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Kody Coste
Blood eosinophilia is a common laboratory abnormality, and its characterization frequently represents a quandary for primary care physicians. Consequently, in France, specialists and particularly hematologists, often must investigate patients who present with blood eosinophilia that often, but not always, occurs because of allergic causes. Both the Departments of Hematology and Parasitology at Toulouse University Hospitals established a collaboration to rule out allergic causes of eosinophilia, particularly helminthiases, prior to initiating more sophisticated investigations.
Since 2004, the authors employed the same protocol to investigate eosinophilic outpatients who attended the clinic of Parasitology at Toulouse University Hospitals, and they reported the performance of this diagnostic procedure that was designed to be rapid (no hospitalization required) and only moderately expensive.
A total of 406 patients who presented with blood eosinophilia greater than 0.5 (109, giga cells per litter, G/L) had an allergic etiology in 350 (86.2%) cases. Among the remaining 56 subjects, 17 did not undergo a follow-up and 39 were referred to another specialized department, mostly Hematology. However, only 21 patients attended then were subsequently investigated. Non-allergic causes of eosinophilia, including 3 cases of the lymphoid variant of hypereosinophilic syndrome and 2 cases of myeloproliferative disorder, were identified in 14 patients, whereas 7 remained diagnosed as having idiopathic eosinophilia.
This study underlines the need to investigate patients presenting with even moderate blood eosinophilia. The work-up that was employed appears to be efficient and versatile and may be used by any medical specialist, such as in hematology, infectious disease, or internal medicine departments, who needs to investigate eosinophilic patients and should initially rule out any etiology of allergic eosinophilia.
Family physicians, as well as internists, pediatricians, and hematologists, can be presented with blood eosinophilia cases. Eosinophilia is a laboratory abnormality that is defined as a permanent increase in the number of circulating eosinophils above a generally accepted threshold of 0.5 G/L [1,2,3,4]. A more recent classification of eosinophilia has been proposed by an international working group [5] (Table 1).
Limited data are available regarding the prevalence of blood eosinophilia in the general population of Western countries. In British Columbia, 225 (0.12%) of 195,000 ambulatory outpatients who attended a large laboratory system displayed a blood eosinophil count that exceeded 0.7 G/L [8]. In Southwestern France, among 532 apparently healthy subjects who underwent a health check-up at a local Social Security center, 13 (2.44%) had a count greater than 0.6 G/L [9]. Secondary allergic causes are thought to account for the greatest proportion of eosinophilia cases because other etiologies appear to be uncommon. The overall prevalence of primary eosinophilia is unknown, although a crude estimate of the hypereosinophilic syndrome (HES) incidence in the USA was 0.035 per 100,000 individuals [10].
This investigation procedure constantly evolved and was improved but became stable by the mid-2000s. This present article details the finalized version and reports the results it yielded from eosinophilic outpatients who attended the clinic of the Department of Parasitology at Toulouse University Hospitals, where this procedure remains in use.
From January 2004 to December 2011, a total of 406 patients (181 females and 225 males) who presented with blood eosinophilia greater than 0.5 G/L were investigated by the same physician (JFM) according to the procedure described below. This cohort included 8 patients who were previously referred to the Department of Hematology by their personal physician, where non-allergic causes of eosinophilia had been ruled out.
We requested that the patient or the referring physician provided a full medical record to the consultant. This was particularly true for the laboratory results that provided, among other things, eosinophilia kinetics records.
In addition to the routine medical and surgical histories, the medical questionnaire probed for the existence of symptoms evocative of an allergic status, such as conjunctivitis, pruritus, sneezing, urticaria, and wheezing. An atopic phenotype could explain, for example, a slight eosinophilia that was permanent or transient during the pollen season. Great attention was paid to the presence of any drug therapy, chronic or recent, because numerous molecules have been recognized as eosinophilia-inducing agents [11]. For example, the frequently used cholesterol-lowering drugs, fibrates and statins, were associated with eosinophilia in 11% of 3,506 long-standing users [12]. Drug addiction was also ruled out, as cocaine or its derivatives may induce both peripheral and pulmonary eosinophilia [13].
Other very important risk factors for helminthiases were not overlooked, principally in patients born and residing in the European Union (EU) or in other westernized countries. Table 2 displays the full content of the questionnaire. Obviously, immigrants were asked about their country of origin. Regarding tourists in at risk areas, we have noticed in our consultative experience that people often forget about countries that they have visited more than a few years ago. We therefore questioned them about the first year they left the EU. This part of the history was of crucial importance because the information gleaned might orientate towards specific laboratory investigations and eventually provide circumstantial evidence in cases where a precise diagnosis might be difficult to establish.
Standard physical examinations were performed, which were systematically completed with two basic imaging studies, a chest radiograph (posterior-anterior and lateral views) and an abdominal ultrasonography. This step of the evaluation might yield decisive information. For example, pathognomonic findings, such as larva currens in strongyloidiasis, or Calabar swellings in loiasis, represent valuable clues about the allergic origin of the eosinophilia. Conversely, the discovery of enlarged cervical or mediastinal lymph nodes is suspicious for causes of non-allergic eosinophilia.
Urinalysis was carried out during the visit using a dipstick assay. Usually, proteinuria is absent in allergic eosinophilia, except in urinary schistosomiasis where it is often combined with hematuria, which was detected with multireagent strips. Conversely, proteinuria may accompany rare non-allergic syndromes associated with hypereosinophilia, such as eosinophilic granulomatosis with polyangiitis (EGPA) (Table 3).
Total immunoglobulin E (IgE) assay. A rise in total IgE levels in patients chronically infected by worms has been primarily reported in Ethiopian children with ascariasis [32] and in most helminthiases. The pathogenesis of this increase remains partially unknown.
Eosinophilia-inducing diseases other than helminthiases are not associated with an elevated total IgE value, apart from an allergic status in some multi-sensitized patients and, rarely, from L-HES [33] or hyper IgE syndrome [34]. Consequently, a result exceeding 1,000 kIU/L (5-fold higher than the upper limit of the normal range) is mostly an excellent indication of acute or chronic helminth infection (Table 3).
Global tests for in vitro specific IgE detection. Atopy is defined by a combination of clinical allergy signs, along with a moderate increase in total IgE counts between 200 and 400 kIU/L [35] and the presence of IgE specific for food or inhalant allergens [36]. A patient meeting these criteria is therefore likely to have mild and/or transient eosinophilia during the pollen season. Therefore, we systematically carried out a global in vitro test detecting specific IgE directed against a mixture of airborne or foodborne allergens [37]. It should be kept in mind that the allergy prevalence is high in westernized countries [38], regardless of age [39], and it is growing in tropical developing countries [40]. Therefore, an atopic status is at risk of being associated with more rare and stringent causes of eosinophilia. Moreover, an atopic status is also present in most L-HES cases [33] (Table 3).
Detection of specific anti-Aspergillus fumigatus IgE. This test was performed in patients with a history of asthma and/or patients presenting with wheezing on examination who were at risk of allergic bronchopulmonary aspergillosis [41] (Table 3).
Only metazoans (helminths and ectoparasites) and certain fungi, but not protozoans, can elicit eosinophilia. Only microscopy and serology were used in this work-up, as molecular methods for the detection of metazoan parasites were investigational by the time of the study (Table 3).
The well-known cellulose tape test for the detection of a pinworm infection [42] was very difficult to implement in our clinics or inpatients and was therefore not included in our panel of microscopic investigations.
A urinalysis was necessary in patients from areas endemic for urogenital schistosomiasis, which now includes Southwestern Europe [46]. We required that the full void, and not just a few milliliters of urine, should be scrutinized, particularly when hematuria is present [42].
Sputum examination for Paragonimus sp. eggs was carried out in subjects from any wet tropical area who presented with a chronic cough and/or chest radiography abnormalities consistent with tuberculosis [47].
During scabies, classical cutaneous signs are often accompanied by an intense pruritus and an erythematous papular eruption, which may come with peripheral blood eosinophilia [48]. Skin scraping followed by a microscopic examination for mites 42] was therefore performed in any eosinophilic patient complaining of itching.
First, it should be underlined that immunodiagnostic tests are a complement and not a substitute for microscopic methods. When an eosinophilic patient presented at our Consultation Board with a clinical picture that was highly suggestive of a given helminthiasis, for example, facial edemas during a trichinellosis outbreak, only the specific serodiagnosis was requested. Otherwise, we used an assay panel (Table 3) that was primarily designed for patients native to Western Europe, where certain helminthiases are only evaluated if their risk factors are identified. As urogenital schistosomiasis has emerged as an autochthonous disease in Western Europe [46], its specific serodiagnosis has been added in 2014 to this panel. Trichinellosis was checked if relevant risk factors were prevalent, e.g., using wild boar or horse meat or traveling outside the EU, as this zoonosis can present as an asymptomatic chronic eosinophilia, as observed in two outbreaks that occurred in 1998 in the Toulouse area [49]. For immigrants or travelers, we added an immunodiagnostic for filariases, including an ELISA for circulating Og4C3 antigens, which is a test that has dramatically improved the diagnosis of bancroftiasis [50] (Table 3).
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