For the full versions of these articles see bmj.com Clinical Review

Cryptosporidiosis

A P Davies,1 R M Chalmers2 LSHTM/SPL 1 is a protozoan parasite that has emerged School of Medicine, Swansea Box 1 | Risk factors for acquisition of Cryptosporidium University, Swansea SA2 8PP as an important cause of diarrhoeal illness worldwide, Drinking contaminated water 2UK Cryptosporidium Reference particularly in young children and immunocompromised Unit, National Public Health Service Travel to less industrialised countries for Wales, Swansea patients. In the UK Cryptosporidium is the commonest pro- Use of swimming pools and water based recreation Correspondence to: A P Davies tozoal cause of acute gastroenteritis, with 3000-6000 labo- Contact with animals in farms or petting zoos, especially [email protected] ratory confirmed cases annually, although this is almost young ruminants certainly an underestimation of the disease burden. Two Contact with animal dung, for example, during outdoor Cite this as: BMJ 2009;339:b4168 doi: 10.1136/bmj.b4168 species, Cryptosporidium hominis and ­Cryptosporidium recreation ­parvum, account for most of these laboratory-confirmed Contact with another person with diarrhoea, especially a child cases. Species distinction between C hominis and C ­parvum Attendance at child care settings is quite recent and for several years both parasites were Changing nappies or toileting young children (even those with referred to as C parvum (sometimes genotypes 1 and no diarrhoea) 2). Large waterborne outbreaks highlight the parasite’s ­clinical and economic importance. Sources and selection criteria The clinical problems associated with Cryptosporid­ We searched MEDLINE for authoritative articles and ium are increasingly becoming recognised interna- studies and by consulting the archived resources of tionally, and the parasite was included in the World the UK Cryptosporidium Reference Unit, Swansea, Health Organization’s Neglected Diseases Initiative of which one of the authors (RMC) is the head. The 2004. These neglected diseases are defined as those Cochrane database contains a systematic review of that “exhibit a considerable and increasing global bur- treatment in the immunocompromised.2 den, and impair the ability of those infected to achieve their full potential, both developmentally and socio- Who gets ? economically”.1 Anyone can be infected and become ill with In this review, we assess the epidemiology, Cryptosporidium­ . Cryptosporidiosis is commoner in ­clinical presentation, diagnosis, and management of young children, particularly in those under age 5 years, ­cryptosporidiosis. but the disease can also affect healthy people of any age. However, most clinical problems are encountered Summary points in patients who are profoundly immunocompromised. Cryptosporidium is a common cause of diarrhoea Asymptomatic carriage of the organism is possible: a worldwide, and is the commonest protozoal cause of acute recent study of young children in day care nurseries gastroenteritis in the UK found that three of 230 (1.3%, upper 95% CI 3.8%) In immunocompetent patients the illness is self-limiting were carrying the parasite without any symptoms.3 Risk but generally lasts one to two weeks and sometimes longer factors for the acquisition of Cryptosporidium identified Laboratory diagnosis is required for confirmation from outbreaks and sporadic cases are listed in box 1. Sources of infection include animals, as well as people, and the parasite is resistant to normal water disinfection How is cryptosporidiosis acquired? In those with T-cell deficiencies the disease is chronic Transmission is usually via the faeco-oral route. As well and protracted and may be severe, with complications including sclerosing cholangitis and rarely, biliary cirrhosis as person-to-person transmission of both C parvum and C and pancreatitis. Specialist tests may be required hominis, particularly within households and nurseries, C Treatment options are limited. In the US is parvum can also be acquired as a , for example, licensed, and available by regular prescription, for disease during children’s farm visits or exposure to animal dung in the immunocompetent, in whom it reduces the severity during outdoor recreation. Oocysts, which are the trans- of symptoms, which may be prolonged. Nitazoxanide is missible form that contains infectious sporozoites, can available in the UK on a named-patient basis survive for prolonged periods in damp soil and ingestion In England the Chief Medical Officer advises that patients of very low numbers can cause disease.w1 w2 whose T-cell function is compromised should boil all The largest outbreaks of cryptosporidiosis are drinking water to reduce the risk of infection associated­ with contamination of drinking water by

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Fig 1 | : modified Ziehl-Neelson Fig 2 | Cryptosporidium parvum: auramine phenol staining with ×100 objective. Courtesy of G Robinson, UK staining with ×50 objective. Courtesy of G Robinson, UK Cryptosporidium Reference Unit, Swansea Cryptosporidium Reference Unit, Swansea

sewage effluent or manure. Ordinary water disinfec- malabsorption, and some elements of inflammation. A tion processes do not kill Cryptosporidium, and filtering 3-12 day dose dependent incubation period7 precedes is required to remove the parasite. Improved qual- watery diarrhoea accompanied by abdominal cramps ity of drinking water, particularly with the installa- (in 96% of patients who present for consultation), vom- tion of filtration at previously unfiltered supplies, has iting (65%), mild fever (59%), and loss of appetite.8 reduced disease ­burden.4 5 Nonetheless, there can still Symptoms can be prolonged, with a mean duration be a background risk in some mains water and many of 12.7 days, and can persist for up to a month.8 The private water supplies. relapse of symptoms, indicating persistent infection, Outbreaks of the disease associated with swimming occurs in over a third of cases,9 but after clearance of pools are well recognised because oocysts are relatively the parasite the epithelium recovers. In one study, 61 resistant to chlorination, and pool water filtration is often of 427 (14%) sporadic cases were hospitalised.8 The inadequate. Patients with diarrhoeal illness should be differential diagnosis is usually of other causes of infec- advised not to go swimming, and in particular, patients tious gastroenteritis. with a confirmed diagnosis of cryptosporidiosis should In the developing world, cryptosporidiosis is asso- be discouraged from using pools for two weeks after ciated with substantial morbidity, and with children diarrhoea has stopped because oocysts can still be shed who are malnourished,10‑12 including those with appar- during this time.6 Advice for patients diagnosed with ently asymptomatic infection who may exhibit poor cryptosporidiosis is outlined in box 2. growth.13 Food borne infection is probably less common but Immunocompromised patients commonly experience can be caused by contaminated fruit or vegetables, food chronic or intractable disease. Those patients most at washed in contaminated water, or inadequate pasteurisa- risk are those with T-cell immune deficiency, including tion of milk. those with haematological malignancies (particularly children), patients with HIV infection with CD4 counts What are the clinical features of cryptosporidiosis? lower than 200 (and in particular those with counts Cryptosporidiosis presents as a gastroenteritis-like below 50), and patients with primary T-cell deficien- syndrome. Symptoms indicate its pathogenesisw3 with cies such as severe combined immunodeficiency and disease predominantly affecting the small bowel, with CD40 ligand deficiency (hyper IgM syndrome). In these immunocompromised patients the entire gastrointesti- Box 2 | Advice for patients diagnosed with cryptosporidiosis nal tract can be affected, including the pancreatic duct Expect the diarrhoea to last longer than with some other and gall bladder. Complications include pancreato-bil- causes of infectious gastroenteritis, and be prepared for iary infection, which can lead to pancreatitis, scleros- the possibility that symptoms may relapse before the ing cholangitis, and rarely, subsequent biliary cirrhosis. infection is completely cleared Tracheo-bronchial involvement, though uncommon, Observe stringent personal hygiene because the organism can occur and sinusitis has been described.14 Rarely, is highly infectious from person to person; wash hands in advanced HIV, cryptosporidiosis is associated with carefully and do not share towels pneumatosis cystoides intestinalis,15 in which cysts con- Avoid using swimming pools for two weeks after the taining gas occur in the gut wall, and can rupture, leading diarrhoea has stopped to ­pneumoretroperitoneum and pneumomediastinum. Children should not attend nursery settings until 48 hours There is also concern about cryptosporidiosis in after diarrhoea has stopped bone marrow and solid-organ transplant patients. A Food handlers and those caring for vulnerable adults (such as patients in hospital and older people) should not attend review of the evidence regarding Cryptosporidium infec- work until 48 hours after diarrhoea has stopped tion in immunocompromised patients found that the severe disease reported in those who had undergone

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A parent’s perspective Our son Sam got Cryptosporidium after visiting the sheep shed during lambing when he was of pre-school age, in a pushchair, but did not actively go into the pens. He got very ill, had a tummy ache, and lost weight. It was a very worrying time as the diagnosis took several weeks and the illness carried on and on. A patient’s perspective The first inkling that something was wrong was when I woke in the night with intense cramping stomach pains. They came in waves over a couple of hours before the vomiting started. By morning I had vomited so much that it felt as though there was nothing left inside me, but I continued to retch on an empty stomach. Around mid-morning the diarrhoea started. It was like nothing I had ever experienced before: the cramps would build and then the most awful, profuse, offensive, and watery diarrhoea would follow. It left me physically weak. I couldn’t leave the bathroom, and certainly couldn’t look after my children, not that I’d have wanted to in case they got it. I could not face eating, but made myself sip water; however this often caused further episodes of vomiting and diarrhoea. I continued night and day like this for three days before finally I could venture out of the bedroom to take drinks and clear soup without immediately being ill again. It was a full ten days before I felt like I had enough energy to start eating normally or functioning. About two weeks after this I woke again in the night with stomach cramps, no way near as severe as the first attack, but it filled me with dread as to what was going to follow. The diarrhoea only lasted 24 hours this time, there was no vomiting, and then all my symptoms resolved. I have not had cryptosporidiosis since, but it is an episode of illness I will never forget, and a disease I have the greatest respect for.

bone-marrow transplant typically depended on the Cryptosporidium may not necessarily be included in a underlying diagnosis for which the transplant was per- request for “ova cysts and parasites” (as the methods of formed.15 Cryptosporidiosis in solid organ recipients examination for the two tests differ). The usual meth- and in patients with non-haematological malignancies ods of detecting Cryptosporidium oocysts in the stool are has been described, but does not seem to be as prob- by acid-fast or auramine-phenol staining and micros- lematic as it is in the highest risk groups.15 copy, which often show the organisms in great num- bers (figs 1 and 2), or by antigen detection. Clinicians What are the long term effects of infection? are advised to become familiar with local laboratory Little is known about the long term effects of practice, and to specify Cryptosporidium on the request Cryptosporidium­ infection. A case-control study found form to ensure appropriate testing is ­carried out. that infection with C hominis (but not C parvum) was asso- More sensitive, specialist tests available in reference ciated with joint pain, eye pain, headaches, and fatigue facilities include PCR, and for maximum sensitivity in during the two months after infection.9 Seronegative exceptional circumstances, immunomagnetic separa- reactive arthritis has been reported in adults16 17 and tion with immunofluorescence microscopy, which can children18 19 including one report of Reiter’s syndrome.18 detect as few as two organisms per gram of stool.w4 It has been suggested that Cryptosporidium infection may In patients with profound T-cell immune deficiency, cause relapse of inflammatory bowel disease.20 There examination of small bowel or gastric biopsies can are anecdotal reports of an association between Crypto­ reveal the parasite or histopathological changes where sporidium and irritable bowel disease but this link, if it the stool sample is negative. Other samples occasion- exists, is very unclear and requires further study. ally examined include bile, in cases of cholangitis, and sputum/blood alcohol level where pulmonary crypt- How is infection with Cryptosporidium diagnosed? osporidiosis is suspected. Possible specimen types are Cryptosporidium causes a spectrum of disease from listed in the table. asymptomatic, through mild, to severe. Incidence of the disease is almost certainly underestimated21 because How is cryptosporidiosis managed? a confirmed diagnosis can only be made after a stool Immunocompetent patients sample is sent to the local microbiology laboratory. In immunocompetent patients, the disease, though Although UK guidance states that all stool samples unpleasant and debilitating, is self-limiting. Rehydra- from community cases of diarrhoea should be tested tion salts may be required. Patients and carers should for Cryptosporidium,22 laboratories have varying crite- be informed that symptoms may persist for longer ria for selecting stools for testing.23 Examination for than with other common causes of acute gastroen-

Types of specimens that can be examined for Cryptosporidium Appropriate patient group Test and availability Stool (most commonly examined specimen) Any patient with community acquired or Routine diagnostic tests available locally or specialist unexplained diarrhoea tests if negative and Cryptosporidium still suspected Jejunal +/− gastric biopsy Persistent idiopathic gastrointestinal symptoms Specialist tests in high risk groups Bile from endoscopic retrograde cholangio- If symptoms of cholangitis in high risk groups Specialist tests pancreatography Sputum/ bronchoalveolar lavage High risk patients with profound Specialist tests immunosuppression and unexplained respiratory symptoms Antral washout High risk patients with profound Specialist tests immunosuppression and unexplained sinusitis

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teritis, making the diagnosis helpful to the clinician. but after a second course of therapy diarrhoea (but Cryptosporidiosis is highly infectious person-to-per- not parasite carriage) had resolved in most. A dou- son, as large numbers of oocysts are excreted and the ble blind placebo controlled study in Mexican HIV infectious dose is low (possibly in single figuresw1 w2), positive patients27 used higher doses of nitazoxanide so scrupulous personal hygiene is required. As with (500 or 1000 mg twice daily), and reported that para- other causes of infectious gastroenteritis, UK guidance site clearance was significantly better than placebo. issued by a working group of the former Public Health Oocyst shedding and diarrhoea resolved in patients ­Laboratory Advisory Committee on Gastrointestinal with CD4 greater than 50 but not in those with a Infections5 states that affected children should not lower CD4 count. Overall the data support the effi- attend day care centres until 48 hours after diarrhoea cacy of nitazoxanide in immunocompetent patients, has stopped, and that food handlers and carers of with some less conclusive evidence of benefit in highly susceptible patients should be excluded from immunosuppressed patients, although not, unfortu- work for the same period. Regulations for notifying nately, in the subgroup with the most advanced HIV infections vary among jurisdictions. In the UK, crypt- disease. Nitazoxanide is well tolerated with a good osporidiosis is notifiable only where believed to be safety profile. food borne or water borne. Elsewhere, for example, in All drugs that are currently available in the UK are the United States, it is a nationally notifiable disease. of unproven benefit and unlicensed for the indication of cryptosporidiosis. Published trials are small and evi- Immunocompromised patients dence is anecdotal and conflicting. Drugs that have In the high risk groups outlined earlier, infection can been used to treat Cryptosporidium infection include be severe and difficult to manage. Because treatment the aminoglycoside paromomycin, and macrolides modalities are limited, prevention and risk reduction such as spiramycin, azithromycin, and clarithromycin, are the most important interventions. The Depart- which all have anti-parasitic activity. A randomised ment of Health in England advises, on the basis of double blind trial of paromomycin in 10 patients with the Bouchier report,24 that those with compromised AIDS and cryptosporidiosis found clinical and para- T-cell function should boil all drinking water (includ- sitological response reaching statistical significance.28 ing bottled water) to reduce the risk of infection.25 Another small open uncontrolled prospective study Whether this permanent, blanket advice is still neces- of paromomycin in HIV positive patients with crypt- sary and should be applied across the UK is currently osporidiosis found that most responded clinically but under review. that continuous maintenance therapy was required The aim of treatment is symptomatic improve- to prevent relapse.29 The largest ­prospective, double ment, with complete clearance of the parasite being blind, placebo controlled trial included 35 adults unlikely unless the underlying immune deficiency can who were HIV positive.30 Paromomycin was not be ­corrected. more effective than placebo but the study lacked power to conclusively refute its usefulness. There are Immune reconstitution ­anecdotal reports of both responsesw7-w9 and failuresw10 In patients with HIV, highly active antiretroviral with ­azithromycin. Case reportsw11 w12 and one uncon- therapy (HAART) is the treatment of choice. As trolled series of patients with AIDSw13 describe success well as improving the CD4 cell level and restoring a with azithromycin and paromomycin combination degree of immunity, protease inhibitors have reduced ­treatments. Cryptosporidium­ host cell invasion and parasite develop- ment in vitro, an effect enhanced with paromomycin.w5 What else is known about the epidemiology of In other patients, improving immunity can also lead cryptosporidiosis? to improvement—for example, in a renal transplant Of the two species accounting for most disease in patient, accidental reduction in immunosuppression humans, C hominis seems to be largely host adapted was associated with parasite clearance and resolution to humans while C parvum can result in infection in of sclerosing cholangitis.w6 both humans and animals. Less commonly, other species such as C meleagridis, C canis, and C felis, and Specific therapy unusual genotypes have also been reported in patients Nitazoxanide (Alinia, Romark Laboratories) is with diarrhoea but their acquisition is not fully under- approved by the United States Food and Drug Admin- stood.31 Interestingly, a recent study of young chil- istration for use in immunocompetent patients older dren in day care centres found that unusual genotypes than 1 year and is available there by regular prescrip- were found proportionately much more frequently in tion. In the UK, nitazoxanide is not licensed but is asymptomatic carriers than in patients with sympto- available on a named patient basis. In a randomised matic disease, raising the possibility that some geno- placebo controlled trial of Zambian children with types may be commoner than previously thought and cryptosporidiosis, 100 mg nitazoxanide twice daily26 possibly have lower pathogenicity.2 resulted in statistically significant improvement in In the UK, C parvum infections peak in spring and C diarrhoea and parasite clearance amongst those who hominis peaks in late summer and autumn. There has were HIV negative. In an HIV positive group, there been a reduction in the number of cases in the first was no benefit after the primary treatment course, half of the year, but the number of cases in the second

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6 Working Group of the former PHLS Advisory Committee on Questions for ongoing and future research Gastrointestinal Infections.Preventing person-to-person spread following What is the true incidence of cryptosporidiosis in the community? gastrointestinal infections: guidelines for public health physicians and environmental health officers. Commun Dis Public Health 2004;7:362- Are there long term health effects of infection with Cryptosporidium, and if so what are they? 84. What are the risk factors for cryptosporidiosis in the second half of the year? 7 Chappell CL, Okhuysen PC, Sterling CR, Wang C, Jakubowski W, Dupont HL. Infectivity of Cryptosporidium parvum in healthy adults with pre- We are currently gathering evidence to discover whether we should be screening for existing anti-C. parvum serum immunoglobulin G. Am J Trop Med Hyg Cryptosporidium carriage in high-risk patients such as those with primary immune 1999;60:157-64. 8 Hunter PR, Hughes S, Woodhouse S, Syed O, Verlander NQ, Chalmers deficiencies. RM, et al. Sporadic cryptosporidiosis case-control study with genotyping. Emerg Infect Dis 2004;10:1241-9. 9 Hunter PR, Hughes S, Woodhouse S, Raj N, Syed Q, Chalmers RM, et Tips for non-specialists al. Health sequelae of human cryptosporidiosis in immunocompetent patients. Clin Infect Dis 2004;39:504-10. Consider cryptosporidiosis in any case of acute gastroenteritis, particularly in young children 10 Sallon S, Deckelbaum RJ, Schmid II, Harlap S, Baras M, Spira DT. and especially if the symptoms are prolonged Cryptosporidium, malnutrition, and chronic in children. A request for “ova cysts and parasites” testing may not routinely include microscopy for Am J Dis Child 1988;142:312-5. 11 Sarabia-Arce S, Salazar-Lindo E, Gilman RH, Naranjo J, Miranda E. Case- Crytosporidium so specify on the request form if you suspect the diagnosis control study of Cryptosporidium parvum infection in Peruvian children In immunocompetent patients no specific treatment is required hospitalized for diarrhea: possible association with malnutrition and nosocomial infection. Pediatr Infect Dis J 1990;9:627-31. If your patient with cryptosporidiosis is severely immunocompromised seek specialist advice 12 Lima AA, Fang G, Schorling JB, De Albuquerque L, Mcauliffe JF, Mota S, et al. Persistent diarrhea in Northeast Brazil: etiologies and interactions with malnutrition. Acta Paediatr 1992;81:39-44. Additional educational resources 13 Checkley W, Gilman RH, Epstein LD, Suarez M, Diaz JF, Cabrera L, et al. Asymptomatic and symptomatic cryptosporidiosis: their acute effect on Resources for healthcare professionals weight gain in Peruvian children. Am Journal of Epidemiol 1997;145:156- Health Protection Agency (www.hpa.org.uk/infections/topics_az/crypto/menu.htm)— 3. 14 Dunand VA, Hammer SM, Rossi R, Poulin M, Albrecht MA, Doweiko Epidemiological data, general information and guidelines JP, et al. Parasitic sinusitis and otitis in patients infected with human Drinking Water Inspectorate (www.dwi.gov.uk/consumer/consumer/crypto.htm)—Webpage immunodeficiency virus: report of five cases and review. Clin Infect Dis about cryptosporidiosis in water supplies 1997;25:267-72. 15 Hunter PR, Nichols G. Epidemiology and clinical features of Chartered Institute of Environmental Health (www.cieh.org/policy/cryptosporidium.html)— cryptosporidium infection in immunocompromised patients. Clin Micro Comprehensive listings of UK guidance and links to other relevant sites Rev 2002;15:145-54. 16 Hay EM, Winfield J, McKendrick MW. Reactive arthritis associated with Resources for patients Cryptosporidium enteritis. BMJ 1987;295:248. Association of Medical Microbiologists (www.amm.co.uk/files/factsabout/fa_crypto. 17 Ozgul A, Tanyuksel M, Yazicioglu K, Arpacioglu O. Sacroiliitis associated htm)—Fact sheet for patients with Cryptosporidium parvum in an HLA-B27-negative patient. Rheumatology 1999;38:288-9. Institute of Child Health/Great Ormond Street (www.ich.ucl.ac.uk/factsheets/families/ 18 Shepherd RC, Smail PJ, Sinha GP. Reactive arthritis complicating F000291)—Factsheet: Reducing Exposure to Cryptosporidial Infection—Advice for Families cryptosporidial infection. Arc Dis Child 1989;64:743-4. 19 Cron RQ, Sherry DD. Reiter’s syndrome associated with cryptosporidial with an Immuno-compromised Child gastroenteritis. J Rheumatol 1995;22:1962-3. 20 Manthey MW, Ross AB, Soergel KH. Cryptosporidiosis and inflammatory bowel disease. Experience from the Milwaukee outbreak. Dig Dis Sci part of the year remains high, with the risk factors not 1997;42:1580-6. clearly identified. 21 Adak GK, Long SM, O’Brien SJ. Trends in indigenous foodborne disease and deaths, England and Wales: 1992-2000. Gut 2002;51:832-41. Risk factors for acquisition of C hominis and C parvum 22 Health Protection Agency. Investigation of specimens other than blood also differ. Infections associated with foreign travel, in for parasites. National Standard Method BSOP 31. Health Protection Agency, 2007. children under one year and in adults, particularly girls 23 Chalmers RM, Hughes S, Thomas AL, Woodhouse S, Thomas PD, Hunter P. and women aged 15 to 44 years, tend to be caused by Laboratory ascertainment of Cryptosporidium and local authority policies 31 for investigating sporadic cases of cryptosporidiosis in two regions of the C hominis. C hominis is also associated with changing United Kingdom. Commun Dis Public Health 2002;5:114-8. children’s nappies (whether or not the child was symp- 24 Expert Group chaired by Bouchier I. Cryptosporidium in water supplies; Third report of the group of experts. London: Department of the tomatic) or swimming in a toddler pool, while C parvum Environment, Transport and the Regions, Department of Health, 1998:1- is associated with farm animal contact.8 171. 25 CMO Update 23. Cryptosporidium in water: advice to the Thus, although routine diagnosis outside a reference immunocompromised. A communication to all doctors from the Chief laboratory is to genus level only, typing to species level Medical Officer (August 1999). 26 Amadi B, Mwiya M, Musuku J, Watuka A, Sianongo S, Ayoub A, et al. Effect yields useful epidemiological information that may shed of nitazoxanide on morbidity and mortality in Zambian children with light on likely sources and routes of transmission. cryptosporidiosis: a randomised controlled trial. Lancet 2002;360:1375- 80. Contributors: APD and RMC contributed equally to this work. Both authors 27 Rossignol JF, Hidalgo H, Feregrino M, Higuera F, Gomez WH, Romero JL, are responsible for the overall content as guarantors. et al. A double ‘blind’ placebo-controlled study of nitazoxanide in the Competing interests: None declared. treatment of cryptosporidial diarrhoea in AIDS patients in Mexico. Trans R Soc Trop Med Hyg 1998;92:663-6. Provenance and peer review: Not commissioned, externally peer reviewed. 28 White AC Jr, Chappell CL, Hayat CS, Kimball KT, Flanigan TP, Goodgame RW. Paromomycin for cryptosporidiosis in AIDS: a prospective, double- 1 Savioli L, Smith H, Thompson A. Giardia and Cryptosporidium join the blind trial. J Infect Dis 1994;170:419-24. ‘Neglected Diseases Initiative’. Trends Parasitol 2006;22:203-8. 29 Bissuel F, Cotte L, Rabodonirina M, Rougier P, Piens MA, Trepo C. 2 Abubakar I, Aliyu S, Hunter P. Prevention and treatment of Paromomycin: an effective treatment for cryptosporidial diarrhea in cryptosporidiosis in immunocompromised patients. Cochrane patients with AIDS. Clin Infect Dis 1994;18:447-9. Database Syst Rev 2007;24(1):CD004932. 30 Hewitt RG, Yiannoutsos CT, Higgs ES, Carey JT, Geiseler PJ, Soave R, et al 3 Davies AP, Campbell B, Evans MR, Bone A, Roche A, Chalmers RM. for the AIDS Clinical Trials Group. Paromomycin: no more effective than Asymptomatic carriage of protozoan parasites inchildren in day care placebo for treatment of cryptosporidiosis in patients with advanced centres in the United Kingdom. Pediatr Infect Dis J 2009;28:838-40. human immunodeficiency virus infection. Clin Infect Dis 2000;31:1084- 4 Lake IR, Nichols G, Bentham G, Harrison FC, Hunter PR, Kovats SR. 92. Cryptosporidiosis decline after regulation, England and Wales, 31 Chalmers RM, Elwin K, Thomas AL, Guy EC, Mason B. Long-term Cryptosporidium typing reveals the aetiology and species-specific 1989-2005. Emerg Infect Dis 2007;13:623-5. epidemiology of human cryptosporidiosis in England and Wales, 2000 to 5 Sopwith W, Osborn K, Chalmers R, Regan M. The changing 2003. Euro surveill 2009;14:pii 19086. epidemiology of cryptosporidiosis in North West England. Epidemiol Infect 2005;133:785-93. Accepted: 4 September 2009

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