Immune Deficiency Disease
Several immune deficiency disorders are associated with allergic manifestations. These include selective IgA deficiency and Common Variable Immunodeficiency. In addition, several primary immune deficiency disorders may demonstrate very high IgE levels[
36]. These include Hyper-IgE syndromes (HIES), Immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX), The Wiskott-Aldrich Syndrome (WAS), Omenn syndrome and some forms of DiGeorge syndrome.
Hyper-IgE syndrome [
37‐
40] is characterized by highly elevated IgE levels, skin disease and repeated infections. IgE levels tend to exceed 10,000 U/mL, although a huge variability in levels may be observed. HIES syndrome can be idiopathic, autosomal dominant (AD) or autosomal recessive (AR). Most cases appear to have a sporadic basis, but mutations in the STAT3 gene is a feature of the autosomal dominant disorder (also referred to as type 1). AD HIES is characterized by typical skeletal changes such as "coarse facies", abnormal dentition and infection (Staphylococcal pneumonia and/or a pneumatocele). In AR HIES (also known as type 2), recurrent pneumonias, severe viral infections (Molluscum, Herpes simplex), neurological disease and vasculitis may be presenting features and mutations in the TYK2 gene may be seen.
IPEX is a rare syndrome mediated by a reduced or absent Treg population [
36,
41]. The syndrome manifests as early-onset enteritis (diarrhea), endocrinopathy (type 1 diabetes or hypothyroidism), elevated IgE levels and dermatitis/eczema. Hematological dyscrazias such as anemia, thrombocytopenia and eosinophilia are also observed. IPEX is secondary to mutations of the FOXP3 gene and a resultant deficiency of Treg cells. An increased Th2 response and elevated IgE levels are observed.
Wiskott-Aldrich syndrome is an X-linked disorder characterized by current infection, thrombocytopenia (with small platelets), neutropenia, eczema, high IgE levels, a very high prevalence of autoimmunity (including arthropathy, vasculitis, and inflammatory bowel disease) and malignancy. The defect lies in the WAS protein (or WASP) that is crucial to T cell, platelet and neutrophil function.
Omenn syndrome is a rare disorder presenting with recurrent infection, diarrhea, alopecia, eczema/erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia and elevated IgE levels. Immune assessment shows elevated IgE levels in spite of deficiency in B cells numbers, panhypogammaglobulinemia, oligoclonal, nonfunctional T cell expansion and excessive Th2 skewing. The patients demonstrate one of several defects: mutations in RAG genes, Artemis gene, IL-7 receptor encoding gene and the RMRP gene (RNA component of mitochondrial RNA-processing endoribonuclease).
A subgroup of patients with DiGeorge syndrome may present not only with the profound T cell defect, seen with thymic aplasia, but also with findings consistent with Omenn syndrome (including elevated IgE levels and eosinophilia).
Systemic Infections
Elevated IgE levels have been described in a variety of bacterial, fungal, mycobacterial and viral infections (listed in Table
4). Leprosy [
42] and tuberculosis [
43] have rarely been associated with elevated IgE levels [
44,
45]. Elevated IgE levels have also been described in viral infections (Epstein-Barr Virus and Cytomegalovirus).
HIV infection is a well-recognized cause for elevated IgE levels [
46‐
48]. Elevated IgE levels have been described in both adults and in children infected with HIV-1 [
49], and are associated with a poorer prognosis [
50]. A hyper-IgE-like syndrome and severe eczema have also been described with advanced HIV-1 infection [
51].
Parasitic Disease
Ascaris [
52], Capillariasis [
53], Paragonimiasis [
54], Fasciola hepatica [
55,
56], Schistosomiasis [
57,
58], Hookworm (Trichuriasis) [
59], Echinococcus [
60], Onchocercariasis [
61] and Malaria [
62] have all been associated with elevated IgE levels. Of the many parasitic disorders, only a few are directly relevant to North American and these will be reviewed below. Giardiasis, Strongyloidiasis,
Trichinella spiralis and Toxocara species occur with some frequency and have certain distinct and unique presentations.
Strongyloidiasis and its systemic consequences were reviewed by the authors recently [
63]. Infection with
S. stercoralis occurs when the skin of the feet contact free-living filariform larvae in the soil. The filariform larvae penetrate the skin and invade the blood vessels and subsequently enter the alveoli of the lung, where they are coughed up, swallowed and undergo maturation in the duodenum and jejunum. Over half the patients who harbor
S. stercoralis have symptoms are related to the GI tract invasion, lung invasion or dissemination with strongyloid hyperinfection. The latter, usually seen in patients treated with glucocorticoids or immunosuppressive agents, can be fatal with complications such as sepsis, gram negative meningitis and/or respiratory distress [
64,
65]. Treatment with ivermectin (200 μg/Kg/day) is associated with a 90% cure rate.
Toxocariasis is a well recognized zoonotic disease mediated by the nematode belonging to the genus Toxocara. Adult worms are present in the intestinal tracts of dogs (
T. canis) or cats (
T. cati) and human infection is caused by egg ingestion [
66,
67]. Infective larvae migrate through the liver and lung and result in a plethora of allergic and inflammatory manifestations, referred to as visceral, ocular or cutaneous larva migrans. Eosinophilia, elevated IgE and involvement of brain, muscle, liver and lungs are responsible for the clinical manifestations. Treatment with albendazole or mebendazole and diethylcarbamazine may be attempted.
Trichinellosis is mediated by the nematode,
Trichinella spiralis, transmitted by eating undercooked pork or larval forms present in cyst form in striated muscle [
68]. Many patients may remain asymptomatic, while some patients develop abdominal pain, diarrhea, fever and excruciating myalgia (calf or masseter muscle). During the invasive stage of the illness, allergic phenomena such as urticaria or periorbital angioedema may occur. The disease is treated with albendazole and some studies have suggested a beneficial effect for glucocorticoids during the allergic and inflammatory stages of the disease.
Giardia lamblia is a protozoan parasite that infects humans following the ingestion of infectious cysts (fecal-oral route or from contaminated food or well water). Symptoms include abdominal cramps, bloating, watery diarrhea and malabsorption. Elevated IgE levels and eosinophilia have been described [
69]. Treatment with metronidazole, tinidazole, nitazoxanide or paramomycin may be variably effective, with paramomycin reserved for infected pregnant women.
Neoplasia
A variety of neoplastic and hematological disorders have been associated with IgE.
Solid tumors such as cancers of the lung, colon, prostate and breast have been reported to elevate IgE levels [
70]. These may be the result of dysregulation of the Th1/Th2-IgE axis [
71]. Other neoplastic conditions known to present with elevated IgE levels include IgE myeloma and malignant lymphoma. Eosinophilia and elevated IL-4 and IgE levels have been shown in both Hodgkin's disease (serum IgE as well as intracellular IgE within Reed-Sternberg cells) and malignant/non-Hodgkin's lymphoma [
72]. In multiple myeloma, polyclonal elevation of IgE is associated with improved survival [
73].
IgE myeloma was first described in 1967 as an "atypical myeloma immunoglobulin" and since then several other cases of this rare myeloma have been reported [
74]. The presentation of IgE myeloma is similar to that of an IgG myeloma, and most patients are diagnosed between the 6
th and 7
th decades of life.
Inflammatory Disorders
Many other inflammatory disorders have been associated with elevated IgE levels. These include Kawasaki syndrome [
75], vasculitides such as polyarteritis nodosa or Churg-Strauss syndrome[
76], Guillian-Barre syndrome [
77,
78], inflammatory neuropathies [
79], burns [
80,
81], Sjogren's syndrome [
82], certain patients with rheumatoid arthritis who may also develop IgE rheumatoid factors [
83], graft-versus-host disease and bone marrow transplantation [
84] and scleroderma-like syndromes [
85]. The prognostic or diagnostic role for IgE in these disorders is unknown
Systemic and Toxic Disorders
Alcohol ingestion has been associated with elevated IgE levels [
91]. Certain forms of nephritides demonstrate IgE elevation [
92]. The elevation of IgE in these disorders may be due to dysregulation of the IL-4-IL-13 axis. In idiopathic nephritic syndrome, IL-13 levels are elevated, while in minimal change disease, polymorphisms of the IL-4 gene have been described [
93]. Other conditions reported to show elevated IgE levels include cystic fibrosis [
94] (with associated ABPA-like disease, probably secondary to increased airway penetration by allergen), nicotine abuse [
95] and pulmonary hemosiderosis (Heiner's syndrome)[
96].