Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV

Epidemiology

Cryptosporidium spp. are protozoan parasites that primarily cause enteric illness (i.e., diarrhea) in humans and animals. Cryptosporidium spp. are distributed worldwide, and some species lack strict host specificity. The two species that infect humans most frequently are Cryptosporidium hominis and Cryptosporidium parvum. In addition, infections caused by Cryptosporidium meleagridis, Cryptosporidium felis, and Cryptosporidium canis have been reported in people with HIV infection. Among adults with HIV infection, risk of morbidity associated with Cryptosporidium infection is greatest in those with advanced immunosuppression, typically CD4 T lymphocyte (CD4) cell counts <100/mm³.^1-3 Cryptosporidium primarily infects the distal small intestine and colon, but in immunocompromised hosts, extraintestinal involvement has been documented.

Infection occurs after ingestion of infectious oocysts that were excreted in the feces of infected animals and humans. The parasite is highly infectious, with an ID₅₀ (median dose that will infect 50% of those exposed to the parasite) ranging from 9 to 1,042 oocysts for C. parvum,⁴ and 10 to 83 oocysts for C. hominis.⁵ Infection occurs when the ingested oocysts release sporozoites, which attach to and invade the intestinal epithelial cells. The parasite preferentially infects the ileum and colon.

Contact with infected persons (particularly children in diapers or in child care settings) or infected animals (particularly pre-weaned calves) is an important cryptosporidiosis risk factor.^6-11 Cryptosporidium oocysts can contaminate recreational water sources (such as swimming pools, water parks, and lakes) and drinking water supplies and cause infection when contaminated water is ingested. Oocysts are environmentally hardy and extremely chlorine tolerant. They can persist for days in swimming pools despite standard chlorination, and typical pool filtration systems do not efficiently remove oocysts. Multi-step treatment processes can be used to remove (i.e., flocculation and filtration) and inactivate (e.g., ultraviolet treatment) oocysts to protect public drinking water supplies and recreational water. Foodborne transmission, particularly involving unpasteurized apple cider, raw milk, and ill food handlers, has been documented. International travelers who drink the water in countries with less stringent drinking water treatment standards than the United States may might be at risk for Cryptosporidium infection.

In a serosurvey of multiple U.S. cities, 21.3% of children aged <10 years and 21.5% of those aged 11 to 20 years had detectable response to Cryptosporidium antigen.¹² Among immunocompetent pediatric patients with diarrhea in Oklahoma, 38% of those aged 5 to 13 years and 58% of those aged 14 to 21 years were seropositive for Cryptosporidium antibodies, compared with >80% of children aged 6 months to 13 years who resided near the U.S.–Mexican border and were seeking well-child care.^13,14 The incidence of reported cryptosporidiosis in the United States has dramatically increased since 2004, peaking at 4 cases per 100,000 people in 2007.¹⁵ National cryptosporidiosis data from 1995 to 2012 demonstrated that there was a clear increase in cases reported during the period from 2005 to 2008, which persisted during the period from 2009 to 2012. Across all time periods, the highest rates were in children from birth to age 14 years, and cases were most frequently reported in children aged 1 to 4 years.¹⁶ However, compared with earlier years, the rates in children decreased from 2009 through 2012.¹⁷

Transmission of Cryptosporidium occurs throughout the United States, with increased reporting in Midwestern states.^15,16 However, cryptosporidiosis is a highly underdiagnosed and underreported diarrheal illness. Infected patients can be asymptomatic, those with symptoms might not seek health care, health care providers might not request laboratory diagnostics when evaluating non-bloody diarrhea, requested ova and parasite testing might not include Cryptosporidium testing, and positive laboratory results are not always reported to public health officials.¹⁶

Before effective antiretroviral therapy (ART) became available, most patients with HIV diagnosed with cryptosporidiosis had advanced disease or AIDS. The incidence of cryptosporidiosis in people with HIV has declined dramatically since the introduction of ART.^18-20 During the pre-ART era, the rate of cryptosporidiosis was 0.6 cases per 100 patient-years in children followed in 13 Pediatric AIDS Clinical Trial Group (PACTG) trials (median age of 5.9 years and median CD4 count of 51/mm³).²¹ Data from the Perinatal AIDS Collaborative Transmission Study indicate that the rate of chronic intestinal cryptosporidiosis decreased from 0.2 cases per 100 person-years in the pre-ART era to 0.0 cases per 100 person-years in the post-ART era.²² PACTG data estimated that the mortality rate in children with HIV infection significantly decreased from 7.2 to 0.8 per 100 person-years between 1994 and 2000 and subsequently stabilized through 2006.²³ The proportion of deaths due to all opportunistic infections decreased between 1994 and 2006, with declines most notable in deaths associated with Cryptosporidium and Mycobacterium avium complex (MAC). A recent prospective, comparative cross-sectional study of ART-treated versus ART-naive pediatric patients with HIV infection in Ethiopia found that Cryptosporidium infections were found only in ART-naive patients with low CD4 counts.²⁴

Clinical Manifestations

Symptoms of cryptosporidiosis develop after an incubation period of approximately 1 week (range, 2 to 14 days). Diarrhea—which can be profuse, usually non-bloody, and watery—and weight loss, abdominal pain, anorexia, fatigue, joint pain, headache, fever, and vomiting have been reported in immunocompetent children and adults with Cryptosporidium infection.²⁵ In immunocompetent hosts, illness is self-limiting, and symptoms most often completely resolve within 2 to 3 weeks. Recurrence of symptoms after apparent resolution often has been reported. Cryptosporidium infection in children can have a significant impact on nutritional status and growth. A comparison of growth parameters in children with and without C. parvum infection in Peru showed that C. parvum infection has a lasting adverse effect on linear (height) growth, especially when acquired during infancy.²⁶ In a cohort of 405 schoolchildren aged 6 to 13 years in Mexico, children with cryptosporidiosis were 2.7 times more likely to be at risk of undernutrition by weight-for-age z score and 2.9 times more likely to be at risk of undernutrition by height-for-age z score than children without Cryptosporidium infection.²⁷

Clinical presentation of cryptosporidiosis in patients with HIV infection varies with level of immunosuppression, ranging from no symptoms or transient disease to relapsing, chronic diarrhea or cholera-like diarrhea, which can lead to life-threatening wasting and malabsorption.²⁸ In immunocompromised children, chronic severe diarrhea can result in malnutrition, failure to thrive, and substantial intestinal fluid losses, resulting in severe dehydration and even death.

Different Cryptosporidium spp. and genotypes have been associated with different clinical manifestations. C. hominis was associated with vomiting in children without HIV in one study and in children and adults with HIV in a different study, whereas C. parvum infection was associated with vomiting in another study in adults with HIV.^29-31 Neither clinical history nor physical examination allows differentiation of cryptosporidial disease from that caused by other pathogens.

Biliary tract disease due to cryptosporidial infection is associated with CD4 counts ≤50/mm³.³² Symptoms and signs include fever, right upper abdominal pain, nausea, vomiting, and elevated alkaline phosphatase. Diagnostic studies show dilatation of the common bile duct, thickening of the gall bladder wall, and pericholecystic fluid collection. Pancreatitis is rare. Although cryptosporidial infection usually is limited to the gastrointestinal (GI) tract, respiratory disease has been reported in which no pathogen other than Cryptosporidium was detected in sputum.^33,34

Diagnosis

Health care providers should specifically request Cryptosporidium testing because standard ova and parasite testing may not include Cryptosporidium spp. Though not extensively evaluated in children with HIV, diagnostic tests for Cryptosporidium are expected to perform similarly as in children without HIV.

Monoclonal antibody-based direct fluorescent assays and antigen-detection assays (such as enzyme-linked immunosorbent assay [EIA]) can be used to diagnose cryptosporidiosis because of their enhanced sensitivity and specificity as compared with microscopy.^35-38 Oocyst excretion can be intermittent; therefore, the parasite might not be detected in every stool, and stool specimens collected on 3 consecutive days should be examined before considering test results to be negative.³⁹ Some immunochromatography assays have been shown to have poor sensitivity and specificity.⁴⁰ With rapid test methods, confirmation by microscopy should be considered.

Commercially available multiplex molecular test panels for GI pathogens that include Cryptosporidium are now available. When compared with microscopy, the sensitivity for detection of parasitic pathogens was 91.7% for Cryptosporidium.⁴¹ In a multicenter evaluation at four geographically distinct clinical sites across the United States, the panel demonstrated a sensitivity of 97.1% and specificity of 98.4% when compared with conventional PCR.⁴² This methodology is becoming the new standard of care as it becomes more widely available.

Molecular characterization tools are being increasingly used to differentiate Cryptosporidium species in outbreak investigations and infection/contamination source tracking. Cryptosporidium isolates cannot be reliably genotyped or subtyped if stool is preserved in formalin, sodium acetate-acetic acid-formalin (SAF), or low-viscosity polyvinyl alcohol (LV-PVA).

Prevention Recommendations

Preventing Exposure

Caregivers and children with HIV infection should be educated and counseled about the different ways Cryptosporidium can be transmitted. Modes of transmission include having direct contact with fecal material from individuals with Cryptosporidium infection (particularly children’s diapers) and from infected young animals, swallowing or drinking contaminated water, including during recreational activities, and eating contaminated food. Maternal infection with Cryptosporidium has been associated with infection in young infants demonstrating the importance of caregiver hygiene.⁴³

Hand washing is probably the most important step to reduce the risk of Cryptosporidium infection. Children with HIV infection should always wash their hands before preparing or eating food; after using the toilet; after contact with children in diapers; after contact with clothing, bedding, toilets, or diapers soiled by anyone who has diarrhea; after touching pets or other animals; and after touching anything that might have come in contact with even the smallest amounts of human or animal feces (such as sand in a sandbox).

Children with HIV infection should avoid contact with pre-weaned bovine calves, other young animals (particularly dogs and cats aged <6 months and lambs and goat kids), ill animals, stray animals, and stool from any animals or humans or surfaces known to be contaminated with animal or human feces.¹¹ Children with HIV infection should avoid petting zoos and animal areas at farms and camps. However, if a child with HIV does visit an animal habitat, an immunocompetent caregiver should clean the child’s shoes and any other surfaces possibly contaminated by feces (such as clothes and stroller wheels).

Children with HIV infection should avoid drinking water directly from ponds, streams, springs, lakes, or rivers, or swallowing water they swim or play in regardless of whether it is chlorinated. Caregivers and children with HIV infection should be aware that recreational water—including lakes, rivers, salt-water beaches, swimming pools, waterparks, hot tubs, spas, water playgrounds, and ornamental water fountains—might be contaminated with human or animal feces that contain Cryptosporidium.

Some outbreaks of cryptosporidiosis have been linked to ingestion of water from contaminated municipal water supplies; the incidence of these outbreaks has dramatically decreased since the mid-1990s because of improved water treatment targeting the inactivation and removal of Cryptosporidium. To decrease the risk of cryptosporidiosis during outbreaks or when otherwise advised by local public health officials to boil water, heat water used for preparing infant formula, drinking, making ice, etc. at a rolling boil for 1 minute. After the boiled water cools, put it in a clean bottle or pitcher with a lid and store it in the refrigerator. Water bottles and ice trays should be cleaned with soap and water before each use. Do not touch the inside of these containers after cleaning. Information on filtering tap water and home water distillers can be found on the Centers for Disease Control and Prevention (CDC) website at Prevention & Control: Immunocompromised Persons.

Nationally distributed brands of bottled or canned carbonated soft drinks are generally safe to drink. Commercially packaged, non-carbonated soft drinks and fruit juices that do not require refrigeration until after they are opened (i.e., those that can be stored unrefrigerated on grocery shelves) also are generally safe. Nationally distributed brands of frozen fruit juice concentrate are safe if they are reconstituted by the user with water from a safe water source. Fruit juices that must be refrigerated from the time they are processed to the time of consumption are either fresh (i.e., unpasteurized) or heat-treated (i.e., pasteurized); only juices labeled as pasteurized should be considered free of risk from Cryptosporidium. Other pasteurized beverages, such as milk, also are considered safe to drink.

All vegetables or fruit to be eaten uncooked should be thoroughly washed. If extra steps are required to make water safe, this safe water should be used to wash fruits and vegetables. When possible, fruit to be eaten raw should be peeled after washing. Unpasteurized dairy products, including raw milk, should not be consumed. Because cooking food kills Cryptosporidium, cooked food and heat-processed foods are generally safe if, after cooking or processing, they are not handled by someone infected with the parasite or exposed to contaminated water.

When traveling internationally, particularly in low-resource settings, people with HIV infection should be warned to avoid drinking tap water and also to not to use it to brush teeth. Ingesting ice made from tap water, raw fruits, and raw vegetables should also be avoided. Steaming-hot foods, self-peeled fruits, bottled and canned processed drinks, and hot coffee or hot tea are generally safe.

In hospitals, standard precautions are recommended. However, if the patient is diapered or incontinent, contact precautions should be used for the duration of illness. In addition, contact precautions may be used to control institutional outbreaks of cryptosporidiosis. Some experts recommend that severely immunocompromised patients with HIV not share a room with a patient with cryptosporidiosis because of the potential for fomite transmission. The potential for respiratory transmission of Cryptosporidium has been suggested.³⁴ However, no specific modifications to current prevention recommendations have been suggested.

Adolescents with HIV infection who are sexually active should be counseled about avoiding sexual practices that could result in oral exposure to feces (such as oral-anal contact). To reduce the risk of exposure to feces, adolescents should use dental dams or similar barrier methods for oral-anal and oral-genital contact, wear latex gloves during digital-anal contact, and change condoms after anal intercourse. Frequent washing of hands and genitals with warm, soapy water during and after sexual activities that could bring these body parts in contact with feces might further reduce the risk of Cryptosporidium infection.

Additional information on prevention can be found on CDC’s website at Prevention & Control: Immunocompromised Persons.

Preventing Disease

Because chronic Cryptosporidium infection occurs most often in patients with HIV with advanced immunodeficiency, ART to prevent or reverse severe immune deficiency is a primary modality for prevention of Cryptosporidium-associated disease in children with HIV infection.

Discontinuing Primary Prophylaxis

Not applicable.

Treatment Recommendations

Treating Disease

Immune reconstitution resulting from ART often results in clearance of Cryptosporidium infection. Effective ART is the primary initial treatment for these infections in children and adults with HIV infection who are not already receiving ART.^19,24,44 In vitro and observational studies, some of which are case series, suggest that ART containing a protease inhibitor (PI) might be preferable to other ART regimens because of a direct effect of the PI on the parasite.^44-53 PIs also increase production of interferon-gamma, which in turn inhibits Cryptosporidium infection. Supportive care with hydration, correction of electrolyte abnormalities, and nutritional supplementation should be provided. Antimotility agents to combat malabsorption of nutrients and drugs should be used with caution.

Other than ART, there is no consistently effective therapy to treat cryptosporidiosis in patients with HIV infection.^54,55 Multiple agents have been investigated in small randomized controlled clinical trials in adults with HIV, including nitazoxanide, paromomycin, spiramycin, bovine hyperimmune colostrum, and bovine dialyzable leukocyte extract.⁵⁶ Azithromycin and roxithromycin have also been investigated in small open-label studies.⁵⁷ No pharmacologic or immunologic therapy directed specifically against Cryptosporidium has yet been shown consistently effective and durable when used alone without concomitant ART.^54,55 The duration of treatment in patients with HIV is also uncertain.

While no agent has consistent, proven efficacy for treating cryptosporidiosis in immunocompromised patients, including patients with HIV, nitazoxanide has been shown to reduce the load of parasites and was associated with clinical improvement in some studies in populations with and without HIV infection.⁵⁸ An Egyptian clinical trial in 100 adults and children without HIV infection randomized patients to a 3-day course of nitazoxanide or placebo.⁵⁹ Nitazoxanide therapy reduced the duration of both diarrhea and oocyst shedding; in children, clinical response was 88% with nitazoxanide and 38% with placebo. No severe adverse events were reported, and adverse events that were reported were similar in the treatment and placebo groups in this study. A study in Zambia in 100 malnourished children (half of whom had HIV) aged 12 to 35 months reported a clinical response in 56% of children without HIV treated with nitazoxanide and in 23% of those receiving placebo.⁶⁰ However, in the children with HIV infection, no benefit from nitazoxanide was observed (clinical response in 8% treated with nitazoxanide and in 25% receiving placebo). In a subsequent study of 60 children with HIV with cryptosporidiosis, the same investigators reported no significant benefit using twice the recommended dose administered for 28 days.⁶¹ It should be noted that the children in the Zambian studies were not receiving ART. In a study in adults with HIV not receiving ART who had CD4 counts >50 cells/mm³, the administration of 14 days of nitazoxanide resulted in a parasitological cure rate of 71% (10 of 14 patients) at a dose of 500 mg twice daily and 90% (9 of 10 patients) at a dose of 1,000 mg twice daily as compared with 20% among placebo recipients.⁶² In a cohort of 365 HIV-positive patients aged >3 years with Cryptosporidium infection who received nitazoxanide as part of a compassionate use program in the United States, sustained clinical response while on treatment was achieved in 59% of the patients. Clinical response was associated with negative stools (P < 0.0001). In this cohort, nitazoxanide was found to be safe at higher doses (up to 3,000 mg/day) and for long durations of treatment.⁶³

Given the seriousness of this infection in immunocompromised individuals and the potential benefit suggested in some studies, use of nitazoxanide should be considered in immunocompromised children with HIV infection (in conjunction with ART for immune restoration).^54,55 Given that ART might directly inhibit the parasite, it is possible that the combination of ART and parasitic therapy might be synergistic. Nitazoxanide is approved in the United States to treat diarrhea caused by Cryptosporidium and Giardia lamblia in immunocompetent children aged ≥1 year and is available in liquid and tablet formulations. The recommended dose for children is 100 mg twice daily for children aged 1 to 3 years and 200 mg twice daily for children aged 4 to 11 years. A tablet preparation (500 mg twice daily) is available for children aged ≥12 years. Nitazoxanide should be administered with food.

Paromomycin, a non-absorbable aminoglycoside indicated for the treatment of intestinal amoebiasis, is not approved for treatment of cryptosporidiosis. Two small, randomized trials evaluating the efficacy of paromomycin for treatment of patients with HIV infection found clinical improvement or reduced oocyst excretion in those treated with paromomycin.^64,65 However, other reports of paromomycin treatment in patients with HIV infection found repeated failure to cure.⁶⁶ Therefore, data do not support a recommendation for use of paromomycin for cryptosporidiosis. Clinical or parasitological cure has been documented with use of paromomycin and azithromycin in combination in case series of patients with HIV with cryptosporidial diarrhea and case reports of patients with HIV with pulmonary cryptosporidiosis.^67-69

Monitoring and Adverse Events, Including IRIS

Patients should be closely monitored for signs and symptoms of volume depletion, electrolyte imbalance, malnutrition, and weight loss. In severely ill patients, total parenteral nutrition might be indicated. One case report describes immune reconstitution inflammatory syndrome, specifically terminal ileitis, in association with treatment of cryptosporidiosis.⁷⁰

In general, nitazoxanide is well tolerated and side effects are mild, transient, and generally limited to the GI tract.

Managing Treatment Failure

The most important steps for managing treatment failure are optimizing ART to increase CD4 counts and providing supportive treatment.

Preventing Recurrence

No pharmacologic interventions, other than ART to prevent or reverse severe immune deficiency, are known to be effective in preventing recurrence of cryptosporidiosis. Good hygiene, including frequent handwashing, and avoiding potentially contaminated water and food and high-risk environmental contact can help prevent reinfection.

Discontinuing Secondary Prophylaxis

Not applicable.

Recommendations

1. In children with HIV infection, what are the best interventions (compared with no intervention) to prevent episodes of cryptosporidiosis?
   • Cryptosporidiosis can be prevented by practicing good hygiene (e.g., frequent handwashing), avoiding drinking water that might be contaminated, avoiding high risk swimming exposures (e.g., drinking swimming water, especially in pools and water playgrounds frequented by very young children), and not eating food that might be contaminated (expert opinion).
   • Children with HIV infection should avoid contact with pre-weaned bovine calves, lambs, goat kids, ill animals, young dogs and cats, stray animals, and stool from any animals or humans or surfaces known to be contaminated with human or animal feces (expert opinion).
   • ART for children with HIV infection to reverse or prevent severe immunodeficiency is the primary mode of prevention of severe enteric cryptosporidiosis (strong, low).
     
     A prospective, comparative cross-sectional study of ART-treated versus ART-naive pediatric patients with HIV infection in Ethiopia found that Cryptosporidium infections were found only in ART-naive patients with low CD4 counts.²⁴ A retrospective/prospective cohort study in adults with HIV infection in South Ethiopia demonstrated that patients who initiated ART with a CD4 count of <500/mm³ and received health interventions including provision of household water treatment, safe water storage, soap, and anti-helminthic drugs had decreased rate of cryptosporidiosis, even among patients with CD4 counts <200 cells/mm³.⁷¹
      
2. In children with HIV infection, what are the best interventions (compared with no intervention) to treat cryptosporidiosis?
   • Treatment with ART is the best intervention in children with HIV infection and cryptosporidiosis (strong, moderate).
   • Immune reconstitution resulting from ART often results in clearance of Cryptosporidium infection, and ART is the primary initial treatment for these infections in children with HIV infection who are not already receiving ART.^19,24,44
   • Nitazoxanide, in addition to ART, can be considered for cryptosporidiosis in children with HIV (strong, moderate).
     
     A clinical trial comparing nitazoxanide versus placebo in children without HIV infection demonstrated that resolution of diarrhea and parasitologic cure were significantly higher in children treated with nitazoxanide.⁵⁹ In a prospective cohort of patients with HIV infection with cryptosporidiosis treated with nitazoxanide, sustained clinical response was achieved in 59% of patients, and 57% of patients had Cryptosporidium-negative stool before completing the study.⁶³ However, a study of malnourished Zambian children demonstrated no benefit from nitazoxanide among children with HIV (clinical response in 8% treated with nitazoxanide and in 25% receiving placebo) but did show benefit when both children with and without HIV infection were included.⁶⁰
   • Dehydration and electrolyte abnormalities should be corrected, and nutritional support should be provided as appropriate (expert opinion).
     
     There are no studies that address this specific management issue in cryptosporidiosis. However, recognition and management of hydration status, electrolyte imbalance, and nutritional needs are key to management of infectious diarrhea.

References

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