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57-Year-Old Man With Fever, Rash, Chronic Watery Diarrhea, Cough, and Sweats
RESIDENTS’ CLINIC
57-Year-Old Man With Fever, Rash, Chronic Watery Diarrhea, Cough, and Sweats Elfriede A. Agyemang, MD, and Abinash Virk, MD
A
57-year-old previously healthy man from Minnesota presented for evaluation of chronic intermittent diarrhea, cough, and sweats of 6 months’ duration. The symptoms started while he was in Fiji (to which he travels to annually) with an urticarial, nontender, nonvesicular rash sparing mucosal surfaces that resolved after 2 days. One week after the rash resolved, he experienced intermittent productive cough, dyspnea, malaise, and diarrhea. Chest radiography in Fiji revealed a left pulmonary infiltrate. He received antibiotics without improvement. He also continued to have watery, nonbloody diarrhea, about 10 bowel movements per day. Because of his illness, he returned to the United States. His condition transiently improved for about 10 days after his return, but the symptoms, including cough, fever, chills, and diarrhea, recurred. He therefore presented to our clinic for further evaluation. In Fiji, his exposures included consuming rainwater and raw fish, walking barefoot on the lawn, and swimming in the ocean and local rivers. His 2 dogs were frequently infected with “dog fluke.” Other travel included trips to Mexico, Australia, and New Zealand. He had no ill contacts. He had no risk factors for human immunodeficiency virus or hepatitis B or C and no history of inflammatory bowel disease or asthma. He took no medications regularly. Laboratory tests from an outside institution revealed persistent eosinophilia ranging from 21.7% to 33.1% (reference range, 0%-7%) with normal lymphocytes and neutrophils. His erythrocyte sedimentation rate was 92 mm/h (reference range, 0-22 mm/h), and his C-reactive protein level was elevated at 23.3 mg/L (reference range, ⱕ8 mg/L). Stool studies were negative for ova and parasites, as were test results for Cyclospora and Giardia antigen, Clostridium difficile toxin, and special bacterial cultures (Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli 0157). Purified protein derivative (tuberculin) skin testing yielded negative results. 1. Which one of the following is the most likely explanation for this patient’s clinical presentation and high-grade eosinophilia? a. Immunologic disorder b. Allergic disorder c. Helminthic infection d. Viral infection e. Malignancy The patient’s presentation with fever and nonbloody diarrhea is seen in patients with immuno-
logic disorders such as inflammatory bowel disease; however, the respiratory symptoms and urticarial, mucosal-sparing rash would be unusual associations. Allergic reactions can cause eosinophilia and in some cases, such as in drug reactions, cause chronic diarrhea. However, our patient had no previous allergies and had not been taking any new medications. Helminthic infection is the most likely cause of this patient’s eosinophilia in the setting of his extensive travel history and food and environmental exposures. Parasitic infections, particularly helminthic infections, are the most common cause of eosinophilia in travelers and refugees.1-3 Certain viral infections such as human immunodeficiency virus and hepatitis B cause eosinophilia but are not likely in this patient who has no risk factors. Malignant disorders such as lymphoma or leukemia can cause eosinophilia, fever, night sweats, malaise, and weight loss. However, this patient did not have splenomegaly, marked lymphadenopathy, or lymphocytosis to support such a diagnosis. The suspicion for a parasitic infection in this patient was very high. His risk factors included walking barefoot on the grass in Fiji, swimming in local rivers, eating raw fish, and having dogs and cats in Fiji with recurrent worm infestations.
See end of article for correct answers to questions. Resident in Internal Medicine, Mayo School of Graduate Medical Education, Rochester, MN (E.A.A.); Adviser to resident and Consultant in Infectious Diseases, Mayo Clinic, Rochester, MN (A.V.).
2. At this time, which one of the following is the best next step? a. Treat with loperamide b. Perform colonoscopy with biopsies c. Send urine for Schistosoma ova examination d. Obtain 3 stool samples for ova and parasite examination e. Perform filaria serology and antigen studies Treating the patient’s diarrhea with loperamide without investigating the cause of his symptoms would be inappropriate because although his symptoms would improve, diagnosis and appropriate treatment of the underlying disorder would be delayed. Performing a colonoscopy with random colonic biopsies would be helpful in excluding inflammatory bowel disease, but it is invasive and would not be the optimal first test for a parasitic infection. Testing urine for schistosomiasis is not the best next step because this organism does not occur in Fiji. The patient has not traveled to Africa or other parts of Southeast Asia where schistosomiasis occurs. Eo-
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org 䡲 © 2012 Mayo Foundation for Medical Education and Research
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sinophilia is more commonly caused by nonschistosomal helminths among travelers to Asia.4 Obtaining 3 stool samples for detection of ova and parasites would be the most appropriate next step to evaluate for intestinal helminthic infections.5 Because filariasis occurs in Fiji and can cause high-grade eosinophilia and pulmonary infiltrates, testing for filaria is appropriate but not as the next step. Filarial serology can yield false-positive results in the presence of other helminths. In addition, filaria antigen tests will not help exclude other helminthic infections that are more prevalent in Asia. Stool samples were sent for ova and parasite testing, and serologic tests for Toxocara, Brucella, and Strongyloides were performed. A previous filarial antigen test result was negative. In less than 12 hours, the first stool specimen was reported as positive for Strongyloides larvae. Subsequently, the Strongyloides serology yielded positive findings. Results of Brucella and Toxocara serology were negative. 3. Which one of the following is the best option for treatment of this patient’s strongyloidiasis? a. Ivermectin b. Albendazole c. Watchful waiting d. Praziquantel e. Metronidazole Ivermectin is the drug of choice for strongyloidiasis and the most appropriate medication for this patient. The usual dosage of ivermectin is 200 g/kg per day given orally as a single dose on 2 separate days.2,6 Oral albendazole at a dosage of 400 mg twice a day for 7 days is an alternative but has lower efficacy.7 Watchful waiting is inappropriate in a symptomatic patient. Praziquantel is not an appropriate treatment for strongyloidiasis. Metronidazole is used for other protozoan infections such as giardiasis but not strongyloidiasis. We prescribed oral ivermectin, 18 mg/d, to be taken for 2 days, and a follow-up visit was scheduled. The other pending tests were followed up because concurrent parasitic infections are possible. 4. To monitor the patient’s response to treatment, which one of the following would be most appropriate? a. Strongyloides serology in 3 months b. Stool Strongyloides culture in 3 months c. Stool ova and parasite examination in 3 months d. Endoscopic evaluation in 3 months e. Repeat complete blood cell count with differential in 3 months Serologic testing could be done, but positive results may persist for an extended period and the test
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is expensive and unnecessary for follow-up. Stool culture on blood agar is labor intensive and time consuming and is used only for diagnosis, not for monitoring treatment efficacy.8 Examination of stool for ova and parasites is only used for diagnosis. Endoscopy is invasive and not necessary for routine monitoring. Repeat complete blood cell count with differential in 3 months would be most appropriate for monitoring treatment response. The absolute eosinophil count decreases markedly within 3 to 6 months after successful therapy.9,10 The patient was examined at our clinic 6 weeks after treatment with ivermectin. A repeat complete blood cell count with differential revealed a decrease of the eosinophil count from 36% (measured at the patient’s initial examination at our institution) to 13%. 5. Which one of the following would you recommend to prevent reinfection with Strongyloides in this patient? a. Stop going to Fiji b. Avoid walking barefoot in Fiji c. Use mosquito nets d. Take prophylactic mefloquine before traveling abroad e. Nothing can be done to prevent reinfection Telling the patient to stop going to Fiji is not practical. He should be advised to avoid walking barefoot and be encouraged to use protective footwear such as flip-flops, especially in areas with poor sanitation. His risk factor for acquiring Strongyloides was walking barefoot in areas in which other humans and dogs infected with Strongyloides had defecated. Frequent use of mosquito nets helps reduce malaria transmission but not strongyloidiasis. Mefloquine is used as prophylaxis against malaria, not strongyloidiasis, and chemoprophylaxis for strongyloidiasis is currently unavailable. It would be inappropriate to not advise this patient regarding preventive behaviors to reduce helminthic infections such as strongyloidiasis. The patient was advised to always use protective footwear while walking outdoors when he returns to Fiji. He was also counseled on proper hygiene, including drinking carbonated drinks or boiling local water before drinking it. A follow-up complete blood cell count with differential was recommended in 6 weeks. If at that time eosinophilia of 10% or more persists, repeated treatment with oral ivermectin, 18 mg/d for 2 days, should be recommended. DISCUSSION Strongyloidiasis is a helminthic infection caused by 2 species in the Strongyloides genus group. The most common species causing human disease worldwide
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org
RESIDENTS’ CLINIC
is Strongyloides stercoralis. The second species, Strongyloides fulleborni, infects chimpanzees and baboons and is found sporadically among humans on the African continent and in Papua New Guinea.11 Strongyloidiasis is estimated to affect 100 million people worldwide and causes mortality in immunocompromised hosts (mortality rate estimated to be 60%-80%).12 It is endemic in Latin America, Southeast Asia, sub-Saharan Africa, and parts of the southeastern United States. Strongyloidiasis is an important cause of eosinophilia (defined as an absolute eosinophil count of ⱖ500 cells/L) among travelers returning from developing countries. Among travelers returning from Africa, eosinophilia is more often secondary to schistosomiasis than strongyloidiasis.4 The S stercoralis life cycle is more complex than that of most nematodes because unlike other helminths, S stercoralis can complete its entire life cycle (from egg to adult worm) in humans (ie, the parasitic cycle).11 It also has an external cycle by which adult worms can develop fully from eggs without entering an intermediate host (ie, the free-living cycle). The major sites of S stercoralis infection are the skin, lungs, and intestines and are related to its life cycle in humans. The infective filariform larvae in contaminated soil penetrate the skin of the human host to enter the lymphatic circulation.13 The larvae are transported through the respiratory tract to the pharynx and then swallowed to reach the small bowel, where they transform into adult worms. The females, which can reproduce without males, are embedded in the duodenal submucosa. They lay embryonated eggs that hatch and release the rhabditiform larvae.8,14 The larvae penetrate the lumen and are either excreted with feces approximately 1 month after skin penetration or mature into filariform larvae to restart the parasitic cycle (autoinfection) by reinfecting the intestinal mucosa or skin of the perianal region.14 Autoinfection can lead to chronic and persistent infection with Strongyloides for many years after being in an endemic region. S stercoralis infection can result in a wide range of clinical manifestations, although most patients are asymptomatic. Symptomatic infections most commonly present as mild gastrointestinal symptoms such as abdominal discomfort and bloating.11,13 Other symptoms include diarrhea, nausea, vomiting, and anorexia.8 Dermatological manifestations are characterized by a migratory, serpiginous, urticarial rash called larva currens commonly involving the buttocks, groin, trunk, and waist.14 Pulmonary symptoms occur during larvae migration through the pulmonary system causing pulmonary infiltrates and eosinophilia (Loeffler syndrome). Symptoms include cough, new-onset wheezing, and dyspnea that may resemble asthma and other obstructive pulmonary diseases.14 Immunocom-
promised hosts including patients taking corticosteroids can experience severe S stercoralis hyperinfection with dissemination. Such patients may present with recurrent gram-negative bacteremias with or without eosinophilia, intestinal obstruction, paralytic ileus, gastrointestinal bleeding, hemorrhagic pneumonitis, respiratory failure, septicemia, or meningitis that can potentially be fatal.8 The diagnosis of strongyloidiasis is challenging because there are no distinctive clinical symptoms. Blood eosinophilia is usually present in acute or chronic Strongyloides infection and should raise suspicion in patients returning from endemic regions. A definite diagnosis of strongyloidiasis is based on microscopic identification of larvae in the stool and sometimes duodenal fluid.8 Stool examination to identify rhabditiform larvae is highly specific for strongyloidiasis; however, sensitivity is so poor that examination of a single sample identifies the larvae in only 30% to 50% of cases.6 Examination of multiple stool specimens is needed to improve diagnostic sensitivity. Stool studies include examination of direct fecal smears or use of formalin-ethyl acetate concentration techniques to identify the presence of rhabditiform larvae. The agar culture method (a small amount of stool is placed on a nutrient agar plate, incubated for 48 hours, and evaluated for visible tracks created by migrating larvae) is 96% sensitive.8 Patients with suspected strongyloidiasis should have 3 to 6 stool samples obtained on different days for ova and parasite testing, and if strongyloidiasis is strongly suspected, an agar culture test should be done. Some studies report increased diagnostic sensitivity of duodenal aspirate examination; however, this method requires invasive endoscopy and is recommended only for immunocompromised patients with an overwhelming infection in whom the presence of the parasites needs to be identified rapidly.8,14 Histologic examination of duodenal or jejunal biopsy specimens may also reveal the parasite embedded in the intestinal mucosa.8 Because failure to detect larvae on stool examination does not exclude strongyloidiasis, serologic testing may be of assistance. Enzyme-linked immunosorbent assay (ELISA) tests for antibodies to S stercoralis antigens extracted from the larvae. Although the ELISA has high sensitivity (88%) and specificity (99%), it does not differentiate present from past infection.4,8 Other helminthic infections limit the predictive value of the test because of crossreactivity.14 Nonetheless, the ELISA is a valuable test in patients for whom there is high suspicion for S stercoralis, especially in those with limited exposures to other helminths.4 All patients with strongyloidiasis should be treated regardless of the severity of their symptoms.
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org
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Treatment of strongyloidiasis is required to eradicate the parasite and avoid potentially serious disease. First-line treatment is ivermectin at 200 g/kg per day.6,8 Two doses are given about 1 to 14 days apart, and the cure rate is 94% to 100%.7,11,14 Ivermectin should be taken on an empty stomach with water. Prolonged or repeated therapy may be required for immunocompromised patients or patients with disseminated disease. An alternative for complicated infections is thiabendazole (25 mg/kg orally twice a day for 3 days), although it is associated with frequent and severe gastrointestinal adverse effects. Oral albendazole at a dosage of 400 mg twice a day for 7 days is another alternative but has lower efficacy.7,9 In severe strongyloidiasis, combination therapy with albendazole and ivermectin has also been reported.15 Case reports have described the use of veterinary parenteral and enema formulations of ivermectin on a compassionate basis following institutional review board approval in patients with severe hyperinfection who are unable to tolerate oral therapy.11,14 Treatment response can be monitored with absolute eosinophil count, which is expected to improve within 3 months after treatment.9 Serologic monitoring may be helpful; antibody levels are expected to markedly decrease within 6 months after treatment.11 Persons involved in international travel, especially to endemic regions, should be informed about the risk of S stercoralis infection and be advised on proper hygiene, including the use of protective footwear and avoidance of drinking from contaminated water bodies. Strongyloidiasis is an important cause of eosinophilia in the United States and among travelers to tropical and subtropical areas. It can be asymptomatic and potentially fatal, especially in immunocompromised patients. Physicians should recognize the risk factors and test patients with eosinophilia with or without systemic symptoms for S stercoralis infection with multiple stool examinations and serologic testing. First-line treatment is ivermectin. Proper hygiene plays a major role in disease prevention. Correspondence: Address to Abinash Virk, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
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REFERENCES 1. 2.
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Gyawali P, Whitty CJ. Investigating eosinophilia in patients returned from the tropics. Hosp Med. 2001;62(1):25-28. Goswami ND, Shah JJ, Corey GR, Stout JE. Persistent eosinophilia and Strongyloides infection in Montagnard refugees after presumptive albendazole therapy. Am J Trop Med Hyg. 2009; 81(2):302-304. Whetham J, Day JN, Armstrong M, Chiodini PL, Whitty CJ. Investigation of tropical eosinophilia: assessing a strategy based on geographical area. J infect. 2003;46(3):180-185. Meltzer E, Percik R, Shatzkes J, Sidi Y, Schwartz E. Eosinophilia among returning travelers: a practical approach. Am J Trop Med Hyg. 2008;78(5):702-709. Seybolt LM, Christiansen D, Barnett ED. Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Clin Infect Dis. 2006;42(3):363-367. Mirdha BR. Human strongyloidiasis: often brushed under the carpet. Trop Gastroenterol. 2009;30(1):1-4. Suputtamongkol Y, Premasathian N, Bhumimuang K, et al. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis. PLoS Negl Trop Dis. 2011;5(5):e1044. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001;33(7):1040-1047. Datry A, Hilmarsdottir I, Mayorga-Sagastume R, et al. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases. Trans R Soc Trop Med Hyg. 1994;88(3):344-345. Biggs BA, Caruana S, Mihrshahi S, et al. Management of chronic strongyloidiasis in immigrants and refugees: is serologic testing useful? Am J Trop Med Hyg. 2009;80(5):788-791. Centers for Disease Control and Prevention, DPDx. Strongyloidiasis. Centers for Disease Control and Prevention DPDx website. http://www.dpd.cdc.gov/dpdx/HTML/Strongyloidiasis. htm. Updated July 20, 2009. Accessed XXX. Olsen A, van Lieshout L, Marti H, et al. Strongyloidiasis—the most neglected of the neglected tropical diseases? Trans R Soc Trop Med Hyg. 2009;103(10):967-972. Iriemenam NC, Sanyaolu AO, Oyibo WA, Fagbenro-Beyioku AF. Strongyloides stercoralis and the immune response. Parasitol Int. 2010;59(1):9-14. Montes M, Sawhney C, Barros N. Strongyloides stercoralis: there but not seen. Curr Opin Infect Dis. 2010;23(5):500504. Lim S, Katz K, Krajden S, Fuksa M, Keystone JS, Kain KC. Complicated and fatal Strongyloides infection in Canadians: risk factors, diagnosis and management. CMAJ. 2004;171(5):479484.
CORRECT ANSWERS: 1. c. 2. d. 3. a. 4. e. 5. b
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org
57-Year-Old Man With Fever, Rash, Chronic Watery Diarrhea, Cough, and Sweats Elfriede A. Agyemang, MD, and Abinash Virk, MD
A
57-year-old previously healthy man from Minnesota presented for evaluation of chronic intermittent diarrhea, cough, and sweats of 6 months’ duration. The symptoms started while he was in Fiji (to which he travels to annually) with an urticarial, nontender, nonvesicular rash sparing mucosal surfaces that resolved after 2 days. One week after the rash resolved, he experienced intermittent productive cough, dyspnea, malaise, and diarrhea. Chest radiography in Fiji revealed a left pulmonary infiltrate. He received antibiotics without improvement. He also continued to have watery, nonbloody diarrhea, about 10 bowel movements per day. Because of his illness, he returned to the United States. His condition transiently improved for about 10 days after his return, but the symptoms, including cough, fever, chills, and diarrhea, recurred. He therefore presented to our clinic for further evaluation. In Fiji, his exposures included consuming rainwater and raw fish, walking barefoot on the lawn, and swimming in the ocean and local rivers. His 2 dogs were frequently infected with “dog fluke.” Other travel included trips to Mexico, Australia, and New Zealand. He had no ill contacts. He had no risk factors for human immunodeficiency virus or hepatitis B or C and no history of inflammatory bowel disease or asthma. He took no medications regularly. Laboratory tests from an outside institution revealed persistent eosinophilia ranging from 21.7% to 33.1% (reference range, 0%-7%) with normal lymphocytes and neutrophils. His erythrocyte sedimentation rate was 92 mm/h (reference range, 0-22 mm/h), and his C-reactive protein level was elevated at 23.3 mg/L (reference range, ⱕ8 mg/L). Stool studies were negative for ova and parasites, as were test results for Cyclospora and Giardia antigen, Clostridium difficile toxin, and special bacterial cultures (Salmonella, Shigella, Yersinia, Campylobacter, Escherichia coli 0157). Purified protein derivative (tuberculin) skin testing yielded negative results. 1. Which one of the following is the most likely explanation for this patient’s clinical presentation and high-grade eosinophilia? a. Immunologic disorder b. Allergic disorder c. Helminthic infection d. Viral infection e. Malignancy The patient’s presentation with fever and nonbloody diarrhea is seen in patients with immuno-
logic disorders such as inflammatory bowel disease; however, the respiratory symptoms and urticarial, mucosal-sparing rash would be unusual associations. Allergic reactions can cause eosinophilia and in some cases, such as in drug reactions, cause chronic diarrhea. However, our patient had no previous allergies and had not been taking any new medications. Helminthic infection is the most likely cause of this patient’s eosinophilia in the setting of his extensive travel history and food and environmental exposures. Parasitic infections, particularly helminthic infections, are the most common cause of eosinophilia in travelers and refugees.1-3 Certain viral infections such as human immunodeficiency virus and hepatitis B cause eosinophilia but are not likely in this patient who has no risk factors. Malignant disorders such as lymphoma or leukemia can cause eosinophilia, fever, night sweats, malaise, and weight loss. However, this patient did not have splenomegaly, marked lymphadenopathy, or lymphocytosis to support such a diagnosis. The suspicion for a parasitic infection in this patient was very high. His risk factors included walking barefoot on the grass in Fiji, swimming in local rivers, eating raw fish, and having dogs and cats in Fiji with recurrent worm infestations.
See end of article for correct answers to questions. Resident in Internal Medicine, Mayo School of Graduate Medical Education, Rochester, MN (E.A.A.); Adviser to resident and Consultant in Infectious Diseases, Mayo Clinic, Rochester, MN (A.V.).
2. At this time, which one of the following is the best next step? a. Treat with loperamide b. Perform colonoscopy with biopsies c. Send urine for Schistosoma ova examination d. Obtain 3 stool samples for ova and parasite examination e. Perform filaria serology and antigen studies Treating the patient’s diarrhea with loperamide without investigating the cause of his symptoms would be inappropriate because although his symptoms would improve, diagnosis and appropriate treatment of the underlying disorder would be delayed. Performing a colonoscopy with random colonic biopsies would be helpful in excluding inflammatory bowel disease, but it is invasive and would not be the optimal first test for a parasitic infection. Testing urine for schistosomiasis is not the best next step because this organism does not occur in Fiji. The patient has not traveled to Africa or other parts of Southeast Asia where schistosomiasis occurs. Eo-
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org 䡲 © 2012 Mayo Foundation for Medical Education and Research
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MAYO CLINIC PROCEEDINGS
sinophilia is more commonly caused by nonschistosomal helminths among travelers to Asia.4 Obtaining 3 stool samples for detection of ova and parasites would be the most appropriate next step to evaluate for intestinal helminthic infections.5 Because filariasis occurs in Fiji and can cause high-grade eosinophilia and pulmonary infiltrates, testing for filaria is appropriate but not as the next step. Filarial serology can yield false-positive results in the presence of other helminths. In addition, filaria antigen tests will not help exclude other helminthic infections that are more prevalent in Asia. Stool samples were sent for ova and parasite testing, and serologic tests for Toxocara, Brucella, and Strongyloides were performed. A previous filarial antigen test result was negative. In less than 12 hours, the first stool specimen was reported as positive for Strongyloides larvae. Subsequently, the Strongyloides serology yielded positive findings. Results of Brucella and Toxocara serology were negative. 3. Which one of the following is the best option for treatment of this patient’s strongyloidiasis? a. Ivermectin b. Albendazole c. Watchful waiting d. Praziquantel e. Metronidazole Ivermectin is the drug of choice for strongyloidiasis and the most appropriate medication for this patient. The usual dosage of ivermectin is 200 g/kg per day given orally as a single dose on 2 separate days.2,6 Oral albendazole at a dosage of 400 mg twice a day for 7 days is an alternative but has lower efficacy.7 Watchful waiting is inappropriate in a symptomatic patient. Praziquantel is not an appropriate treatment for strongyloidiasis. Metronidazole is used for other protozoan infections such as giardiasis but not strongyloidiasis. We prescribed oral ivermectin, 18 mg/d, to be taken for 2 days, and a follow-up visit was scheduled. The other pending tests were followed up because concurrent parasitic infections are possible. 4. To monitor the patient’s response to treatment, which one of the following would be most appropriate? a. Strongyloides serology in 3 months b. Stool Strongyloides culture in 3 months c. Stool ova and parasite examination in 3 months d. Endoscopic evaluation in 3 months e. Repeat complete blood cell count with differential in 3 months Serologic testing could be done, but positive results may persist for an extended period and the test
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is expensive and unnecessary for follow-up. Stool culture on blood agar is labor intensive and time consuming and is used only for diagnosis, not for monitoring treatment efficacy.8 Examination of stool for ova and parasites is only used for diagnosis. Endoscopy is invasive and not necessary for routine monitoring. Repeat complete blood cell count with differential in 3 months would be most appropriate for monitoring treatment response. The absolute eosinophil count decreases markedly within 3 to 6 months after successful therapy.9,10 The patient was examined at our clinic 6 weeks after treatment with ivermectin. A repeat complete blood cell count with differential revealed a decrease of the eosinophil count from 36% (measured at the patient’s initial examination at our institution) to 13%. 5. Which one of the following would you recommend to prevent reinfection with Strongyloides in this patient? a. Stop going to Fiji b. Avoid walking barefoot in Fiji c. Use mosquito nets d. Take prophylactic mefloquine before traveling abroad e. Nothing can be done to prevent reinfection Telling the patient to stop going to Fiji is not practical. He should be advised to avoid walking barefoot and be encouraged to use protective footwear such as flip-flops, especially in areas with poor sanitation. His risk factor for acquiring Strongyloides was walking barefoot in areas in which other humans and dogs infected with Strongyloides had defecated. Frequent use of mosquito nets helps reduce malaria transmission but not strongyloidiasis. Mefloquine is used as prophylaxis against malaria, not strongyloidiasis, and chemoprophylaxis for strongyloidiasis is currently unavailable. It would be inappropriate to not advise this patient regarding preventive behaviors to reduce helminthic infections such as strongyloidiasis. The patient was advised to always use protective footwear while walking outdoors when he returns to Fiji. He was also counseled on proper hygiene, including drinking carbonated drinks or boiling local water before drinking it. A follow-up complete blood cell count with differential was recommended in 6 weeks. If at that time eosinophilia of 10% or more persists, repeated treatment with oral ivermectin, 18 mg/d for 2 days, should be recommended. DISCUSSION Strongyloidiasis is a helminthic infection caused by 2 species in the Strongyloides genus group. The most common species causing human disease worldwide
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org
RESIDENTS’ CLINIC
is Strongyloides stercoralis. The second species, Strongyloides fulleborni, infects chimpanzees and baboons and is found sporadically among humans on the African continent and in Papua New Guinea.11 Strongyloidiasis is estimated to affect 100 million people worldwide and causes mortality in immunocompromised hosts (mortality rate estimated to be 60%-80%).12 It is endemic in Latin America, Southeast Asia, sub-Saharan Africa, and parts of the southeastern United States. Strongyloidiasis is an important cause of eosinophilia (defined as an absolute eosinophil count of ⱖ500 cells/L) among travelers returning from developing countries. Among travelers returning from Africa, eosinophilia is more often secondary to schistosomiasis than strongyloidiasis.4 The S stercoralis life cycle is more complex than that of most nematodes because unlike other helminths, S stercoralis can complete its entire life cycle (from egg to adult worm) in humans (ie, the parasitic cycle).11 It also has an external cycle by which adult worms can develop fully from eggs without entering an intermediate host (ie, the free-living cycle). The major sites of S stercoralis infection are the skin, lungs, and intestines and are related to its life cycle in humans. The infective filariform larvae in contaminated soil penetrate the skin of the human host to enter the lymphatic circulation.13 The larvae are transported through the respiratory tract to the pharynx and then swallowed to reach the small bowel, where they transform into adult worms. The females, which can reproduce without males, are embedded in the duodenal submucosa. They lay embryonated eggs that hatch and release the rhabditiform larvae.8,14 The larvae penetrate the lumen and are either excreted with feces approximately 1 month after skin penetration or mature into filariform larvae to restart the parasitic cycle (autoinfection) by reinfecting the intestinal mucosa or skin of the perianal region.14 Autoinfection can lead to chronic and persistent infection with Strongyloides for many years after being in an endemic region. S stercoralis infection can result in a wide range of clinical manifestations, although most patients are asymptomatic. Symptomatic infections most commonly present as mild gastrointestinal symptoms such as abdominal discomfort and bloating.11,13 Other symptoms include diarrhea, nausea, vomiting, and anorexia.8 Dermatological manifestations are characterized by a migratory, serpiginous, urticarial rash called larva currens commonly involving the buttocks, groin, trunk, and waist.14 Pulmonary symptoms occur during larvae migration through the pulmonary system causing pulmonary infiltrates and eosinophilia (Loeffler syndrome). Symptoms include cough, new-onset wheezing, and dyspnea that may resemble asthma and other obstructive pulmonary diseases.14 Immunocom-
promised hosts including patients taking corticosteroids can experience severe S stercoralis hyperinfection with dissemination. Such patients may present with recurrent gram-negative bacteremias with or without eosinophilia, intestinal obstruction, paralytic ileus, gastrointestinal bleeding, hemorrhagic pneumonitis, respiratory failure, septicemia, or meningitis that can potentially be fatal.8 The diagnosis of strongyloidiasis is challenging because there are no distinctive clinical symptoms. Blood eosinophilia is usually present in acute or chronic Strongyloides infection and should raise suspicion in patients returning from endemic regions. A definite diagnosis of strongyloidiasis is based on microscopic identification of larvae in the stool and sometimes duodenal fluid.8 Stool examination to identify rhabditiform larvae is highly specific for strongyloidiasis; however, sensitivity is so poor that examination of a single sample identifies the larvae in only 30% to 50% of cases.6 Examination of multiple stool specimens is needed to improve diagnostic sensitivity. Stool studies include examination of direct fecal smears or use of formalin-ethyl acetate concentration techniques to identify the presence of rhabditiform larvae. The agar culture method (a small amount of stool is placed on a nutrient agar plate, incubated for 48 hours, and evaluated for visible tracks created by migrating larvae) is 96% sensitive.8 Patients with suspected strongyloidiasis should have 3 to 6 stool samples obtained on different days for ova and parasite testing, and if strongyloidiasis is strongly suspected, an agar culture test should be done. Some studies report increased diagnostic sensitivity of duodenal aspirate examination; however, this method requires invasive endoscopy and is recommended only for immunocompromised patients with an overwhelming infection in whom the presence of the parasites needs to be identified rapidly.8,14 Histologic examination of duodenal or jejunal biopsy specimens may also reveal the parasite embedded in the intestinal mucosa.8 Because failure to detect larvae on stool examination does not exclude strongyloidiasis, serologic testing may be of assistance. Enzyme-linked immunosorbent assay (ELISA) tests for antibodies to S stercoralis antigens extracted from the larvae. Although the ELISA has high sensitivity (88%) and specificity (99%), it does not differentiate present from past infection.4,8 Other helminthic infections limit the predictive value of the test because of crossreactivity.14 Nonetheless, the ELISA is a valuable test in patients for whom there is high suspicion for S stercoralis, especially in those with limited exposures to other helminths.4 All patients with strongyloidiasis should be treated regardless of the severity of their symptoms.
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org
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Treatment of strongyloidiasis is required to eradicate the parasite and avoid potentially serious disease. First-line treatment is ivermectin at 200 g/kg per day.6,8 Two doses are given about 1 to 14 days apart, and the cure rate is 94% to 100%.7,11,14 Ivermectin should be taken on an empty stomach with water. Prolonged or repeated therapy may be required for immunocompromised patients or patients with disseminated disease. An alternative for complicated infections is thiabendazole (25 mg/kg orally twice a day for 3 days), although it is associated with frequent and severe gastrointestinal adverse effects. Oral albendazole at a dosage of 400 mg twice a day for 7 days is another alternative but has lower efficacy.7,9 In severe strongyloidiasis, combination therapy with albendazole and ivermectin has also been reported.15 Case reports have described the use of veterinary parenteral and enema formulations of ivermectin on a compassionate basis following institutional review board approval in patients with severe hyperinfection who are unable to tolerate oral therapy.11,14 Treatment response can be monitored with absolute eosinophil count, which is expected to improve within 3 months after treatment.9 Serologic monitoring may be helpful; antibody levels are expected to markedly decrease within 6 months after treatment.11 Persons involved in international travel, especially to endemic regions, should be informed about the risk of S stercoralis infection and be advised on proper hygiene, including the use of protective footwear and avoidance of drinking from contaminated water bodies. Strongyloidiasis is an important cause of eosinophilia in the United States and among travelers to tropical and subtropical areas. It can be asymptomatic and potentially fatal, especially in immunocompromised patients. Physicians should recognize the risk factors and test patients with eosinophilia with or without systemic symptoms for S stercoralis infection with multiple stool examinations and serologic testing. First-line treatment is ivermectin. Proper hygiene plays a major role in disease prevention. Correspondence: Address to Abinash Virk, MD, Division of Infectious Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905 ([email protected]).
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Gyawali P, Whitty CJ. Investigating eosinophilia in patients returned from the tropics. Hosp Med. 2001;62(1):25-28. Goswami ND, Shah JJ, Corey GR, Stout JE. Persistent eosinophilia and Strongyloides infection in Montagnard refugees after presumptive albendazole therapy. Am J Trop Med Hyg. 2009; 81(2):302-304. Whetham J, Day JN, Armstrong M, Chiodini PL, Whitty CJ. Investigation of tropical eosinophilia: assessing a strategy based on geographical area. J infect. 2003;46(3):180-185. Meltzer E, Percik R, Shatzkes J, Sidi Y, Schwartz E. Eosinophilia among returning travelers: a practical approach. Am J Trop Med Hyg. 2008;78(5):702-709. Seybolt LM, Christiansen D, Barnett ED. Diagnostic evaluation of newly arrived asymptomatic refugees with eosinophilia. Clin Infect Dis. 2006;42(3):363-367. Mirdha BR. Human strongyloidiasis: often brushed under the carpet. Trop Gastroenterol. 2009;30(1):1-4. Suputtamongkol Y, Premasathian N, Bhumimuang K, et al. Efficacy and safety of single and double doses of ivermectin versus 7-day high dose albendazole for chronic strongyloidiasis. PLoS Negl Trop Dis. 2011;5(5):e1044. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis. 2001;33(7):1040-1047. Datry A, Hilmarsdottir I, Mayorga-Sagastume R, et al. Treatment of Strongyloides stercoralis infection with ivermectin compared with albendazole: results of an open study of 60 cases. Trans R Soc Trop Med Hyg. 1994;88(3):344-345. Biggs BA, Caruana S, Mihrshahi S, et al. Management of chronic strongyloidiasis in immigrants and refugees: is serologic testing useful? Am J Trop Med Hyg. 2009;80(5):788-791. Centers for Disease Control and Prevention, DPDx. Strongyloidiasis. Centers for Disease Control and Prevention DPDx website. http://www.dpd.cdc.gov/dpdx/HTML/Strongyloidiasis. htm. Updated July 20, 2009. Accessed XXX. Olsen A, van Lieshout L, Marti H, et al. Strongyloidiasis—the most neglected of the neglected tropical diseases? Trans R Soc Trop Med Hyg. 2009;103(10):967-972. Iriemenam NC, Sanyaolu AO, Oyibo WA, Fagbenro-Beyioku AF. Strongyloides stercoralis and the immune response. Parasitol Int. 2010;59(1):9-14. Montes M, Sawhney C, Barros N. Strongyloides stercoralis: there but not seen. Curr Opin Infect Dis. 2010;23(5):500504. Lim S, Katz K, Krajden S, Fuksa M, Keystone JS, Kain KC. Complicated and fatal Strongyloides infection in Canadians: risk factors, diagnosis and management. CMAJ. 2004;171(5):479484.
CORRECT ANSWERS: 1. c. 2. d. 3. a. 4. e. 5. b
Mayo Clin Proc. 䡲 November 2012;87(11):e83-e86 䡲 http://dx.doi.org/10.1016/j.mayocp.2012.05.028 www.mayoclinicproceedings.org