Journal of the Egyptian Society of Parasitology, Vol.48, No.2, August 2018 J. Egypt. Soc. Parasitol. (JESP), 48(2), 2018: 433 – 442

EOSINOPHILIA WITH SPECIAL REFERENCE TO HELMINTHIASIS By EMAN EBRAHIM ABDEL FADIL1, MOUSA ABDEL GAWAD M. ISMAIL2 and TOSSON A. MORSY3 Military Medical Academy Cairo112911 and Departments of Parasitology, Faculties of Medicine, Cairo University2 and Ain Shams University, Cairo 115663, Egypt Abstract Eosinophilia (e-o-sin-o-FILL-e-uh) is a higher than normal level of eosinophils. Eosinophils are a type of disease-fighting white blood cell, indicating a parasitic infection, an allergic reaction or cancer. There are blood eosinophilia and tissue eosinophilia. Tissue eosinophilia may be found in samples taken during an exploratory procedure or in samples of certain fluids, such as mucus released from nasal tissues. If you have tissue eosinophilia, the level of eosinophils in your bloodstream is likely normal. Blood eosinophilia may be detected with a blood test, usually as part of a complete blood count. More than 500 eosinophils per microliter of blood is generally considered eosinophilia in adults. More than 1,500 eosinophils per microliter of blood that lasts for several months is called hypereosinophilia. This reviewed the correlation between high eosinophila and helminthiasis. Key words: Eosinophilia, Helminthiasis, Organic diseases, Health disorders Introduction cal conditions that may contribute to eosino- A great variety of allergic, infectious, neo- philia. Blood eosinophilia is labile, and ab- plastic, and idiopathic diseases are associa- solute thresholds for many clinical condi- ted with increased blood and/or tissue eosi- tions cannot be definitively established. In nophilia and range in severity from self-li- asthma, eosinophils levels were usually less mited conditions to life-threatening disor- than 1500/mm3 (Bass et al, 1980). In Churg- ders. The major causes of blood and tissue Strauss Syndrome (often with asthma), eosinophilia are many diseases and health however, blood eosinophil levels were grea- disorders. These are allergic diseases, atopic ter than 1500/mm3. Low levels of blood eo- and related diseases (Noh et al, 2010), me- sinophils were found in the setting of eosi- dication-related eosinophilias, infectious dis- nophil-mediated cardiac damage (Blauwet et eases, parasitic infections, mostly helmin- al, 2005). But, sustained elevated levels of thes (Liu et al, 2004), specific fungus, other blood eosinophilia should prompt ongoing infections (infrequent), hematologic and ne- pursuit of an etiology for eosinophilia and oplastic disorders, hypereosinophilic synd- monitoring for organ-associated damage. rome, leukemia, lymphomas (Samoszuk et al, Definitions: Although accepted upper 1993), tumor-associated (Szor et al, 2018), limits of normal blood eosinophil numbers mastocytosis and diseases with specific or- vary somewhat, a value above 500 eosino- gan involvement, skin and subcutaneous dis- phils/microL of blood is abnormal in the eases, pulmonary diseases, gastrointestinal vast majority of cases (Roufosse and Weller, diseases, neurologic diseases, rheumatolog- 2010). Eosinophilia degree was categorized ic diseases (Samoszuk and Nansen, 1990), into mild (500 to 1500 cells/microL), mode- cardiac diseases, renal diseases, immunolo- rate (1500 to 5000 cells/microL) or severe gic reactions, specific immune deficiency (>5000 cells/microL). Term “hypereosino- diseases (Paganelli et al, 1995), transplant philia” refers to eosinophil levels >1500/ rejection, endocrine and hypoadrenalism. microL, which can be associated with tissue Considerations and Discussion and organ damage, regardless of underlying Given the diversity of medical conditions cause. Term “hypereosinophilic syndrome” that may be associated with increased blood has been variously defined, with one pro- eosinophilia, the evaluation of such patients posal being the presence of an eosinophil must include consideration of diverse medi- count >1500/microL in absence of a discern-

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able secondary cause e.g., allergic diseases, PDGFRalpha-associated variant affects mos- drug hypersensitivity, parasitic helminthes, tly males, whereas other variants appear to HIV-infection, nonhematologic malignanci- affect males and females in roughly equal es (Simon et al, 2010). proportions. Important subtypes include my- Categories of eosinophilia: Peripheral eo- eloproliferative variants, T cell lymphocytic sinophilia can be divided into categories of variants, and familial eosinophilia. These primary, secondary, or idiopathic one (Tef subtypes are associated with a more clearly- feri, 2005). defined clinical presentation and prognosis, Primary eosinophilia usually occurs in the and in the case of FIP1L1-PDGFRA asso- context of hematologic malignancies, such ciated myeloproliferative variant, response as acute leukemias or chronic myeloid dis- to specific therapies. Other complex forms orders, when there is evidence of clonal ex- of HES have still-uncertain etiologies, yet pansion of eosinophils. represent the bulk of subjects with HES and The most common infectious cause for se- may be difficult to distinguish from other condary eosinophilia is the tissue invasive eosinophil-associated disorders, including parasite. Noninfectious causes of secondary CSS vasculitis. Organ systems most com- eosinophilia include allergic disorders, me- monly affected in HES are the heart, ner- dications, toxins, autoimmune diseases, and vous system, skin, lungs, and gastrointes- endocrine disorders, such as Addison's dis- tinal tract. Patients with HES might be pre- ease. Eosinophils can occur in Hodgkin's & sent with gradually progressive symptoms, non-Hodgkin lymphoma and other metasta- or with life-threatening cardiac and neurolo- tic cancers, but the associated eosinophils gic events, such as thromboembolic stroke are not of a clonal nature in this situation. or encephalopathy. Once secondary causes A diagnosis of idiopathic eosinophilia is of eosinophilia are excluded, patients with considered when a thorough evaluation does persistent eosinophilia must be con-sidered not identify either a primary or secondary as possible HES and evaluated accordingly, cause of eosinophilia. Hypereosinophilic regardless of the presence or absence of syndromes (HES) are a group of disorders symptoms. This evaluation involves an asse- marked by sustained overproduction of eosi- ssment of end-organ involvement and spe- nophils, in which eosinophilic infiltration cialized studies to identify patients with and mediator release cause damage to myeloproliferative or clonal lymphocytic multiple organs (Sheikh and Weller, 2007). variants (Bain and Fletcher, 2007). Although these disorders had long been Patient evaluation: Blood eosinophilia considered idiopathic (e.g., as in "idiopathic most commonly reflects an allergic, infec- hypereosinophilic syndrome", IHES), etiolo- tious, or neoplastic process. A thorough exa- gies for some forms of HES have now been mining of a patient with eosinophilia needed described. HES are a heterogeneous group consideration of the patient's history, physic- of disorders, encompassing a number of cal examination, laboratory information and etiologically distinct diseases. Underlying imaging studies (Brito-Babapulle, 2003). molecular or immunologic defects can be In initial evaluation, information regarding identified in about 25% of cases. Diagnosis allergic symptoms, international travel, cur- of HES should be suspected in patients with rent and recent medications, and constitu- sustained blood eosinophilia of ≥ 1500/ tional symptoms should be sought. If the microliter, documented on at least two occa- medication and allergy history is unrevea- sions, no other apparent etiologies for eosi- ling, three stool specimens must be exa- nophilia, and often signs and/or symptoms mined for ova and parasites. In the setting of of end-organ dysfunction. HES are commo- international travel or other geographic ex- nest in patients 20-50 years of age. FIP1L1- posures to helminthic parasites, then more

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work-up including serologic tests depended philic syndrome-related illness or adrenal on the geographic area that the patient insufficiency. The mechanisms responsible visited (Lombardi and Passalacqua, 2003). for infection-related eosinopenia have not Those with symptoms consistent with aller- been precisely delineated but the phenom- gic rhinitis may be diagnosed by examina- enon probably is due to heightened endo- tion of a nasal smear for eosinophils. Those genous corticosteroid production and the with a suspected clonal disorder will need a actions of various inflammatory mediators hematologic evaluation. (Jenerowicz et al, 2007). Medication-related eosinophilia: Adminis- Parasitic infections: Eosinophilia is promi- tration of many conventional or alternative nent in a number of helminthic parasitic medications may produce eosinophilia; thus, diseases. Eosinophilic response to helminths a detailed history of current or past medica- is determined both by host's immune res- tion use is required when evaluating a ponse and by the parasite, including its dis- patient with this condition. tribution, migration, and development within The attribution of eosinophilia to a specific the infected host. Level of eosinophilia medication were identified in many drug re- parallels the magnitude and extent of tissue qactions 1- Cytokine-mediated as GM-CSF, invasion by helminthic larvae or adults. The IL-2, 2- Pulmonary infiltrates as Non-ster- height of the eosinophilia peaks early in the oidal antiinflammatory agents, 3- Pleuro-pu- course of infection with several helminthes lmonary as Dantrolene, 4- Interstitial neph- since the migration of larvae is greatest at ritis as Semisynthetic penicillins, cephalo- this time (Tab. 1). But, absence of eosino- sporins, 5- Necrotizing myocarditis as Ran- philia does not exclude the presence of these itidine, 6- Hepatitis as semisynthetic penic- parasites. illins, tetracyclines, 7- Hypersensitivity vas- For established infections, tissue eosino- culitis as Allopurinol, phenytoin 8- Gastro- philia around helminths may not be acco- enterocolitis as Nonsteroidal anti-inflamm- mpanied by blood eosinophilia when the atory agents, 9- Asthma, nasal polyps as organism is antigenically sequestered within Aspirin, 10- Pharmacologic as Beta bloc- tissues (e.g., intact echinococcal cysts) or is kers, 11- Eosinophilia-myalgia syndrome as limited solely to the intestinal lumen (e.g., L-tryptophan contaminant, and 12- Asymp- tapeworms or adult Ascaris roundworms). tomatic as ampicillin, penicillins, cephalos- Intermittent leakage of fluids from echinoco- porins. Blood eosinophilia by itself need not ccal cysts were transiently stimulated incre- necessitate cessation of drug therapy but ase in blood eosinophilia and elicit urticaria, must lead to an evaluation of organs likely bronchospasm, or anaphylaxis (Georgiou et to be involved in eosinophil-associated drug al, 2005). Several helminthes can lead to reactions, including the lungs, kidneys, and long-lasting eosinophilia (Tab. 2). heart (Weller, 1991). Infections with a diversity of helminthic Infectious Diseases: Most acute bacterial parasites elicit eosinophilia via stimulation or viral infections characteristically produce of Th2-like lymphocyte responses (Liu et al, eosinopenia. Even in patients with eosino- 2004). TH2 response is characterized by philia due to parasitic or allergic diseases, production of IL-4 & IL-5, subsequently the development of intercurrent bacterial or generating IgG1 & IgE-secreting cells, and viral infections leads to suppression of blood eliciting eosinophilia. eosinophilia until the superimposed acute Diagnosis: Amongst helminthes, the main infection has resolved. Thus, heightened or parasites that need to be evaluated are Stron- even normal blood eosinophil numbers in a gyloides stercoralis, hookworm, filariae, and febrile patient should prompt consideration Toxocara canis. The diagnostic value can of a noninfectious cause, such as an eosino- also vary according to geographic origin. In

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128 Indochinese patients, eosinophilia was brosis (S. mansoni and S. japonicum). not find by routine screening (Nutman et al, b- Strongyloides spp. can persist for decades 1987). Hookworm (55%) and S. stercoralis without causing major symptoms. The infec- (38%) were the most common organisms tion elicits varying degrees of eosinophilia identified. In contrast, in African Immigrants ranging from minimal to such high magni- the commonest parasites were 30% in filar- tude that it was mistaken for a hypereo- iae, 17% in each schistosomes or hookworm sinophilic syndrome. Disseminated fatal dis- and 8% in whipworms (Pardo et al, 2006). ease (hyperinfection syndrome) developed The following caveats must be considered in patients unsuspectingly given cortices- when evaluating a patient with eosinophilia: teroids and/or immune-suppressive therapies a- Fascioliasis is a zoonotic foodborne trem- (Nucci et al, 1995). In the patient with eo- atode caused by Fasciola spp. that are flat sinophilia, serology proved useful to detect leaf-like worms known as liver flukes. Two strongyloidiasis when fecal examinations are species that infect man are F. hepatica and unrevealing (Gill and Bailey, 1989). Fasciola gigantica. Ectopic of immature flu- In strongyloidiasis developing hyperinfec- kes involved subcutaneous tissue, intestinal tion syndrome increased if cell-mediated wall, lungs, pancreas, eye, brain, stomach immunity was impaired by congenital imm- wall, pharyngeal mucosa, skin and others unodeficiency, underlying malignancy, mal- were very rare (Rashed et al, 2010). Eosi- nutrition, alcoholism, hematopoietic stem nophilic pneumonia can be caused aside cell transplantation (HSCT), or corticoster- from Fasciola spp., by others, especially As- oids or cytotoxic drugs administration (Ke- caris, Strongyloides, Paragonimus, Trichin- iser and Nutman, 2004). The pathophysio- ella, and Toxocara (Bhatt and Allen, 2012). logy underlying these risk factors, whether With the exception of helminthiasis, the se- disease-related or iatrogenically induced, is condary causes of eosinophilia rarely cause a compromised immune system leading to an absolute eosinophil count of >1500 cells/ dysfunction of TH-2 helper cells, and thus mm3. Parasites which cause tissue invasion eradicated infection prior to initiation of im- resulted in extreme eosinophilia (Bayhan et munosuppressive therapy (Concha et al, al, 2016). The commonest abnormalities of 2005). But, whether this effect was suffic- fascioliasis were the increased levels of total ient or not to reduce the risk of hyperinfec- IgE, total IgG, leukocytosis and eosinophilia tion in patients receiving cyclosporine? elevations in the erythrocyte sedimentation Patients with HTLV-1 infection have high rate (Kaya et al, 2011). Other most promi- levels of interferon-gamma production, nent liver flukes are Clonorchis sinensis, which decreases the production of IL-4, IL- Opisthorchis felineus and O. viverrini (Fürst 5, IL-13, & IgE, important molecules in host et al, 2012). Hwang et al. (2012) in Korea defense against strongyloidiasis (Carvalho stated that C. sinensis should be considered and Porto, 2004). Disseminated strongyloid- as a cause of multiple microembolic stroke iasis can occur in patients with AIDS but associated with idiopathic hypereosinophilic less frequently than in patients with HTLV-1 syndrome. This fluke invaded Egypt with and is much less common than might be immigrant workers back from Saudi Arabia predicted given the coendemicity of the two (Morsy and Al-Mathal, 2011). infections (Kim and Lupatkin, 2004). But, Gryseels et al. (2006) reported that in chro- immune reconstitution might be a risk factor nic schistosomiasis, immunopathologic reac- for strongyloidiasis dissemination (Brown et tions against tissues trapped eggs led to infl- al, 2006) and in HIV positive patients at risk ammatory and obstructive disease in urinary for strongyloidiasis treatment failure (Viney system (S. haematobium) or intestinal disea- et al, 2004). Other conditions or medications se, hepatosplenic inflammation, and liver fi- may be associated with strongyloidiasis in-

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creased risk: hypogammaglobulinemia, anti- uno-regulatory eosinophils function in helm- TNF receptor therapy (Krishnamurthy et al, inthiasis. Eosinophils entered infection sites 2007) and immunosuppression associated immediately after tissue invasion by larvae with organ transplantation (Valar et al, that were essential for their survive (Huang 2007). et al, 2014). c- Visceral larva migrans due to Toxocara e- Filariasis is a vector borne disease espe- canis should be considered in children with cially prevalent in tropical and subtropical a propensity for geophagous pica and inges- regions and caused by slender thread-like tion of dirt contaminated by dog Toxocara filarial worms which has an affinity towards eggs. Serologic testing confirmed diagnosis. skin and subcutaneous tissue or lymphatic Ocular involvement occurred as the sole ma- system (WHO, 2012). While Onchocerca nifestation of visceral larva migrans, often volvulus and Loa loa affected the skin, presenting in those without an antecedent Wuchereria bancrofti, Brugia malayi and history of symptomatic visceral larva mig- Brugia timori cause lymphatic filariasis in rans (Good et al, 2004). Ocular lesion is due the descending order (Oza et al, 2014). W. to larval localization in the eye and the bancrofti causes a wide range of clinical pic- granulomatous response around the larva. tures depending upon its phase and duration. Common symptoms are strabismus and fail- Microfilaremia and paradoxical eosinophilia ing vision. Typical lesion is a whitish eleva- (lowest count at night) are striking features ted granuloma measuring 1 to 2 diameters in the acute phase. Chronic phase is usually and located in the retina posterior pole. Occ- characterized by lymphadenopathy in lower asionally, ocular larva migrans may occur as limbs, retroperitoneal tissues, lymphedema, uveitis or endophthalmitis (Stewart et al, hydrocele and elephantiasis (Abdel-Shafi et 2005). In Egypt, T. canis eggs were detected al, 2017). in 9.83% of pet dogs (Haridy et al, 2009). In contrast to infections with multicellular d- Uspensky et al. (2018) in Russia report- helminthic parasites, infections with single- ed that trichinellosis, a zoonotic disease is celled protozoan parasites, including enteric still a public health concern in the Arctic Giardia lamblia and Entamoeba histolytica, with highest prevalence among people do not characteristically elicit blood eosino- consuming traditional local foods made from philia. Identification of these protozoa in the meat of marine mammals. T. nativa lar- stool examinations did not complete a diag- vae survived for up to 24 months in a ferm- nostic workup for eosinophilia since other ented and frozen marine mammal meat pro- potential pathogens should still be sought duct called kopalkhen. As larvae life cycle (Nutman, 2006). There are two exceptions to could be completed in absence of humans, it general rule that protozoa, including those in persisted in the environment as a cause of the GI tract, do not elicit eosinophilia: Dien- morbidity in human populations living these tamoeba fragilis and Isospora belli. Thus, in regions. Despite prominence in infection patients with symptoms of enteric infection response to intestine-dwelling worms, T. spi- (loose stools or diarrhea) and eosinophilia, ralis in eosinophil ablated strains of mice diagnostic trophozoites of D. fragilis or oo- consistently showed that eosinophils do not cysts of I. belli must be sought in stool exa- contribute in a discernable way to intestinal minations. Diarrhea was 38.5% of Egyptian immunity (Svensson et al, 2011). In trichi- patients infected with D. fragilis compared nellosis, eosinophils promo-ted growth and to 50% of patients infected with G. lamblia, survival of larvae, which colonized skeletal while abdominal pain was in significanlty muscle (Gebreselassie et al, 2012). By com- encountered with D. fragilis in 41% com- bining eosinophil ablation & restoration with pared to 33.3% with G. lamblia (Rayan et al, the natural infection documented new imm- 2007). Eassa et al. (2016) in Alexandria re-

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ported that about half of 346 municipality cal intensive care unit, 40/570 assessable solid-waste workers, apart from helminthes, patients (7%) had relative eosinophilia more were infected with E. histolytica (3.2%), G. than 3% (Beishuizen et al, 1999). Low-dose lamblia (2.9%), Cryptosporidium (23.4%), adrenocorticotropin stimulation testing was Microsporidia (20.25%), Cyclospora spp. abnormal in 10/40 patients (25%). Clinical (2.0%), B. hominis (1.7%), and Cystoiso- suspicion of adrenal insufficiency was high spora belli (1.2%). in 8/10 patients, and treatment with hydro- Laboratory evaluation: Differential diagn- cortisone resulted in hemodynamic impro- osis can be narrowed based upon clinical vement in seven. Sakao et al. (2014) in Ja- findings and geographic considerations. pan analyzed retrospectively the clinical ch- Depending on travel history, stool examina- aracteristics of five HD patients who were tion for ova and parasites should be done presented with hypercalcemia due to adrenal when certain helminthiasis are encountered insufficiency (age: 69±7), time on HD: (as Strongyloides sp., Hookworm, Fasciolo- 13±11years old. All patients had critical ill- psis buski, Clonorchis sinensis). In the case nesses at hypercalcemia onset, with at least of light infections, multiple stools may need one symptom, such as eosinophilia, hypog- to be examined. lycemia, or fever. Hypercalcemia prevalence Patients with negative stool examinations due to adrenal insufficiency was 1.3% in may have tissue- or blood-dwelling helmin- maintenance HD patients on admission. The thic infections that require serologic tests for causes of adrenal insufficiency were isolated diagnosis as Trichinella spiralis, Wuchereria ACTH deficiency, pituitary apoplexy, pitui- bancrofti, Toxocara canis, Schistosoma sp., tary atrophy, glucocorticoid withdrawal syn- Echinococcus sp. (Plumelle et al, 1997). drome, & unilateral adrenalectomy. Serum Urine sedimentation can be considered for calcium levels corrected by serum albumin suspected Schistosoma haematobium or in were maximally increased to 12.9 to 14.3 the setting of chyluria due to W. bancrofti. mg/dL in four anuric HD patients and mildly Also, sputum analysis must be ordered for elevated to 10.4mg/dL in a patient with re- suspected pulmonary infection with Strongy- sidual diuresis. Basal serum cortisol levels loides sp. or Paragonimus sp. ranged from <1.0 to 15.4μg/dL. Single CRH The optimal management of asymptomatic injections failed to increase serum cortisol in traveler or immigrant with eosinophilia is any of the patients. Glucocorticoid replace- uncertain. Up to 50% of patients never have ment acutely normalized serum Ca and dec- a cause of their eosinophilia identified des- reased levels of carboxy-terminal telopep- pite exhaustive evaluation (Libman et al, tide of type I collagen, a marker of bone re- 1993). Others suggested a strategy of using sorption. They concluded that adrenal insuf- empiric anthelminthic therapies (Muennig et ficiency was an occult cause of hypercalce- al, 1999). mia in anuric HD critically ill patients Miscellaneous causes: 1- Adrenal insuffici- 2- Atheroembolic disease: Cholesterol emb- ency: The loss of endogenous glucocortic- olization could lead to an increased erythro- oids in any cause of adrenal insufficiency cyte sedimentation rate, hypocomplemente- results in blood eosinophilia. Glucocortico- mia, thrombocytopenia, eosinophilia, eosin- ids exert eosinopenic effects, at least in part ophiluria, renal insufficiency, livedo reticu- by stimulating eosinophil, but not neutron- laris, and/or purple toes (Wilson et al, 1991) phil, apoptosis (Meagher et al, 1996). The Blood eosinophilia might be the sole clinical presence of relative eosinophilia in critically clue to this disorder (Levine et al, 1992). ill patients was associated with clinical signs Murono et al. (2018) found that cholesterol of relative adrenal insufficiency. Among 612 crystal embolism (CCE) was caused by sma- consecutive admissions to a medical-surgi- ll cholesterol crystals dispersed from athero-

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sclerotic plaques of the aorta. There was an was identified in one patient with autosomal increasing in CCE because of increased use recessive HIES (Minegishi et al, 2006). In- of endovascular treatments. They reported fectious pulmonary complications was fatal an intestinal anastomotic stenosis as a rare in patients with HIE syndrome, followed by CCE case. Intestinal CCE was difficult to lymphoma. Pneumatoceles caused subseque- diagnose preoperatively and associated with nt pneumonia, systemic infection, and/or su- poor prognosis. When eosinophilia or shag- dden pulmonary hemorrhage. Vascular inva- gy aorta was observed, CCE must be suspec- sion by fungi raised mycotic aneurysms with ted to reach an accurate diagnosis and lungs and other organs hemorrhagic compli- reduce the recurrence risk. cations. Pneumatoceles colonise with fungi 3- Immunodeficiency states: Some primary & gram negative bacteria; including Asper- immunodeficiency syndromes are associated gillus fumigatus and Pseudomonas aerugi- with eosinophilia, including the hyper-IgE nosa (Freeman et al, 2007). syndrome; characterized by chronic derma- T cell negative, B cell negative, NK cell titis and re-current infections (Hochreutener positive severe combined immunodeficien- et al, 1991) and Omenn's syndrome; com- cy: An extreme form of severe combined bined immune-deficiency with hypereosino- immunodeficiency disease (SCID) is T cell philia (Schandené et al, 1993). Thymoma negative (T-), B cell negative (B-), natural was associated with bone marrow eosino- killer cell positive (NK+) SCID phenotype philia (Fitzmaurice and Gardner, 1990). A accounted for 20 to 30% of all SCID cases syndrome of recurrent staphylococcal absce- (Stephan et al, 1993). Children with T-B- sses, sinopulmonary infections, and severe NK+ SCID present early in life with serious eczema, initially called Job Syndrome, based infections, failure to thrive, low to absent T upon a description of the biblical character and B cell numbers & function, and normal Job: "so went Satan forth from the presence numbers and function of natural killer (NK) of the Lord and smote Job with sore boils cells. Defects in at least five autosomal re- from the sole of his foot unto his crown" cessive genes in man and one in animals, all (Job, II, 7). The cutaneous abscesses in involved in V(D)J recombination, resulted in patients appeared cold or, lacked the typical this form of SCID (Meek et al, 2001). Since inflammation signs. It was speculated that some of the proteins encoded by genes were immune defect in Job syndrome lay in an involved in DNA repair, defects in pathways abnormality in nonspecific mechanisms of were associated with radiation/chemothera local bacterial resistance and perhaps in ab- py sensitivity. Genetic mutations, both natu- normalities of mediators of acute inflamm- rally occurred and engineered, resulted in a atory response that was termed hyperimm- better known of this critical step in T & B unoglobulin E syndrome (HIES) when an cell maturation (van der, Burg et al, 2009). associated increase in serum levels of IgE No conditioning or immunosuppressive con- was described (Buckley et al, 1972). Also, ditioning alone (low cyclophosphamide) for elevated levels of serum IgE, there were in- initial HCT in children with non-RAG1 or termittent defects in polymorphonuclear leu- RAG2 types of T-B-NK+SCID) was a must. kocyte chemotaxis and associated immune Donor marrow 'boosts' or repeat BMT with regulatory defects. Dominant-negative muta- myeloablative conditioning must be reserved tions in the DNA-binding domain of signal for those with initial procedure results in in- transducer and activator of transcription 3 adequate T cell immune reconstitution or gr- (STAT3) caused the autosomal dominant aft failure (Kwan and Puck, 2015). form of hyperimmunoglobulin IgE synd- Conclusion rome (Holland et al, 2007). A homozygous An increase in eosinophils in blood occurs null mutation in tyrosine kinase 2 (TYK2) in response to some allergens, drugs, parasit-

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Table 1: Helminthic diseases causing marked eosinophilia (>3000/µL) after (Weller, 1991). Parasite Notes Angiostrongyliasis costaricensis Ascariasis Early transpulmonary larval migration, often absent when mature Hookworm infection Early transpulmonary larval migration, often mild when mature Strongyloidiasis, Trichinosis, Gnathostomiasis Visceral larva migrans Primarily in children Filaria Tropical pulmonary eosinophilia Especially in expatriates Loiasis, Onchocerciasis Schistosomiasis During early infection in non-immunes (Katayama fever) Fascioliasis, Fasciolopsiasis, Clonorchiasis, During early infection Paragonimiasis,

Table 2: Helminthtic diseases causing eosinophilia of years’ duration (Weller, 1992). Parasite Notes Hookworm infection Common cause of low-grade eosinophilia Strongyloidiasis Self-perpetuating, auto-infection cycle; may last >50 yrs. Cysticercosis, Echinococcosis, Gnathostomiasis Filaria Tropical pulmonary eosinophilia Especially in expatriates Loiasis, Onchocerciasis, Mansonelliasis, Schistoso- miasis, Fascioliasis, Clonorchiasis, Paragonimiasis

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