Diarrhea

Persistent and recurrent diarrheas are amongst the most frequent manifestations of HIV/AIDS in both children and adults, especially in developing countries, where diarrhea is associated with growth failure, weight loss and death. In Zaire, 85% of adults admitted with persistent diarrhea had HIV infection.31 Among children presenting to a primary health care facility in South Africa, a history of persistent diarrhea in the preceding 3 months strongly predicted HIV infection (odds ratio 4.8; CI 2.5-9.3 and positive predictive value of 63%). In South Africa, the profile of children admitted with diarrheal diseases has changed, with increasing prevalence of persistent diarrhea and loss of seasonal peaks of acute diarrhea. HIV-infected children admitted to hospital with diarrhea have more severe symptoms than children uninfected by HIV;32 they frequently have severe co-infections such as pneumonia, pseudomonal skin sepsis and tuberculosis (TB). These result in longer periods of admission and case fatality rates in the order of 27%. In Zaire, children with HIV and persistent diarrhea had an 11-fold increased risk of death compared with uninfected controls. Hence, in developing countries, HIV-related diar-rheal diseases represent a major burden on both caregivers and health resources. The availability of antiretroviral drugs in North America and Europe has dramatically altered the natural history of HIV infection and has reduced the incidence of gastrointestinal disease due to opportunistic infections.33,34 This has shifted much of the scientific interest and research funding to other complications such as lipodystrophy.

Although there is considerable knowledge of the pathophysiology and management of diarrhea in adults with AIDS, less is known about this problem in children. Opportunistic infections and fat malabsorption are common causes of prolonged and recurrent diarrhea in infected adults.35,36 Among children with HIV, carbohydrate intolerance is common and may follow acute infections with rotavirus or other common entero-pathogens.37-39 In resource-poor settings, the optimal management of HIV-related diarrhea remains largely unexamined. Even after 25 years of the epidemic, fewer than 40% of countries with a high HIV seroprevalence have published national recommendations for the management of HIV-associated diarrhea.40

Mucosal structure and function in HIV-related diarrhea

A number of intestinal mucosal structural and functional abnormalities have been described in HIV-infected children with diarrhea. Their patho-genesis is multifactorial and includes the direct effect of pathogens, other inflammatory processes, malnutrition and the direct effect of HIV itself. Variable degrees of villous atrophy, crypt hyper-plasia and increased inflammatory cells in the lamina propria are found in the small intestine of children with diarrhea (Figure 8.1), although these can be present without symptoms, and are often diffusely spread throughout the upper duodenum and jejunum.41,42 Even when the mucosa appears normal on conventional histology, short and irregular microvilli may be evident on electron microscopy and tubuloreticular inclusions may be seen in endothelial cells.43 In the large bowel, loss

Figure 8.1 Villous blunting with crypt hyperplasia and increased inflammatory cells in the lamina propria are evident in this small-intestinal biopsy of an HIV-infected child.

of mucin-producing cells is accompanied by an increase in inflammatory cells, especially mast cells; crypt abscesses and apoptosis are also detected. Although up to 75% of adult HIV-related diarrhea has been attributed to enteric pathogens, causal agents have not been demonstrated with the same frequency in children.44 This may be explained by the difficulty of obtaining appropriate specimens from small children or identifying pathogens such as microsporidia; in addition, alternative pathways of diarrhea may be involved, as seen in other causes of severe malnutrition.

Carbohydrate malabsorption is commonly found in HIV-infected children with persistent diar-rhea.37 This may be the consequence of preceding enteric infection but in most cases the precipitant is unknown. Intestinal biopsies in these children do not always demonstrate villous atrophy.45,46 An abnormal breath H2 analysis in the presence of relatively normal mucosal architecture suggests a non-specific brush-border disorder rather than a specific enzyme deficiency.37,46 Gut permeability, measured by the dual sugar absorption test, is increased, especially in patients with more advanced disease;41 however, this may also be increased in asymptomatic patients and early in disease.3,47 Furthermore, lactose malabsorption is not always associated with clinical symptoms such as diarrhea or growth failure.48 Monosaccharide intolerance has been described in African children with HIV and severe diarrhea, and has an 87% positive predictive value for identifying HIV infection in children presenting with diarrhea.49 It is associated with prolonged recovery, probably due to delayed regeneration of ente-rocytes and return of absorptive capacity. In adults, monosaccharide intolerance is associated with accelerated small bowel transit times, especially in protozoal infections such as cryp-tosporidiosis,50 but this is unlikely to be the sole explanation. Although monosaccharide intolerance does occur in HIV-uninfected children with severe malnutrition, in settings where HIV is highly prevalent, it can be useful as an indication for HIV testing.

Other macronutrients and micronutrients may not be adequately absorbed or there may be increased losses in stools. Bile salt and fat malabsorption are associated with low-grade enteropathies in adult patients with AIDS,51 but are not consistent find ings in HIV-infected children.39,52 Protein maldigestion and malabsorption are seen in children with severe carbohydrate malabsorption and indicate a profound disruption of normal gastrointestinal function and absorptive capacity. Enteric cytomegalovirus or bacterial infections, and occasionally intestinal Kaposi's sarcoma, may present in adults as a protein-losing enteropathy.53,54 In children, protein-losing enteropathy, suggested by increased fecal a^antitrypsin, has also been reported, but specific enteric pathogens were not identified.39 Iron malabsorption has been reported in children with symptomatic HIV with decreased D-xylose absorption, suggesting a general loss of absorptive capacity rather than a specific iron transport defect.55 Vitamin A is absorbed even in the presence of severe diarrhea;56 health-care personnel should aim, therefore, to provide vitamin A supplements, according to the WHO/UNICEF Integrated Management of Childhood Illnesses protocol, to all children presenting with persistent diarrhea at primary health-care facilities.57

Host responses and susceptibility

The relationship between the risk and type of enteric infection and HIV-viral activity, or host immune competence as measured by CD4 counts, has been established in HIV-infected adults in developed countries, and to a limited extent in developing countries. The rapid and pronounced loss of CD4 T-helper cells in gut mucosa that precedes losses in the peripheral blood might explain the loss of local defenses to opportunistic infections. In Uganda, HIV-infected adults with lower CD4 counts were at greater risk of non-typhi salmonellae septicema and other opportunistic infections58 (Figure 8.2).

Children with reduced CD4 counts have more severe diarrhea, i.e. higher fluid losses and more prolonged disease; this is often due to cryp-tosporidiosis.45,59 Local gut immunity may also play an important role in both local susceptibility and disease progression. Total IgA in stool is decreased in symptomatic children with severe diarrhea; elevated serum IgA, which may be due to selective increase of the IgAl subclass, is related to decreased CD4 counts.26,60 These changes occur early in pedi-atric HIV infection and reflect the disturbance of the gut mucosal immune system.

120 I 100

IS 20

120 I 100

IS 20

Plasmodium falciparum malariae M Tuberculosis k. Cryptococcus X Non-typhi salmonellae % Pneumococci 0 Gram-negative bacteremia

200-500 CD4+ count

200-500 CD4+ count

Plasmodium falciparum malariae M Tuberculosis k. Cryptococcus X Non-typhi salmonellae % Pneumococci 0 Gram-negative bacteremia

Figure 8.2 CD4 counts in HIV-infected adults presenting with specific infections in Uganda.

HIV enteropathy

HIV enteropathy is typified by weight loss, diarrhea and characteristic endoscopic and pathological appearances without any identifiable enteric pathogens.61 These include reduced villous height, increased crypt length, focal enterocyte vacuoliza-tion, and hyporegeneration and dysmaturation of intestinal cells.62,63 Several hypotheses have been proposed to explain these findings, including a mucosal immune reaction to HIV-infected cells64 or to signals from regulatory T cells, the effect of bacterial overgrowth or bile salt malabsorp-tion,65,66 unidentified enteric pathogens, or direct small-intestinal damage by HIV itself. The latter hypothesis is supported by the finding of HIV-infected mononuclear cells in the gut, epithelial hypoproliferation, altered intestinal cell differenti-ation67 and reduced apoptotic lymphoid cells following the onset of antiretroviral therapy.68 Intestinal cell lines directly infected with HIV clade B strains have reduced brush-border enzyme activity and altered calcium responses, suggesting that direct infection of enterocytes with HIV may modify absorptive and secretory function.69 Some of these effects may be due to activation of the HIV-1 transactivating factor protein gene (Tat) which is an early immediate regulatory gene that is essential for virus integration and protein expres-sion.70 Circulating cytokines and lymphokines such as interleukin-1p and tumor necrosis factor-a may have a role in diarrhea due to bacteria, proto zoa, cytomegalovirus or where there is no identifiable infection.30,53 These may produce diarrhea through their secretory effects in the colon rather than by altering mucosal barriers. There are isolated reports of collagenous colitis in adults with chronic watery diarrhea, but none in chil-

dren.71

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