for titles and abstracts, 292 articles were selected and the full-
texts were assessed. 198 articles were excluded as they did not present data on autoimmune disorders
(Figure S1). Furthermore, nine case reports were excluded. In studies included in the meta-analysis,
sample sizes of CVID patients varied from 5 up to 990. The studies have been conducted in 37 unique
countries [mostly originated in Turkey (n=5), USA (n=3), Iran (n=3), and Germany (n=3)], three were
multicenter international studies, and the location of three studies was unknown; the oldest study was
published out in 1998 and the latest in 2020.

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3.2- The total prevalence of autoimmunity

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The prevalence of autoimmunity reported in 28 studies ranged from 13.6% by Ardeniz, et al. from Turkey

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(95% CI: 0.04-0.33) [19] to 54.1% by Llobet, et al. from Spain (95%, CI: 0.38-0.69) [20], respectively.

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Based on the results of the random-effects method, the pooled prevalence of autoimmunity in 4870 CVID
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patients was 29.8% (95% CI: 26.4-33.3; I =82.8%) (Figure 1). Only four studies reported the prevalence
of autoimmunity by more than 45% [19,21-23].

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3.3- The frequency of various types of autoimmunity
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We further categorized various types of autoimmune manifestation in CVID patients into hematological,
endocrinopathy, gastrointestinal, dermatological, and rheumatological subgroups. As depicted in Figure
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2, the prevalence of autoimmune cytopenia or at least one type of hematologic autoimmune disease
(isolated ITP, isolated AIHA, autoimmune neutropenia, or pernicious anemia) in 31 studies was between
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4.2% to 44.7%. According to the meta-analysis result, the pooled prevalence of hematologic
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autoimmunity in 3991 CVID patients was 18.9% (95% CI: 15.4-22.5; I =87.0%) (Figure 2). The meta-
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analysis result and pooled prevalence of various types of hematologic autoimmune disease are detailed
in Table 1.
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The prevalence of autoimmune endocrinopathy reported in 19 distinct studies was between 0.8% to
9.7%. Based on the results of the random-effect method, the pooled prevalence of at least one
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autoimmune endocrinopathy in 3558 CVID patients was 2.5% (95% CI: 1.7-3.3; I =38.9%) (Figure 3). Of
this autoimmune group, the pooled prevalence of autoimmune thyroiditis (Graves' and Hashimoto's) was
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higher than diabetes (2.0% vs. 1.4%, p <0.001) (Table 1).

The prevalence of autoimmune gastrointestinal disorders in 23 studies was between 2.6% to 64.9%. Only
in two studies the prevalence of autoimmune gastrointestinal disorder was higher than 40% [19,24].
However, based on the results obtained from the random-effects method performed in this study, the
pooled prevalence of at least one gastrointestinal autoimmunity in 3464 CVID patients was 11.5% (95%
CI: 8.7-14.4; I2=84.1%) (Figure 4). Of this autoimmune group, the pooled prevalence of celiac disease

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 was 13.5% (95% CI: 6.5-20.4; I2=91.9%) which was higher than other gastrointestinal diseases. The
supplementary data is provided in Table 1.

Our systematic review of original reports revealed that autoimmune skin disorders prevalence ranged
between 0.7% to 40.0% and the pooled prevalence of at least one autoimmune skin disorder in 3358
CVID patients was 5.9% (95% CI: 3.9-7.8; I2=86.5%) (Figure 5). Only one study reported Atopic
dermatitis [25] with a prevalence of 6.3% (95% CI: 1.1-28.3). Psoriasis, lichen planus, vitiligo, and
alopecia were assessed in 9, 4, 12, and 8 studies respectively. The pooled prevalence of vitiligo was
4.8% (95% CI: 2.9-6.8; I2=73.5%), higher than that of other mentioned cutaneous diseases (Table 1).

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19 studies assessed the prevalence of autoimmune rheumatologic disorders and it ranged between 1.4%

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to 24.4%. According to the meta-analysis result in the current study, the pooled prevalence of at least one
autoimmune rheumatologic disorder in 3335 CVID patients was 6.4% (95% CI: 3.8-9.0; I2=88.3%) (Figure

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6). Only two studies reported the prevalence of Behcet’s disease [26,27] and it was 2.3% and 21.7%. The

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meta-analysis result and pooled prevalence of various types of autoimmune rheumatologic disorders are
summarized in Table 1.

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3.4- Comparison of CVID patients with and without autoimmunity
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To achieve more insights into the characteristics of CVID patients with autoimmunity, we compared
demographic, immunological, and clinical data of CVID patients with and without autoimmunity among 17
completely defined studies. These studies comprised 571 CVID patients, of which 187 patients were
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diagnosed with autoimmunity during childhood or adolescence. Female gender was associated with a
higher prevalence of autoimmune phenomena as 53% of CVID patients with autoimmunity were females
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compared with 44% of patients without autoimmunity (p=0.06). The median (IQR) ages at onset and
diagnosis of CVID in patients with autoimmunity [5.0 (13.0) and 14.0 (24.0) years] was higher than that of
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patients without autoimmunity [3.0 (12.05) and 12.0 (19.8) years], although it was not statistically
significant (Table S1). The CVID patients with autoimmunity had higher IgG, IgM, and IgA serum levels
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as well as, NK cells percentage compared to those without autoimmunity, however, the results were not
statistically significant. In contrast, there were significantly higher absolute lymphocyte count [median
(IQR): 2601 (1824-4099) vs. 2000 (1400-3139), p = 0.003], CD3+ T cell count [median (IQR): 1815
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(1158-3011) vs. 1603 (983-1995), p=0.011], CD4+ T cell count [median (IQR): 769 (500-1390) vs. 576
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(320-970), p=0.003] and CD19+ B cell count [median (IQR):171 (85-358) vs. 116 (68-269), p=0.019]
among CVID patients without autoimmunity than patients with autoimmunity. The detailed compared
parameters are shown in Table 2.
The most frequent clinical manifestation in these selected 571 CVID patients were sinusitis (75.9%),
lower respiratory tract infection (72.4%), granulomatous lesion (62.1%), nodular lymphoid hyperplasia
(56.1%), diarrhea (48.2%), otitis media (48.0%), enteropathy (44%), splenomegaly (40.3%) clubbing
(27.2%), bronchiectasis (24.7%), septic arthritis (21.6%) and skin infections (21.4%) (Table 3). Among
these clinical features, FTT was significantly higher in CVID patients with autoimmunity compared in

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 patients without autoimmunity [22.3% vs. 10%, p =0.007]. Moreover, CVID patients suffering from
autoimmunity was found to have higher rates of organomegaly including splenomegaly (53.4% vs. 32.7%,
p<0.001), hepatomegaly (36.2% vs. 20.0%, p=0.003), and lymphadenopathy (33.9% vs. 20.6%, p=0.008)
compared to patients without autoimmunity. In addition, enteropathy, diarrhea, and meningitis were more
frequently seen in CVID patients with autoimmunity compared to patients without autoimmunity (p = 0.04,
p = 0.03, and p = 0.01, respectively). Only two patients were suffering from malignancy and autoimmunity
simultaneously in which one patient had lymphoma and inflammatory bowel disease (IBD) and the other
showed concurrence of B-cell lymphoma of mucosa-associated lymphoid tissue (MALToma) and Evans

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syndrome. The frequency of all types of autoimmunity between mono-autoimmunity and
polyautoimmunity is presented in Table S2.

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Among CVID patients with autoimmunity,70.5% (n = 130) had a history of only one type of autoimmunity,

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while 29.5% (n = 54) had a history of polyautoimmunity; 44 patients (23.9%) had two and 10 patients
(5.4%) had three types of autoimmunity. Furthermore, hematologic, gastrointestinal, rheumatologic,

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dermatological, and endocrine autoimmune disorders have been observed in 44.3%, 21.1%, 10.3%,
5.2%, and 4.1% of CVID patients with CVID, respectively. Also, the co-occurrence of gastrointestinal or
rheumatologic autoimmunity with hematologic autoimmunity was found in 3.1% and 2.1% of CVID

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patients with autoimmunity, respectively. (Figure S2)
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4. Discussion
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CVID is one of the most common inborn errors of immunity associated with heterogeneous complications.
While recurrent infections are known to be the major manifestations of CVID, autoimmune disorders have
also been frequently reported. The ages at onset and diagnosis of CVID, in patients with autoimmunity,
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was higher than that of patients without autoimmunity, this can be due to the chronicity and slow
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progression of autoimmune disorders which may also predominate disease manifestation, leading to
delayed diagnosis of CVID.
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The pooled prevalence of autoimmunity among CVID patients was estimated to be 29.8%. To our
knowledge, this systematic review of 28 studies is among the first attempts to determine the prevalence
of autoimmune disorders in CVID patients. Several studies demonstrated different prevalence rates of
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autoimmune disorders in CVID patients. Chapel et al. showed that 42% of 334 CVID patients had
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autoimmune disorders [1]. In another study, Resnick et al. [14] observed non-infectious complications in
68% of 473 CVID individuals and 28.6% of these patients had hematologic or organ-specific autoimmune
manifestations. In 2017, a large retrospective study on 2183 patients with IEIs revealed that autoimmune
disorders may complicate up to 26% of patients. The reason for such a high prevalence of autoimmunity
in CVID is still a matter of speculation. It has been suggested that during the B-cell maturation and before
the onset of somatic hypermutation, specific autoreactivity checkpoints prevent the development of self-
reactive antibodies [28]. This selection process may become compromised in CVID patients leading to
the production of multiple autoantibodies against various self-antigenic targets. While B cell memory

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 defect is the hallmark of CVID, CD4 + T lymphocytopenia and altered suppressive function of regulatory T
cell (T reg) may contribute to the autoimmune pathogenesis [29-31]. In addition, apoptosis regulation
defects [32] and higher expression of toll-like receptors [33] have been observed among CVID patients
with autoimmunity. Finally, these mechanisms culminate in immune dysregulation, when accompanied by
immunodeficiency become more complex and difficult to manage. Therefore, autoimmune disorders in
CVID deserve special considerations because immune dysregulations and dysfunctions of the immune
system along with persistent inflammation can prolong the process of diagnosis and treatment.
The prevalence of autoimmune cytopenia or at least one type of autoimmune hematologic diseases in 31

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studies was between 4.2% to 44.7% and the pooled prevalence of hematologic autoimmunity was 18.9%.
ITP and AIHA are the most common CVID associated autoimmune disorders. A report from the USIDNET

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registry reported autoimmune cytopenias in 10.2% of CVID patients. It was also shown that the

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prevalences of ITP and AIHA in CVID individuals were 7.4% and 4.5%, respectively [34]. Notably, 19% of
CVID patients were complicated with ITP and the diagnosis of ITP preceded the diagnosis of CVID in

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more than 60% of patients. Another retrospective study of 326 CVID patients also revealed ITP and AIHA
in 11% of patients, 50% of whom presented autoimmune hematologic diseases before CVID diagnosis.
Treatments for autoimmunity mostly included corticosteroids and intravenous immuneglobulin (IVIG). It

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was also reported that the recurrences of autoimmune disease episodes mostly occurred for subjects
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who did not receive maintenance IVIG.[35]. Therefore, it is possible that IVIG may provide some
protection against autoimmune disorders or recurrences of them.
In our previous study, 7.0% of CVID patients had shown an autoimmune complication (ITP, insulin-
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dependent diabetes mellitus (IDDM), vitiligo, AIHA, and IBD) as the first presentation of the disease [31].
Accordingly, it is worth noting that autoimmunity could be the first manifestation in CVID, highlighting the
significance of early immunoglobulin screening for those with autoimmunity.
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Our findings showed that the incidence of autoimmune gastrointestinal complications in CVID patients is
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higher than 11%. Ho et al. also indicated that the incidence of gastrointestinal disorders in CVID patients
was 17.5% [26], however, Khan et al. reported gastrointestinal comorbidities in up to 67% of CVID
patients [36]. In another study conducted in Finland, gastrointestinal disorders founded in 21% of CVID
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patients [37], mainly including IBD (7%), celiac disease (3.7%), pernicious anemia (0.4%), autoimmune
enteropathy (1.6%), and autoimmune hepatitis (2%). It seems that different reported prevalences are due
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to different study designs, follow up of the studies, and non-specific histopathologic features.
In CVID, inflammatory gastrointestinal complications are mostly reported as “IBD-like”, “celiac-like”, or
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“sprue-like” disorders due to the lack of autoantibodies in the serum and plasma cells in the biopsy. In the
histopathology of jejunal mucosa, the lack of plasma cells is typical and the most striking finding, while an
increased number of intraepithelial lymphocytes, granulomas, and crypt distortion could also be observed
[38]. Therefore, when a question of CVID exists, due to lack of the unique pathologic features and/or lack
of thereof (e.g., plasma cells), asking an expert pathologist to review slides is mostly helpful.
The present systematic review showed that hematological and gastrointestinal autoimmune disorders are
the most prevalent autoimmune manifestations in CVID individuals. One of the probable causes of this
phenomenon is due to several monogenic CVID-like disorders with predominant hematological and

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 gastrointestinal autoimmunity (e.g. patients with mutations in FOXP3, LRBA, IL-10, and CTLA-4) which
clinically diagnosed with CVID like phenotype [39-41]. In a recent report of monogenic disorder
associated with CVID and autoimmunity, LRBA deficiency with predominant clinical problems including
ITP, AIHA, and an autoimmune enteropathy was the most prevalent monogenic disorder in 63% of
patients [40].

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5. Conclusions

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Many diagnosed CVID patients could present with autoimmunity as a part of the disease or even as the
first or only clinical manifestation of the disease. Care providers may need to pay particular attention to

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the possible association of these two disorders since the co-occurrence of CVID and autoimmunity could
be a misleading clue, with due consideration to the undeniable fact that prolonged immunosuppressive

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drugs are completely undesirable in the case of CVID. Therefore, it is highly recommended that clinicians
be aware of the heterogeneous signs and symptoms of CVID and immunologic workup should also be

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performed in complicated patients with autoimmunity who do not respond to conventional therapy.
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The evolution of new outstanding diagnostic techniques like next-generation sequencing (NGS) has
paved the way towards the understanding of the pathology and underlying disease causes. As NGS
based tests are becoming more accessible nowadays, numbers of monogenic defects such as LRBA,
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CTLA4, FOXP3, CD25, and AIRE have been identified as the root cause of immune dysregulation in
CVID patients with autoimmunity. This in turn has opened up a new era in the treatment of autoimmune
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complications in CVID patients as well as in non-CVID patients, such as employing targeted therapeutic
regimens like monoclonal antibodies against specific immunologic markers or targeted bioengineered
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molecule against pro-inflammatory cytokines.

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Funding
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This work was supported by CinnaGen Medical Biotechnology Company.

Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants
or patents received or pending, or royalties.

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 Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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2. Aghamohammadi A, Abolhassani H, Moazzami K, et al. Correlation between common variable

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immunodeficiency clinical phenotypes and parental consanguinity in children and adults. Journal
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8. Oksenhendler E, Gerard L, Fieschi C, et al. Infections in 252 patients with common variable
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Epidemiology and clinical manifestations in 69 patients]. Medicina. 2013;73(4):315-23.

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 14. Resnick ES, Moshier EL, Godbold JH, et al. Morbidity and mortality in common variable immune
deficiency over 4 decades. Blood. 2012 Feb 16;119(7):1650-7.
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research & therapy. 2012 Sep 24;14(5):223.
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dysregulation and autoimmunity. Cellular immunology. 2016 Dec;310:14-26.
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19. Ardeniz O, Cunningham-Rundles C. Granulomatous disease in common variable
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20. Llobet MP, Soler-Palacin P, Detkova D, et al. Common variable immunodeficiency: 20-yr
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21. Arshi S, Nabavi M, Bemanian MH, et al. Phenotyping and follow up of forty-seven Iranian patients
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with common variable immunodeficiency. Allergologia et immunopathologia. 2016 May-
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selected IgA deficiency. Przeglad gastroenterologiczny. 2013;8(6):370-6.
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immunopathologia. 2014 May-Jun;42(3):235-40.
28. Tsuiji M, Yurasov S, Velinzon K, et al. A checkpoint for autoreactivity in human IgM+ memory B
cell development. J Exp Med. 2006 Feb 20;203(2):393-400.

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 29. Genre J, Errante PR, Kokron CM, et al. Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+)
cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: a
link to autoimmunity? Clinical immunology (Orlando, Fla). 2009 Aug;132(2):215-21.
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Nov 21;9(12):1156.
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Variable Immunodeficiency in Finland [Original Research]. Frontiers in immunology. 2017 2017-

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Immunodeficiency. Scand J Immunol. 2017 Jan;85(1):13-29.

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immunodeficiency (CVID). Autoimmun Rev. 2016 Sep;15(9):877-82.

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Syndrome. The journal of allergy and clinical immunology In practice. 2020 Sep;8(8):2747-2760
e7.

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Autoimmunity

IP
First Sample %
author Year Country n size ES (95% CI) Weight

R
Ho, H. 2020 USA 207 623 0.332 (0.296, 0.370) 5.04
Lopez-herrera, G. 2019 Mexico 14 36 0.389 (0.248, 0.551) 2.51
Feuille, E.J. 2019 USA 216 990 0.218 (0.194, 0.245) 5.19
Slad, C.A. 2018 Australia 44 116 0.379 (0.296, 0.470) 3.97

SC
Azizi, G. 2018 Iran 70 227 0.308 (0.252, 0.371) 4.61
Alkan, G. 2018 Turkey 5 12 0.417 (0.193, 0.680) 1.20
Stuchly, J. 2017 Czech Republic 25 88 0.284 (0.200, 0.386) 3.83
Azizi, G. 2017 Iran 104 244 0.426 (0.366, 0.489) 4.57
Arduini, S. 2017 Ireland 6 23 0.261 (0.125, 0.465) 2.20
Janssen, W.J.M. 2017 Netherland 9 55 0.164 (0.089, 0.283) 3.75
Arshi, S 2016 Iran 23 47 0.489 (0.353, 0.628) 2.80

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Lin, L.J. 2015 China 6 40 0.150 (0.071, 0.291) 3.46
Gathmann, B. 2014 Europen Society 249 902 0.276 (0.248, 0.306) 5.15
Ramirez-Vargas, N. 2014 Mexico 10 43 0.233 (0.132, 0.377) 3.13
Pituch-Noworolska, A.2013 Poland 20 43
AN 0.465 (0.325, 0.611) 2.69
Karaulov, A.V. 2012 Moscow 14 57 0.246 (0.152, 0.371) 3.44
Maarschalk-E, L.J. 2012 Netherland 14 61 0.230 (0.142, 0.349) 3.58
Boileau, J. 2010 France 116 311 0.373 (0.321, 0.428) 4.74
Urschel, S. 2009 Germany 10 32 0.313 (0.180, 0.486) 2.49
Gregersen, S. 2009 Norway 28 65 0.431 (0.318, 0.552) 3.25
Llobet, M.P. 2009 Spain 3 22 0.136 (0.047, 0.333) 2.79
Ardeniz, O. 2009 Turkey 20 37 0.541 (0.384, 0.690) 2.49
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Wehr, C. 2008 Eight country 58 286 0.203 (0.160, 0.253) 4.88

Ward, C. 2008 UK 50 108 0.463 (0.372, 0.557) 3.84
Quinti, I. 2007 Italy 58 224 0.259 (0.206, 0.320) 4.66
Ogershok, P.R. 2006 West Virginia 3 12 0.250 (0.089, 0.532) 1.46
Kokron, C.M. 2004 Brasil 11 71 0.155 (0.089, 0.257) 4.07
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Kainulainen, L. 2001 Finland 18 95 0.189 (0.123, 0.280) 4.19

Overall (I^2 = 82.817%, p = 0.000) 0.298 (0.264, 0.333) 100.00
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0 .25 .5 .75 1

Figure 1- Forest plot of autoimmunity in CVID patients

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C
AC

Information Classification: General

 Hematologic autoimmune disease
First Sample %
author Year Country Disease n size ES (95% CI) Weight
Ho, H. 2020 USA 2,3 149 623 0.239 (0.207, 0.274) 4.45
Lopez-herrera, G. 2019 Mexico 2 11 36 0.306 (0.180, 0.469) 2.50
Feuille, E.J. 2019 USA 1 101 990 0.102 (0.085, 0.122) 4.58
Slad, C.A. 2018 Australia 1 24 116 0.207 (0.143, 0.289) 3.85
Alkan, G. 2018 Turkey 2 2 12 0.167 (0.047, 0.448) 1.73
Azizi, G. 2017 Iran 2,3,5 39 244 0.160 (0.119, 0.211) 4.30
Almejún, M.B. 2017 Ireland 2,3 5 25 0.200 (0.089, 0.391) 2.41
Arduini, S. 2017 Ireland 2,3,4,5 4 23 0.174 (0.070, 0.371) 2.43
Hartono, S. 2017 Minnesota 2,3 20 26 0.769 (0.579, 0.890) 2.33
Arshi, S 2016 Iran 2,3,5 21 47 0.447 (0.314, 0.588) 2.63
Caliskaner, A.Z. 2016 Turkey 2 3 25 0.120 (0.042, 0.300) 2.88
Ramirez-Vargas, N.2014 Mexico 2,3 3 43 0.070 (0.024, 0.186) 3.81
Karaulov, A.V. 2012 Moscow 2,3,4 6 57 0.105 (0.049, 0.211) 3.74

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Maarschalk-E, L.J. 2012 Netherland 2,3 18 61 0.295 (0.196, 0.419) 3.11
Wang L.L. 2011 China 4 6 27 0.222 (0.106, 0.408) 2.41
Ochtrop, M.L. 2011 Germany 1 13 48 0.271 (0.166, 0.410) 2.91
Boileau, J. 2010 France 2,3,4 68 311 0.219 (0.176, 0.268) 4.30

IP
Gregersen, S. 2010 Norway 1 21 54 0.389 (0.270, 0.522) 2.83
Huck, K. 2009 Germany 1 2 16 0.125 (0.035, 0.360) 2.33
Urschel, S. 2009 Germany 2,3 4 32 0.125 (0.050, 0.281) 3.10
Llobet, M.P. 2009 Spain 3 1 22 0.045 (0.008, 0.218) 3.61
Ardeniz, O. 2009 Turkey 2,3 14 37 0.378 (0.241, 0.539) 2.41

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Wehr, C. 2008 Eight country 1,5 52 213 0.244 (0.191, 0.306) 4.12
Chapel, H. 2008 Five country 1 33 334 0.099 (0.071, 0.136) 4.47
Quinti, I. 2007 Italy 2,3,4 25 224 0.112 (0.077, 0.160) 4.36
Carbone, J. 2006 Spain 2,3 3 14 0.214 (0.076, 0.476) 1.69

SC
Alachkar, H. 2006 UK 1 4 34 0.118 (0.047, 0.266) 3.22
Tanaka, N. 2006 USA 2 4 46 0.087 (0.034, 0.203) 3.71
Ogershok, P.R. 2006 West Virginia 2,4 3 12 0.250 (0.089, 0.532) 1.42
Kokron, C.M. 2004 Brasil 3,5 3 71 0.042 (0.014, 0.117) 4.29
Kainulainen, L. 2001 Finland 2,3,5 10 95 0.105 (0.058, 0.183) 4.06
Overall (I^2 = 87.029%, p = 0.000) 0.189 (0.154, 0.225) 100.00

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0 .25
AN .5 .75 1

Figure 2- Forest plot of hematologic autoimmune disease (Disease code: 1; Autoimmune cytopenias, 2;
Isolated immune thrombocytopenic purpura, 3; Isolated autoimmune hemolytic anemia, 4; Autoimmune
neutropenia, and 5; Pernicious anemia)
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AC

Information Classification: General

 Autoimmune endocrinopathy
First Sample %
author Year Country Disease n size ES (95% CI) Weight

Ho, H. 2020 USA 2 5 623 0.008 (0.003, 0.019) 17.09

Feuille, E.J. 2019 USA 1,2 26 990 0.026 (0.018, 0.038) 14.95
Slad, C.A. 2018 Australia 2 8 116 0.069 (0.035, 0.130) 2.46
Azizi, G. 2017 Iran 1,2 7 244 0.029 (0.014, 0.058) 8.08
Almejún, M.B. 2017 Ireland 1 1 25 0.040 (0.007, 0.195) 0.96
Arduini, S. 2017 Ireland 2 2 23 0.087 (0.024, 0.268) 0.44
Musabak, U.H. 2017 Turkey 2 3 31 0.097 (0.033, 0.249) 0.54
Arshi, S 2016 Iran 1 1 47 0.021 (0.004, 0.111) 2.98
Caliskaner, A.Z. 2016 Turkey 2 1 25 0.040 (0.007, 0.195) 0.96
Ramirez-Vargas, N. 2014 Mexico 2 2 43 0.047 (0.013, 0.155) 1.40
Maarschalk-E, L.J. 2012 Netherland 1,2 2 61 0.033 (0.009, 0.112) 2.60
Boileau, J. 2010 France 2 12 311 0.039 (0.022, 0.066) 7.87

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Urschel, S. 2009 Germany 1 1 32 0.031 (0.006, 0.157) 1.52
Wehr, C. 2008 Eight country 2 5 286 0.017 (0.007, 0.040) 11.24
Chapel, H. 2008 Five country 1 10 334 0.030 (0.016, 0.054) 9.41

IP
Quinti, I. 2007 Italy 2 6 224 0.027 (0.012, 0.057) 7.99
Carbone, J. 2006 Spain 1 1 14 0.071 (0.013, 0.315) 0.32
Alachkar, H. 2006 UK 1 2 34 0.059 (0.016, 0.191) 0.91
Kainulainen, L. 2001 Finland 2 1 95 0.011 (0.002, 0.057) 8.28
Overall (I^2 = 38.943%, p = 0.043) 0.025 (0.017, 0.033) 100.00

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0 .1 .2 .3

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Figure 3- Forest plot of autoimmune endocrinopathy [Disease code: 1; Diabetes, 2; Autoimmune
thyroiditis (Graves' and Hashimoto's)]

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AN
M
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Autoimmune gastrointestinal disorders

First Sample %
author Year Country Disease n size ES (95% CI) Weight
EP

Feuille, E.J. 2019 USA 1,2,3 100 990 0.101 (0.084, 0.121) 7.00
Slad, C.A. 2018 Australia 1 3 116 0.026 (0.009, 0.073) 6.72
Azizi, G. 2017 Iran 1,2,3,4 35 244 0.143 (0.105, 0.193) 6.16
Arduini, S. 2017 Ireland 2,5 2 23 0.087 (0.024, 0.268) 3.32
Arshi, S 2016 Iran 3 8 47 0.170 (0.089, 0.301) 3.57
Caliskaner, A.Z. 2016 Turkey 3,4,5 9 25 0.360 (0.202, 0.555) 1.75
Gathmann, B. 2014 Europen Society 2 77 902 0.085 (0.069, 0.105) 7.01
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Ramirez-Vargas, N. 2014 Mexico 1,3 5 43 0.116 (0.051, 0.245) 3.98

Pituch-Noworolska, A. 2013 Poland 3,5 9 43 0.209 (0.114, 0.352) 3.13
Wang L.L. 2011 China 1,3 4 27 0.148 (0.059, 0.325) 2.79
Huck, K. 2009 Germany 3 1 16 0.063 (0.011, 0.283) 3.22
AC

Urschel, S. 2009 Germany 4 1 32 0.031 (0.006, 0.157) 5.46

Llobet, M.P. 2009 Spain 1 1 22 0.045 (0.008, 0.218) 4.32
Ardeniz, O. 2009 Turkey 4 24 37 0.649 (0.488, 0.782) 2.33
Chapel, H. 2008 Five country 2,5 49 334 0.147 (0.113, 0.189) 6.40
Aydogan, M. 2008 Turkey 3 3 10 0.300 (0.108, 0.603) 0.89
Quinti, I. 2007 Italy 4 9 224 0.040 (0.021, 0.075) 6.82
Carbone, J. 2006 Spain 3,4 6 14 0.429 (0.214, 0.674) 1.04
Alachkar, H. 2006 UK 2 5 34 0.147 (0.064, 0.301) 3.20
Tanaka, N. 2006 USA 3,4 6 46 0.130 (0.061, 0.257) 3.93
Kokron, C.M. 2004 Brasil 1,5 3 71 0.042 (0.014, 0.117) 6.04
Kainulainen, L. 2001 Finland 3,5 4 95 0.042 (0.016, 0.103) 6.30
Morris, A. 1998 UK 3 9 69 0.130 (0.070, 0.230) 4.63
Overall (I^2 = 84.125%, p = 0.000) 0.115 (0.087, 0.144) 100.00

0 .25 .5 .75 1

Figure 4- Forest plot of autoimmune gastrointestinal disorders (Disease code: 1; Autoimmune hepatitis,

Information Classification: General

 2; Autoimmune enteropathy, 3; IBD (Ulcerative colitis and Crohn's disease), 4; Celiac disease, and 5;
Atrophic gastritis)

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IP
Autoimmune skin disorders
First Sample %

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author Year Country Disease n size ES (95% CI) Weight

Ho, H. 2020 USA 5 5 623 0.008 (0.003, 0.019) 11.26

SC
Lopez-herrera, G. 2019 Mexico 4 2 36 0.056 (0.015, 0.181) 4.28
Feuille, E.J. 2019 USA 1,2,4,5 43 990 0.043 (0.032, 0.058) 10.90
Alkan, G. 2018 Turkey 1 1 12 0.083 (0.015, 0.354) 1.38
Azizi, G. 2017 Iran 1,2,4,5 15 244 0.061 (0.038, 0.099) 8.99
Arduini, S. 2017 Ireland 1,4,5 7 23 0.304 (0.156, 0.509) 0.99
Arshi, S 2016 Iran 1,2,4,5 9 47 0.191 (0.104, 0.325) 2.40
Ramirez-Vargas, N. 2014 Mexico 4 2 43 0.047 (0.013, 0.155) 5.24

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Maarschalk-E, L.J. 2012 Netherland 5 3 61 0.049 (0.017, 0.135) 6.09
Al-Herz, W. 2011 Kuwait 2,5 2 5 0.400 (0.118, 0.769) 0.20
Boileau, J. 2010 France 4 12 311 0.039 (0.022, 0.066) 10.05
Huck, K. 2009 Germany 3,4 2 16
AN 0.125 (0.035, 0.360) 1.30
Urschel, S. 2009 Germany 1,4 2 32 0.063 (0.017, 0.201) 3.69
Wehr, C. 2008 Eight country 1 2 286 0.007 (0.002, 0.025) 11.12
Chapel, H. 2008 Five country 1,4 24 334 0.072 (0.049, 0.105) 9.30
Quinti, I. 2007 Italy 4,5 38 224 0.170 (0.126, 0.224) 6.65
Kokron, C.M. 2004 Brasil 1,4 4 71 0.056 (0.022, 0.136) 6.15
M
Overall (I^2 = 86.518%, p = 0.000) 0.059 (0.039, 0.078) 100.00

0 .2 .4 .6
D

Figure 5- Forest plot of autoimmune skin disorders (Disease code: 1; Psoriasis, 2; Lichen planus, 3;
Atopic dermatitis, 4; Vitiligo, and 5; Alopecia)
TE
EP
C
AC

Information Classification: General

 Autoimmune rheumatologic disorders
First Sample %
author Year Country Disease n size ES (95% CI) Weight

Ho, H. 2020 USA 2,5 152 623 0.244 (0.212, 0.279) 6.49
Lopez-herrera, G. 2019 Mexico 1 1 36 0.028 (0.005, 0.142) 5.56
Feuille, E.J. 2019 USA 1,2,4 40 990 0.040 (0.030, 0.055) 7.16
Azizi, G. 2018 Iran 1,2,3,4 23 227 0.101 (0.068, 0.147) 6.24
Alkan, G. 2018 Turkey 1,2 2 12 0.167 (0.047, 0.448) 1.26
Azizi, G. 2017 Iran 2,3,4 17 244 0.070 (0.044, 0.109) 6.56
Arshi, S 2016 Iran 1,2 4 47 0.085 (0.034, 0.199) 4.32
Caliskaner, A.Z. 2016 Turkey 1 1 25 0.040 (0.007, 0.195) 4.45
Ramirez-Vargas, N. 2014 Mexico 2,4,5 3 43 0.070 (0.024, 0.186) 4.48
Maarschalk-E, L.J. 2012 Netherland 1,2 3 61 0.049 (0.017, 0.135) 5.53
Boileau, J. 2010 France 1,2,3 22 311 0.071 (0.047, 0.105) 6.69
Urschel, S. 2009 Germany 4 1 32 0.031 (0.006, 0.157) 5.23

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Llobet, M.P. 2009 Spain 1 1 22 0.045 (0.008, 0.218) 4.01
Ardeniz, O. 2009 Turkey 2 1 37 0.027 (0.005, 0.138) 5.63
Wehr, C. 2008 Eight country 2 9 286 0.031 (0.017, 0.059) 6.97

IP
Aydogan, M. 2008 Turkey 2 1 10 0.100 (0.018, 0.404) 1.54
Quinti, I. 2007 Italy 1,2 9 224 0.040 (0.021, 0.075) 6.80
Alachkar, H. 2006 UK 2 2 34 0.059 (0.016, 0.191) 4.35
Kokron, C.M. 2004 Brasil 3 1 71 0.014 (0.002, 0.076) 6.73
Overall (I^2 = 88.255%, p = 0.000) 0.064 (0.038, 0.090) 100.00

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0 .1 .2 .3

SC
Figure 6- Forest plot of autoimmune rheumatologic disorders (Disease code: 1; SLE, 2; RA, JRA, or JIA,
3; Sjögren's syndrome, 4; Vasculitis, and 5; Behcet’s disease)

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AN
M
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C
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Table 1- The meta-analysis result and pooled prevalence of deferent type of autoimmunity
Type of autoimmunity N, Sum of Range of Meta-analysis result

Information Classification: General

 sample size prevalence Pooled prevalence I2, %
(95% CI)

Hematologic autoimmune disease

Autoimmune cytopenias 8, 1805 9.9 to 38.9 17.4 (12.3 to 22.4) 83.1
ITP 23, 3530 3.2 to 38.5 10.7 (8.3 to 13.1) 76.7
AIHA 20, 3492 1.1 to 38.5 5.1 (3.4 to 6.8) 80.2
Autoimmune Neutropenia 8, 1978 0.9 to 22.2 1.9 (0.7 to 3.0) 56.7
Pernicious Anemia 6, 766 0.4 to 6.3 2.4 (0.5 to 4.2) 61.1

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IP
Autoimmune endocrinopathy
Diabetes 9, 1781 0.8 to 7.1 1.4 (0.8 to 1.9) 53.3
Autoimmune Thyroiditis 13, 3072 0.8 to 8.7 2.0 (1.2 to 2.7) 42.5

R
SC
Autoimmune gastrointestinal disorders
Hepatitis 7, 1513 0.2 to 1.3 1.8 (1.1 to 2.5) 0.0
Autoimmune Enteropathy 6, 2527 1.6 to 14.7 5.6 (2.4 to 8.8) 91.2

U
IBD 13, 1669 1.1 to 30.0 7.6 (4.8 to 10.4) 67.4
Celiac 7, 622 2.2 to 64.9 13.5 (6.5 to 20.4) 91.9
AN
Atrophic Gastritis 6, 591 2.8 to 6.0 4.5 (2.8 to 6.2) 0.0

Autoimmune skin disorders

M

Psoriasis 9, 2039 0.7 to 21.7 1.7 (0.7 to 2.7) 52.7

Lichen Planus 4, 1286 0.1 to 2.1 0.1 (0.0 to 0.3) 0.0
Atopic Dermatitis 1, 16 - 6.3 (1.1 to 28.3) -
D

Vitiligo 12, 2371 1.5 to 13.4 4.8 (2.9 to 6.8) 73.5

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Alopecia 8, 2217 0.1 to 20.0 1.2 (0.3 to 2.2) 65.4

Autoimmune rheumatologic disorders

EP

SLE 10, 1955 0.4 to 8.3 0.7 (0.3 to 1.1) 3.4

RA/JRA/JIA 14, 3149 1.3 to 10.0 3.1 (2.1 to 4.1) 48.9
Sjögren's syndrome 4, 853 0.4 to 4.2 1.2 (0.0 to 2.5) 71.5
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Vasculitis 5, 1536 0.4 to 3.1 0.8 (0.3 to 1.3) 13.0

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Behcet’s disease 2, 666 2.3 to 21.7 15.1 (12.5 to 17.7) -

ITP; idiopathic thrombocytopenic purpura, AIHA; Autoimmune hemolytic anemia, IBD; Inflammatory
bowel disease, SLE; Systemic lupus erythematosus, RA;Rheumatoid arthritis, JRA;Juvenile
rheumatoid arthritis, JIA; Juvenile idiopathic arthritis

Information Classification: General

 Table 2- Immunologic profile of CVID patients with autoimmunity and without autoimmunity.
Parameters, (evaluated patients with/without Total With Without p-

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autoimmunity) autoimmunity autoimmunity value
WBC (cell/uL), median (IQR) (n=239) (84/155) 7500 (5200- 6900 (4825- 8240 (5690- 0.025*

IP
11000) 8875) 11800)
Absolute lymphocytes count (cells /µL), median 2416 (1695- 2000 (1400- 2601 (1842- 0.003*

R
(IQR) (n=242) (86/156) 3909) 3139) 4099)

SC
+
CD3 T cells (cell/μL), median (IQR, %) (n=238) 1699 (1121- 1603 (983- 1815 (1158- 0.011
(86/152) 2578) 1995) 3011)
CD4+ T cells (cell/μL), median (IQR, %) (n=240) 691 (423-1218) 576 (320-970) 769 (500-1390) 0.003*

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(87/153)
CD8+ T cells (cell/μL), median (IQR, %) (n=233) 834 (485-1437) 739 (460-1286) 917 (503-1557) 0.131
AN
(85/148)
CD16+/56+ % of lymphocyts, median (IQR) (n=101) 65 (10-115) 68 (15-139) 65 (9-104) 0.855
M

(39/62)
CD19+ B cells (cell/μL), median (IQR, %) (n=290) 147 (72-330) 116 (68-269) 171 (85-358) 0.019*
(105/185)
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IgG, mg/dL, median (IQR) (n=448) (157/291) 293 (100-456) 310 (100-437) 285 (100-467) 0.905
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IgA (mg/dL), median (IQR) (n=424) (253/271) 9.0 (4-30) 10 (4-32) 9 (3-30) 0.264
IgM (mg/dL), median (IQR) (n=422) (151/271) 23 (10-46) 28 (12-54) 20 (9-43) 0.099
IgE (IU/ml), median (IQR) (n=140) (49/91) 2 (0.1-7) 1.1 (0.0-7.5) 2 (0.6-7) 0.468
EP

Response to vaccine (n=45) (23/22) 8 (17.8) 4 (17.4) 4 (18.2) 0.945

* p-value is statistically significant <0.05
C

WBC; White blood cell, Ig; Immunoglobulin,

The median is shown [with 25th and 75th percentiles].
AC

Information Classification: General

Table 3- Clinical manifestations of CVID patients with autoimmunity and without autoimmunity
Parameters (evaluated Total patients Patients with Patients p-value
patients with/without with clinical autoimmunity without
autoimmunity) presentation, and clinical autoimmunity
n; (%) presentation, n; and clinical
(%) presentation, n;
(%)
URTI, 66 (16/50) 35 (530.) 8 (50.0) 27 (54.0) 0.780
LRTI, 58 (14/44) 42 (72.4) 8 (57.1) 34 (77.3) 0.142

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Bronchitis, 46 (13/33) 10 (21.7) 3 (23.1) 7 (21.2) 0.890
Sinusitis, 249 (83/166) 198 (75.9) 59 (71.1) 139 (83.7)

IP
0.04*
Pneumonia, 371 (125/246) 233 (62.8) 73 (58.4) 160 (65.0) 0.211
Otitis media, 327 (104/223) 157 (48.0) 48 (46.2) 109 (48.9) 0.646

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GI- infection, n=58 (14/44) 15 (25.9) 2 (13.3) 13 (29.5) 0.235

SC
Enteropathy, 317 (107/210) 141 (44.5) 56 (52.3) 85 (40.5) 0.044*
Diarrhea, n=110 (47/63) 53 (48.2) 28 (59.6) 25 (39.7) 0.038*
Skin infection, 313 (102/211) 67 (21.4) 26 (25.5) 41 (19.4) 0.221

U
Conjunctivitis, 268 (89/179) 41 (15.3) 16 (18) 25 (14) 0.395
AN
Meningitis, 283 (91/192) 29 (10.2) 15 (16.5) 14 (7.3) 0.017*
Septic arthritis, 88 (42/46) 19 (21.6) 10 (23.8) 9 (19.6) 0.629
Bronchiectasis, 373 (119/254) 92 (24.7) 26 (21.8) 66 (26.0) 0.388
M

Malignancy, 79 (36/43) 2 (2.5) 2 (5.6) 0 (0.0) 0.073

Clubbing, 84 (34/50) 23 (27.4) 7 (20.6) 16 (32.0) 0.244
D

Splenomegaly, 439 (161/278) 177 (40.3) 86 (53.4) 91 (32.7) <0.001*

Hepatomegaly, 289 (94/195) 73 (25.3) 34 (36.2) 39 (20.0) 0.003*
TE

Lymphadenopathy, 338 85 (25.1) 39 (33.9) 46 (20.6) 0.008*

(115/223)
EP
C
AC

Information Classification: General

Nodular lymphoid hyperplasia, 37 (56.1) 11 (61.1) 26 (54.2) 0.61
n=66 (18/48)
Granuloma, 95 (35/60) 59 (62.1) 25 (71.4) 34 (56.7) 0.15
FTT, 278 (94/184) 40 (14.4) 21 (22.3) 19 (10.3) 0.007*
Allergy/Asthma, n=139 (47/92) 29 (20.9) 7 (14.9) 22 (23.9) 0.216
* P-value is statistically significant <0.05.
CVID: common variable immune deficiency; URTI: upper respiratory tract infection; LRTI: lower
respiratory tract infection; GI: gastrointestinal; FTT: Failure to thrive.

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IP
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M
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EP
C
AC

Supplementary materials

Information Classification: General

 T
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Figure S1- Flow diagram of the systematic review and meta-analysis for autoimmunity in CVID
AC

Information Classification: General

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Figure S2- Venn diagrams illustrating the overlap between five different categories of autoimmunity in
D

patients with CVID.

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Table S1- Demographic data of patients with polyautoimmunity and mono-autoimmunity

Information Classification: General

 Table S2- The frequency of autoimmune manifestations of patients with polyautoimmunity and mono-

Parameters, number of evaluated patients Total Patients With Patients Without p-value
autoimmunity autoimmunity

Number of patients (%) 571 187 (32.7) 384 (67.3) ---

Sex ratio, M/F n=465 245/220 78/88 167/132 0.06
Age, y, median (IQR) n=323 23.0 (21.0) 25.0 (22.5) 23.0 (20.0) 0.99
Age at onset, y, median (IQR) n=326 4.0 (12.0) 5.0 (13.0) 3.0 (12.05) 0.83
Age at diagnosis, y, median (IQR) n=408 12.75 (22.75) 14.0 (24.0) 12.0 (19.8) 0.31

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Delay in diagnosis, y, median (IQR) n=318 3.25 (8.0) 4.0 (7.13) 3.0 (8.40) 0.27

IP
Follow up, y, median (IQR) n= 71 15.0 (17.0) 15.5 (13.0) 15.0 (18.25) 0.38
Consanguinity, n=286 (%) 170 (59.4) 57 (64.8) 1113 (57.1) 0.22

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M, Male; F, Female; Y, Year.
The median is shown [with 25th and 75th percentiles].

SC
* p-value is statistically significant <0.05

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Information Classification: General

 autoimmunity
Parameters Total (n=187) Polyautoimmunity Mono-autoimmunity p-value
ITP (%) 66 (42%) 32 (48.5) 34 (51.5) <0.001*
AIHA (%) 40 (27.2%) 27 (67.5) 13 (32.5) <0.001*
Neutropenia (%) 12 (8%) 10 (83.3) 2 (16.7) <0.001*
IDDM (%) 5 (3%) 5 (100.0) 0 (0) 0.325
AIE (%) 53 (52%) 17(32) 36(68) 0.53
SS (%) 2 (1%) 1 (50.0) 1 (50.0) 0.55

T
RA/JRA/JIA (%) 20 (13%) 7 (35.0) 13 (65.0) 0.597

IP
AIT (%) 8 (5%) 4 (50.0) 4 (50.0) 0.203
Vitiligo (%) 8 (5%) 3 (37.5) 5 (62.5) 0.667

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Celiac disease (%) 14 (8%) 1 (7.7) 12 (92.3) 0.09
Alopecia (%) 5 (3%) 3 (60.0) 2 (40.0) 0.645

SC
IBD (%) 27 (16%) 7 (26) 20 (74) 0.462
AH (%) 8 (5%) 5 (62.5) 3 (37.5) 0.04*

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PA 6 (3%) 0 6 (100) 0.18
Atrophic gastritis 2 (1%) 1 (50.0) 1 (50.0) 0.49
AN
Psoriasis 2 (1%) 1 (50.0) 1 (50.0) 0.55
SLE 3 (2%) 0 3 (100) 0.24
* P-value is statistically significant <0.05. CVID: common variable immune deficiency; ITP: idiopathic
M

thrombocytopenic purpura; AIHA: autoimmune hemolytic anemia; IDDM: insulin-dependent diabetes

mellitus; RA: rheumatoid arthritis; JRA: juvenile rheumatoid arthritis; IBD: inflammatory bowel disease;
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AIE: autoimmune enteropathy; AIT: autoimmune thyroiditis; AIH: autoimmune hepatitis; SS: Sjogren's
TE

syndrome; PA: Pernicious Anemia; SLE: systemic lupus erythematosus

EP
C
AC

Information Classification: General