Surprisingly little is known about the patterns of enteric infection in HIV-infected children, timing of their acquisition, their individual effects on children's health and nutrition, and their relationship to HIV activity and host immune status. There is reasonable consistency between the few studies that have been conducted in Africa describing the pathogens isolated in children presenting with HIV and diarrhea.44,72 Enteric pathogens that commonly cause acute diarrhea in children uninfected by HIV also frequently result in diarrhea in HIV-infected children.73 Adenovirus 40/41 and astrovirus have been identified in children with persistent diarrhea, but their relative contribution to the burden of diarrheal disease in HIV infection is not known.74-76 Only a few pathogens seem to be opportunistic in HIV-infected children with diarrhea. The most prevalent of these are Candida, Cryptosporidium parvum and cytomegalovirus (CMV); these usually cause oropharyngeal lesions and invasive lesions elsewhere in the gut or persistent diarrhea. Additional pathogens, which occasionally cause diarrhea or other symptoms in children with symptomatic HIV disease, may include herpes simplex virus and Mycobacterium avium intracellulare. Mycobacterium tuberculosis may be isolated from stools in both adults and children with no evidence of pulmonary TB. Perhaps surprisingly, there is little to suggest any association between shigellosis and HIV. One study from North America described an increase in prevalence in HIV-infected homosexuals; however, numerous reports from the African continent do not support this finding. It may be that the virulence of Shigella readily overcomes even the intact mucosal defense system and so the immunocom-promised individual is not at any greater risk. Another possibility is that because Shigella must be taken up by enteric immune cells in order to be invasive, an immune system that is not competent may, paradoxically, be protective. Isospora belli, a significant enteric pathogen in HIV-infected adults77-79 has not been commonly reported amongst HIV-infected children in Africa.72,80 Little is known about the role of the Microsporidia spp and the newly recognized protozoan enteric pathogen Cyclospora cayetanensis in AIDS-associated diarrhea in children.81-83 Laboratory identification of several of these infections may be very difficult, requiring special stains or techniques that are expensive or unavailable in most developing countries. In children, the proportion of diarrhea cases due to infective agents may, therefore, be underestimated.
C. parvum is a common cause of diarrhea in both HIV-infected and uninfected children, but in the immunocompromised child it results in prolonged disease and high fluid losses.84-86 It may be responsible for up to 25% of persistent diarrhea in HIV-infected children in sub-Saharan Africa.59,72 Infection is usually through person-to-person contact, food contamination (e.g. unwashed raw vegetables or fruit) and contaminated water. Two distinct genotypes cause clinical disease in HIV-infected children: human and bovine (calf) types.87 The clinical and epidemiological differ ences between these genotypic variations is unclear, but the human genotype may be associated with a less severe clinical course in HIV-infected adults. Identifying C. parvum is difficult on direct microscopy; without experienced laboratory staff and appropriate stains, the diagnosis is easily missed.88 In most developing countries, enzyme-linked immunosorbent assay (ELISA) or immunofluorescence methods to enhance identification rates are not routinely available. Shedding of the parasite is sporadic, and several stools should be examined to confirm or reject the diagnosis. Endoscopy and duodenal biopsy and aspirate examination further enhance the diagnostic yield.45
The most common site of infection is the duodenum, where it causes marked, though sometimes patchy, villous atrophy and reactive epithelial changes. Co-infection with CMV may exacerbate these responses. Other sites of infection include the stomach and colon (where cryptitis and apop-tosis may occur) and the bile tract (which may be associated with pancreatitis).89 Gut permeability may be markedly increased and fat malabsorption may be significant.90,91 Protracted, or even intractable, secretory diarrhea with high fluid losses follows. It is often associated with weight loss, and up to 2-4% loss of body weight has been reported.36 In HIV-infected children infection and a higher case fatality rate are more common in those with a lower CD4 count.59
In developing countries management is largely supportive to prevent severe dehydration and to recover lost weight through extended nutritional support. Several antimicrobial agents including spiromycin, parmomycin, azithromycin and nita-zoxanide, and other approaches such as oral bovine immunoglobulin have been used with limited benefit.92-94 The most effective treatment by far remains highly active antiretroviral treatment, which restores gut mucosal CD4 cells with eradication of opportunistic infections including C. parvum.95
Oral thrush is one of the most characteristic signs in young children with HIV/AIDS, appearing as white-yellow plaques that cannot be easily scraped off the buccal mucosa. It is not, however, reliable or specific as an indicator of HIV infection; recurrent episodes are better markers of HIV-infection in both children and adults. Thrush is often reported as a risk factor for breast-feeding transmission of HIV, presumably by inducing mucosal breaks facilitating viral entry, but the direction of causality is unclear from the available data.96,97 Gut colonization follows oral infection with Candida species. Candidiasis of the mouth and esophagus is associated with poor appetite and weight loss. Esophageal inflammation is reported in up to 40% of children with AIDS and can be severe;45,98 occasionally a necrotizing esophagitis which may bleed or even perforate can occur. The main differential diagnosis is herpes, CMV and Mycobacterium avium intracellulare. Candida may also produce inflammation and erosions in the gastric mucosa and the large and small intestines. The parasite can occasionally cause local abscesses, which may disseminate resulting in generalized candidiasis. Endoscopy and biopsy are generally required to diagnose invasive Candida, but in developing countries a high index of suspicion may be all that is available. Fluconazole is generally effective, although resistance does occur and higher doses are sometimes needed.
Gastrointestinal CMV infection in children most commonly presents with fever and persistent diarrhea.99,100 CMV-associated disease including retinitis, pneumonia, encephalitis and gastrointestinal involvement is estimated to affect up to 40% of adult AIDS patients, but is probably less frequent in children.101 Symptomatic infection is more common and severe in HIV-infected children less than 12 months of age and with low age-corrected CD4 counts.99 In children the colon is the most common site of gastrointestinal infection, followed by the small intestine and then the esophagus. Mucosal ulceration may sometimes result in massive hemorrhage and perforation of the large bowel, and strictures may follow CMV infection of the esophagus.102 Diagnosis can be difficult. The virus may remain latent for long periods of time and neither serological tests nor positive urine cultures necessarily imply active disease. Children with chronic diarrhea, fever and no other identifiable pathogen should be investigated for CMV infection with lower gastrointestinal endoscopy and biopsy.
CMV DNA quantification (CMV viral load) by polymerase chain reaction (PCR) can be used to decide when to offer prophylactic or active treatment. Prophylaxis and treatment with ganciclovir can prevent complications and significantly reduce morbidity, although the infection is not eradicated and relapses are still frequent.103 Multiple pinpoint perforations or near perforations of the bowel may occur in the small bowel, ascending colon or both.104 The prognosis is poor with or without ganciclovir.
Studies in sub-Saharan Africa show that rotavirus is a common cause of diarrhea in HIV-infected children.105 It is not, however, found more commonly, shed for longer or associated with greater clinical severity than in children uninfected by HIV in similar settings; nor do children with more advanced HIV disease demonstrate any additional susceptibility.106 Rotavirus was not associated with changes in viral load or CD4 counts in a small study in Malawi.107 The pending availability of two new live oral rotavirus vaccines highlights the importance of understanding the relationship, and potential interaction, between these two viral infections. Clinical trials are necessary to ensure that any vaccine is safe and immunogenic in this population.
Intestinal microsporidiosis is increasingly being reported in patients with HIV.83,108 These intracellular protozoa are able to infect most animal species and, in humans, five genera (Enterocytozoon, Encephalitozoon, Septata, Pleistophora and Nosema) are associated with pulmonary, ocular, muscular, renal, intestinal and hepatic clinical disease. In Thailand, Enterocytozoon bieneusi was diagnosed in 25% and 15% of HIV-infected and uninfected children presenting with diarrhea, respectively.81 In Uganda, however, it was found in 17% of children of unknown HIV status attending hospital out-patient clinics for conditions other than diarrhea.82 In contrast, microsporidiosis in HIV-infected adults produces chronic watery diarrhea and wasting, suggesting that responses in children may be quite different.82,109 Villous atrophy and reduced brush-border enzyme activity may cause lactose intolerance.110
Diagnosis is made on stool microscopy using a modified trichrome stain, but this requires considerable technical skill to identify organisms correctly. Identification of parasites in stool or biopsy can be optimized by using PCR methods or electron microscopy on upper gastrointestinal biopsy.111 Albendazole is an effective treatment for Encephalitozoon spp infections.77
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