Diarrheal disease remains the second leading cause of mortality in children in developing countries. Cryptosporidium is a leading cause and its importance stands to increase as rotavirus vaccine becomes used around the world. Cryptosporidium is particularly problematic in children younger than 2 years old and in the immunocompromised. Giardia lamblia is a common intestinal protozoan that is associated with diarrhea and, perhaps, growth faltering in impoverished settings. This review establishes the current prevalence of these infections in global settings and reviews current diagnosis and management approaches.
Key points
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Consider Cryptosporidium in any child, particularly younger than 2 years old, with severe acute watery diarrhea.
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Diagnosis of Cryptosporidium can be made by acid-fast microscopy, enzyme-linked immunosorbent assay (ELISA), or immunofluorescent antibody staining, or molecular diagnostics.
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Diarrhea due to Cryptosporidium is usually self-limited in 1 to 2 weeks but vigilance is needed in immunocompromised patients in whom the clinical course may be protracted and severe.
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Nitazoxanide is approved for treatment of Cryptosporidium in immunocompetent children older than the 1 year old.
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Inquire about possible sources of exposure, such as recreational water and close contacts, with similar symptoms because outbreaks occur and Cryptosporidium and Giardia are reportable disease in many jurisdictions and Consider giardiasis in cases of prolonged diarrhea, particularly in travelers.
Cryptosporidium
Cryptosporidium is an apicomplexan protozoan parasite that was first identified as a human pathogen in 1976 in a 3-year-old child with severe acute enterocolitis ( Figs. 1 and 2 ). Another publication later that year described an immunosuppressed adult with a similar presentation of severe diarrhea without clear cause. In both instances, biopsy of intestinal tissue with electron microscopy was performed and lesions showed mucosal injury and tiny 2 to 4 μm organisms on the intestinal epithelial surface that were determined to be Cryptosporidium based on morphology. These are now known to be intracellular forms, such as trophozoites, schizonts, and gametes. When these forms produce oocysts that are excreted into the environment then transmission to other hosts can continue.
Since that original description, cases of severe and fatal disease in patients with acquired immune deficiency syndrome (AIDS), and the massive 1993 outbreak of waterborne Cryptosporidium affecting 403,000 persons in Milwaukee, Wisconsin, have increased attention to the pathogen. Now Cryptosporidium is recognized as a leading cause of childhood diarrhea around the world, revealed largely by the large Global Enteric Multicenter Study (GEMS). According to the Global Burden of Disease Study, it is now the second most implicated diarrheal pathogen after rotavirus, causing 60,400 deaths alone in 2015, or 12% of the total diarrhea mortality burden. This article provides an overview of this enigmatic pathogen, focusing on pediatric disease, which merits investment to research better treatments and vaccines.
Cryptosporidium Epidemiology
The authors reviewed the recent literature on Cryptosporidium diarrhea in children, summarizing several studies published since 2000 involving children 15 years of age and younger who had diarrhea in Africa, Asia, and Latin America ( Table 1 ). Across diverse settings, the prevalence of diarrhea cases is 1% to 35% (median 18%), with variations in hospital versus community settings and diagnostic methodology. Many studies included control stools for comparison, whereby the rates of Cryptosporidium were virtually always lower (median 6%), confirming Cryptosporidium ’s association with diarrhea. Most studies focused on Cryptosporidium alone or on a small number of pathogens. The largest studies were the multisite GEMS and Malnutrition and Enteric Disease Study (MAL-ED) studies, which tested case and control stools for dozens of enteropathogens and allowed an examination of the importance of Cryptosporidium relative to others. Because these are the most recent and comprehensive studies to date, they are explored in further detail.
| Region (Reference) | Country | Age Included (y) | Setting | Diagnostic Method | Diarrhea Samples (N) | Cryptosporidium % | Comments |
|---|---|---|---|---|---|---|---|
| Asia | |||||||
| Khan et al, 2004 | Bangladesh | 0–5 | H | Microscopy | 1672 | 3 | — |
| Haque et al, 2009 | Bangladesh | 0–14 and adults | H & C | ELISA | 3646 | 3 | Rate in nondiarrhea 2% (n = 2575) |
| Bera et al, 2014 | India | 0–5 | H | ELISA | 175 | 27 | — |
| Mirzaei et al, 2007 | Iran | 0–15 | C | Microscopy | 89 | 35 | Rate in nondiarrhea 3% (n = 51) |
| Hawash et al, 2014 | Saudi Arabia | 0–9 | C | PCR | 95 | 17 | — |
| Wongstitwilairroong et al, 2007 | Thailand | 0–5 | C | ELISA | 236 | 1 | Rate in nondiarrhea 3% (n = 236) |
| Africa | |||||||
| Wegayehu et al, 2013 | Ethiopia | 0–14 | C | Microscopy | 0 | NA | Rate in nondiarrhea 7% (n = 384) |
| Firdu et al, 2014 | Ethiopia | 0–13 | H | Microscopy | 230 | 10 | Rate in nondiarrhea 6% (n = 115) |
| Adjei et al, 2004 | Ghana | 0–5 | H | Microscopy | 304 | 28 | Rate in nondiarrhea 16% (n = 304) |
| Eibach et al, 2015 | Ghana | 0–15 | H | PCR | 2232 | 5 | Includes gastrointestinal symptoms |
| Moyo et al, 2011 | Tanzania | 0–5 | H | ImmunoCard | 270 | 19 | — |
| Elfving, 2014 | Tanzania | 0–5 | H | PCR | 165 | 30 | Rate in nondiarrhea 11% (n = 165) |
| Desilva et al, 2016 | Tanzania | 0–5 | H | PCR | 701 | 16 | Rate in nondiarrhea 3% (n = 558) HIV+ 24% vs HIV− 4% |
| Tumwine et al, 2005 | Uganda | 0–5 | H | Microscopy | 243 | 32 | HIV+ 74% vs HIV− 6% |
| Tumwine et al, 2003 | Uganda | 0–5 | H | PCR | 1779 | 25 | Rate in nondiarrhea 9% (n = 667) |
| Amadi et al, 2001 | Zambia | 0–5 | H | Microscopy | 200 | 26 | HIV+ 29% vs HIV− 19% |
| Latin America | |||||||
| Medeiros et al, 2001 | Brazil | 0–10 | H & C | Microscopy | 1836 | 2 | — |
| Carvalho-Costa et al, 2007 | Brazil | 0–5 | H | Microscopy | 193 | 9 | — |
| Laubach et al, 2004 | Guatemala | 0–5 | C | Microscopy | 100 | 32 | — |
| Worldwide multisite | |||||||
| Kotloff et al, 2013 | Bangladesh, India, Pakistan, Gambia, Mali, Kenya, Mozambique | 0–5 | H & C | ELISA | 9439 | Attributable fraction = 5.3%–14.7% in year 1 of life | |
| Platts-Mills et al, 2015 | Bangladesh, India, Nepal, Pakistan, Tanzania, South Africa, Brazil Peru | 0–2 | C | ELISA | 7318 | Attributable fraction = 2.0% in year 1 of life; 3.8% in year 2 | |
The GEMS study was a case control study of children younger than 5 years old performed in 4 sites in Africa and 3 in Asia. Cases had moderate-to-severe diarrhea and controls were age, sex, and geographically matched. Enzyme-linked immunosorbent assay (ELISA) was used for Cryptosporidium diagnosis. This study found that Cryptosporidium was the second most attributable pathogen among infants (a metric that combines both prevalence and magnitude of diarrhea-association) after rotavirus in all 4 African sites (located in Gambia, Mali, Mozambique, and Kenya) plus India, and was also common in the other South Asian sites. In the second year of life, Cryptosporidium remained the second most important pathogen in Mali, Kenya, and India. Moreover, Cryptosporidium diarrhea was associated with a high risk of death in 90-day follow-up. After 2 years of age, Cryptosporidium ’s importance declined dramatically. These Cryptosporidium burden estimates were reaffirmed in a reanalysis of the GEMS study that used quantitative polymerase chain reaction (PCR) for diagnosis. Although the burden was similar, Cryptosporidium ’s position in the enteropathogen hierarchy dropped slightly relative to other pathogens, particularly Shigella , which was better detected with the molecular diagnostics. That said, Cryptosporidium remained extremely important; for example, accounting for 17% of cases in Malian infants, second to only rotavirus at 23%. Note that the GEMS study was performed in 2007 to 2011 in regions before implementation of the rotavirus vaccine.
The MAL-ED study was conducted in 2009 to 2014 in similar settings in Africa, Asia, as well as South America, at which time a few sites had implemented rotavirus vaccine. This was a community-based active surveillance study that captured milder diarrheal episodes. Cryptosporidium was also diagnosed by ELISA and was measured to be the fourth most attributable diarrheal pathogen in the first year of life (overall ∼2% of episodes) and sixth most in the second year of life (overall ∼4% of episodes). Cryptosporidiosis was enriched among more severe episodes, consistent with the higher rates in the GEMS study. Taken together, these studies point to the clear importance of Cryptosporidium as a major cause of diarrhea in Africa and parts of Asia in children younger than 2 years, and this importance will likely increase as rotavirus vaccine is implemented.
Cryptosporidium is a risk factor for mortality in malnourished children with diarrhea. Breastfeeding seems to confer some protection. In high-income countries, disease has been linked to water-borne outbreaks. In resource-limited settings, contaminated water has been associated with Cryptosporidium in some studies but not others. An increase during the rainy season has been repeatedly noted. For instance, in the MAL-ED study, during the rainy season in Pakistan, more than half of diarrheal episodes could be attributed to Cryptosporidium. There does not seem to be a consistent gender predisposition to infection.
Cryptosporidium
Cryptosporidium is an apicomplexan protozoan parasite that was first identified as a human pathogen in 1976 in a 3-year-old child with severe acute enterocolitis ( Figs. 1 and 2 ). Another publication later that year described an immunosuppressed adult with a similar presentation of severe diarrhea without clear cause. In both instances, biopsy of intestinal tissue with electron microscopy was performed and lesions showed mucosal injury and tiny 2 to 4 μm organisms on the intestinal epithelial surface that were determined to be Cryptosporidium based on morphology. These are now known to be intracellular forms, such as trophozoites, schizonts, and gametes. When these forms produce oocysts that are excreted into the environment then transmission to other hosts can continue.
Since that original description, cases of severe and fatal disease in patients with acquired immune deficiency syndrome (AIDS), and the massive 1993 outbreak of waterborne Cryptosporidium affecting 403,000 persons in Milwaukee, Wisconsin, have increased attention to the pathogen. Now Cryptosporidium is recognized as a leading cause of childhood diarrhea around the world, revealed largely by the large Global Enteric Multicenter Study (GEMS). According to the Global Burden of Disease Study, it is now the second most implicated diarrheal pathogen after rotavirus, causing 60,400 deaths alone in 2015, or 12% of the total diarrhea mortality burden. This article provides an overview of this enigmatic pathogen, focusing on pediatric disease, which merits investment to research better treatments and vaccines.
Cryptosporidium Epidemiology
The authors reviewed the recent literature on Cryptosporidium diarrhea in children, summarizing several studies published since 2000 involving children 15 years of age and younger who had diarrhea in Africa, Asia, and Latin America ( Table 1 ). Across diverse settings, the prevalence of diarrhea cases is 1% to 35% (median 18%), with variations in hospital versus community settings and diagnostic methodology. Many studies included control stools for comparison, whereby the rates of Cryptosporidium were virtually always lower (median 6%), confirming Cryptosporidium ’s association with diarrhea. Most studies focused on Cryptosporidium alone or on a small number of pathogens. The largest studies were the multisite GEMS and Malnutrition and Enteric Disease Study (MAL-ED) studies, which tested case and control stools for dozens of enteropathogens and allowed an examination of the importance of Cryptosporidium relative to others. Because these are the most recent and comprehensive studies to date, they are explored in further detail.
| Region (Reference) | Country | Age Included (y) | Setting | Diagnostic Method | Diarrhea Samples (N) | Cryptosporidium % | Comments |
|---|---|---|---|---|---|---|---|
| Asia | |||||||
| Khan et al, 2004 | Bangladesh | 0–5 | H | Microscopy | 1672 | 3 | — |
| Haque et al, 2009 | Bangladesh | 0–14 and adults | H & C | ELISA | 3646 | 3 | Rate in nondiarrhea 2% (n = 2575) |
| Bera et al, 2014 | India | 0–5 | H | ELISA | 175 | 27 | — |
| Mirzaei et al, 2007 | Iran | 0–15 | C | Microscopy | 89 | 35 | Rate in nondiarrhea 3% (n = 51) |
| Hawash et al, 2014 | Saudi Arabia | 0–9 | C | PCR | 95 | 17 | — |
| Wongstitwilairroong et al, 2007 | Thailand | 0–5 | C | ELISA | 236 | 1 | Rate in nondiarrhea 3% (n = 236) |
| Africa | |||||||
| Wegayehu et al, 2013 | Ethiopia | 0–14 | C | Microscopy | 0 | NA | Rate in nondiarrhea 7% (n = 384) |
| Firdu et al, 2014 | Ethiopia | 0–13 | H | Microscopy | 230 | 10 | Rate in nondiarrhea 6% (n = 115) |
| Adjei et al, 2004 | Ghana | 0–5 | H | Microscopy | 304 | 28 | Rate in nondiarrhea 16% (n = 304) |
| Eibach et al, 2015 | Ghana | 0–15 | H | PCR | 2232 | 5 | Includes gastrointestinal symptoms |
| Moyo et al, 2011 | Tanzania | 0–5 | H | ImmunoCard | 270 | 19 | — |
| Elfving, 2014 | Tanzania | 0–5 | H | PCR | 165 | 30 | Rate in nondiarrhea 11% (n = 165) |
| Desilva et al, 2016 | Tanzania | 0–5 | H | PCR | 701 | 16 | Rate in nondiarrhea 3% (n = 558) HIV+ 24% vs HIV− 4% |
| Tumwine et al, 2005 | Uganda | 0–5 | H | Microscopy | 243 | 32 | HIV+ 74% vs HIV− 6% |
| Tumwine et al, 2003 | Uganda | 0–5 | H | PCR | 1779 | 25 | Rate in nondiarrhea 9% (n = 667) |
| Amadi et al, 2001 | Zambia | 0–5 | H | Microscopy | 200 | 26 | HIV+ 29% vs HIV− 19% |
| Latin America | |||||||
| Medeiros et al, 2001 | Brazil | 0–10 | H & C | Microscopy | 1836 | 2 | — |
| Carvalho-Costa et al, 2007 | Brazil | 0–5 | H | Microscopy | 193 | 9 | — |
| Laubach et al, 2004 | Guatemala | 0–5 | C | Microscopy | 100 | 32 | — |
| Worldwide multisite | |||||||
| Kotloff et al, 2013 | Bangladesh, India, Pakistan, Gambia, Mali, Kenya, Mozambique | 0–5 | H & C | ELISA | 9439 | Attributable fraction = 5.3%–14.7% in year 1 of life | |
| Platts-Mills et al, 2015 | Bangladesh, India, Nepal, Pakistan, Tanzania, South Africa, Brazil Peru | 0–2 | C | ELISA | 7318 | Attributable fraction = 2.0% in year 1 of life; 3.8% in year 2 | |
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