aDepartment of Medicine, Centre Hospitalier de l’Universite de Montreal (CHUM), Montreal, QC, H2W1T8, Canada bCorresponding Author: Frederic Chalut, General Internal Medicine, Department of Medicine, CHUM, 3840 St-Urbain str, Montreal, QC, H2W1T8, Canada
Manuscript submitted May 29, 2017, accepted June 27, 2017 Short title: Strongyloides Hyperinfection Syndrome doi: https://doi.org/10.14740/cii66e
Strongyloides stercoralis is a soil transmitted intestinal nematode affecting millions of people worldwide. The strongyloides hyperinfection syndrome (SHS) is an uncommon presentation leading to a life-threatening infestation. As the small bowel is often involved, enteric absorption of anthelmintic drugs such as ivermectin could be impaired. No parenteral anthelmintics have been licensed for use in humans. We report a case of a patient with SHS who was successfully treated with unlabeled subcutaneous veterinary preparations of ivermectin.
Strongyloides stercoralis (SS) is an intestinal nematode affecting over 100 million people worldwide [1]. Strongyloides hyperinfection syndrome (SHS) is a rare presentation characterized by a catastrophic infestation of larvae mostly in the lungs and gastrointestinal (GI) tract [1]. As ileus, intestinal obstruction and malabsorption syndrome are possible complications, enteric absorption of drugs can be impaired [2, 3]. No licensed parenteral anthelmintic drugs exist in humans. Very few publications in the literature have reported successful treatment of patients with unlabeled parenteral preparations of ivermectin [2, 3]. We report a case of a patient who presented with a malabsorption syndrome due to severe intestinal strongyloides. Despite multiple complications and a prolonged intensive care unit (ICU) stay, the patient was successfully treated with unlabeled subcutaneous veterinary preparations of ivermectin.
A 72-year-old female of a Haitian origin consulted our emergency department with a 2-month history of deterioration of her general health associated with nausea, vomiting, anorexia (35 lb weight loss), diarrhea, and chills. The symptoms started during her 3-month vacation in Haiti. Her past medical history included type 2 insulin-dependent diabetes mellitus, hypertension, dyslipidemia and mild cognitive impairment.
Upon admission, her laboratory workup showed leukocytosis (17.2 × 109 cells/L) (normal values (N): 4.0 - 11.0 × 109 cells/L), thrombocytosis (530 × 109 cells/L) (N: 145 - 470 × 109 cells/L), microcytic anemia (86 g/L) (N: 120 - 160 g/L), normal peripheral blood eosinophil count and an increased C-reactive protein (30 mg/L) (N: < 9.99mg/L). Abdominal CT revealed colic fat remodeling. Stool for ova and parasites was negative.
She continued to deteriorate in the following days. Laboratory results revealed an eosinophilia (1.03 × 109 cells/L), an acute renal failure (creatinine: 114 µmol/L) (N: 42 - 89 µmol/L) and progressive anemia (69 g/L). GI endoscopies and biopsies were then performed and demonstrated a non-specific patchy hemorrhagic colitis. A working diagnosis of amoebic colitis was then evoked and metronidazole was started.
The GI biopsies demonstrated chronic active gastritis and moderate colitis. SS larvae were present in both stomach and colon specimens, suggesting SHS. Ivermectin was considered but could not be given immediately due to restrictions in Canada (known as the “exception drug status program”).
During this time, rapid deterioration of the patient’s general status ensued with occurrence of an altered level of consciousness, lethargy, tachypnea and metabolic acidosis (pH 6.95, HCO3 2 mm Hg, and PCO2 10 mm Hg). Serum lactates were normal, suggesting a combined effect of ketoacidosis and acute renal failure.
Oral preparation of ivermectin (200 µg/kg/day) was initiated as soon as available. Oral albendazole (400 mg twice daily) was added due to persistent larvae excretion in feces. Despite this treatment regimen, a bronchoalveolar lavage performed a week later showed SS larvae. The patient continued to deteriorate clinically with persistent hypereosinophilia (2.58 × 109 cells/L) and diarrhea. In the absence of clinical improvement, a malabsorption syndrome was suspected. Subcutaneous veterinary preparation of ivermectin (200 µg/kg/day) was given until 2 weeks after first negative stool culture report and was then provided monthly for the subsequent 6 months.
The patient had a long ICU stay: multiple infections (enteric germ bacterial septic shock, bacterial meningitis, and ventilator acquired pneumonia), Takotsubo cardiomyopathy, acute tubular necrosis requiring hemodialysis, ICU myopathy and neuropathy, and multifactorial encephalopathy. She was discharged to a long-term care facility with some residual encephalopathy and impaired functional status.
SS is endemic in southern Europe, the Caribbean, Southeast Asia, Latin America, and sub-Saharan Africa [1]. Transmission usually occurs through skin penetration by direct contact with infected environment harboring the parasite [4]. Inoculation following solid organ transplantation has also been described [4].
After entering the derma, the infective (filariform) larva spreads hematogenously to the lungs. It then passes through alveoli to the upper respiratory tract and is swallowed [4]. In the intestine, it matures in an adult worm that produces eggs [4]. Most of non-infective (rhabdiform) larvae are cleared through feces [4]. Some of rhabdiform larvae could mature into filariform form and re-infect the host through GI mucosa or perianal skin [4]. Due to this unique auto-infective cycle, exposition to SS could have occurred decades before SHS occurs [4].
In the immunocompetent host, excessive replication of SS is kept in check by Th2 activation with IL-3, IL-4 and IL-13 secretion resulting in eosinophilia and immunoglobulin production [5]. In SHS, immunosuppression leads to accelerated auto-infective cycle and increased larval migration [5]. Table 1 [3-6] presents the various immunosuppressive states associated with SHS [5].
Table 1. Immunosuppressive States Associated With Strongyloides Stercoralis Hyperinfection Syndrome*
Clinical manifestations
SS is usually asymptomatic; mild eosinophilia, intermittent mild GI, respiratory and/or dermatologic symptoms can occur. At the other end of the spectrum, massive infestation of the lungs and GI tract is the hallmark of SHS [1]. Disseminated strongyloides is a disseminated disease of other organs that could happen during the course of SHS [1]. It should be emphasized that severe cases of strongyloides can involve directly or indirectly nearly any part of the body and that no routine test is diagnostic of the infection. Hence, a high index of suspicion is warranted. Common features of SHS are presented in Table 2 [4, 7-15].
Table 2. Clinical Features Associated With Strongyloides Stercoralis Hyperinfection Syndrome*
In one series, most common findings were fever, respiratory symptoms, GI symptoms, neurologic symptoms, rash and hypereosinophilia [6]. Nearly 40% of patients presented bacterial infection, most often enterobacteriacae bacteremia due to damage to bowel mucosa [4]. The bacteremia can recur despite antibiotic treatment because of repeated translocation and enteric germ meningitis could ensue [4]. Bronchospasm that worsens with steroid treatment and unexplained concomitant GI and respiratory features are other clues of SHS.[7]. Larva currens is a pruritic serpiginous urticarial rash associated with larvae migration under the skin [8]. Confluent pruritic periumbilical macules harvesting SS could appear after institution of positive pressure ventilation due to retrograde venous larvae migration [9].
Diagnosis
SS detection in feces could be challenging since conventional smear examination failed to detect larvae in as much as 70% of cases [1, 5]. In fact, excretion of SS can be scanty even in SHS and hence missed. To overcome this problem, various specialized stool examination techniques have been developed, the most sensitive being agar plate culture (96%), albeit being time and resource consuming [1, 4, 5]. It involves incubation of stools on agar plate for 2 days. Presence of larvae can be detected by microscopic examination or suggested by pattern of bacterial growth. Indeed, serpiginous bacterial growth can ensue in the tract of crawling SS larvae. Another strategy is a repeated stool microscopy with nearly 100% sensitivity after seven samples examination [4].
Duodenal aspiration and biopsy has been shown to detect SS in 70% of cases [1, 2]. Examination of cerebrospinal, pleural, ascites and bronchoalveolar lavage specimens as well as skin and GI tract biopsies have also been used to demonstrate SS larvae in disseminated infection [1, 4, 13]. These studies should be obtained upon clinical judgment.
Various serologies have been developed to detect SS antibodies or antigens. Advocates of these techniques evoke increased sensitivity compared to stool examination per se, and the possibility to follow antibody titer as a potential surrogate of treatment response [1, 13]. Drawbacks include suboptimal sensitivity in the immunosuppressed population, cross-reaction with other parasites and difficulty in differentiation between past and current infection [13]. PCR for detection of SS antigen in feces and luciferase immunoprecipitation system (LIPS) are newer techniques that could become more available in years to come [1, 4, 13].
Management and prognosis
Due to the paucity of SHS described cases, treatment options are suggested by expert’s opinions based on case reports. There have been reports of cure with daily oral or subcutaneous ivermectin (with or without oral albendazole adjunct therapy) [2, 3]. Intravenous and rectal enemas preparations seem less successful [2-4]. It has been suggested that the treatment duration should be titrated upon clinical status of the patient. It should also be continued until after the parasitic tests are negatives for 2 weeks (one auto-infective cycle) [3].
Failure of oral treatment can occur due to an intestinal obstruction, ileus or malabsorption [2, 3]. A recent review suggests that subcutaneous veterinary preparation of ivermectin can be an alternative for these patients, with 75% of patients achieving microbiological cure [2]. Same dose as for oral treatment (200 mg/kg/day) has been used in most cases [2].
Most patients with SHS will require an ICU setting for management of hemodynamic instability, ventilation compromise and other complications. These patients should be isolated, and health care providers and visitors should wear gowns, gloves and masks to avoid transmission [1]. Indeed, SS larvae could be found in the immediate environment of the patients such as bedding sheets [1]. Despite best management, SHS yields a poor prognosis with around 60% mortality [2, 6].
Conclusion
Albeit rare in northern industrialized countries, SHS is a not-to-be-missed diagnosis since it involves numerous implications in term of patient’s outcome, cost for society and public health (both for the health-care professionals and general population). Moreover, clinicians need to be aware of SHS as the incidence may increase over the years to come due to immigration and travels to and from endemic countries. Prompt diagnosis requires a high degree of suspicion as well as the appropriate laboratory expertise and resources. Unlabeled subcutaneous veterinary preparations of ivermectin need to be considered and should be promptly available when SHS is suspected.
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