Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation

While elevated peripheral eosinophilia can be found in patients with parasitic infection, significant atopic disease, drug hypersensitivity reactions, connective tissue disorders, malignancy, and rare hypereosinophilic syndromes, monogenic disorders of immune deficiency or dysregulation should be considered, particularly in the pediatric age group. Some of these syndromes include clinical manifestations of atopy, such as atopic dermatitis or food allergy, which may contribute to the eosinophilia; however the mechanism driving the eosinophilia is not well understood. Many of these monogenic diseases are characterized by increased production of Th2 cytokines, such as IL-5, which is an essential promoter of eosinophil differentiation, maturation and survival [1]. This article reviews several disorders of immune deficiency or dysregulation that have documented eosinophilia as part of the syndrome (Figure 1). The clinical features, common infections, laboratory findings, diagnostic methods, and genetic basis of disease of each syndrome will be discussed. Figure 1 Flow diagram showing disorders of immune deficiency or dysregulation with variable levels of peripheral and tissue eosinophilia. Characteristics of each disorder are listed once under the most prevalently featured category. AD-HIES: autosomal dominant ... 2 Syndromic causes of elevated IgE and eosinophilia 2.1 Autosomal dominant HIES Job’s syndrome was first described in 1966 with two patients who had recurrent staphylococcal abscesses, similar to the boils borne by the prophet Job in the Bible [2]. This clinical syndrome, which was first characterized as a triad of recurrent staphylococcal abscesses, pulmonary infections, and an eczematous dermatitis, was later found to be associated with elevated serum IgE levels leading to the name autosomal dominant Hyper IgE syndrome (AD-HIES) [3]. 2.1.1 Clinical features, infections, and management AD-HIES typically presents within the first few days of life as neonatal acne or erythema toxicum neonatorum secondary to the pustular rash that often encompasses the face, scalp, and upper body [4, 5]. Histologically, the skin infiltration is predominantly eosinophils [6]. The rash usually evolves to resemble an eczematous dermatitis, which is papular, pruritic, lichenified, and typically driven by Staphylococcus aureus colonization and superinfection [7]. Patients with AD-HIES classically have recurrent, “cold” S. aureus abscesses, which have frank pus when excised despite their lack of dolor, rubor, and calor [2]. Recurrent sinopulmonary infections generally start in the first several years of life with S. aureus being the most common pathogen implicated in the pneumonias. Streptococcus pneumoniae and Haemophilus influenzae also occur frequently, and the first presentation of pneumonia in infancy may be caused by Pneumocystis jirovecii [8, 9]. As with the cold abscesses, AD-HIES patients with pneumonia lack systemic signs of inflammation, including fever, frequently delaying diagnosis leading to parenchymal lung damage (Figure 2). Pneumatoceles and bronchiectasis increase the patients’ susceptibility to difficult to treat microbes, like Aspergillus, Scedosporium, Pseudomonas, and nontuberculous mycobacteria, which contribute significantly to their morbidity and mortality [9–11]. Figure 2 Parenchymal lung findings and complications in AD-HIES. Chest CT from a 43-year-old woman with AD-HIES, multiple pneumatoceles and an evident aspergilloma (arrows). Fungal susceptibility is apparent with more than 80% of patients having chronic mucocutaneous candidiasis [12] (Figure 3). Unlike patients with DOCK8 deficiency, those with AD-HIES do not commonly have severe viral infections (Table 1) [13, 14]. Figure 3 Characteristic clinical features found in AD-HIES. From left to right: characteristic facies, chronic mucocutaneous candidiasis, and severe scoliosis. Table 1 Comparison of the clinical features among the key syndromes of elevated IgE: STAT3, DOCK8, and PGM3 Despite the very elevated levels of serum IgE characteristic of these patients, allergy and asthma are not typically severe or difficult to manage in AD-HIES. Siegel et al. reported a diminished allergic phenotype in patients with AD-HIES compared to other patients with a comparably elevated IgE and atopic dermatitis, although allergies are more frequent than those with normal IgE levels [15]. AD-HIES is a multi-system disease with many non-immunologic abnormalities. A characteristic facial appearance usually emerges during adolescence with porous skin, a prominent forehead, deep-set eyes, and a bulbous and broad nose (Figure 3). Most patients fail to shed their primary teeth, requiring medical removal to allow the secondary teeth to emerge normally. Patients also have a high-arched hard palate and palatal and lingual ridges or grooves [8, 10, 16]. Extensive musculoskeletal abnormalities include scoliosis, osteopenia or osteoporosis, minimal trauma fractures, craniosynostosis, and joint hyperextensibility [8, 17] (Figure 3). Joint hyperextensibility occurs in more than two-thirds of AD-HIES patient and may contribute to the high frequency of degenerative bone disease [12]. Recently, manifestations of gastrointestinal disease in AD-HIES patients have been described. In a cohort of 70 individuals, nearly two-thirds of those with AD-HIES who underwent gastrointestinal endoscopy had eosinophilic esophagitis as defined by the updated consensus guidelines [18, 19]. Food allergy was not as common as in DOCK8 deficiency [18]. As with several other primary immunodeficiency diseases, patients with AD-HIES are at increased risk of developing malignancy, particularly non-Hodgkin’s lymphoma [13, 20]. Because the clinical impact of recurrent infections can be profound, the primary focus in management is treatment of infections and prophylaxis to prevent future infections, especially with S. aureus. Suppression of skin colonization with S. aureus through antiseptics, such as dilute bleach baths and chlorhexidine washes, frequently leads to minimal dermatitis. Patients with chronic mucocutaneous candidiasis, or in areas endemic for Coccidioides or histoplasmosis, may also benefit from antifungal prophylaxis. Parenchymal lung disease and subsequent chronic infection with molds, such as Aspergillus, and Gram-negative bacteria, such as Pseudomonas, contribute to most cases of death in AD-HIES [11]. Because of this, pyogenic pneumonias should be aggressively diagnosed and treated to minimize parenchymal damage. Immunoglobulin replacement should be considered in those patients with impaired specific antibody responses, bronchiectasis and breakthrough infections while on prophylaxis. Hematopoietic stem cell transplant (HSCT) has been performed infrequently as a possible curative treatment for AD-HIES with varying clinical results [21–23].