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Chiang Mai Med Bull 2003;42(3):121-130. Review article GASTROINTESTINAL MANIFESTATIONS IN HIVINFECTED CHILDREN Nuthapong Ukarapol, M.D. Department of Pediatrics, Faculty of Medicine Chiang Mai University Infection from human immunodeficiency virus (HIV) is still an important problem in Southeast Asia. The incidence of HIV-infected patients has been increasing over the last two decades. The problem also affects infants born to HIVinfected mothers. Preventive programs and health education seem to be the most important measures, although the zidovudine (AZT) protocol has been able to reduce the risk of vertical transmission from 25% to 3-8%. However, there have been many HIV-infected children suffering from various illnesses. Diarrhea and other gastrointestinal complications are the most common ailments found in the HIV-infected child. Thea DM, et al. reported that thirty-seven percent of HIVinfected infants experienced diarrhea.(1) Gastrointestinal manifestations in HIV- infected children The gastrointestinal tract is a common site of opportunistic infections and neoplasms, particularly when the gastro- intestinal immunity becomes weakened, resulting in decreased gastric secretion, diminished IgA response, and altered gastrointestinal motility.(2) The common gastrointestinal symptoms and signs in HIV-infected patients are summarized in Table 1.(3-5) I. Diarrhea Diarrhea is a common cause of death in HIV-infected infants. Thea DM, et al. reported a mortality rate of 132 per 1,000 live births, compared to 12 per 1,000 live births in normal infants.(1) Diarrhea can be categorized into acute, recurrent, persistent, and chronic, according to the duration of the symptoms. Persistent and chronic diarrhea is approximately 3 times Table 1. Common gastrointestinal symptoms and signs in HIV-infected patients Diarrhea Abdominal pain Dysphagia and Odynophagia Gastrointestinal bleeding Weight loss and anorexia Address requests for reprints: Nuthapong Ukarapol, M.D. Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand. E-mail:[email protected] Received 23 June 2003, and in revised from 22 August 2003. Ukarapol N. 122 more common in HIV-infected infants than in uninfected ones. The bacterial pathogens, however, are not much different. The factors that predispose the HIV-infected child to persistent diarrhea include 1) more than 3 episodes of acute diarrhea and 2) a symptomatic HIVinfected mother. The etiology of diarrhea in HIV-infected patients seems to be diverse. They are summarized in Table 2.(2,3,6-12) The most common cause of diarrhea in HIV-infected patients is opportunistic infection, including bacteria, viruses, funguses, and parasites. Kelly P, et al. reported Microsporidia, Isospora belli, and Cryptosporidium parvum infection as the first 3 most common pathogens detected in HIV-infected patients with chronic diarrhea.(6) In nearly two-thirds of the patients, the pathogens could be identified by stool examination and cultures,(13) whereas as many as 44-65% of the patients required an endoscopy to establish the correct diagnosis, particularly in those with cytomegalovirus (CMV), Mycobacterium avium-intracellu- lare, esophageal candidiasis, and Cryptoccoccus neoformans infection.(3,13) We studied the utility of pediatric gastrointestinal (GI) endoscopy in HIV-infected children with various GI symptoms and found that gross endoscopic abnormalities were observed in 78.3%; whereas histologic inflammation and opportunistic pathogens were identified in 87% and 43.5%, respectively. Cytomegalovirus was the most common pathogen identified. Abnormal gross findings were significantly associated with histologic inflammation and identification of pathogens (p=0.006 and 0.046, respectively). Specific changes in medical management were made in 50% of cases as a result of endoscopic investigation.(14) Miller TL, et al. concluded that 1) AIDS stage, 2) serious bacterial infection, treated with antibiotics, which finally predisposed the patients to fungal infections, and 3) many gastrointestinal symptoms and signs, were the predictive factors useful as a guide to the possibility of endoscopic abnormalities.(3) Nevertheless, normal gross endoscopic findings could predict a Table 2. Etiology of diarrhea in HIV-infected patients Bacteria Salmonella, Shigella, Campylobacter, Yersinia enterocolitica, E. coli, C. difficile, Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Plesiomonas shigelloides, Aeromonas hydrophilia Virus Cytomegalovirus, adenovirus, rotavirus, Norwalk virus, calcivirus Parasite E. histolytica, Giardia, Cryptosporidium, Isospora, Microsporidia Fungus Candida albicans, Penicillium marneffei, Cryptoccocus neoformans, Histoplasma spp, Coccidoides immitis Neoplasm Kapasi’s sarcoma, lymphoma Miscellaneous Diffuse infiltrative lymphocytosis syndrome, HIV enteropathy, malabsorption, bacterial overgrowth, Zn deficiency Gastrointestinal manifestations of HIV-infected children normal histologic study in 83%, 79% and 65% associated with esophagus, stomach, and duodenum abnormalities, respectively. The authors recommended that tissue biopsies and cultures should be carried out while doing endoscopy. In contrast, Lim SG, et al. found that only 9.3% of their patients with a normal endoscopic study were associated with histologic abnormalities.(4) However, the incidence of these abnormalities tended to increase in the patients with CDC stage IV. Therefore, they did not recommend a routine surveillance biopsy in the patients who still had a CD4 count of over 200 /cumm, except in those with diarrhea. The benefits of doing endoscopy are detailed in Table 3. Pathogenesis of HIV enteropathy Apart from skin and mucous membrane, the GI tract is the major route for perinatal HIV infection.(15) Acquired HIV infection postnatally from breastfeeding is one of the major concerns. In these patients, gastrointestinal diseases, in particular diarrhea, are the most common clinical presentations. Although enteric pathogens are responsible in a majority of cases, the etiology cannot be identi- 123 fied in up to one-third of cases. These patients have been diagnosed as HIV enteropathy, in which there is evidence of 1) increased small bowel permeability, 2) malabsorption of lipids and sugar, 3) certain histopathologic changes, and 4) absence of pathogens identified. Pathogenesis of HIV enteropathy, however, has yet to be clearly elucidated. Either direct HIV-mediated effect or cytokinemediated mucosal change has been postulated.(8,9,16-18) (Figure 1) Concept of CD4+ T cell activation and cytokine-mediated enteropathy There has been evidence demonstrating that HIV is capable of infecting directly into enterocytes.(19) After crossing the GI epithelium, HIV will infect macrophages and lymphocytes in the lamina propria, and some will be quiescent in the mesenteric lymph nodes. GI infection by HIV causes dysregulation of the gut immunity, for instance decreased IgA secretion, and increased CD8+ T cell and lymphoid population in the lamina propria. These changes would promote bacterial overgrowth and then production of endotoxins. These processes would activate CD4+ T cells, and Table 3. The benefits of doing endoscopy to access any feasible GI pathologies in HIV infected patients. 1. Many etiologies require specific treatment and cannot be diagnosed by routine investigations. 2. Prescribing empirical treatment without performing upper endoscopy might put the patients at risk of many side effects from unnecessary medicines, for instance H2 blocker for abdominal pain may predispose the patient to fungal overgrowth, and antiviral drugs may cause hepatotoxicity and hematotoxicity. 3. EGD can be helpful in identifying AIDS defined illnesses. Ukarapol N. 124 Figure 1. Pathogenesis of diarrhea, malabsorption, and malnutrition in HIV-infected patients as a result hasten viral replication, and an eventually decrease in the CD4 population would invariably occur.(15) Activation of T cells results in the release of various cytokines, particularly tumor necrotic factor α and interferon γ. These cytokines can cause microscopic changes on the intestinal absorptive area, includeing villous atrophy and crypt hyperplasia, resulting in a decreased villus to crypt ratio.(6,15) The ultrastructures were also studied, which revealed irregular, joined bases, shortened and broadened microvilli, mitochondrial swelling, formation of lysosomal and vesicular bodies, dilated endoplasmic reticulum in the enterocyte as well as tubuloreticular inclusions in the endothelial cells.(9,20) As the CD4 population continues to decrease, the histopathology will show villous atrophy and crypt hypoplasia.(17) As a result, the patients develop carbohydrate and fat malabsorption, demonstrated by the abnormal breath hydrogen test, 14C-glycerol tripalmitin test, and D-Xylose test(8,18,21), in which they invariably develop diarrhea, malnutrition, growth retardation, and immune dysfunction. However, there have also been some studies that do not support inflammatory mediators and CD4+ T cell activation as a role of HIV enteropathy. (16,22,23) Concept of direct HIV-mediated enteropathy The direct effect of HIV on the enterocyte function has also been studied. A recent study demonstrated that Gp120 of HIV envelop could stimulate a calcium Gastrointestinal manifestations of HIV-infected children signal of HT-29 intestinal cell lines through a G-protein coupled receptor GPR15/Bob at the basolateral membrane of intestinal epithelium. This resulted in microtubular changes and led to increased intestinal permeability, malabsorption and diarrhea, as seen in the patients with HIV enteropathy.(24) This microtubule change was confirmed by a study of the small bowel and a rectal biopsy that were stained immunocytochemically for acetylated tubulin in HIV-infected individuals.(25) Diagnostic approach to the HIVinfected child with diarrhea In addition to recording history carefully and physical examination, stool examination for parasites and cultures are the most important tools for diagnosing causative agents. As mentioned above, endoscopy with a tissue biopsy for histopathologic studies and cultures might be essential in some patients.(14) An ultrasound and CT abdomen would be useful for diagnosing Penicillium marneffei infection,(12) Mycobacterium 125 tuberculosis, and Mycobacterium aviumintracellulare infection.(26) Radin DR, et al. retrospectively reviewed the CT findings in HIV-infected patients with Mycobacterium tuberculosis and Mycobacterium avium-intracellulare infection, which are summarized in Table 4.(26) II. Abdominal pain Thuluvath PJ, et al. recommended basic laboratories carried out routinely, including complete blood count, urinalysis, electrolytes, stool examination and culture, serum amylase, and plain abdomen for all HIV-infected patients presenting with abdominal pain.(27) In patients with upper abdominal pain, an ultrasound abdomen, upper endoscopy, and endoscopic retrograde cholangiography (ERCP) might be needed. Barium enema and colonoscopy would be required for patients with lower abdominal pain. If the etiology of abdominal pain cannot be identified, the CT abdomen might be necessary to establish the diagnosis of Mycobacterium aviumintracellulare and Penicillium marneffei Table 4. Comparison of abdominal CT findings between Mycobacterium tuberculosis and Mycobacterium avium-intracellulare infection in HIV-infected patients Mycobacterium tuberculosis Necrotic lymph nodes Multiple focal visceral lesions Hepatosplenomegaly Bowel involvement 93% 44% 19% (liver) 26% (spleen) Segmental ileocecal wall thickening and extraluminal gas due to duodenal fistula Mycobacterium aviumintracellulare 14% 14% 45% (liver) 23% (spleen) Jejunal wall thickening Ukarapol N. 126 infection.(12) Thuluvath PJ also reported that the most common causes of abdominal pain in HIV-infected patients are sclerosing cholangitis, which is caused by CMV and Cryptosporidium infection, and CMV colitis. Apart from those mentioned previously, shigella colitis, lymphoma, Kaposi’s sarcoma, acute pancreatitis, and Penicillium marneffei mesenteric lymphadenitis are also responsible for abdominal pain in AIDS patients.(12) III. Dysphagia and odynophagia Lesions leading to dysphagia and odynophagia primarily locate in the esophagus, including esophagitis and esophageal ulcer. Candida albicans, cytomegalovirus, and Herpes simplex virus are commonly responsible for these symptoms. Table 5 details the distinction between 3 causative agents.(2) IV. Gastrointestinal bleeding Aside from noninfectious causes and acute infectious diarrhea, e.g. salmonella, shigella, Campylobacter, E. coli, and E. histolytica, CMV ileitis and CMV colitis are the most common causes of gastrointestinal bleeding in HIV-infected children.(5) If severe enough, they can lead to bowel perforation and eventual death.(28) Gangcyclovir and foscarnet are administered for this infection with a fair result. Recently, we found a patient with chronic diarrhea and lower GI bleeding that was caused by Penicillium marneffei infection, and another case with upper GI bleeding that resulted from diffuse infiltrative lymphocytosis syndrome, in which the stomach produced significant gastritis. Mycobacterium tuberculosis and Mycobacterium avium-intracellulare are also able to produce colitis and cause hematochezia.(2) Hepatobiliary and pancreatic diseases in HIV-infected children There have been many reports regarding the diversity of etiologies contributing to hepatobiliary disorders in HIVinfected patients, including infections, drugs, and malignancies.(29-33) The patients might present with jaundice, right upper quadrant pain, nausea, vomiting, and abnormal liver function tests, in particu- Table 5. Endoscopic findings in esophagitis and ulcer in HIV-infected patients Endoscopic findings Location Site of infection Candida White-yellowish plaque Extending from the mouth into the entire esophagus Attached to the epithelium CMV Herpes simplex Erythema, ulcers which Erythema, shallow are deeper than those ulcers seen in HSV infection Distal esophagus Mid esophagus, the near the level of the left main bronchus Endothelial cell Epithelium cell Gastrointestinal manifestations of HIV-infected children lar, an elevation of transaminases and alkaline phosphatase. Neither clinical symptoms and signs nor the liver function tests could definitely predict the etiology and liver pathology of HIVinfected patients.(30,33) Infections are still the most common causes which contribute to these symptoms. Cappell MS, et al. reviewed the causative agents, consisting of Mycobacterium avium-intracellulare, Mycobacterium tuberculosis, salmonella, Cryptoccoccus neoformans, Candida albicans, Histoplama, Coccidioides immitis, CMV, Herpes simplex, viral hepatitis, Pneumocystis carinii, Cryptosporidium, Microsporidia, and HIV.(29) In Southeast Asia, disseminated Penicillium marneffei infection should be included in the differential diagnosis. Concerning CMV and Cryptosporidium, there have been studies that report the association between these pathogens and sclerosing cholangitis.(31,32) Among these infections, CMV and Mycobacterium avium-intracellulare are the most common organisms, at 14% and 11%, respectively.(30) Hepatitis B viral infection is more common in adults who acquire HIV via intravenous drug abuse and homosexual behavior. HBV infection in these patients tends to become chronic and the risk of coinfection with a delta virus is also increased. The incidence of hepatitis C virus infection has risen as well. Apart from infections, malignancy, for instance Kaposi’s sarcoma and non-Hodgkin lymphoma, is one of the frequent complications in HIV- 127 infected patients. Since HIV-infected patients have a tendency to be put on various medications, drug-induced hepatotoxicity should be strongly considered. Table 6 shows lists of drugs reputed to cause hepatotoxicity.(30) Jonas MM, et al. reported histologic studies in HIV-infected children.(33) They found that non-specific findings, including portal inflammation, pericentral necrosis, steatosis, and lymphoma, accounted for nearly half of the abnormalities noted in this study. Giant cell transformation was the second most common histologic finding, associated with CMV infection, Kaposi’s sarcoma, and non-Hodgkin lymphoma. Seventeen percent of the liver tissues were attributed to CMV infection. Kaposi’s sarcoma, lymphoplasmocytic infiltration, and granuloma were also noted in this study. Approach to HIV-infected patients suspected of having hepatobiliary diseases(29-31, 33) As shown in Figure 2, recording history carefully on medications and any specific infections is an important initial step for reaching the correct diagnosis. Table 6. Lists of drugs commonly used in HIVinfected patients and reputed to cause hepatotoxicity Trimethoprim-sulfamethoxazole Petamidine Ketoconazole, Fluconazole 2’,3’-dideoxyinosine (ddI) Ganciclovir Antituberculosis drugs Ukarapol N. 128 Jaundice, RUQ pain, abnormal liver function tests History - drugs and infection Initial investigation Serology for CMV, HAV, HBV, HDV, HCV Blood culture for bacteria, Mycopbacterium, funguses, viruses Bone marrow aspiration Ultrasound and CT abdomen Dilated bile duct Focal lesion Liver biopsy with special stains and cultures ERCP No diagnosis Diagnosis Liver biopsy with special stains and cultures Figure 2. A guideline for approaching an HIV-infected patient suspected of having hepatobiliary diseases. Serology for CMV and viral hepatitis should be carried out as well as blood cultures for bacteria, Mycobacterium, fungus, and viruses. Occasionally, bone marrow culture might be helpful for diagnosing disseminated fungal and Mycobacterium avium-intracellulare infection. An ultrasound abdomen and CT scan are also useful for the discovery of any focal lesions. Then, a liver biopsy can be performed under the guidance of an ultrasound or a CT scan. On the contrary, if these radiologic studies reveal evidence of bile duct dilatation, the ERCP should be the next step in investigations. This method is the greatest tool for diagnosing sclerosing cholangitis. Besides diagnosis, it also provides various treatment for some patients, e.g. sphincteromy in the presence of stones in the common bile duct. If the ERCP cannot give any helpful information, a liver biopsy with special stains and cultures is crucial. Pancreatitis in HIV-infected children The incidence of pancreatitis in HIVinfected children reported by Miller TL, et al.(34) was 17%. It was associated with CMV, Cryptosporidium, Mycobacterium avium-intracellulare, and P. carinii infection. The important risk factors attributed to pancreatitis were 1) exposure to pentamidine isethionate and 2) low CD4 count. Other medications that could be responsible for this condition were trimethoprimsulfamethoxazole and 2’, 3’–dideoxyinosine. Serum amylase is much less sensi- Gastrointestinal manifestations of HIV-infected children tive than serum lipase. Unfortunately, HIV-infected patients with pancreatitis have a poor prognosis. References 1. Thea DM, Michael E, Atido U, et al. A prospective study of diarrhea and HIV-1 infection among 429 Zairian infants. N Engl J Med 1993;329:1696-702. 2. Stoane JM, Haller JO, Orentlicher RJ. 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