Sabbatani, Sergio MD*; Manfredi, Roberto MD*; Baccarini, Paola MD†; Marinacci, Ginevra MD*; Chiodo, Francesco MD*
Strongyloides stercoralis infestation is responsible forelevated morbidity and mortality rates in numerous tropical and subtropical areas of the world, and it is estimated to affect over 100 million individuals.1-4 The transmission of the nematode worm S. stercoralis is almost exclusively interhuman, although in some areas an animal, mammalian reservoir (dogs and cats) has been identified.1,2,5 In the European continent, this helminthiasis is sporadically found, mostly in travelers coming from endemic areas of the world.1,2,6,7 It can also be occasionally found in closed communities such as institutions for patients with chronic psychiatric disorders or mental retardation, military barracks, and communities of refugees escaping from at-risk countries.1,4,7 In Italy, S. stercoralis can be found with an estimated attack rate of around 550 adult patients per year, among subjects who usually live or have spent many years in the countryside of the Po valley and some other areas of northern-central Italy reputed to be hypoendemic for the disease.1,2,8 Moreover, the well-known "autoinfection" cycle of this parasite may explain a prolonged or recurring strongyloidiasis in the absence of evident further exposure to exogenous larvae. This is especially true in the immunocompromised host,1,2,9 as already demonstrated by appropriate animal models.5
In most otherwise healthy subjects, this helminthiasis leads to an asymptomatic or paucisymptomatic infestation, which may be missed and is, consequently, underestimated in the current clinical practice.1,3,4 On the other hand, when some primary or secondary (often iatrogenic) immunodeficiency is of concern, a more symptomatic disease is more frequent, and the disease spectrum may involve multiple organs, outside the more obvious intestinal localization, and may also lead to a disseminated and life-threatening disease, or to relapsing and difficult-to-treat manifestations.1,4,9-16
The aim of our report is to describe a unique case of relapsing and difficult-to-treat S. stercoralis infestation, which occurred in a patient affected by the autoimmune Sjögren disease (a pathologic association never reported before), and to discuss the related pathogenetic, diagnostic, and therapeutic issues.
The subject is a 76-year-old female patient without history of cigarette smoke and alcohol intake but who has since suffered over 20 years from a Sjögren syndrome complicated by a hand microangiopathy, which required the implant of a cervical electrostimulating device during the decade 1990-1999. She chronically receives cyclic courses of oral corticosteroids to control her collagen vascular disease, but doses and times of administration were variable during time. After cataract surgery in the year 2000, the patient received a right hip prosthesis in 2001 (revised in the year 2004) and suffered from a pelvic fracture due to an accidental fall in the year 2002 while a chronic venous insufficiency of lower limbs concurred. One month before admission at our division, the patient underwent a right hemicolectomy due to a moderately differentiated but infiltrating colonic adenocarcinoma, which was complicated by muscle, vascular, and visceral peritoneum involvement (disease stage 2, Dukes B classification). Oncologic chemotherapy was not performed due to the late healing of surgical wound.
In March 2004, after the occurrence and progression of dyspeptic signs and symptoms and a mild epigastric pain, the patient underwent an endoscopy examination that detected a gastroduodenal S. stercoralis infection, confirmed by histopathologic studies (Figs. 1-4). In particular, the duodenal histopathology pointed out long, roundish structures clearly referred to parasites, located over the intestinal mucosa and inside gastric foveolae. In April 2004, at the time of referral to our division due to the parasitic infestation, prednisone (25 mg/d) was the underlying therapy for the concomitant Sjögren syndrome. After a first cycle of antihelminthic treatment performed with albendazole (400 mg/d for 3 days), the intestinal parasite was not eradicated, as shown by a repeated gastroduodenoscopy. In July 2004, the recrudescence of dyspeptic signs and symptoms prompted another duodenal biopsy. This again tested positive for S. stercoralis infection so that a further 3-day albendazole cycle was carried out. Despite this, 2 subsequent endoscopy controls (August 2004 and February 2005) demonstrated the persistence of S. stercoralis infection, which was also associated to a moderate Candida esophagitis in the last instrumental examination.
Upon hospital admission (February 2005), the patient suffered from a moderate (15%) weight loss, but both hematological and blood chemistry profiles were within normal limits, except for a moderate anemia that was characterized by a hemoglobin value of 9.8 g/dL and a hematocrit of 30.6%. A normal blood leukocyte count and differential was accompanied by the absence of eosinophilia, abnormal serum IgE levels, and alteration of T-lymphocyte subsets (because an absolute CD4+ count of around 1200 cells/μL was detected). Repeated stool, sputum, and urine search for S. stercoralis always tested negative after admission at our inpatient unit. Both HIV-1/2 and HTLV-1 infection serologies tested negative, as well as all available laboratory tumoral markers. During admission, the patient was treated with ivermectin at 12 g/d (2 consecutive days) and fluconazole at 400 mg/d (14 days), followed by 200 mg/d for further 10 days. One week after hospital discharge, the patient was again treated with albendazole (400 mg twice daily for 3 days), and 2 weeks later with mebendazole (at 500 mg/d for 3 days). After the last mentioned albendazole-mebendazole cycles, a repeated endoscopy with multiple bioptic examinations was performed. Chronic, nonspecific duodenitis associated with a grade 2 esophagitis and a chronic follicular gastritis were detected, with negative Helicobacter pylori testings: no signs of strongyloidiasis and esophageal candidiasis were found. Seven weeks after the last antiparasitic therapy, a repeated esophagogastroduodenoscopy confirmed a sustained cure of strongyloidiasis, associated with a 10% body weight regain compared with the admission time, and complete disappearance of dyspeptic signs and symptoms.
During the entire, prolonged evaluation and treatment periods followed by us (over than 1 year), the concurrent steroidal therapy deemed necessary for the control of the concurrent Sjögren disease (prednisone, 25 mg daily) was never interrupted.
From a clinical and epidemiological point of view, because strongyloidiasis is particularly frequent in tropical-subtropical endemic regions, a number of studies demonstrated its association with the retroviral human T-cell leukemia virus type 1 (HTLV-1) infection, which shares similar geographical locations.1,3,17-19 In these last occurrences, patients suffering from HTLV-1 coinfection (either symptomatic or not, such as HTLV-1 carriers with an increased proviral load) are very difficult to cure. This is because the immune response against this parasite is impaired, as expressed by a reduced production and release of interleukin-4 (IL-4), IL-5, IL-13, an impaired IgE-mediated antiparasitic response (as expressed by very low serum IgE levels), a global dysregulation of TH1 and TH2 immune response, and an affected IFN-γ secretion. These are all factors that have been shown to be critical in the immune control of S. stercoralis,3,6,7,17-23 while CD4+ lymphocyte count usually remains within normal limits.7 The globally down-regulated activation of type 1 immune cells prompted by the concomitant HTLV-1 infection leads to a much more frequent atypical presentation and course of strongyloidiasis (like meningeal, genital, respiratory, intra-abdominal, or muscle localizations),6,7,19,22 with rare but possible lethal outcome.6 As a consequence, clinicians should remember that a relapsing strongyloidiasis may herald a missed, concurrent HTLV-1 infection,7 and the association of strongyloidiasis with HTLV-1 infection may result in a remarkable increase of disseminated or recurring forms of this helminthiasis, also due to a reduced therapeutic response,3,17-19 so that a careful and probably lifetime monitoring is recommended for these coinfected patient.1,4,7
As anticipated, S. stercoralis infestation involves not only patients with poor hygiene. In fact, in countries with evolved health care facilities, patients with a broad spectrum of underlying diseases or chronically treated with immunosuppressive drugs (corticosteroids, in particular)1,12 are progressively increasing due to the steady improvement of life expectancy and advances in the treatment of solid and hematologic malignancies, diabetes mellitus, chronic kidney failure, and collagen vascular diseases, which are indirectly responsible for a proportional rise of reports of S. stercoralis infestations, and their increased possibility to become refractory to common first-line antiparasitic treatment.1,4 From a pathogenetic point of view, in the year 1992 Genta10 claimed also a possible role of corticosteroid treatment in acting on the intraintestinal Strongyloides larvae as molting hormones, thus promoting indirectly disease dissemination, but this hypothesis has not been supported by further investigation. The abovementioned clinical occurrences of strongyloidiasis are particularly severe in their manifestation and evolution due to the impaired immune response, which cannot avoid frequent reinfestation, and diffusion and visceralization of this helminthic disease,1,2,4,8,9,12,13,24 with a possible nonnegligible rate of fatal outcome due to visceralization followed by multiorgan failure, a possible septic shock-like syndrome (sometimes associated with a petechial rash), and increased susceptibility to serious bacterial superinfections. As a consequence, anecdotal case reports and small series of complicated S. stercoralis infestations have been described in variously immunocompromised subjects, such as those with solid and hematologic malignancies (where a prevalence of 1 case per 10,000 new cancer episodes was recognized in a 34-year retrospective survey performed at a large comprehensive cancer center of the United States, where nearly 50% of the 25 identified patients received corticosteroids).9 While most literature series pointed out an increased risk to develop a strongyloidiasis for patients with solid tumors compared with hematologic malignancies,9 however, several episodes and a significantly increased frequency have been described also in subjects suffering from leukemia and lymphoma, from an endemic country like Brazil,25 and from Germany too;26 in all these last cases, the malignancy itself, the related immunodeficiency, and its chemotherapy and/or radiotherapy seemed to act as supporting factors for serious or disseminated strongyloidiasis.
Also collagen vascular disease (including systemic lupus erythematosus, lupus glomerulonephritis, hemolytic anemia, chronic idiopathic thrombocytopenia, and uveitis), especially when chronically treated with steroids and immunosuppressive drugs, were anecdotally reported as factors supporting intestinal or disseminated strongyloidiasis,2,11-16 but no patient with an underlying Sjögren syndrome has been reported to date, as far as we know. Furthermore, strongyloidiasis has been reported in subjects with inflammatory bowel diseases (where an enteric parasite localization may be confused with a reactivation of the underlying illness).13 Other chronic disorders, like diabetes mellitus, chronic alcoholism, and malnutrition, have been underlined as possible risk factors for strongyloidiasis,1,4 along with kidney failure and related hemodialysis,27 severe and chronic pulmonary disease,2,8 and chronic asthma (showing a paradoxical clinical worsening under systemic steroid treatment),29 on the ground of anecdotal clinical reports. More recently, increased attention has been also driven on solid organ transplant recipients because in these last individuals strongyloidiasis may become fatal.16 Finally, 2 isolated cases of severe strongyloidiasis occurring during combined interferon plus ribavirin treatment of chronic hepatitis C infection have been reported,30 and a supporting role from the immunomodulatory and immunosuppressive action of both drugs has been postulated. On the other hand, S. stercoralis infection association with HIV disease remains a very rare event because the characteristic, HIV-related quantitative and functional deficiency of CD4+ helper T-lymphocytes is not expected to play a significant role in the immune defense against S. stercoralis.1,2,7
In the entire group represented by immunocompromised patients, hyperacute or prolonged, relapsing courses of strongyloidiasis have been described, sometimes complicated by focal involvement of heart (myocarditis), lower respiratory tract, skin and soft tissues, and central nervous system.2,9,12,14,15 Because disseminated strongyloidiasis associated with some grade of immunodeficiency may prove fatal in up to 80% of cases (and it is sometimes recognized only at necropsy), a prompt diagnosis and treatment of this parasite infestation is strongly needed, and some authors recommend to rule out strongyloidiasis before administration long-term steroids11 and other immunosuppressive agents1,2 (like most rheumatological patients), as well as in subjects who are candidate to organ transplantation.16
The described case report is representative of a unique association of a prolonged and apparently resistant and difficult-to-treat S. stercoralis infestation occurring in a elderly patient with multiple comorbidity (but no HTLV-1 coinfection), and especially an underlying collagen vascular disease lasting from many years and controlled by chronic prednisone treatment (and continued with unmodified dosage during the described disease course). After an extensive a careful literature search performed with electronic databases (such as Medline-PubMed and Embase), we failed in retrieving other cases of combined strongyloidiasis and Sjögren disease controlled by chronic steroid administration, so that to the best of our knowledge we present the first report of these 2 associated disorders. The described, prolonged evolution observed in our patient allows us to underline the risks stemming from long-term, chronic corticosteroid treatment that, although undoubtedly useful to control invalidating disorders, may prompt the emerging of true opportunistic infections, as in our case of severe and apparently resistant helminthiasis, while the cured colonic cancer should not have played a significant role.
From a therapeutic point of view, in the absence of controlled clinical trials and also extensive open studies and patient series, either albendazole, thiabendazole, ivermectin, or mebendazole (and sometimes pyrvinium pamoate), have been used at different dosages and with a different length and schedule of administration, whereas the pharmacologic management of eventual relapses mostly affecting patients with impaired immune defenses was even more variable, based on the limited literature reports and reviews.1,4,7,15,27-29 Moreover, potential adverse events should be taken into careful consideration when administering all these antihelminthic compounds to a somewhat compromised patients,4 especially when combination therapy is selected for refractory disease; however, less toxicity is expected with ivermectin, compared with other antihelminthic compounds that are active on S. stercoralis. As a result, high-dose ivermectin has been suggested for immunocompromised patient at risk for visceralization or recurrences of strongyloidiasis;1,2 also our experience seems to support a significant role for ivermectin administration, introduced after some attempts with other drugs, which initially failed in eradicating strongyloidiasis, but probably contributed later to its final and sustained cure. The interval of administration of therapeutic courses seems to represent a key point for treatment because S. stercoralis is expected to multiply and resume its life cycle when the autoinfective migrating larvae are not fully eradicated due to a very broad spectrum of possible, concomitant reasons.4 Periodic laboratory stool monitoring seems to be the better diagnostic tool for the long-term surveillance of treatment outcome, but its predictive value has not been fully established, and in many patients relapses may occur after apparently negative and repeated stool examinations.1 When concurred steroidal therapy cannot be interrupted (as in our case), the antihelminthic therapy achieved favorable results in some instances,1,4,24 although a temporary suspension of immunosuppressive agents should be recommended whenever possible. Based on the course of our patient, we can think that a rotation of all available and potentially effective antihelminthic drugs, with repeated therapeutic cycles, may have contributed to the final, favorable response because it remains difficult to distinguish the role played by the multiple and different treatment courses carried out during the prolonged disease course. When supporting factors are present, an appropriately prolonged follow-up of strongyloidiasis, proportional to the comprehensive illness duration, is expected to be followed to be sure of the sustained and definitive patient's response to treatment, as performed in our case.
A prompt and systematic search of S. stercoralis in stools, sputum, and urine (which has been initially delayed in our case, whose diagnosis was posed only after histopathologic recognition), especially in patients who chronically receive corticosteroids or suffered from a primary or (more often) secondary or iatrogenic immunodeficiency, seems mandatory.1,4,12,13 Such a careful search seems recommended not only in patients who spent some time in endemic or subendemic countries because (as previously reported) this helminthic disease is not characterized by prominent, pathognomonic, or highly predictive signs and symptoms, and laboratory alterations (like an unexplained hypoalbuminemia, or signs and symptoms of a possible enteropathy and malabsorption) may include multiple disease in the differential diagnosis.11,27 The eosinophilia typical of most parasite disease may be delayed or absent especially when immunodeficiency concurs11-13 (as in our case), although some reports seem to reenforce the relevance of this last finding in the laboratory workout of strongyloidiasis.14
Clinicians and rheumatologists who face patients at risk for strongyloidiasis should also take into consideration that in the next future this parasitic disorder is expected to increase its frequency, on the ground of environmental changes (ie, increased temperature and humidity),2,6,7 just in countries where an elevated number of patients become at risk for opportunistic disorders, due to chronic immunosuppression linked to underlying diseases and their treatment, especially when systemic steroids are of concern.
Finally, because complicated strongyloidiasis show an unpredictable therapeutic response to all available antihelminthic agents, especially when some form of long-term immunodeficiency or a concurrent HTLV-1 infection is of concern,1,4,7,9,12,20 controlled trials on appropriate patient samples are strongly needed to compare the different available drugs, their dosage, and their schedules of administration (ie, duration of therapeutic cycles, with possibility to increase their length, or administer a combined therapy when risk factors for a reduced response or a relapse are expected) to reach some evidence-based validated guidelines of initial treatment and eventual pharmacological management of disease relapses. The possible role of concurrent, adjuvant therapies (ie, the administration of recombinant leukocyte growth factors)12 should also deserve appropriate attention in immunosuppressed individuals.
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