Primary immunodeficiencies associated with eosinophilia

Background Eosinophilia is not an uncommon clinical finding. However, diagnosis of its cause can be a dilemma once common culprits, namely infection, allergy and reactive causes are excluded. Primary immunodeficiency disorders (PID) are among known differentials of eosinophilia. However, the list of PIDs typically reported with eosinophilia is small and the literature lacks an inclusive list of PIDs which have been reported with eosinophilia. This motivated us to review the literature for all PIDs which have been described to have elevated eosinophils as this may contribute to an earlier diagnosis of PID and further the understanding of eosinophilia. Methods A retrospective PubMed, and Google Scholar search using the terms “eosinophilia” and “every individual PID” as classified by Expert Committee of the International Union of Immunological Societies with the limit of the English language was performed. Results were assessed to capture case(s) which reported eosinophilia in the context of PID conditions. Absolute eosinophil counts (AEC) were retrieved from manuscripts whenever reported. Results In addition to the typical PID conditions described with eosinophilia, we document that MHC class II deficiency, CD3γ deficiency, STAT1 deficiency (AD form), Kostmann disease, cyclic neutropenia, TCRα deficiency, Papillon-Lefevre syndrome, CD40 deficiency, CD40L deficiency, anhidrotic ectodermal dysplasia with immune deficiency, ataxia-telangiectasia, common variable immunodeficiency disorders (CVID), Blau syndrome, CARD9 deficiency, neonatal onset multisystem inflammatory disease or chronic infantile neurologic cutaneous and articular syndrome (NOMID/CINCA), chronic granulomatous disease, MALT1 deficiency and Roifman syndrome have been noted to have elevated eosinophils. Severe eosinophilia (>5.0 × 109/L) was reported in Omenn syndrome, Wiskott Aldrich syndrome, ADA deficiency, autoimmune lymphoproliferative syndrome, immunodysregulation polyendocrinopathy enteropathy X-linked, STAT3 deficiency, DOCK8 deficiency, CD40 deficiency, MHC II deficiency, Kostmann disease, Papillon-Lefevre syndrome, and CVID. Conclusions This literature review shows that there is an extensive list of PIDs which have been reported with eosinophilia. This list helps clinicians to consider an extended differential diagnoses when tasked with exclusion of PID as a cause for eosinophilia. Electronic supplementary material The online version of this article (doi:10.1186/s13223-016-0130-4) contains supplementary material, which is available to authorized users.

Knowledge of the PIDs reported to have eosinophilia could assist clinicians assessing patients with eosinophilia when PID is considered. Given the current small list of PIDs reported with eosinophilia, we considered if a more comprehensive list could be generated by reviewing the literature. This review aimed to primarily capture PIDs reported with eosinophilia, and secondarily determine degree of eosinophilia where possible. Finally, some possible mechanisms driving eosinophilia in PID are highlighted.

Methods
A review of the literature was undertaken to generate a list of PIDs reported with eosinophilia and to attempt to determine the degree of eosinophilia. PubMed and subsequently Google Scholar searches with English language filter were performed using the terms "eosinophilia" AND "every individual PID" as classified by Expert Committee of the International Union of Immunological Societies (IUIS) [9]. Abstracts of the PubMed results, and the title and the text of Google Scholar results were reviewed to find any case reports, case series or review articles, in which case eosinophilia and absolute eosinophil counts (AEC) were sought in the manuscript. Moreover, references of review articles and case series were assessed for any additional cases. This led to inclusion of CHD7 and CARD11 as genetic defects of OS [10,11], and PGM3 deficiency [6,12]. Lastly, Roifman syndrome [13,14] and MALT1 deficiency [15] were included due to authors' knowledge that they have been reported with eosinophilia.
As the primary goal was to capture the PIDs reported with eosinophilia we did not cite every article which describes eosinophilia. Once a condition was captured, we aimed to cite references with reported AEC but not necessarily all references which described eosinophilia for that condition. No minimum number of reports was required to be included in this review.

Results
Here, PIDs reported in association with eosinophilia are briefly described. The cumulative range of eosinophilia in each condition and the retrieved AECs with their sources are respectively compiled in Table 1 and Additional file 1:   Table S1. Online Mendelian Inheritance in Man (OMIM) numbers are provided in brackets after each condition.

MHC class II deficiency (#209920)
MHC class II plays a pivotal role in CD4 T cell development and function [31,32]. Reduced CD4+T cells, hypogammaglobulinemia, and an inability to mount immune responses are among the immunologic characteristics [32]. Eosinophilia has been reported in few cases [31,33].

Hyper-IgE syndromes (HIES)
AD-HIES (Job's syndrome; #147060) AD-HIES is distinguished by its connective tissue, skeletal system, and dentition involvements in addition to recurrent infections, atopic dermatitis, elevated IgE, and eosinophilia [55]. STAT3 is the key to signal transduction of many cytokines, and memory B cells generation and mutations are causative [56][57][58]. Eosinophilia is noted in 80 % of AD-HIES patients [59]. A gain of function of STAT3 (p.Y640F) has recently been identified in lymphocytic variant of hypereosinophilic syndrome [60]. Therefore STAT3 appears to have an important role in eosinophil regulation.
Tyk2 deficiency (#611521) To date there have been few reported cases of Tyk2 deficiency [67,68]. Only the first patient had features of HIES including atopic dermatitis, eosinophilia, and high serum IgE levels [69]. However, mycobacterial and/or viral infections have been the most common phenotype among these patients [67,68]. Eosinophilia is described in 2 of 8 total reported cases [68,69].

Predominantly antibody deficiencies Common variable immunodeficiency disorders (CVID)
CVID is one of the more common immunodeficiencies with variable phenotypes mostly presents by recurrent infections, and low IgG and IgA and/or IgM [9, 76,77]. There are few cases of CVID with eosinophilia [78][79][80]; however, it is difficult to determine prevalence of eosinophilia in CVID.

Selective IgA deficiency (#137100)
IgA deficiency is usually asymptomatic and characterized by a decreased or absent level of serum IgA with normal IgG and IgM [9, 88,89]. It is considered on differential diagnoses of secondary eosinophilia [8, 90,91].

Congenital defects of phagocyte number or function or both SCN3 (Kostmann disease; #610738)
Kostmann disease typically presents with recurrent bacterial infections from early infancy, severe non-cyclic neutropenia, maturation arrest of myeloid differentiation, and compensatory monocytosis and eosinophilia [106][107][108][109]. Eosinophilia is considered to be a component of the classic presentation.

Cyclic neutropenia (#162800)
Cyclic neutropenia presents with recurrent fever, oral ulcers, recurrent oropharyngeal infections and periodic neutropenia [106]. In a review by Lang et al. eosinophilia was seen in 8.6 % of pediatric and 3.7 % of adult cases [110].

X-linked chronic granulomatous disease (CGD; #306400)
CGD is characterized by susceptibility to catalase-positive bacterial and fungal infections [114]. One CGD patient with mild eosinophilia despite taking prednisone every other day for eosinophilic colitis was reported [115]. There have also been reports of eosinophilia and eosinophilic inflammatory conditions in CGD patients including eosinophilic gastroenteritis and eosinophilic cystitis [115,116].

STAT1 deficiency (AD form) (#600555)
Partial STAT1 deficiency can present as Mendelian Susceptibility to Mycobacterial Disease due to IFN-γ signaling defects [117][118][119]. There is one case with persistent leukocytosis and hypereosinophilia in a 2 month of age child who later was diagnosed as STAT1 deficiency [118].

Evaluation of possible PID in a patient with eosinophilia
Many patients with eosinophilia will be explained by secondary causes such as parasitic infections, allergies, or hematological problems which are well reviewed elsewhere [2, 5-7]. If PID is being considered as a potential cause of eosinophilia, a wide range of PIDs have been associated with eosinophilia including disorders of Tcell development and signalling, cytokine signalling, cytoskeletal formation, autoimmunity, thymic development, innate immunity, humoral immunity and phagocytic function.
The history and physical examination may reveal clues which lead to likely diagnoses and further immune evaluation. Despite lack of sensitive and or specific signs and symptoms in respect to PIDs, many red flags including specific patterns of infections, autoimmunity, need for intravenous antibiotics, and prolonged oral antibiotics use with little effects have been previously reviewed [143][144][145]. Additionally, a detailed practice parameter for the evaluation of PID was recently published [146]. A patient history including infections, autoimmunity, malignancy and a review of systems including the presence of constitutional symptoms, allergies, and diarrhea may assist in deciding the likelihood of an immunodeficiency. A family history including consanguinity, early deaths and malignancy will also assist in evaluating for serious causes. The physical exam may note growth parameters, dysmorphism, skin abnormalities, thrush, lymphatic tissue, skin/nail abnormalities and neurological features.
A phenotypic guide to immunological conditions with eosinophilia has been published [6] which contains many of the conditions in this review. Here we present a complimentary approach which focuses on the severity of the conditions followed by some diagnostic clues (Fig. 1). After a detailed history and physical exam, quantitative immunoglobulins could be ordered if a clinical concern of PID exists. Laboratory results of a complete blood count (CBC) and differential will already be available if the reason for referral is eosinophilia. If the patient is lymphopenic or hypogammaglobulinemic then a work up for PID independent of the eosinophilia and comprehensive resources are recommended [146,147]. A patient with SCID/Omenn syndrome presents a medical emergency so active consideration of these life threatening conditions is warranted in an infant. After considering SCID/Omenn syndrome, other significant or transplantable conditions could be considered such as WAS, IPEX, DOCK8 deficiency, EDA-ID and CD40L/CD40 deficiency and others. Next, consideration of the hyper IgE syndromes is suggested because they are well known to be associated with eosinophilia and some can be severe. Finally, a consideration of the other reported causes may be needed depending on the circumstances and whether an alternate diagnosis has been achieved.

Limitations of this study
By the nature of a review of published literature, we are limited by what authors have reported. There may be some PIDs with eosinophilia which were not captured due to reporting omission. This limitation is not a weakness because the purpose was to see the basis of the assertion that PID should be considered in a patient with eosinophilia and to catalogue the previously reported conditions. Our strategy did allow the capture of even single case reports and documented many PIDs not typically thought to have been noted with eosinophilia but may have missed some diseases including those which may list the laboratory values in a table in a way not captured by our search, or in non-English language journals.
Determining the true frequency of eosinophilia in individual PID conditions is also subject to reporting omissions and biases. We have provided some information about how commonly eosinophilia has been noted such as from case series of patients, but we cannot provide an exact frequency with this methodology.
The AEC is not described for every PID and therefore the degree and the range of eosinophilia is derived from a low number of cases. The AEC range reported in Table 1 is the cumulative results of the cases which mentioned eosinophil count(s). They are intended to serve as a guide when considering severe eosinophilia. The degree of eosinophilia can be markedly varied in each PID. As summarized in Table 1 and reported in detail in Additional file 1: Table S1, there is a broad variability in the degree of eosinophilia associated with each individual PID and or subtype(s). Given the variability of the degree of eosinophilia this is unlikely to be of major diagnostic assistance, but severe eosinophilia is less common and may have more diagnostic utility.
We agree with previous reviews that PIDs should be considered in patients with eosinophilia, especially children, when typical causes have been ruled out [2, 5-8]. This list of reported PID conditions with eosinophilia will help with the assessment of such patients. Eosinophilia can be driven by varied processes including imbalances in Th1/Th2, cytokine derangements, infections and medications.

Additional file
Additional file 1: Table S1. Absolute eosinophil counts (AEC) in Primary Immunodeficiency Diseases (PID): number of patients reported and references cited.