Chronic Strongyloidiasis – Don't Look and You Won't Find

CLINICAL

Chronic strongyloidiasis – Don’t look and you won’t find

Wendy Page, Rick Speare

Background hronic strongyloidiasis in humans is immunosuppressive therapy (especially caused by the remarkably persistent corticosteroids and chemotherapy), Strongyloidiasis is one of the most C roundworm Strongyloides as this can cause the hyperinfective neglected tropical diseases and it exists stercoralis, distinguished by its syndrome. in Australia. Patients may have acquired unique autoinfective lifecycle. General Patients who are immunocompromised, their initial infection while in an endemic practitioners (GPs) have an important such as those with diabetes, systemic area. Because of the autoinfective role in diagnosing and treating chronic lupus erythematosus (SLE), human cycle of Strongyloides stercoralis, the strongyloidiasis to prevent cases of fatal T-cell lymphotropic virus type 1, or organ causative agent, these patients may hyperinfection. Unless strongyloidiasis is transplant recipients, as well as patients remain infected for life unless effectively deliberately considered, the diagnosis is who are malnourished and infected, treated. Corticosteroids have precipitated 8 death in more than 60% of disseminated unlikely to be made. are at risk of dissemination. Aboriginal strongyloidiasis cases. and Torres Strait Islander patients from Epidemiology rural and remote areas in Australia Objective An estimated 370 million people should not be given immunosuppressive worldwide are infected with S. stercoralis.1 treatment without being tested or treated The aim of this article is to raise Strongyloidiasis is endemic in tropical and prophylactically for strongyloidiasis.9 awareness of the unique features of subtropical regions of the world where S. stercoralis and outline the important warmth, moisture and poor sanitation Life cycle role that general practitioners (GPs) favour its spread. A prevalence greater The traditional mode of S. stercoralis have in diagnosing and treating chronic than 5% is considered hyperendemic.2 infection is penetration of the skin by strongyloidiasis, as well as in preventing Some remote Aboriginal and Torres Strait microscopic, infective filariform larvae. cases of fatal hyperinfection. Islander communities in Australia have The larvae are then carried in the Discussion had prevalences up to 60%.3 In Australia, bloodstream to the right side of the heart. strongyloidiasis should be considered in They exit the pulmonary capillaries, enter Chronic strongyloidiasis is not an overt residents of endemic areas, immigrants the alveolar spaces in the lungs, ascend disease – if you don’t look for it, you (including older patients from southern the bronchial tree and are swallowed by won’t find it. In particular, patients who Europe), refugees, war veterans (World the host. In the small intestine, the larvae have lived in an endemic area or have War II and Vietnam War), and workers and mature into adult female worms (2–3 mm unexplained eosinophilia must be checked travellers returning from endemic areas with long) and penetrate the mucosa of the for the presence of the parasite before ‘a souvenir you don’t want to bring home’.4–7 proximal small intestine, where they can initiation of steroid or immunosuppressive lay up to 40 eggs a day. This occurs 17–28 therapy. These patients, if infected, may Who is at risk? days after the initial infection. The eggs develop hyperinfective syndrome, which Although history is important to identify hatch in the intestinal mucosa to release has a high fatality rate. those at risk of strongyloidiasis, the initial rhabditiform larvae that migrate to the exposure to infective larvae may have lumen of the intestine.2 occurred decades earlier. Doctors should The life cycle of S. stercoralis has three consider infection with S. stercoralis unusual features that make its eradication in all patients who are to receive difficult:

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• Autoinfective larvae: these can • Skin: larva currens is the only • Multiple end-organ failure: this penetrate the colonic wall or perianal pathognomonic sign in patients with is an outcome of disseminated skin, and enter the body to repeat the S. stercoralis infection. Erythematous strongyloidiasis with a poor prognosis migration that establishes ongoing serpiginous lesions appear and move despite treatment.2,14,24 internal reinfection. This autoinfective rapidly (2–10 cm per hour). This is cycle allows strongyloidiasis to persist more commonly seen on the trunk Early diagnosis improves for decades after the host has left and buttocks (Figure 1). Other signs outcome an endemic area. Hyperinfection or include pruritus, recurrent urticaria or Prevention of high morbidity and disseminated strongyloidiasis occurs a ‘rash that comes and goes’.2,4,14 A mortality from strongyloidiasis is because large numbers of parasitic ‘rapidly progressive purpuric petechial dependent on clinicians’ awareness. females develop in the small intestine eruption with a reticulated pattern’ Most cases of disseminated and thousands of autoinfective larvae has been described in disseminated strongyloidiasis are diagnosed at autopsy migrate through the organs.2 Prescribing strongyloidiasis.16 or in the late disseminated phase, when immunosuppressants, especially • Respiratory: pulmonary millions of parasites are in the body, corticosteroids, to undiagnosed strongyloidiasis manifestations which means they are more easily patients who are infected is a include dyspnoea, bronchospasm, identified in body fluids. Unfortunately, common precipitant for disseminated haemoptysis, bronchopneumonia, this is too late for the majority, who will strongyloidiasis because it stimulates pleural effusion, lung abscess and die from this disease. All individuals the autoinfective cycle.2,8,10 interlobular septal fibrosis.14,17 There who are infected, including those who • Parthenogenesis: the ability of the are reported cases of immigrants are asymptomatic, should be treated parasitic female to reproduce without in Australia with cavitary lesions on because hyperinfection is unpredictable a male contributes to the challenges of chest X-ray that mimicked tuberculosis and potentially fatal.14,15 successful treatment in humans. One but resolved after treatment with GPs have an important role in the remaining female parasite can result in anthelmintics.18 diagnosis, treatment and follow-up of recrudescence of infection. • Gastrointestinal: manifestations may patients with chronic strongyloidiasis by: • External phase of life cycle and free- include diarrhoea, hypokalaemia, • identifying patients at risk (who may living adults: S. stercoralis has the ability protein-losing enteropathy, be asymptomatic) to produce one generation of short- malnutrition, wasting, epigastric • considering strongyloidiasis as a lived, free-living adult male and female pain and tenderness that simulates differential diagnosis or underlying worms in the external environment. peptic ulcers, subacute obstruction cause for non-specific clinical Only one generation of free-living adults or segmental ileus, paralytic ileus, manifestations as outlined above. are produced by S. stercoralis and they ulcerative enteritis with intestinal Gram-negative sepsis should be a die within 10 days.2,11,12 The infective perforation and peritonitis, melaena, prompt to consider strongyloidiasis as larvae can survive in the soil for several and haematochezia.14,15,19 an underlying factor11,23,24 weeks if the environment is moist and • Genitourinary: manifestations may temperature is suitable (23–28°C).11 include nephrotic syndrome and renal abscess.15,20 Clinical presentations • Hepatic: manifestations may include The autoinfective larvae of S. stercoralis hepatomegaly and hepatic abscess.15,21 can invade any organ of the body, • Cardiac: manifestations may include including the central nervous system, pericardial effusion.22 through random migration.2,13–15 The • Haematological: eosinophilia is present symptoms of chronic strongyloidiasis may in 10–70% of chronic strongyloidiasis be protean, non-specific and intermittent, cases, but is less prevalent in making the underlying diagnosis elusive. disseminated strongyloidiasis. Signs and symptoms vary with the • Central nervous system (CNS): location and number of worms, and manifestations may include bacterial Figure 1. Larva currens on the trunk of female whether the autoinfective larvae have meningitis and abnormal CNS patient from northern New South Wales carried bacteria to extraintestinal locations. signs.2,13,23 These erythematous, serpiginous lesions appear and move rapidly (2–10 cm per hour), and are the • Sepsis: Gram-negative septicaemia or The following clinical presentations may pathognomonic sign of strongyloidiasis. alert the clinician to consider the diagnosis sepsis in any organ may occur due to Source: W. Page of strongyloidiasis: enteric bacteria.15,24

• screening patients who are at risk Faecal testing has been the mainstay of strongyloidiasis and hyperinfection.27 False and advising prophylaxis prior to testing for ova, cysts and parasites. The negatives can occur when new cases have immunosuppressant therapy8,9,25 presence of live larvae, rather than eggs, not yet seroconverted. Also, patients who • considering strongyloidiasis in patients in fresh faecal specimens is a feature of are severely immunocompromised may be with unexpected clinical deterioration S. stercoralis. Cool storage, transportation unable to generate adequate IgG or a raised on immunosuppressive therapy (eg and delays before microscopic examination eosinophil count. Strongyloides-specific IgG asthma,26 malignancy). in a laboratory reduce the chance of a serology decreases with effective treatment positive diagnosis. Agar plate testing relies and is useful in monitoring eradication.29–32 Diagnosis on live larvae to track across the plate.28 The usefulness and sensitivity of More recent molecular diagnostics hold Treatment diagnostic testing is affected by the hope for improved sensitivity.8 Including The goal of therapy is eradication of all phase of strongyloidiasis – acute, chronic ‘strongyloides’ as a possible diagnosis on S. stercoralis parasites. One remaining or disseminated. The different phases, the clinical indication section would assist parasite has the ability to replicate and likely larval load per millilitre of faeces, laboratory scientists in selecting the most cause a recrudescence of infection.2 and immune responses are described in appropriate faecal diagnostic test. Ivermectin is currently the most effective Table 1. Faecal testing has high sensitivity therapy for the eradication of in acute and disseminated strongyloidiasis, Serology S. stercoralis. Albendazole can be used whereas serology is most useful in Strongyloides serology using the when ivermectin is not suitable (eg diagnosing chronic strongyloidiasis in strongyloides immunoglobulin G (IgG) concurrent loiasis, which is caused by patients who are immunocompetent. enzyme-linked immunosorbent assay the parasitic worm Loa loa).8 However, (ELISA) has a high sensitivity and although the intensity of infection will be Faecal examinations specificity for chronic strongyloidiasis.2,8,15,27 reduced with albendazole, the cure rate Patients with chronic strongyloidiasis Strongyloides-specific IgG relies on is lower.4,32–34 If immunosuppressants may have multiple negative test results measuring the body’s immune response to are required for a patient at risk of on faecal specimens.27 Faecal testing the presence of S. stercoralis. The immune strongyloidiasis, prophylactic treatment has a higher sensitivity in acute and response varies for different phases of is warranted. Hyperinfection is life disseminated phases because of the high strongyloidiasis and is described in Table 1. threatening and requires specialist numbers of larvae in faeces (see Table 1). Sensitivity may be reduced in acute advice.8,35

Table 1. Interpreting faecal and serology diagnostic tests for phases of strongyloidiasis 2,11,27,32

Strongyloides Larvae serum IgG Phase (mL of faeces) antibody levels Immune response and parasite activity Acute – 0 to >1000 Negative, Large number of parasitic females in intestine, Initial infection may have significant Standard usually equivocal or then larval output slows as immune response and gastrointestinal and non-specific positive positive eosinophils increases. ‘Window period’ before symptoms specific IgG antibody levels become raised Chronic – 0– 400 Positive or Immune response keeps the number of parasites Non-specific, intermittent symptoms over Standard faecal equivocal lower. decades. tests usually Higher IgG titre is indicative of appropriate immune A control study found up to 70% of negative response rather than high parasite numbers. patients with intermittent symptoms2 Special tests using Eosinophilia intermittent: 10–70% multiple specimens required Hyperinfective/disseminated 400 to >1000 Positive, Immune response decreases and accelerated strongyloidiasis – Standard faecal equivocal or autoinfection: Exponential increase in parasites test usually positive negative Autoinfective cycle is ‘out of control’. Patients who throughout body. Increased rates of Sputum and are immunosuppressed, immunocompromised sepsis and multiple end-organ failure. body fluids likely and malnourished have reduced ability to generate High fatality rate to be positive for adequate immune response. Eosinophilia is less autoinfective larvae common in hyperinfection

IgG, immunoglobulin G

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Follow-up of chronic Primary prevention • All patients who are infected, including strongyloidiasis Transmission can be decreased by: those who are asymptomatic, should be Best practice involves follow-up to • improving access to sanitation facilities treated. ensure eradication. Strongyloides and environmental health education • Eradication to the last worm is the goal serology is useful to monitor the • eradicating S. stercoralis infection of therapy. effectiveness of therapy. A negative in all people in a community to Authors result after approximately six months eliminate the source of the infective Wendy Page MBBS, FRACGP, FACRRM, MPH&TM, indicates successful therapy. Repeated larvae. Population health strategies PhD candidate, Miwatj Health Aboriginal courses of treatment and further need implementation in endemic Corporation, Nhulunbuy, NT. [email protected]. follow-up may be required. Eosinophilia communities.12,27 edu.au may be an indication of recrudescence. Rick Speare PhD, MBBS (Hons), BVs (Hons), FAFPHM, FACTM, MACVS, Emeritus Professor, Current criteria for cure require negative Conclusion Public Health and Tropical Medicine, James Cook serology, negative faeces and no Strongyloidiasis is a potentially fatal University, Townsville, QLD symptoms, although an element of disease that is rarely seen in mainstream Competing interests: None. Provenance and peer review: Not commissioned, uncertainty as to whether the last Australian communities where access externally peer reviewed. parasite has been eradicated will to First World standards of sanitation remain. facilities prevents transmission. It is References a condition that is preventable and 1. Bisoffi Z, Buonfrate D, Montresor A, et al. Strongyloides control Strongyloides stercoralis: A plea for action. PLoS treatable if diagnosed early. GPs must be Negl Trop Dis 2013;7:e2214. programs in endemic vigilant to ensure that cases are detected 2. Grove DI. Human Strongyloidiasis. Adv Parasitol communities and the risks of fatal, disseminated 1996:38:281–309. 3. Flannery G, White N. Immunological parameters Control strategies in endemic disease reduced. in northeast Arnhem Land Aborigines: communities are now possible with Consequences of changing settlement and improved diagnostic testing and Key points lifestyles. In: Schell LM, Smith MT, Bilsborough A, editors. Urban ecology and health in the third 12 effective treatment regimens. Some • Think of strongyloidiasis world. New York: Cambridge University Press, health services in endemic communities before starting a patient on 1993;202–20. have incorporated strongyloides immunosuppressant therapy, including 4. Lim L, Biggs B. Fatal disseminated strongyloidiasis in a previously treated patient. serology into biennial adult health corticosteroids, especially those from Med J Aust 2001;174:355–56. checks to ensure better management of endemic areas or with unexplained 5. Hanson HJ. Strongyloidiasis in veterans. Med J patients with chronic strongyloidiasis.27,32 eosinophilia. Aust 2001;175:503. 6. Caumes E, Keystone JS. Acute strongyloidiasis: A rarity. Chronic strongyloidiasis: A time bomb! J Trav Medicine 2011;18:71–72. 7. Soulsby HM, Hewagama S, Brady S. Case 35,36 Table 2. Therapeutic Guidelines for strongyloidiasis series of four patients with strongyloides after occupational exposure. Med J Aust 2012;196:444. To treat strongyloidiasis (Strongyloides stercoralis) in immunocompetent patients, use: 8. Mejia R, Nutman TB. Screening, prevention, • Ivermectin (adults and children weighing 15 kg or more) – 200 µg/kg orally with fatty food for and treatment for hyperinfection syndrome and one day and repeat after 7–14 days (Category B3 in pregnancy). disseminated infections caused by Strongyloides stercoralis. Curr Opin Infect Dis 2012;25:458–63. OR 9. Davis JS, Currie BJ, Fisher DA, et al. • Albendazole – 400 mg (200 mg for children weighing 10 kg or less) orally with fatty food; Prevention of opportunistic infections in 12-hourly for three days and repeat after 7–14 days (Category D in pregnancy). immunosuppressed patients in the tropical top end of the Northern Territory. Comm Dis Intell To treat immunocompromised patients, use: Q Rep 2003;27:526–32. • Ivermectin (adults and children weighing 15 kg or more) – 200 µg/kg orally with fatty food 10. Genta RM. Dysregulation of strongyloidiasis: on days 1, 2, 15, 16. Immunocompromised patients requiring immunosuppression are at A new hypothesis. Clin Microbiol Rev high risk of disseminated strongyloidiasis (hyperinfection) and may require longer courses of 1992;5:345–55. therapy. Seek expert advice. 11. Speare R. Identification of species of Strongyloides. In: Grove DI, editor. Prophylaxis prior to immunosuppression for patients at risk: Strongyloidiasis: A major roundworm infection of • If strongyloides serology is positive, treat with ivermectin 200 mcg/kg orally with fatty food, man. London: Taylor Francis, 1989;11–82. once weekly for two doses. 12. Conway DJ, Lindo JF, Roberton DM, Bundy • If strongyloides serology is negative (from remote Aboriginal and Torres Strait Islander DA. Towards effective control of Strongyloides communities), use ivermectin 200 mcg/kg orally with fatty food as a single dose. stercoralis. Parasitology Today 1995;11:420–24. 13. Lahn MM, Staub-Schmidt T, Him R, et al. • Ongoing primary prophylaxis once every three months is recommended for patients requiring Strongyloides stercoralis infection in a non- significant immunosuppression and returning to endemic communities. immunosuppressed tourist with involvement Current for March 2015. Refer to Therapeutic Guidelines. of the central nervous system. Trop Geogr Med 1994;46:368–70.

14. Plorde JJ, Ramsey PG. Strongyloidiasis. In: Wilson 32. Page WA, Dempsey K, McCarthy J. Utility of JD, Braunwald E, Isselbacher KJ, et al (editors). serological follow-up of chronic strongyloidiasis Harrison’s principles of internal medicine. New after anthelminthic chemotherapy. Trans R Soc York: McGraw Hill, 1991; p. 822–23. Trop Med Hyg 2006;100:1056–62. 15. Eddleston M, Pierini S. Oxford handbook of 33. Suputtamongkol Y, Premasathian N, Bhumimuang tropical medicine. Oxford: Oxford University K, et al. Efficacy and safety of single and double Press, 2000; p. 158. doses of ivermectin versus 7-day high dose 16. Galimberti R, Pontón A, Zaputovich FA, albendazole for chronic strongyloidiasis. PLoS et al. Disseminated strongyloidiasis in Negl Trop Dis 2011;5:e1044. immunocompromised patients – Report of three 34. Toma H, Sato Y, Shiroma Y, Kobayashi J, cases. Int J Dermatol 2009;48:975–78. Shimabukuro I, Takara M. Comparative studies 17. Mukerjee CM, Carrick J, Walker JC, et al. on the efficacy of three anthelminthics on Pulmonary strongyloidiasis presenting as chronic treatment of human strongyloidiasis in Okinawa, bronchitis leading to interlobular septal fibrosis Japan. Southeast Asian J Trop Med Pub Health and cured by treatment. Respirology 2003;8:536– 2000;31:147–51. 40. 35. Antibiotic Expert Group. Strongyloidiasis. In: eTG 18. Mukerjee CM, Walker J. Pulmonary Complete. Melbourne: Therapeutic Guidelines strongyloidiasis mimicking cavitary pulmonary Ltd, 2014. Available at tg.org.au [Accessed tuberculosis. Cairns: ASM conference, 2000. 4 November 2015]. 19. Kukuruzovic R, Robins-Browne RM, Anstey 36. Antibiotic Expert Group. Strongyloides stercoralis. In: eTG Complete. Melbourne: Therapeutic NM, Brewster DR. Enteric pathogens, intestinal Guidelines Ltd, 2014. Available at tg.org.au permeability and nitric oxide production in acute [Accessed 4 November 2015]. gastroenteritis. Pediatr Infect Dis J 2002;21: 730–39. 20. Chan JFW, Choy BY, Lai KN. Nephrotic syndrome secondary to strongyloidiasis: A common infection with an uncommon presentation. Hong Kong J Nephrol 2008;10:37–41. 21. Gulbas Z, Kebapci M, Pasaoglu O, et al. Successful ivermectin treatment of hepatic strongyloidiasis presenting with severe eosinophilia. South Med J 2004;97:907–10. 22. Lai CP, Hsu YH, Wang JH, Lin CM. Strongyloides stercoralis infection with bloody pericardial effusion in a non-immunosuppressed patient. Circulation J 2002;66:613–14. 23. Mak DB. Recurrent bacterial meningitis associated with strongyloides hyperinfection. Med J Aust 1993;159:354. 24. Einsiedel L, Fernandes L. Strongyloides stercoralis: A cause of morbidity and mortality for indigenous people in Central Australia. Intern Med J 2008;38:697–703. 25. Page W, Shield J. Strongyloidiasis – An update on best practice. ACCNS J Community Nurs 2005;10:15–16. 26. Pansegrouw D. Strongyloides stercoralis infestation masquerading as steroid resistant asthma. Monaldi Arch Chest Dis 1994;49:399–402. 27. Shield JM, Page W. Effective diagnostic tests and anthelmintic treatment for Strongyloides stercoralis make community control feasible. PNG Med J 2008;51:105–19. 28. Uparanukraw P, Phongsri S, Morakote N. Fluctuation of larval excretion in Strongyloides stercoralis infection. Am J Trop Med Hyg 1999:60:967–73. 29. Kobayashi J, Sato Y, Toma H, Takara M, Shiroma Y. Application of enzyme immunoassay for postchemotherapy evaluation of human strongyloidiasis. Diag Microbiol Infect Dis 1994;18:19–23. 30. Loutfy MR, Wilson M, Keystone JS, et al. Serology and eosinophil count in the diagnosis and management of strongyloidiasis in a non-endemic area. Am J Trop Med Hyg 2002;66:749–52. 31. Lindo JF, Atkins NS, Lee MG, et al. Short report: Long-term serum antibody isotype responses to Strongyloides stercoralis filariform antigens in eight patients treated with ivermectin. Amer J Trop Med Hyg 1996;55:474–76.