BioMed Research International
Volume 2016 (2016), Article ID 4872473, 11 pages
http://dx.doi.org/10.1155/2016/4872473

Review Article

Strongyloides stercoralis Infection in Alcoholic Patients

Marcia C. A. Teixeira, Flavia T. F. Pacheco, Joelma N. Souza, Mônica L. S. Silva, Elizabete J. Inês, and Neci M. Soares

Faculdade de Farmácia, Universidade Federal da Bahia, 40170115 Salvador, BA, Brazil

Received 15 September 2016; Accepted 13 November 2016

Academic Editor: João S. Silva

Copyright © 2016 Marcia C. A. Teixeira et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

The course of Strongyloides stercoralis infection is usually asymptomatic with a low discharge of rhabditoid larva in feces. However, the deleterious effects of alcohol consumption seem to enhance the susceptibility to infection, as shown by a fivefold higher strongyloidiasis frequency in alcoholics than in nonalcoholics. Moreover, the association between S. stercoralis infection and alcoholism presents a risk for hyperinfection and severe strongyloidiasis. There are several possible mechanisms for the disruption of the host-parasite equilibrium in ethanol-addicted patients with chronic strongyloidiasis. One explanation is that chronic ethanol intake stimulates the hypothalamic-pituitary-adrenal (HPA) axis to produce excessive levels of endogenous cortisol, which in turn can lead to a deficiency in type 2 T helper cells (Th2) protective response, and also to mimic the parasite hormone ecdysone, which promotes the transformation of rhabditiform larvae to filariform larvae, leading to autoinfection. Therefore, when untreated, alcoholic patients are continuously infected by this autoinfection mechanism. Thus, the early diagnosis of strongyloidiasis and treatment can prevent serious forms of hyperinfection in ethanol abusers.

1. Introduction

Strongyloides stercoralis infection is prevalent in countries with tropical and subtropical climates and affects approximately 370 million people worldwide [1, 2]. The helminth has the ability to multiply within a host, regardless of the mode of exogenous contamination, due to the transformation of rhabditoid larvae into infective filariform larvae, leading to persistent infections. However, in most hosts, the course of parasitism remains quiescent with no significant morbidity. This parasite-host balance can be disrupted under conditions of impaired cellular immunity, resulting in the life-threatening strongyloidiasis condition [3]. Immunosuppressed patients with chronic strongyloidiasis are at high risk of developing serious complications, such as hyperinfection syndrome and the dissemination of the parasite to several organs, causing sepsis and even death. High risk groups for S. stercoralis infection and hyperinfection include patients under massive corticoid therapy, HTLV-1 coinfected individuals, and chronic alcoholics [4–6].

Many studies have demonstrated that chronic alcohol abuse predisposes an individual to S. stercoralis infection. In alcoholics with hepatic cirrhosis, the infection may evolve to hyperinfection and life-threatening strongyloidiasis. The high predisposition to S. stercoralis infection has been associated with poor hygiene practices, malnutrition, the impairment of protective immune responses induced by excessive alcohol intake, and increase in endogenous corticoid levels, favoring S. stercoralis autoinfection [5, 7].

Correct diagnoses, treatments, and clinical follow-ups of parasitological cures are essential because strongyloidiasis relapse events have often been observed in patients receiving improper treatment [8]. Despite the high prevalence of strongyloidiasis in endemic countries and an increasing number of fatal cases, the World Health Organization (WHO) did not include strongyloidiasis in its original list of 17 neglected tropical diseases. Therefore, the main purpose of this article is to review the association between strongyloidiasis and chronic alcoholism, including describing the organic changes induced by both pathologies; the adverse effects of alcohol that predispose an individual to S. stercoralis infection and hyperinfection; and the current diagnostic tools and therapies for strongyloidiasis.

2. Strongyloides stercoralis Infection and Strongyloidiasis

The Strongyloides stercoralis threadworm is a soil-transmitted nematode that resides in the small intestine of human hosts. The parasitic infection takes place when filariform larvae penetrate through the skin, usually of the feet, and migrate through the bloodstream to the lungs [9]. After ascending the respiratory tract to the oropharynx, larvae are swallowed and reach the duodenal mucosal crypts to grow into parthenogenetic females that produce embryonated-eggs. Thereafter, rhabditoid larvae hatch from the eggs and are excreted in feces. However, some larvae may transform into the filariform infective stage and penetrate the perirectal mucosa or skin, thereby reentering the circulatory system and starting the cycle again. Therefore, if not treated, because this is an autoinfection process, the host may remain in a chronic carrier state for decades [10].

Strongyloides stercoralis usually causes an asymptomatic infection and a small rhabditoid larvae load in feces [11]. However, hyperinfection and dissemination can occur in high risk groups, such as patients undergoing glucocorticoid therapy [12], patients coinfected with HTLV-1 [13] or HIV [14], lymphoma patients [15], and people with malnutrition [16] or with liver cirrhosis due to alcoholism [17].

The clinical manifestations of infection with S. stercoralis comprise a broad spectrum of signs and symptoms and can be divided into four clinical presentations: (a) acute strongyloidiasis, (b) chronic strongyloidiasis, (c) hyperinfection syndrome, and (d) disseminated disease. The clinical signs of acute strongyloidiasis are associated with the penetration of larva in the host and their passage through the lungs. Infected individuals may experience an itchy papular rash at the site of invasion. Depending on the number of larvae, their passage through the lungs can produce bronchospasm, coughing, and respiratory distress stemming from eosinophilic pneumonitis and leading to Loeffler syndrome, which is characterized by pulmonary infiltrations in chest radiographies and peripheral blood eosinophilia. When parthenogenetic females reach and colonize the intestinal mucosa, recurrent abdominal pain may occur sometimes resembling peptic ulcers [6, 18].

Chronic strongyloidiasis most frequently leads to an asymptomatic infection in immunocompetent individuals. Peripheral eosinophilia or elevated total IgE levels greater than 250 IU/mL may be observed in up to 75% of infected hosts [19], serving as a marker for differential diagnoses for travelers to or immigrants from endemic areas with high and persistent levels of eosinophilia [20]. In symptomatic patients with chronic diseases, nonspecific gastrointestinal manifestations, such as abdominal pain, vomiting, diarrhea, and constipation, may also be observed [11].

S. stercoralis hyperinfection is considered to be an enhanced form of autoinfection and is typically, but not always, a result of changes in the immune status [21]. In hyperinfection syndrome, signs and symptoms of increased larval migration appear: Larva Currens in the perianal region, recurrent asthma, and exacerbation of gastrointestinal symptoms, followed by the detection of large numbers of larvae in sputum and feces [22, 23]. Radiographs frequently demonstrate focal or bilateral interstitial infiltrates in lungs. A retrospective study analyzed the endoscopic findings of 25 patients, mostly being treated for HTLV-1 or under corticosteroid therapy. These patients presented with S. stercoralis hyperinfection before beginning parasitological treatments for strongyloidiasis and revealed mostly edematous and erythematous mucosa, intestinal mucosa erosion, white villi, stenosis, and hemorrhage [24]. Duodenitis, including villous atrophy and destruction and inflammatory cell infiltration, was more severe in patients whose duodenal biopsies were positive for larvae than in those with negative biopsies [24]. As described above, hyperinfection syndrome implies, as interpreted by many clinicians, the presence of signs and symptoms attributable to increased number of migrating larvae through intestinal tract and lungs. However, some patients may continuously excrete huge parasite loads in feces and remain asymptomatic, likely due to the protection afforded by high levels of specific IgE [25]. Independent of these symptoms, in hyperinfection, the larvae are located in organs which normally carry the infection cycle without spreading to ectopic locations [6, 22].

Disseminated infection indicates the migration of the larvae to organs away from the normal cycle path inside a host (i.e., the lungs and the intestine). Infective larvae can be found virtually in any organ or system, such as the central nervous system, lymph nodes, heart, pancreas, kidneys, ovaries, and skeletal muscles, as indicated by clinical manifestations [26]. Large numbers of larvae penetrating through the intestinal wall may carry bacteria into the bloodstream and result in systemic infections, which may occur even during hyperinfection. The disseminated strongyloidiasis is often fatal, because of its rapid evolution and late diagnoses [3].

3. Epidemiology of Strongyloidiasis and Association with Alcoholism

Strongyloidiasis has a wide geographic distribution especially in populations of developing countries of tropical and subtropical areas. Various factors can influence S. stercoralis prevalence, including the integrity of immunity, socioeconomic status, sanitary and hygiene conditions of individuals, the level of heat and humidity, which affect parasite development in soil [27, 28], and the laboratory methods used for diagnosis [29, 30]. The prevalence of strongyloidiasis in a population can be divided into three categories: sporadic (<1%), endemic (1–5%), and hyperendemic (>5%) [31].

According to a systematic review based on published Strongyloides infection rates and taking into account the sensitivity of the used diagnostic methods, the prevalence of Strongyloides in Africa varied from 0.1% in the Central African Republic to up to 91.8% in Gabon. In South America and Central America, Haiti reported a prevalence of 1.0%, while in Peru the infection rate was as high as 75.3%. In Cambodia, the infection rate was 17.5%, whereas in Thailand, the rate was 23.7% and in Lao PDR, the rate was 26.2% [29]. Brazil is considered a hyperendemic country with 5.5% of S. stercoralis infection in general population and 11.8% in immunosuppressed individuals, considering the parasitological diagnosis [32]. Moreover, there are areas of low endemicity in western European countries (France, Italy, and Switzerland), Eastern Europe (Poland and areas of the former Soviet Union), the United States (Appalachia and southern states), Japan (Okinawa), and Australia (Aboriginal people) [29, 33, 34].

In patients who chronically use alcohol, the prevalence of infection by S. stercoralis is usually high, ranging from 20.5% to 40.2% [5, 7, 17, 35]. A study conducted in Brazil showed a 33.3% infection frequency in alcoholic patients. This value was even higher (44.4%) in patients with liver cirrhosis, whereas only 5.5% of nonalcoholic individuals were infected [35]. The amount of alcohol intake was proportional to the increased infection frequency, reaching 48% in patients who drank more than 450 g of alcohol per day [5]. Moreover, 40.2% of patients with liver cirrhosis of alcoholic etiology treated in a university hospital of Brazil had S. stercoralis infection [17]. Another interesting study conducted in Brazil showed that, in a group of 100 patients with HIV/AIDS, 12% were infected with S. stercoralis and of these, 64.3% were chronic alcoholics [14], suggesting a synergism between the susceptibility factors. In addition, a recent meta-analysis of three case-control studies showed an association between alcoholism and S. stercoralis infection with a significant increase in the risk of infection in alcoholics (OR: 6.69; CI: 1.47 to 33.8) [29]. Conversely, a study in Costa Rica found a lower rate of 5.7% (6/106) of S. stercoralis infection in alcoholic patients when compared with the frequencies found in Brazil. However, the rate of infection in the entire Costa Rica population was 0.1%, indicating that alcoholics were four to five times more susceptible to S. stercoralis infection [36], as observed in Brazilian studies. In fact, our group reported an occurrence of 23.5% of S. stercoralis infection in alcoholics from the Brazilian Northeast [37].

There are also case reports that have shown the association between alcoholism and S. stercoralis infection. A patient attended by our laboratory without gastrointestinal or pulmonary symptoms presented with very intense anemia and a high discharge of Strongyloides larvae in his stool. He was not under glucocorticoid therapy and tested negative for HTLV and HIV but had a history of alcohol addiction for more than 20 years [25]. Another case described a colitis caused by S. stercoralis in a woman dependent on alcohol and without the HTLV-1 virus. The patient had been infected for 27 years with worsening chronic strongyloidiasis due in part to the impairment of her cellular immune response resulting from the chronic use of alcohol and malnourishment [38].

In immunocompromised patients, including alcohol addicts, chronic strongyloidiasis may persist for decades. Additionally, due to the autoinfection mechanism of the parasite, chronic strongyloidiasis may result in hyperinfection and spread to other organs [6, 18, 25]. Despite the fact that alcoholism is one of the conditions observed in patients with S. stercoralis hyperinfection, only in the past decade controlled studies showed that strongyloidiasis is more frequent in alcoholic than nonalcoholic patients [7, 35].

Of the factors contributing to the high susceptibility to S. stercoralis infection, the poor hygiene of alcoholics promotes heteroinfection in environments with inadequate sanitary conditions and autoinfection by larvae present in fecal residue on the perianal skin [5]. Another factor that contributes to high infection rates could be attributed to reductions in gastrointestinal transit, which are caused by the effects of ethanol on intestinal muscle proteins or on vagal stimulation [39, 40]. Because the reduced intestinal motility enables the rhabditoid larvae to mature to the filariform infective stage, the risk of autoinfection is increased. Other authors have also emphasized that the dysregulation of the immune system caused by excessive ethanol intake may promote the survival of the parasite and autoinfection by increasing the endogenous production of corticosteroids [7, 35]. Ethanol intoxication has been shown to activate the HPAaxis, which elevates corticosteroids levels [41–44], which in turn suppresses T-cell function and decreases intestinal immunity [45, 46]. Alcoholics may also present reduced numbers of macrophages in the duodenal mucosa and deficiencies in IgA secretion, which could be partially responsible for the high incidence of S. stercoralis intestinal infections [47, 48]. A schematic figure with the suggested mechanisms for higher predispositions of ethanol-addicted individuals for strongyloidiasis is presented in Figure 1.

Figure 1: Factors associated with increased Strongyloides stercoralis infection and hyperinfection susceptibility in alcoholics.

4. Immune Response to S. stercoralis and Immunity Alterations Induced by Chronic Alcohol Intake

As in most helminth infections, the dominant cellular immune response to S. stercoralis is Th2. The IL-4 and IL-5 interleukins stimulate the production of IgE, which in turn induces mast cell degranulation and mucus secretion by goblet cells [49]. Peristalsis induced by IL-4 and IL-13 with the mucus facilitates the expulsion of the helminths, while toxic granules released by mast cells can cause direct damage to the parasite [50]. Moreover, IL-4 and IL-5 promote the activation of eosinophils, which plays an important role in host defense. Eosinophils are not only directly involved in the innate immune response against helminth larvae but are also involved in the adaptive immune response [49, 51, 52]. They act as antigen-presenting cells and increase the production of Th2 cytokines, such as IL-4, IL-5, and IL-13, and, consequently, the production of specific antibodies IgE, IgG, and IgM that eliminate the parasite [51, 53, 54]. Furthermore, the degranulation of eosinophils on the surface of the parasite through antibody-dependent cellular cytotoxicity (ADCC) results in the release of toxic molecules that induce the removal of helminth [55].

In patients infected with S. stercoralis, eosinophilia can be more frequent than in other parasite infections. This phenomenon is caused by the habitation of parthenogenetic females in the intestinal submucosa and not in the lumen, which results in a more intense eosinophilic reaction [2, 56]. The eosinophil-dependent mechanisms are also involved in filarial larvae killing of Strongyloides [57, 58]. Therefore, the absence of eosinophils is a poor prognostic indicator for infection by S. stercoralis, particularly for immunocompromised patients [59].

The role of antibodies in protective immune responses against S. stercoralis has been demonstrated in the passive transfer of anti-S. stercoralis antibodies to naïve animals [60]. Furthermore, the humoral immune response plays an important role in autoinfection control because IgA antibodies limit the amount of secreted larvae presumably by inhibiting the fecundity of the parthenogenetic female and the viability of eggs. The binding of IgE to effector cell receptors, especially those of mast cells and basophils, induces degranulation and the release of inflammatory mediators, which lead to the death and expulsion of the worm. In addition, the binding of IgE to mast cells present in the intestine releases sulfated proteoglycans, which not only hamper the establishment of S. stercoralis in the intestinal epithelium but also stimulate muscle contraction. These mechanisms contribute to the expulsion of the intestinal parasite [58, 61, 62]. Conversely, IgG4 can block the IgE-mediated immune response, contributing to the persistence of asymptomatic strongyloidiasis [63]. Strongyloides infection can also stimulate regulatory T cells (T reg), an escape mechanism of the parasite, which suppresses the protective immune response, such as the eosinophil-dependent activation by IL-5 [64].

Current medical literature recognizes that excessive alcohol use is associated with reduced host defense, including antimicrobial defense, antiviral immunity, and altered host repair [65–67]. Alcohol leads to the stimulation of the HPA axis and produces excessive levels of cortisol [68]. There is high correlation between the neuroendocrine and immune systems, especially in the sensitivity of the immune system to stress and its interaction with the HPA axis. This interaction was principally revealed by the immunosuppressive actions of glucocorticoids, especially cortisol, which can affect the transcription of numerous inflammatory molecules [68]. This interaction between the HPA axis and the immune system is crucial for body homeostasis; however, in alcohol abuse conditions, the equilibrium of this interaction is compromised. At excessive quantities, glucocorticoids have serious adverse effects due to their immunosuppressive action and metabolic abnormalities [69, 70]. Moreover, glucocorticoids upregulate IL-18, which enhances myeloperoxidase activity and alters the intestinal barrier function [71]. Neutrophils may also play a role in increasing intestinal permeability in both acute and chronic ethanol intoxication [45, 72]. The IL-18-mediated increase in chemokines and adhesion molecules likely causes intense neutrophil accumulation in the intestinal tissue, contributing to the impairment of intestinal immunity [45, 71].

The strong association between high alcohol use and heightened cortisol levels also indirectly contributes to S. stercoralis autoinfection. Hydrocortisone, or cortisol, is a corticosteroid hormone produced by the cortex of adrenal glands directly involved in stress response. Corticosteroids produce metabolites that resemble hydroxyecdysone (Figure 2), an ecdysteroid hormone that regulates the fertility of parthenogenetic S. stercoralis females, induces the transformation of rhabditiform to infective filariform larvae, and increases the rate of autoinfection [8, 18, 25]. The presence of a steroid receptor on S. stercoralis could be involved in the pathogenesis of hyperinfection syndrome and disseminated strongyloidiasis [18, 73]. The cortisol metabolites could bind to this receptor and exacerbate the transformation of rhabditoid larvae to the filarial stage. This action leads to the invasion of the intestinal mucosa, resembling the autoinfection mechanism observed in patients under massive corticosteroid therapy [73, 74]. In fact, we have recently observed that high endogenous cortisol levels in alcoholic patients may not be associated with susceptibility to S. stercoralis infection; however, once infected, this may lead to a high parasite load [37].

(a)

(b)

Figure 2: Chemical structure of cortisol (a) and ecdysone (b). Adapted from Wikipedia.

In contrast to the inhibitory effects of acute alcohol ingestion, prolonged alcohol intake results in increased macrophage TNF-α production and the activation of the inflammatory cascade [75, 76]. In alcoholic hepatitis, a disease resulting from chronic alcohol intake, the levels of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, are highly elevated [77]. The highest TNF-α levels were correlated with liver dysfunction. However, light-to-moderate drinking had no significant effect on the levels of serum TNF-α [78].

There are two proposed mechanisms by which chronic alcohol use can induce inflammation: (1) gut microflora-derived lipopolysaccharides (LPS), which act as key players in alcohol-mediated inflammation [79] and alcohol metabolism through the production of reactive oxygen species (ROS), and (2) cell damage, which initiates the production of proinflammatory cytokines, such as TNF-α and IL-6 [80]. Regarding cytokine production, one possible mechanism is an increase in the TLR4 stimulation-induced proinflammatory cytokine production and NF-kB activation [75]. However, during the overactivation of monocytes, such as during the combined stimulation of TLR2 and TLR4, proinflammatory cytokine production can be increased even with acute alcohol ingestion [75]. A few studies have demonstrated that both acute and chronic alcohol consumption enhanced the expression of anti-inflammatory cytokines [76, 81].

Acute and chronic alcohol exposure can interfere with several aspects of the adaptive immune response [82]. Acute alcohol intoxication impairs the antigen-presenting ability and differentiation of dendritic cells (DC). This effect is more potent in affecting antigen presentation and antigen-specific T-cell activation than in monocytes or macrophages [83]. The alcohol-induced defects in DC functions include reduced levels of CD80 and CD86 on the cell surfaces (essential to induce activation of T cells) and decreased production of IL-12 (critical for stimulating naïve CD4⁺ T cells to develop into Th1 cells) [82]. Thus, acute alcohol intake may inhibit the Th1 immune response and may predispose the host organism to Th2 responses. The suppression of IL-12 seems to be partially responsible for this shift [82]. The activation of Th2 as an anti-inflammatory response seems to coincide with the cytokine expression profiles observed during acute alcohol intake. It is expected that during chronic alcohol use, a Th1 response dominates over a Th2 response. Therefore, the hyperinfection of S. stercoralis in chronic alcoholics could be explained by the same mechanism observed in the S. stercoralis-HTLV-1 coinfection. The shift from Th2 to Th1 immune responses resulted in decreased levels of IL-4, IL-5, IL-13, and IgE and the synergistic severity of the disease [84]. Another possible mechanism for the impaired Th2 response in alcoholics may be associated with Th2 cell apoptosis induced by increased endogenous glucocorticoid levels, leading to S. stercoralis hyperinfection [74]. However, it was demonstrated that chronic alcoholics have elevated levels of IgE, a typical immunoglobulin involved in Th2 response [85]. Therefore, further studies are needed to clarify the mechanisms of immune response in alcoholic individuals coinfected with S. stercoralis.

5. S. stercoralis Diagnosis and Treatment

The clinical diagnosis of strongyloidiasis is presumptive because the signs and symptoms are nonspecific and can be confused with those of other intestinal parasitosis [86]. Currently, laboratory diagnoses are routinely performed to identify rhabditoid larvae in feces. However, in most cases, the parasite load is low and the shedding of larvae is intermittent, which can interfere with the efficiency of parasitological methods [87, 88]. Therefore, to increase the sensitivity of parasitological examination, at least three stool samples must be analyzed on alternate days using different diagnostic methods [89–91]. However, the repeated delivery of samples to the laboratory may be inconvenient for patients due to distances between residences and the laboratory and extended travel times. Because of these factors, a sufficient number of samples are not always examined.

Several parasitological methods are used for the detection of S. stercoralis larvae in feces, such as the Baermann-Moraes [92], Harada-Mori filter paper culture [93], agar plate culture (CPA) [94], TF-Test® [95], and formol-ether concentration techniques [96]. In these methods, several technical factors can alter the sensitivity of strongyloidiasis diagnosis, for example, sample homogenization, stool processing delays, erroneous morphological differentiations from nematode larvae, and inadequate numbers or preservation of samples [97]. The Baermann-Moraes is inexpensive and simple to perform and one of the most used parasitological methods for nematode larva identification in routine laboratories; however, it is less sensitive than the CPA technique [98–100]. Additionally, CPA allow the differential diagnosis between species of S. stercoralis and hookworms based on the type of migration paths (furrows) left by the larvae in agar plates [100].

Due to the limitations of parasitological methods, the use of more sensitive immunological tests is critical for the diagnosis of strongyloidiasis. ELISAs are the most widely used immunodiagnostic methods and have shown sensitivities and specificities above 70.0%, depending on the screened antigen and antibody isotype [101–104]. However, because of difficulties in the production and the standardization of antigens capable of providing reproducible results, the use of ELISAs remains limited [30]. Uncertainties regarding positive reactions may occur in cases of hidden strongyloidiasis (i.e., low parasite burdens), immunological memory of past infections, or the presence of similar antigens among helminths [104]. In fact, the presence of cross-reactivity with other helminths is considered to be one of the most important limitations in strongyloidiasis immunoassays [101, 105], especially in endemic countries. Conversely, in areas where the infection is uncommon, the detection of specific antibodies is more reliable.

In a recent study, the diagnosis of strongyloidiasis by IgE-ELISA, using as antigen the “strongylastacin,” an enzyme secreted by infective larvae of S. stercoralis, showed high sensitivity and high specificity [106]. The detection of IgA anti-S. stercoralis can also aid in the diagnosis of strongyloidiasis [107], especially in patients without excretion of rhabditoid larvae in feces. Due to the immunomodulation of IgA during infections, the results of stool tests are usually negative [63]. The suggested mechanisms by which IgA modulates the removal of host larvae include reductions of female fertility and of the intensity of the autoinfection [108]. ELISAs can also be applied for the detection of S. stercoralis antigens in stool samples (coproantigen), even though these tests have not yet been standardized [109, 110].

Other immunoassays, such as western blots, can be used to confirm strongyloidiasis diagnoses in cases of discordant serological tests or negative parasitological samples. Silva et al. [105] demonstrated that 96.0% of sera from patients with strongyloidiasis recognized immunodominant antigens of Strongyloides ratti. According to western blots, the sera from infected patients can recognize different molecular antigenic patterns. For instance, Sato et al. [111] revealed four antigens with molecular weights of 97, 66, 41, and 26 kDa; Ravi et al. [112] described a 38 kDa molecule and Sudré et al. [113] identified 26 and 33 kDa immunodominant molecules. However, no consensus or agreement in the literature has been reached regarding immunodominant S. stercoralis molecular patterns that can be used as standardized references for the diagnosis of strongyloidiasis.

Polymerase chain reaction (PCR) assays are also considered to be sensitive and specific method for the diagnosis of S. stercoralis [114, 115]. However, as in the parasitological analysis of feces, PCR assays depend on the shedding of larvae, which only occurs on an intermittent basis. Moreover, PCR assays are expensive and require skilled labor and complex infrastructure not commonly used in routine clinical laboratories, especially in those of endemic areas.

Eosinophilia has also been considered as a nonspecific laboratory marker for the screening of chronic strongyloidiasis, especially for asymptomatic individuals from endemic areas [27, 116, 117]. The location of parthenogenetic females in intestinal mucosa and larvae transit through tissues, especially the lungs, stimulate immune responses mediated by eosinophils [2, 56].

Despite the several existing strongyloidiasis diagnosis methods, there remains no ideal standard tool. A reliable diagnosis is particularly important for patients from endemic areas, especially those in groups at higher risk of developing hyperinfection or disseminated strongyloidiasis.

Due to the autoinfection process, all patients should be treated to prevent the development of strongyloidiasis severe cases. Albendazole, thiabendazole, and ivermectin have been used as therapeutic agents for strongyloidiasis. For many years, thiabendazole was the treatment of choice. However, the use of the drug was associated with unpleasant side effects, such as nausea, vomiting, malaise, and neuropsychiatric symptoms, and is no longer available in some countries [118–120]. Albendazole, another benzimidazole compound with board-spectrum anthelmintic activity, remains widely used for strongyloidiasis treatment in some countries where oral ivermectin is not yet available [119, 121]. However, the efficacy of albendazole in S. stercoralis treatment is inconsistent, especially for hyperinfection risk groups [8, 122–124].

Currently, ivermectin seems to provide the best outcomes for treating S. stercoralis and is strongly recommended for severe cases, such as hyperinfection and disseminated disease. Ivermectin—a member of a family of macrolytic lactones, the avermectins—has broad spectrum activity against parasites. It binds to glutamate-gated chloride ion channels, which are present in invertebrate nerve and muscle cells, and causes paralysis and death of the parasite. It does not easily cross the blood-brain barrier in humans and has a low affinity for mammalian ligand-gated chloride channels [125]. Ivermectin demonstrated better efficacy than albendazole and had less adverse effects than thiabendazole. Moreover, adverse reactions after ivermectin treatment are rarely experienced, transient, and well tolerated [119, 122, 126].

The administration of two single doses of 200 μg/kg ivermectin given two weeks apart is more suitable for treating chronic strongyloidiasis than a single dose [120, 127]. In immunocompromised patients, to prevent the recurrence of hyperinfection syndrome, two doses of ivermectin are administered every two weeks, for six weeks [128]. Thereafter, patients with hyperinfection require follow-up stool exams. These exams use highly sensitive diagnostic methods and are performed for 2–4 weeks to confirm the clearance of the infection because the internal parasite development cycle is a two-week long process [128–130]. In patients presenting with stool examinations positive for Strongyloides or persistent symptoms, if a recrudescence of larvae is observed, retreatment is indicated.

6. Conclusion

Chronic alcoholism can cause damage to a patient, including adverse effects in the gastrointestinal tract and the immune system. These effects may render patients more susceptible to parasitic infections. Studies have demonstrated a higher frequency of Strongyloides stercoralis in chronic alcoholics when compared with nonalcoholics. This phenomenon has been attributed to the breakdown of local protective barriers, higher exposure to pathogens, malnutrition, endogenous production of corticosteroids, and alterations to host immune defense mechanisms.

Although many hypotheses have been raised, due to the multifactorial pathogenic effects induced by alcohol, the specific mechanism or group of mechanisms involved in the high susceptibility of alcoholics to S. stercoralis infection and hyperinfection are not completely understood. Further studies with large numbers of alcoholic patients, infected and noninfected with S. stercoralis, should be conducted. These studies should focus on cortisol levels, local and systemic immune responses to parasites, mucosa alterations, and estimations of parasite loads.

In high risk groups, such as patients with chronic alcoholism, the diagnosis of strongyloidiasis should be performed using more sensitive parasitological methods, such as with agar plate cultures, combined with an immunological test for the detection of anti-S. stercoralis antibodies. The recommended treatment is ivermectin, even in the absence of symptoms, due to possibility of autoinfection and the development of severe cases of hidden strongyloidiasis.

Additional Points

Chronic alcoholism is a risk factor that leads to strongyloidiasis infection and hyperinfection. Regular ethanol intake may lead to an immune modulation or alteration in corticosteroid metabolism, favoring S. stercoralis autoinfection. Both chronic ethanol addiction and S. stercoralis hyperinfection can significantly damage the intestinal mucosa. The shedding of large numbers of larva may synergistically act with alcohol in eroding the mucosal layer and cause blood loss in the intestine, leading to malabsorption. Early diagnoses and treatments of strongyloidiasis in alcoholic patients are essential in endemic areas to prevent hyperinfection and the dissemination of the parasite.

Competing Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ Contributions

Marcia C. A. Teixeira, Joelma N. Souza, Flavia T. F. Pacheco, and Mônica L. S. Silva performed the literature review and wrote the paper; Elizabete J. Inês and Neci M. Soares provided expertise in the diagnosis of Strongyloides and critical revision of the manuscript.

References

D. Greaves, S. Coggle, C. Pollard, S. H. Aliyu, and E. M. Moore, “Strongyloides stercoralis infection,” BMJ (Online), vol. 347, article f4610, 2013.

A. Requena-Méndez, P. Chiodini, Z. Bisoffi, D. Buonfrate, E. Gotuzzo, and J. Muñoz, “The laboratory diagnosis and follow up of strongyloidiasis: a systematic review,” PLoS Neglected Tropical Diseases, vol. 7, no. 1, Article ID e2002, 2013.

C. S. Lam, M. K. H. Tong, K. M. Chan, and Y. P. Siu, “Disseminated strongyloidiasis: a retrospective study of clinical course and outcome,” European Journal of Clinical Microbiology & Infectious Diseases, vol. 25, no. 1, pp. 14–18, 2006.

D. Buonfrate, A. Angheben, F. Gobbi et al., “Imported strongyloidiasis: epidemiology, presentations, and treatment,” Current Infectious Disease Reports, vol. 14, no. 3, pp. 256–262, 2012.

C. C. Marques, M. D. P. Zago-Gomes, C. S. Gonçalves, and F. E. L. Pereira, “Alcoholism and Strongyloides stercoralis: daily ethanol ingestion has a positive correlation with the frequency of Strongyloides larvae in the stools,” PLoS Neglected Tropical Diseases, vol. 4, no. 6, article no. e717, 2010.

P. B. Keiser and T. B. Nutman, “Strongyloides stercoralis in the immunocompromised population,” Clinical Microbiology Reviews, vol. 17, no. 1, pp. 208–217, 2004.

M. P. Zago-Gomes, K. F. Aikawa, S. F. Perazzio, C. S. Gonçalves, and F. E. Pereira, “Prevalence of intestinal nematodes in alcoholic patients,” Revista da Sociedade Brasileira de Medicina Tropical, vol. 35, no. 6, pp. 571–574, 2002.

J. N. De Souza, P. R. L. Machado, M. C. A. Teixeira, and N. M. Soares, “Recurrence of strongyloides stercoralis infection in a patient with Hansen's disease: a case report,” Leprosy review, vol. 85, no. 1, pp. 58–62, 2014.

H. O. Dada-Adegbola, O. A. Oluwatoba, and R. A. Bakare, “Strongyloidiasis: prevalence, risk factors, clinical and laboratory features among diarrhea patients in Ibadan Nigeria,” African Journal of Medicine and Medical Sciences, vol. 39, no. 4, pp. 285–292, 2010.

V. Prendki, P. Fenaux, R. Durand, M. Thellier, and O. Bouchaud, “Strongyloidiasis in man 75 years after initial exposure,” Emerging Infectious Diseases, vol. 17, no. 5, pp. 931–932, 2011.

D. I. Grove, “Human strongyloidiasis,” Advances in Parasitology, vol. 38, pp. 251–309, 1995.

L. B. Lemos, Z. Qu, R. Laucirica, and H. L. Fred, “Hyperinfection syndrome in strongyloidiasis: report of two cases,” Annals of Diagnostic Pathology, vol. 7, no. 2, pp. 87–94, 2003.

M. A. F. Porto, A. Muniz, J. Jr. Oliveira, and E. M. Carvalho, “Clinical and immunological consequences of the association between HTLV-1 and strongyloidiasis,” Revista da Sociedade Brasileira de Medicina Tropical, vol. 35, no. 6, pp. 641–649, 2002.

C. V. da Silva, M. S. Ferreira, A. S. Borges, and J. M. Costa-Cruz, “Intestinal parasitic infections in HIV/AIDS patients: experience at a teaching hospital in central Brazil,” Scandinavian Journal of Infectious Diseases, vol. 37, no. 3, pp. 211–215, 2005.

A. Safdar, K. Malathum, S. J. Rodriguez, R. Husni, and K. V. I. Rolston, “Strongyloidiasis in patients at a comprehensive cancer center in the United States: a retrospective study covering the years 1971–2003,” Cancer, vol. 100, no. 7, pp. 1531–1536, 2004.

H. Dada-Adegbola and R. Bakare, “Strongyloidiasis in children five years and below,” West African Journal of Medicine, vol. 23, no. 3, pp. 194–197, 2004.

D. Gaburri, A. K. Gaburri, E. Hubner et al., “Intestinal parasitosis and hepatic cirrhosis,” Arquivos de Gastroenterologia, vol. 34, no. 1, pp. 7–12, 1996.

L. A. Marcos, A. Terashima, M. Canales, and E. Gotuzzo, “Update on strongyloidiasis in the immunocompromised host,” Current Infectious Disease Reports, vol. 13, no. 1, pp. 35–46, 2011.

C. L. Rossi, E. E. H. Takahashi, C. D. Partel, L. G. V. L. Teodoro, and L. J. da Silva, “Total serum IgE and parasite-specific IgG and IgA antibodies in human strongyloidiasis,” Revista do Instituto de Medicina Tropical de São Paulo, vol. 35, no. 4, pp. 361–365, 1993.

G. G. Baaten, G. J. Sonder, T. van Gool, J. A. Kint, and A. van den Hoek, “Travel-related schistosomiasis, strongyloidiasis, filariasis, and toxocariasis: the risk of infection and the diagnostic relevance of blood eosinophilia,” BMC Infectious Diseases, vol. 11, article no. 84, 2011.

R. N. Husni, S. M. Gordon, D. L. Longworth, and K. A. Adal, “Disseminated Strongyloides stercoralis infection in an immunocompetent patient,” Clinical Infectious Diseases, vol. 23, no. 3, article 663, 1996.

R. Mejia and T. B. Nutman, “Screening, prevention, and treatment for hyperinfection syndrome and disseminated infections caused by Strongyloides stercoralis,” Current Opinion in Infectious Diseases, vol. 25, no. 4, pp. 458–463, 2012.

L. D. Corte, M. V. S. da Silva, and P. R. M. Souza, “Simultaneous larva migrans and larva currens caused by Strongyloides stercoralis: a case report,” Case Reports in Dermatological Medicine, vol. 2013, Article ID 381583, 3 pages, 2013.

K. Kishimoto, A. Hokama, T. Hirata et al., “Endoscopic and histopathological study on the duodenum of Strongyloides stercoralis hyperinfection,” World Journal of Gastroenterology, vol. 14, no. 11, pp. 1768–1773, 2008.

M. C. A. Teixeira, E. J. Inês, F. T. F. Pacheco et al., “Asymptomatic strongyloides stercoralis hyperinfection in an alcoholic patient with intense anemia,” Journal of Parasitology, vol. 96, no. 4, pp. 833–835, 2010.

A. Basile, S. Simzar, J. Bentow et al., “Disseminated Strongyloides stercoralis: hyperinfection during medical immunosuppression,” Journal of the American Academy of Dermatology, vol. 63, no. 5, pp. 896–902, 2010.

C. D. Ericsson, R. Steffen, A. A. Siddiqui, and S. L. Berk, “Diagnosis of Strongyloides stercoralis infection,” Clinical Infectious Diseases, vol. 33, no. 7, pp. 1040–1047, 2001.

A. Hall, D. J. Conway, K. S. Anwar, and M. L. Rahman, “Strongyloides stercoralis in an urban slum community in Bangladesh: factors independently associated with infection,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 88, no. 5, pp. 527–530, 1994.

F. Schär, U. Trostdorf, F. Giardina et al., “Strongyloides stercoralis: global distribution and risk factors,” PLoS Neglected Tropical Diseases, vol. 7, no. 7, Article ID e2288, 2013.

F. M. De Paula, E. De Castro, M. D. R. D. F. Gonçalves-Pires, M. D. G. Marçal, D. M. B. Campos, and J. M. Costa-Cruz, “Parasitological and immunological diagnoses of strongyloidiasis in immunocompromised and non-immunocompromised children at Uberlândia, state of Minas Gerais, Brazil,” Revista do Instituto de Medicina Tropical de Sao Paulo, vol. 42, no. 1, pp. 51–55, 2000.

M. L. Pires and G. Dreyer, “Revendo a importancia do Strongyloides stercoralis,” Revista do Hospital das Clínicas Faculdade de Medicina Universidade de Sao Paulo, vol. 48, pp. 175–182, 1993.

F. M. Paula and J. M. Costa-Cruz, “Epidemiological aspects of strongyloidiasis in Brazil,” Parasitology, vol. 138, no. 11, pp. 1331–1340, 2011.

S. Puthiyakunnon, S. Boddu, Y. Li et al., “Strongyloidiasis—an insight into its global prevalence and management,” PLoS Neglected Tropical Diseases, vol. 8, no. 8, Article ID e3018, 2014.

A. Miller, M. L. Smith, J. A. Judd, and R. Speare, “Strongyloides stercoralis: systematic review of barriers to controlling strongyloidiasis for Australian indigenous communities,” PLoS Neglected Tropical Diseases, vol. 8, no. 9, p. e3141, 2014.

L. C. Marques De Oliveira, C. T. Ribeiro, D. De Melo Mendes, T. C. Oliveira, and J. M. Costa-Cruz, “Frequency of Strongyloides stercoralis infection in alcoholics,” Memorias do Instituto Oswaldo Cruz, vol. 97, no. 1, pp. 119–121, 2002.

L. Avendaño, F. Hernandez, F. Jimenez, A. Avila, and D. Castro, “Strongyloides stercoralis en pacientes alcohólicos,” Parasitología al día, vol. 23, no. 3-4, 1999.

M. L. S. Silva, E. J. Inês, A. B. S. Souza et al., “Association between Strongyloides stercoralis and cortisol in alcoholic patients,” Acta Tropica, vol. 154, pp. 133–138, 2016.

A. O. Lashof, W. J. Lesterhuis, G. Wanten, P. Beckers, and M. Keuter, “Colitis in an alcohol-dependent woman,” The Lancet, vol. 369, no. 9578, p. 2050, 2007.

G. Addolorato, E. Capristo, G. Gasbarrini, and G. F. Stefanini, “Depression, alcohol abuse and orocaecal transit time,” Gut, vol. 41, no. 3, pp. 417–418, 1997.

M. Wegener, J. Schaffstein, U. Dilger, C. Coenen, B. Wedmann, and G. Schmidt, “Gastrointestinal transit of solid-liquid meal in chronic alcoholics,” Digestive Diseases and Sciences, vol. 36, no. 7, pp. 917–923, 1991.

J. F. Thayer, M. Hall, J. J. Sollers III, and J. E. Fischer, “Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: evidence for impaired inhibitory control of the HPA axis in heavy drinkers,” International Journal of Psychophysiology, vol. 59, no. 3, pp. 244–250, 2006.

M. A. Choudhry, N. Fazal, M. Goto, R. L. Gamelli, and M. M. Sayeed, “Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 282, no. 6, pp. G937–G947, 2002.

F. A. László, C. Varga, I. Pávó et al., “Vasopressin pressor receptor-mediated activation of HPA axis by acute ethanol stress in rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 280, no. 2, pp. R458–R465, 2001.

K. Ogilvie, S. Lee, B. Weiss, and C. Rivier, “Mechanisms mediating the influence of alcohol on the hypothalamic-pituitary-adrenal axis responses to immune and nonimmune signals,” Alcoholism: Clinical and Experimental Research, vol. 22, no. 5, pp. 243S–247S, 1998.

M. A. Choudhry, X. Li, and I. H. Chaudry, “A role for corticosterone in impaired intestinal immunity and barrier function in a rodent model of acute alcohol intoxication and burn injury,” Journal of Neuroimmune Pharmacology, vol. 1, no. 4, pp. 428–434, 2006.

M. A. Choudhry, S. N. Rana, M. J. Kavanaugh, E. J. Kovacs, R. L. Gamelli, and M. M. Sayeed, “Impaired intestinal immunity and barrier function: a cause for enhanced bacterial translocation in alcohol intoxication and burn injury,” Alcohol, vol. 33, no. 3, pp. 199–208, 2004.

A. Maier, C. Bode, P. Fritz, and J. C. Bode, “Effects of chronic alcohol abuse on duodenal mononuclear cells in man,” Digestive Diseases and Sciences, vol. 44, no. 4, pp. 691–696, 1999.

G. Pelletier, M. J. Briantais, C. Buffet, J. Pillot, and J. P. Etienne, “Serum and intestinal secretory IgA in alcoholic cirrhosis of the liver,” Gut, vol. 23, no. 6, pp. 475–480, 1982.

N. C. Iriemenam, A. O. Sanyaolu, W. A. Oyibo, and A. F. Fagbenro-Beyioku, “Strongyloides stercoralis and the immune response,” Parasitology International, vol. 59, no. 1, pp. 9–14, 2010.

D. N. Onah and Y. Nawa, “Mucosal immunity against parasitic gastrointestinal nematodes,” Korean Journal of Parasitology, vol. 38, no. 4, pp. 209–236, 2000.

U. M. Padigel, J. J. Lee, T. J. Nolan, G. A. Schad, and D. Abraham, “Eosinophils can function as antigen-presenting cells to induce primary and secondary immune responses to Strongyloides stercoralis,” Infection and Immunity, vol. 74, no. 6, pp. 3232–3238, 2006.

M. H. Shin, Y. A. Lee, and D.-Y. Min, “Eosinophil-mediated tissue inflammatory responses in helminth infection,” Korean Journal of Parasitology, vol. 47, pp. S125–S131, 2009.

A. M. Galioto, J. A. Hess, T. J. Nolan, G. A. Schad, J. J. Lee, and D. Abraham, “Role of eosinophils and neutrophils in innate and adaptive protective immunity to larval Strongyloides stercoralis in mice,” Infection and Immunity, vol. 74, no. 10, pp. 5730–5738, 2006.

U. M. Padigel, J. A. Hess, J. J. Lee et al., “Eosinophils act as antigen-presenting cells to induce immunity to Strongyloides stercoralis in mice,” Journal of Infectious Diseases, vol. 196, no. 12, pp. 1844–1851, 2007.

A. D. Klion and T. B. Nutman, “The role of eosinophils in host defense against helminth parasites,” Journal of Allergy and Clinical Immunology, vol. 113, no. 1, pp. 30–37, 2004.

S. A. Repetto, P. A. Durán, M. B. Lasala, and S. M. González-Cappa, “High rate of strongyloidosis infection, out of endemic area, in patients with eosinophilia and without risk of exogenous reinfections,” The American Journal of Tropical Medicine and Hygiene, vol. 82, no. 6, pp. 1088–1093, 2010.

D. Negrão-Corrêa, “Importance of immunoglobulin E (IgE) in the protective mechanism against gastrointestinal nematode infection: looking at the intestinal mucosae,” Revista do Instituto de Medicina Tropical de São Paulo, vol. 43, no. 5, pp. 291–299, 2001.

H. Maruyama, Y. Yabu, A. Yoshida, Y. Nawa, and N. Ohta, “A role of mast cell glycosaminoglycans for the immunological expulsion of intestinal nematode, Strongyloides venezuelensis,” Journal of Immunology, vol. 164, no. 7, pp. 3749–3754, 2000.

P. R. S. Lagacé-Wiens and G. K. M. Harding, “A Canadian immigrant with coinfection of Strongyloides stercoralis and human T-lymphotropic virus 1,” CMAJ, vol. 177, no. 5, pp. 451–453, 2007.

J. A. Ligas, L. A. Kerepesi, A. M. Galioto et al., “Specificity and mechanism of immunoglobulin M (IgM)- and IgG-dependent protective immunity to larval Strongyloides stercoralis in mice,” Infection and Immunity, vol. 71, no. 12, pp. 6835–6843, 2003.

W. Dawicki and J. S. Marshall, “New and emerging roles for mast cells in host defence,” Current Opinion in Immunology, vol. 19, no. 1, pp. 31–38, 2007.

H. Maruyama, Y. Osada, A. Yoshida et al., “Protective mechanisms against the intestinal nematode Strongyloides venezuelensis in Schistosoma japonicum-infected mice,” Parasite Immunology, vol. 22, no. 6, pp. 279–286, 2000.

N. S. Atkins, J. F. Lindo, M. G. Lee et al., “Humoral responses in human strongyloidiasis: correlations with infection chronicity,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 91, no. 5, pp. 609–613, 1997.

B. Blankenhaus, U. Klemm, M.-L. Eschbach et al., “Strongyloides ratti infection induces expansion of Foxp3+ regulatory T cells that interfere with immune response and parasite clearance in BALB/c Mice,” The Journal of Immunology, vol. 186, no. 7, pp. 4295–4305, 2011.

G. Szabo and P. Mandrekar, “A recent perspective on alcohol, immunity, and host defense,” Alcoholism: Clinical and Experimental Research, vol. 33, no. 2, pp. 220–232, 2009.

C. S. Pavia, M. La Mothe, and M. Kavanagh, “Influence of alcohol on antimicrobial immunity,” Biomedicine & Pharmacotherapy, vol. 58, no. 2, pp. 84–89, 2004.

G. Szabo, “Consequences of alcohol consumption on host defence,” Alcohol and Alcoholism, vol. 34, no. 6, pp. 830–841, 1999.

N. Rachdaoui and D. K. Sarkar, “Effects of alcohol on the endocrine system,” Endocrinology Metabolism Clinics of North America, vol. 42, pp. 593–615, 2013.

P. J. Barnes, “How corticosteroids control inflammation: quintiles prize lecture 2005,” British Journal of Pharmacology, vol. 148, no. 3, pp. 245–254, 2006.

M. N. Silverman and E. M. Sternberg, “Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction,” Annals of the New York Academy of Sciences, vol. 1261, no. 1, pp. 55–63, 2012.

X. Li, S. N. Rana, M. G. Schwacha, I. H. Chaudry, and M. A. Choudhry, “A novel role for IL-18 in corticosterone-mediated intestinal damage in a two-hit rodent model of alcohol intoxication and injury,” Journal of Leukocyte Biology, vol. 80, no. 2, pp. 367–375, 2006.

Ö. Sir, N. Fazal, M. A. Choudhry, R. L. Gamelli, and M. M. Sayeed, “Neutrophil depletion prevents intestinal mucosal permeability alterations in burn-injured rats,” American Journal of Physiology—Regulatory Integrative and Comparative Physiology, vol. 278, no. 5, pp. R1224–R1231, 2000.

R. S. Vadlamudi, D. S. Chi, and G. Krishnaswamy, “Intestinal strongyloidiasis and hyperinfection syndrome,” Clinical and Molecular Allergy, vol. 4, article 8, 2006.

R. Concha, W. Harrington Jr., and A. I. Rogers, “Intestinal strongyloidiasis: recognition, management, and determinants of outcome,” Journal of Clinical Gastroenterology, vol. 39, no. 3, pp. 203–211, 2005.

F. T. Crews, R. Bechara, L. A. Brown et al., “Cytokines and alcohol,” Alcoholism: Clinical and Experimental Research, vol. 30, no. 4, pp. 720–730, 2006.

P. Mandrekar, S. Bala, D. Catalano, K. Kodys, and G. Szabo, “The opposite effects of acute and chronic alcohol on lipopolysaccharide- induced inflammation are linked to IRAK-M in human monocytes,” Journal of Immunology, vol. 183, no. 2, pp. 1320–1327, 2009.

C. J. McClain, S. Barve, I. Deaciuc, M. Kugelmas, and D. Hill, “Cytokines in alcoholic liver disease,” Seminars in Liver Disease, vol. 19, no. 2, pp. 205–220, 1999.

A. Gonzalez-Quintela, J. Campos, L. Loidi, C. Quinteiro, L.-F. Perez, and F. Gude, “Serum TNF-α levels in relation to alcohol consumption and common TNF gene polymorphisms,” Alcohol, vol. 42, no. 6, pp. 513–518, 2008.

H. J. Wang, S. Zakhari, and M. K. Jung, “Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development,” World Journal of Gastroenterology, vol. 16, no. 11, pp. 1304–1313, 2010.

J. Haorah, S. H. Ramirez, N. Floreani, S. Gorantla, B. Morsey, and Y. Persidsky, “Mechanism of alcohol-induced oxidative stress and neuronal injury,” Free Radical Biology and Medicine, vol. 45, no. 11, pp. 1542–1550, 2008.

R. Heinz and C. Waltenbaugh, “Ethanol consumption modifies dendritic cell antigen presentation in mice,” Alcoholism: Clinical and Experimental Research, vol. 31, no. 10, pp. 1759–1771, 2007.

P. E. Molina, K. I. Happel, P. Zhang, J. K. Kolls, and S. Nelson, “Focus on: alcohol and the immune system,” Alcohol Research and Health, vol. 33, no. 1-2, pp. 97–108, 2010.

D. Kabelitz, D. Wesch, and H.-H. Oberg, “Regulation of regulatory T cells: role of dendritic cells and toll-like receptors,” Critical Reviews in Immunology, vol. 26, no. 4, pp. 291–306, 2006.

T. Hirata, N. Uchima, K. Kishimoto et al., “Impairment of host immune response against Strongyloides stercoralis by human T cell lymphotropic virus type 1 infection,” American Journal of Tropical Medicine and Hygiene, vol. 74, no. 2, pp. 246–249, 2006.

M. J. Domínguez-Santalla, C. Vidal, J. Viñuela, L. F. Pérez, and A. González-Quintela, “Increased serum IgE in alcoholics: relationship with Th1/Th2 cytokine production by stimulated blood mononuclear cells,” Alcoholism: Clinical and Experimental Research, vol. 25, no. 8, pp. 1198–1205, 2001.

A. Olsen, L. van Lieshout, H. Marti et al., “Strongyloidiasis—the most neglected of the neglected tropical diseases?” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 103, no. 10, pp. 967–972, 2009.

P. Uparanukraw, S. Phongsri, and N. Morakote, “Fluctuations of larval excretion in Strongyloides stercoralis infection,” American Journal of Tropical Medicine and Hygiene, vol. 60, no. 6, pp. 967–973, 1999.

L. X. Liu and P. F. Weller, “Strongyloidiasis and other intestinal nematode infections,” Infectious Disease Clinics of North America, vol. 7, no. 3, pp. 655–682, 1993.

Y. Sato, J. Kobayashi, H. Toma, and Y. Shiroma, “Efficacy of stool examination for detection of Strongyloides infection,” American Journal of Tropical Medicine and Hygiene, vol. 53, no. 3, pp. 248–250, 1995.

G. Dreyer, E. Fernandes-Silva, S. Alves, A. Rocha, R. Albuquerque, and D. Addiss, “Patterns of detection of Strongyloides stercoralis in stool specimens: implications for diagnosis and clinical trials,” Journal of Clinical Microbiology, vol. 34, no. 10, pp. 2569–2571, 1996.

S. Jongwutiwes, M. Charoenkorn, P. Sitthichareonchai, P. Akaraborvorn, and C. Putaporntip, “Increased sensitivity of routine laboratory detection of Strongyloides stercoralis and hookworm by agar-plate culture,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 93, no. 4, pp. 398–400, 1999.

R. G. Moraes, “Contribuição para o estudo do Strongyloides stercoralis e da estrongiloidíase no Brasil,” Revista de Saúde Pública, vol. 1, pp. 507–624, 1948.

P. Martín-Rabadán, P. Muñoz, J. Palomo, and E. Bouza, “Strongyloidiasis: the harada-mori test revisited,” Clinical Microbiology and Infection, vol. 5, no. 6, pp. 374–376, 1999.

T. Arakaki, H. Hasegawa, R. Asato et al., “A new method to detect Strongyloides stercoralis from human stool,” Japanese Journal of Tropical Medicine and Hygiene, vol. 16, no. 1, pp. 11–17, 1988.

J. F. Gomes, S. Hoshino-Shimizu, L. C. Dias, A. J. S. A. Araujo, V. L. P. Castilho, and F. A. M. A. Neves, “Evaluation of a novel kit (TF-Test) for the diagnosis of intestinal parasitic infections,” Journal of Clinical Laboratory Analysis, vol. 18, no. 2, pp. 132–138, 2004.

L. S. Ritchie, “An ether sedimentation technique for routine stool examinations,” Bulletin of the U.S. Army Medical Department, vol. 8, article 326, 1948.

C. Ukaga, P. Onyeka, and B. E. Nwoke, Practical Medicine Parasitology, Avan Global, 1st edition, 2002.

J. M. Blatt and G. A. Cantos, “Evaluation of techniques for the diagnosis of Strongyloides stercoralis in human immunodeficiency virus (HIV) positive and HIV negative individuals in the city of Itajaí, Brazil,” The Brazilian journal of Infectious Diseases: An Official Publication of the Brazilian Society of Infectious Diseases, vol. 7, no. 6, pp. 402–408, 2003.

P. M. Intapan, W. Maleewong, T. Wongsaroj, S. Singthong, and N. Morakote, “Comparison of the quantitative formalin ethyl acetate concentration technique and agar plate culture for diagnosis of human strongyloidiasis,” Journal of Clinical Microbiology, vol. 43, no. 4, pp. 1932–1933, 2005.

E. D. J. Inês, J. N. Souza, R. C. Santos et al., “Efficacy of parasitological methods for the diagnosis of Strongyloides stercoralis and hookworm in faecal specimens,” Acta Tropica, vol. 120, no. 3, pp. 206–210, 2011.

E. J. Inês, M. L. S. Silva, J. N. Souza, M. C. A. Teixeira, and N. M. Soares, “The role of glycosylated epitopes in the serodiagnosis of Strongyloides stercoralis infection,” Diagnostic Microbiology and Infectious Disease, vol. 76, no. 1, pp. 31–35, 2013.

A. L. R. Gonalves, C. A. Rocha, H. T. Gonzaga, M. D. R. D. F. Gonalves-Pires, M. T. Ueta, and J. M. Costa-Cruz, “Specific IgG and IgA to larvae, parthenogenetic females, and eggs of Strongyloides venezuelensis in the immunodiagnosis of human strongyloidiasis,” Diagnostic Microbiology and Infectious Disease, vol. 72, no. 1, pp. 79–84, 2012.

N. D. Feliciano, H. T. Gonzaga, M. D. R. F. Gonçalves-Pires et al., “Hydrophobic fractions from strongyloides venezuelensis for use in the human immunodiagnosis of strongyloidiasis,” Diagnostic Microbiology and Infectious Disease, vol. 67, no. 2, pp. 153–161, 2010.

H. R. Van Doorn, R. Koelewijn, H. Hofwegen et al., “Use of enzyme-linked immunosorbent assay and dipstick assay for detection of Strongyloides stercoralis infection in humans,” Journal of Clinical Microbiology, vol. 45, no. 2, pp. 438–442, 2007.

L. P. Silva, I. S. C. Barcelos, A. B. P. Lima, F. S. Espindola, D. M. B. Campos, and J. M. Costa-Cruz, “Western blotting using Strongyloides ratti antigen for the detection of IgG antibodies as confirmatory test in human strongyloidiasis,” Memórias do Instituto Oswaldo Cruz, vol. 98, no. 5, pp. 687–691, 2003.

R. Varatharajalu, V. Parandaman, M. Ndao, J. F. Andersen, and F. A. Neva, “Strongyloides stercoralis excretory/secretory protein strongylastacin specifically recognized by IgE antibodies in infected human sera,” Microbiology and Immunology, vol. 55, no. 2, pp. 115–122, 2011.

V. S. Ribeiro, N. D. Feliciano, H. T. Gonzaga et al., “Detergent fraction of heterologous antigen to detect IgA and IgG in strongyloidiasis using saliva and serum paired samples,” Immunology Letters, vol. 134, no. 1, pp. 69–74, 2010.

N. S. Atkins, D. J. Conway, J. F. Lindo, J. W. Bailey, and D. A. P. Bundy, “L3 antigen-specific antibody isotype responses in human strongyloidiasis: correlations with larval output,” Parasite Immunology, vol. 21, no. 10, pp. 517–526, 1999.

A. M. Sykes and J. S. McCarthy, “A coproantigen diagnostic test for Strongyloides infection,” PLoS Neglected Tropical Diseases, vol. 5, no. 2, article e955, 2011.

P. Taweethavonsawat, W. Chaicumpa, U. Chaisri et al., “Specific monoclonal antibodies to Strongyloides stercoralis: a potential diagnostic reagent for strongyloidiasis,” Asian Pacific Journal of Allergy and Immunology, vol. 20, no. 4, pp. 247–256, 2002.

Y. Sato, F. Inoue, R. Matsuyama, and Y. Shiroma, “Immunoblot analysis of antibodies in human strongyloidiasis,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 84, no. 3, pp. 403–406, 1990.

V. Ravi, S. Ramachandran, R. W. Thompson, J. F. Andersen, and F. A. Neva, “Characterization of a recombinant immunodiagnostic antigen (NIE) from Strongyloides stercoralis L3-stage larvae,” Molecular and Biochemical Parasitology, vol. 125, no. 1-2, pp. 73–81, 2002.

A. P. Sudré, R. C. Siqueira, M. G. M. Barreto, R. H. S. Peralta, H. W. Macedo, and J. M. Peralta, “Identification of a 26-kDa protein fraction as an important antigen for application in the immunodiagnosis of strongyloidiasis,” Parasitology Research, vol. 101, no. 4, pp. 1117–1123, 2007.

S. Kramme, N. Nissen, H. Soblik et al., “Novel real-time PCR for the universal detection of Strongyloides species,” Journal of Medical Microbiology, vol. 60, no. 4, pp. 454–458, 2011.

J. J. Verweij, M. Canales, K. Polman et al., “Molecular diagnosis of Strongyloides stercoralis in faecal samples using real-time PCR,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 103, no. 4, pp. 342–346, 2009.

G. V. Gill and J. W. Bailey, “Eosinophilia as a marker for chronic strongyloidiasis: use of a serum ELISA test to detect asymptomatic cases,” Annals of Tropical Medicine and Parasitology, vol. 83, no. 3, pp. 249–252, 1989.

T. B. Nutman, E. A. Ottesen, S. Ieng et al., “Eosinophilia in Southeast Asian refugees: evaluation at a referral center,” Journal of Infectious Diseases, vol. 155, no. 2, pp. 309–313, 1987.

D. I. Grove, “Treatment of strongyloidiasis with thiabendazole: an analysis of toxicity and effectiveness,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 76, no. 1, pp. 114–118, 1982.

A. A. Adenusi, A. O. Oke, and A. O. Adenusi, “Comparison of ivermectin and thiabendazole in the treatment of uncomplicated human Strongyloides stercoralis infection,” African Journal of Biotechnology, vol. 2, no. 11, pp. 465–469, 2004.

Y. Suputtamongkol, N. Premasathian, K. Bhumimuang et al., “Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis,” PLoS Neglected Tropical Diseases, vol. 5, no. 5, Article ID e1044, 2011.

A. A. Adenusi, “Cure by ivermectin of a chronic, persistent, intestinal strongyloidosis,” Acta Tropica, vol. 66, no. 3, pp. 163–167, 1997.

A. Datry, I. Hilmarsdottir, R. Mayorga-Sagastume et al., “Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 88, no. 3, pp. 344–345, 1994.

N. Mbendi, M. N. Mashako, M. Lukuni, and Z. L. Ndongala, “Anguillulose et albendazole: traitement en un seul jour avec une dose unique répartie en trois prises,” Médecine et Chirurgie Digestive, vol. 17, pp. 129–131, 1988.

S. Pungpak, D. Bunnag, D. Chindanond, and B. Radmoyos, “Albendazole in the treatment of strongyloidiasis,” Southeast Asian Journal of Tropical Medicine and Public Health, vol. 18, no. 2, pp. 207–210, 1987.

A. J. Wolstenholme and A. T. Rogers, “Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics,” Parasitology, vol. 131, supplement 1, pp. S85–S95, 2005.

Z. Bisoffi, D. Buonfrate, A. Angheben et al., “Randomized clinical trial on ivermectin versus thiabendazole for the treatment of strongyloidiasis,” PLoS Neglected Tropical Diseases, vol. 5, no. 7, article e1254, 2011.

O. Zaha, T. Hirata, N. Uchima, F. Kinjo, and A. Saito, “Comparison of anthelmintic effects of two doses of ivermectin on intestinal strongyloidiasis in patients negative or positive for anti-HTLV-1 antibody,” Journal of Infection and Chemotherapy, vol. 10, no. 6, pp. 348–351, 2004.

B. R. Mirdha, “Human strongyloidiasis: often brushed under the carpet,” Tropical Gastroenterology: Official Journal of the Digestive Diseases, vol. 30, no. 1, pp. 1–4, 2009.

M. A. Miller, L. W. P. Church, and C. D. Salgado, “Strongyloides hyperinfection: a treatment dilemma,” The American Journal of the Medical Sciences, vol. 336, no. 4, pp. 358–361, 2008.

P. Lichtenberger, I. Rosa-Cunha, M. Morris et al., “Hyperinfection strongyloidiasis in a liver transplant recipient treated with parenteral ivermectin: case report,” Transplant Infectious Disease, vol. 11, no. 2, pp. 137–142, 2009.