Transactions of the Royal Society of Tropical Medicine and Hygiene (2009) 103, 242—246
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Intestinal strongyloidiasis: a diagnosis frequently missed in the tropics Vinita Agrawal a,∗, Tanu Agarwal a,1, Uday C. Ghoshal b a
Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow 226014, Uttar Pradesh, India b Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India Received 3 April 2008; received in revised form 6 August 2008; accepted 6 August 2008 Available online 20 September 2008
KEYWORDS Diarrhoea; Immunocompromised host; Intestinal parasites; Strongyloidiasis; Malabsorption; India
Summary Strongyloides stercoralis, a nematode parasite, is endemic in tropical and subtropical regions. Infection usually remains asymptomatic, but in immunocompromised hosts hyperinfection and dissemination can occur, which has a high mortality. Early detection of S. stercoralis may alter the fatal course of infection. We present our experience of ﬁve patients with S. stercoralis hyperinfection diagnosed by endoscopic duodenal and jejunal biopsy in northern India. A predisposing factor was present in all patients in the form of corticosteroid intake, chronic liver disease and panhypogammaglobulinaemia. Common gastrointestinal symptoms were abdominal pain, diarrhoea, gastrointestinal bleeding, nausea, vomiting and weight loss with evidence of malabsorption. The initial stool examination and peripheral blood eosinophil count were normal in all patients. Strongyloidiasis was not suspected clinically in any patient and the diagnosis was achieved on endoscopic biopsy. Three of the patients with disseminated disease developed fatal Gram-negative systemic infection. This study highlights the importance of considering strongyloidiasis in all patients on immunosuppressive drug therapy who present with gastrointestinal symptoms so that the patient can be appropriately investigated and promptly treated. In endemic regions, patients with systemic Gram-negative bacterial infections without an obvious cause should be tested for strongyloidiasis. © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
∗ Corresponding author. Tel.: +91 522 266 8004—8x2253; fax: +91 522 2668 017/078. E-mail address: [email protected]
(V. Agrawal). 1 Present address: Department of Pathology, Shri Ram Murti Smarak Institute of Medical Sciences, Bareilly 243001, India.
Strongyloidiasis, caused by the nematode Strongyloides stercoralis, is often an asymptomatic infection of the upper small intestine. However, gastrointestinal symptoms are common. Autoinfection causes chronic infection and, in patients with defective cell-mediated immunity, may lead to an increased parasite burden and dissemination to almost all organs, including the lungs, liver and central
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.trstmh.2008.08.009
36 000 0 Negative Negative 15 000 300 Negative Negative
32 Male Constipation, abdominal pain, vomiting Duodenal mucosal thickening with ulcers Lepromatous leprosy, steroid
nervous system.1 Dissemination of S. stercoralis is potentially lethal as it is often associated with bacterial sepsis, thought to result from transfer of enteric organisms into the bloodstream concomitant with larval penetration. Although patients may survive if diagnosed at an early stage, hyperinfection syndrome has a mortality rate ranging from 15% to as high as 87%.2 Relatively non-speciﬁc clinical features of this disease lead to diagnostic difﬁculty. A high index of suspicion by clinicians as well as thorough evaluation using sensitive techniques are essential to diagnose this potentially fatal infection. Treatment of strongyloidiasis is limited to oral formulations with ivermectin, albendazole and thiabendazole. We present our experience of ﬁve cases of S. stercoralis hyperinfection diagnosed on small bowel biopsy, with the aim of determining: (i) how often the diagnosis was clinically suspected; (ii) how often the diagnosis was made ante-mortem; and (iii) how often stool microscopy detected larvae.
Chronic liver disease
65 Male Melena, anorexia, weight loss Normal
Intestinal strongyloidiasis: a diagnosis frequently missed in the tropics
11 400 228 1 negative, 1 positive Negative 11 700 0 Negative Negative
Upper gastrointestinal endoscopic ﬁndings Associated illness/medication
Laboratory ﬁndings Total leukocyte count (/l) Eosinophils (/l) Stool examination HIV serology
14 100 282 Negative Negative
Corticosteroid abuse Bronchial asthma, panhypogammaglobulinaemia
50 Male Abdominal pain, vomiting Thickened folds and erosions in duodenum Arthritis, steroid Age (years) Gender Clinical features
Case 1 Feature
Clinical features in patients with strongyloidiasis
2.1.2. Case 2 A 30-year-old asthmatic man, resident of central India, whose case has been previously reported, presented in February 2001 with a 1-year history of large-volume semisolid to watery diarrhoea (600—900 g) associated with borborygmi, anorexia and weight loss.3 Examination
2.1.1. Case 1 A 50-year-old man presented in October 1996 with a 2month history of abdominal pain, anorexia, vomiting and weight loss. He had been taking prednisolone (60 mg/day tapered to 10 mg/day) during the previous 1.5 months for polyarthritis. Examination revealed pedal oedema. Laboratory investigations revealed haemoglobin (Hb) 105 g/l, total leukocyte count (TLC) 11.7 × 109 /l (82% polymorphonuclear leukocytes (PML), 17% lymphocytes, 1% monocytes and no eosinophils) and platelets 130 × 109 /l. Serum total protein and albumin were 41 g/l and 15 g/l, respectively. ELISA for HIV was negative. Stool examination did not reveal any ova, cysts or larvae. A barium study showed duodenal mucosal fold thickening and dilated small bowel loops. Endoscopy showed thickened folds and erosions in the duodenum. Biopsy from the duodenum revealed S. stercoralis larvae and adult worms within the crypts. The patient was treated with albendazole 400 mg twice daily for 3 days following which his symptoms improved.
2.1. Case reports
19 Male Diarrhoea, anorexia, weight loss Normal
Five patients diagnosed as having strongyloidiasis on histology of an upper gastrointestinal biopsy over a 12-year period (1996—2007) were identiﬁed from the records of the Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, a tertiary referral centre in northern India. The diagnosis was based on demonstration of larvae and/or adult worms in the intestinal biopsy. Pertinent clinical and endoscopic ﬁndings and laboratory results were obtained from the patients, records and are summarised in Table 1.
30 Male Diarrhoea, weight loss
2. Patients and methods
244 revealed marked pedal oedema and hepatomegaly. Haematological examination was normal. Serum total protein and albumin were 44 g/l and 12 g/l, respectively. Stool examination did not reveal any ova, cysts or larvae. Faecal fat excretion was raised (Sudan III stain >50 droplets per highpower ﬁeld and quantitative average faecal fat 16.5 g/day (normal <7 g/day)). Urinary D-xylose excretion was abnormal. ELISA for HIV was negative. Duodenal biopsy showed partial villous atrophy but no parasite. He was diagnosed as having malabsorption syndrome, small intestinal bacterial overgrowth (using glucose hydrogen breath test) and oesophageal candidiasis. He was treated with tetracycline 500 mg three times daily and ﬂuconazole. However, the patient did not respond and was re-admitted 3 weeks later. Laboratory investigations revealed Hb 101 g/l, TLC 14.1 × 109 /l (80% PMLs, 13% lymphocytes, 5% monocytes and 2% eosinophils) and serum total protein and albumin of 34 g/l and 7 g/l, respectively. A barium study and push-type enteroscopy revealed thickening, nodularity and ulcerations in the duodenum and proximal jejunum, and a biopsy was taken. Considering the diagnosis of small intestinal bacterial overgrowth, severe malnutrition and septicaemia, the patient was treated with parenteral nutrition, albumin infusion, oral tetracycline and i.v. ceftriaxone. However, on the ﬁfth day of admission the patient suffered a cardiac arrest from which he could not be revived. The investigation reports available post-mortem showed panhypogammaglobulinaemia, Escherichia coli in the blood and jejunal aspirate cultures, and subtotal villous atrophy and larval forms of S. stercoralis in the small intestinal biopsy.
2.1.3. Case 3 A 19-year-old male, resident of north India, presented in September 2003 with a 6-month history of diarrhoea, anorexia, vomiting and weight loss. Physical examination revealed pedal oedema, tinea corporis and onychomycosis. The patient had taken glucocorticoids in the past (dexamethasone 1 mg/day for 2 years) for an unknown reason leading to secondary adrenal insufﬁciency. He was receiving replacement steroid therapy. Laboratory investigations revealed Hb 76 g/l, TLC 11.4 × 109 /l (73% PMLs, 25% lymphocytes and 2% eosinophils) and platelets 284 × 109 /l. Serum total protein and albumin were 40 g/l and 10 g/l, respectively. The basal and stimulated (60-min post adrenocorticotropic hormone (ACTH)) cortisol levels were 395 nmol/l and 390.1 nmol/l, respectively. Stool examination did not reveal any ova, cysts or larvae. ELISA for HIV was negative. Nail and skin scrapings were positive for septate fungal hyphae. Upper gastrointestinal endoscopy was normal. Duodenal biopsy revealed partial villous atrophy and larval and adult forms of S. stercoralis in the mucosal crypts. The patient was treated with albendazole 400 mg orally twice daily for 3 days following which he became asymptomatic. Nine months later he presented with progressively increasing body swelling, loss of appetite, and excoriation and rash over the hands, legs and scrotum (suggestive of larva currens). Pus culture from a scrotal abscess showed growth of Streptococcus sp., Enterobacter aerogenes and Proteus mirabilis. The patient was treated with antibiotics and albendazole 400 mg twice daily for 7 days followed by repeated courses at 15, 30 and 45 days. Two
V. Agrawal et al. months later he presented to the emergency department in a state of hypovolaemic shock along with marked body swelling, severe dependent scrotal oedema, and purpura and superﬁcial ulcers all over the body. His pulse and blood pressure were not recordable. Laboratory investigations at this stage revealed Hb 75 g/l, TLC 17 × 109 /l (88% PMLs, 10% lymphocytes and 2% eosinophils) and platelets 100 × 109 /l. Serum total protein and albumin were 35 g/l and 17 g/l, respectively. Stool microscopic examination revealed larvae of S. stercoralis. He was treated with supportive measures along with ivermectin 12 mg/day for 2 days and i.v antibiotics. However, on the third day of admission he developed severe abdominal pain, extensive coarse crepitations over both lung ﬁelds, sepsis and had a cardiac arrest from which he could not be revived. 2.1.4. Case 4 A 32-year-old man, resident of north-east India, presented in January 2005 with constipation, and lower abdominal pain and distension for 10 days. He had lepromatous leprosy; its treatment led to lepra reaction for which he received prednisolone (70 mg/day) for 1 month, which he had stopped 10 days previously. On physical examination the patient was thin built and poorly nourished with lepromatous patches on his lower limbs and body. Bowel loops were palpable on abdominal examination. Laboratory investigations revealed Hb 107 g/l, TLC 15 × 109 /l (81% PMLs, 16% lymphocytes, 1% monocytes and 2% eosinophils) and platelets 389 × 109 /l. Serum total protein and albumin were 55 g/l and 20 g/l, respectively. Stool examination did not reveal any ova, cysts or larvae. ELISA for HIV was negative. Slit-smear examination of a skin biopsy for acid-fast lepra bacilli was negative. An abdominal radiograph showed dilated small and large bowel loops with faecaliths. Colonoscopy was normal. Upper gastrointestinal endoscopy showed ulcerated and oedematous duodenal mucosa. The duodenal biopsy showed mucosal ulceration and multiple adult and larval forms of S. stercoralis. The patient was treated with ivermectin 12 mg/day for 2 days following which his symptoms resolved. A repeat duodenal biopsy 3 months later did not show any worms or larvae. 2.1.5. Case 5 A 65-year-old man, resident of north-east India, suffering from chronic liver disease was admitted in February 2006 with a history of melena, loss of appetite and signiﬁcant weight loss for 2 months, abdominal pain and vomiting for 10 days, and altered sensorium for 1 day. Examination revealed grade III hepatic encephalopathy and mild ascites. Laboratory investigations revealed Hb 82 g/l, TLC 36 × 109 /l (60% PMLs, 40% lymphocytes and no eosinophils) and platelets 323 × 109 /l. Prothrombin time, activated partial thromboplastin time and liver enzymes were elevated. Serum total protein and albumin were 34 g/l and 16 g/l, respectively. ELISA for HIV was negative. Upper gastrointestinal endoscopy was normal and a duodenal biopsy was taken. Lower gastrointestinal endoscopy revealed a polypoid sessile lesion in the rectum. The patient was managed with i.v. antibiotics and supportive measures; however, due to ﬁnancial constraints he left the hospital against medical advice. Ascitic ﬂuid examination and duodenal biopsy reports avail-
Intestinal strongyloidiasis: a diagnosis frequently missed in the tropics
Figure 1 (A) Duodenal biopsy showing villous blunting and presence of larvae of Strongyloides embedded in the mucosa (haematoxylin—eosin, 400×). (B) Smear of ascitic ﬂuid. Coiled ﬁlariform larva with internal structures associated with a dense neutrophilic inﬁltrate (May—Grünwald—Giemsa, 400×).
able later revealed S. stercoralis larvae (Figure 1). The ascitic ﬂuid culture also grew E. coli. The rectal biopsy revealed only mild oedema and inﬂammation of the lamina propria. Subsequent enquiry revealed that the patient had expired on his way back from the hospital, presumably due to disseminated S. stercoralis infection.
3. Discussion Strongyloides stercoralis is a common and globally distributed intestinal nematode endemic in Africa, Asia, Southeast Asia, Latin America and the Southeastern USA.4 Although most infected individuals are asymptomatic, S. stercoralis infection is capable of transforming into a fulminant fatal illness under conditions associated with compromised host immunity. Of all the immunosuppressive drugs prescribed, glucocorticoids are the most widely used and the most speciﬁcally associated with transformation of chronic strongyloidiasis to hyperinfection.5 There are case reports of Strongyloides from India, but ours is the fourth and largest series reported from India.6—8 We presented ﬁve patients with Strongyloides hyperinfection, all of whom were immunosuppressed, diagnosed by endoscopic small intestinal biopsy. Three of the patients had a history of corticosteroid intake, one had chronic liver disease and one patient had panhypogammaglobulinaemia, which could be the primary reason for fulminant strongyloidiasis. Thus, it is important to consider the possibility of strongyloidiasis in all immunosuppressed patients who present with gastrointestinal symptoms so that the patient can be appropriately investigated and promptly treated. The usual gastrointestinal symptoms are abdominal pain, diarrhoea, gastrointestinal bleeding, nausea, vomiting and weight loss with evidence of malabsorption or protein-losing enteropathy. All ﬁve patients in this series were HIV-negative. The present study highlights the importance of endoscopic biopsy in patients with intestinal strongyloidiasis. The diagnosis of S. stercoralis infestation in all ﬁve cases was made by demonstration of larvae and/or adult worms in the small intestinal biopsy. Duodenal aspirate examination is
also a sensitive method for the diagnosis of strongyloidiasis.9 During the study period, 12 other patients were diagnosed as having strongyloidiasis by stool and/or duodenal aspirate microscopy in the study centre. Initial clinical diagnosis of strongyloidiasis was not suspected in any of the ﬁve cases in the present series. The intestinal biopsy yielded an ante-mortem diagnosis in three of the patients. In the others, diagnosis of strongyloidiasis was made post-mortem. Initial stool examination failed to detect S. stercoralis larvae in all ﬁve cases in this series. However, in one patient stool examination detected larvae at the second admission in an already diagnosed and treated case of intestinal strongyloidiasis. In one of the patients, S. stercoralis larvae were also detected in the ascitic ﬂuid, which is due to hyperinfection and dissemination. There are occasional reports in the literature of detection of the worm from peritoneal ﬂuid.10—12 The peripheral blood eosinophil count is not a reliable indicator of parasitic infection, and absolute eosinophil counts were not raised in any of our patients (range 0—0.23 × 109 /l; normal <0.4 × 109 /l). Eosinophilia is a common ﬁnding in patients with chronic S. stercoralis infection, but the eosinophil count is unreliable in hyperinfection and in patients receiving immunosuppressant therapy.13 Clinical diagnosis of S. stercoralis infection is conﬁrmed by detection of larvae in the stool. Duodenal aspiration or biopsy may reveal larvae. The diagnostic yield of strongyloidiasis is not higher than 50%, even after three stool examinations. Stool culture by the blood agar plate method increases the sensitivity of detection of Strongyloides larvae.5,14 An ELISA test (Strongyloides antibody) for detecting serum IgG against a crude extract of the ﬁlariform larvae of S. stercoralis has a sensitivity of 82—95% and a variable speciﬁcity of 29—99% in different studies.5,15,16 It can be used for early detection of infection or for screening of highrisk patients before more invasive tests such as duodenal biopsy or aspiration are undertaken, but has a drawback of not being widely available and also not being able to distinguish antibodies produced by past or recent infection.5 The Strongyloides antibody test is known to show cross-reactivity with other helminth infections, including ﬁlariasis, Ascaris
246 lumbricoides and acute schistosomiasis.17 In approximately 90% of cases the diagnosis is made by a duodenal or jejunal biopsy.9 This illustrates the poor sensitivity of stool examination and the need for endoscopic duodenal biopsy or aspirate microscopy in all patients with clinical features suggestive of strongyloidiasis. Duodenal biopsy or aspiration is indicated even in cases with endoscopically normal appearing mucosa, as was seen in two of our cases. Disseminated strongyloidiasis is often associated with enteric bacterial infections.18 It has been hypothesised that intestinal luminal bacteria may accompany the parasite during its transmural migration across the intestinal wall. This is supported in three of our patients: Case 2 had septicaemia with growth of E. coli in blood and jejunal aspirate cultures; Case 3 had Gram-negative sepsis; and Case 5 had peritonitis with growth of E. coli and the presence of ﬁlariform larvae simultaneously in ascitic ﬂuid. The present study highlights some important points. The diagnosis of strongyloidiasis is often delayed and overlooked owing to non-speciﬁc gastrointestinal symptoms. Clinicians should have a high index of suspicion, especially in immunosuppressed patients such as those with congenital or acquired immunodeﬁciency states and those on immunosuppressive drugs following organ transplantation or autoimmune diseases and inﬂammatory bowel disease, in order to diagnose this potentially fatal condition early and thus alter the course of the illness resulting in a better outcome.19 Conﬁrmation of infection depends on recovery and identiﬁcation of adult worms, larvae or eggs from the stool, duodenal aspirate or biopsy. Stool examination has a poor sensitivity for detection of this parasite. Serology, if available, may be a useful modality for screening patients to prompt further investigation for detection of Strongyloides. It is noteworthy that eosinophilia is often absent in hyperinfection. In endemic areas, patients with systemic enteric bacterial infections without an obvious cause should be tested for the presence of strongyloidiasis. Because of the poor sensitivity of stool examination for the diagnosis of S. stercoralis, upper gastrointestinal endoscopy, duodenal aspirate microscopy and biopsy are indicated so that the diagnosis is not delayed or missed in patients with clinical and demographic features suggestive of strongyloidiasis. With the increasing number of immunocompromised individuals throughout the world, increased awareness of this relatively common infection will likely decrease the morbidity and mortality associated with this potentially fatal disease. Authors’ contributions: VA and TA conceived and designed the study; VA, TA and UCG studied the case ﬁles and collected the clinical and pathological details, reviewed, analysed and interpreted the data after retrieval of cases, and drafted the manuscript; VA and UCG revised the paper critically for intellectual content. All authors read and approved the ﬁnal manuscript. VA and UCG are guarantors of the paper. Funding: None. Conﬂicts of interest: None declared.
V. Agrawal et al. Ethical approval: Not required; all patients were assessed, investigated and treated in accordance with standard clinical procedures at the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.
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