Acta Paediatr Suppl 381: 45-8. 1992
Persistent diarrhea associated with AIDS G T Keusch, DM Thea, M Kamenga, K Kakanda, M Mbala, C Brown and F Davachi [CAR Unit, Projet SIDA. and Department of Pediatrics, Mama Yemo Hospital, Kinshasa, Zaire: Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Boston, MA
Keusch GT, Thea DM, Kamenga M, Kakanda K, Mbala M, Brown C, Davachi F. Persistent diarrhea associated with AIDS. Acta PEdiatr 1992;(suppl 381):45-8. Stockholm. ISSN 0803-5326 Chronic diarrhea and wasting are very common manifestations of AIDS in adults in developing countries. Etiologic studies show that protozoa (including Cryptosporidium parvum, Isospora belli, and Enterocytozoon bieniusi) and Mycobacterium avium-intracellulara are the most frequently identified pathogens. Limited data in children suggest that common enteric pathogens are equally as likely in HIV+ and HIV- babies. Preliminary analysis of an ongoing longitudinal study of 469 babies born to mothers with known HIV serostatus in Kinshasa, Zaire, reveals progression of acute to persistent diarrhea is six times greater in HIV+ compared to HIV- babies, and 3.5 times greater in HIV- babies born of HIV+ mothers in comparison to HIV- babies with HIV- mothers. HIV+ babies were also at greater risk than HIV- babies to have recurrent episodes of diarrhea (RR=2.3). Fifty percent of the deaths were due to acute or persistent diarrhea, and were strongly associated with HIV infection. Efforts to improve child survival in AIDS infected populations will need to address HIV infections in both mothers and infants. 0 Acute diarrhea, AIDS, HIV infection, malnutrition. perinatal AIDS, persistent diarrhea. wasting syndrome GT Keusch, Department of Medicine, New England Medical Center, 750 Washington Street, Box 041. Boston, M A 02111. USA
Although persistent diarrhea was recognized as a complication in adult AIDS patients early in the course of the epidemic (l), there are still few published data on the possible interactions of perinatally acquired HIV infection and enteric pathogens. Hence, the extent of diarheal disease morbidity and mortality in young AIDS babies remains unclear. However, based on the tremendous impact of HIV on diarrheal disease and wasting in adults, especially in Africa, we might predict that a similar or even exaggerated effect would occur in infants and children, who are so susceptible to diarrheal diseases even in the absence of HIV infection. A large, well controlled perinatal HIV transmission study carried out in Zaire by Ryder et al. (2) evaluated mortality rates and reported causes of death in HIV infected and non-infected infants. Subjects were selected from cohorts enrolled at birth from mothers with known HIV serology. Neonatal deaths in infants born of HIV+ mothers were increased three-fold compared to those born of HIV- mothers, with prematurity accounting for nearly two-thirds of the fatal outcomes. During the remainder of the first year of life, however, mortality was increased five-fold in those born of HIV+ mothers. Diarrhea was the second leading listed cause of death after AIDS itself, and accounted for approximately 50% of the potentially preventable deaths in all infants, whether born of HIV+ or HIV- mothers. A preliminary analysis of the second and third year
mortality in these cohorts suggests that diarrheal disease becomes the leading preventable cause of death in the babies born of HIV+ mothers, especially in infants with serologically documented HIV infection (3). It is of both considerable interest and importance that mortality rates in HIV- children born of HIV+ mothers appeared to be intermediate between that of the HIV+ children and the offspring of HIV seronegative mothers. One interpretation of this finding is that it may represent a consequence of an impaired ability of AIDS parents to care for their children. If so, the implication of this is that programs to improve child survival in regions with high HIV prevalence may need to target resources to adult AIDS patients as well. This is because appropriate care to reduce adult AIDS morbidity and delay death will permit parents with AIDS to continue to care for their infants, at least through the most vulnerable first few years of life. These children are at great risk of becoming early AIDS orphans (4),a growing and serious problem in areas of the world where underdevelopment, poverty and rising prevalence of HIV infections occur together. This is extremely important, since only around one-quarter to one-third of the babies born of HIV+ mothers will themselves develop HIV infection and AIDS (2). Diarrheal disease appears to be extremely prevalent in young children with AIDS. In a preliminary report of a study from Zambia, 192 of 198 (97%) HIV seropositive
46 GTKeusch el a/.
children, most 1-2 years of age, had a diarrheal illness at presentation or during follow-up, with severe malnutrition in 172 (87%) (5). In another study from Zambia, 44% of children under two presented with chronic watery diarrhea, compared to 18% of children 2-14 years of age, and 28% of those 15 years and older (6). However, when the predictive value of chronic diarrhea for HIV was evaluated in hospitalized young children in another Central African country with high rates of HIV seroprevalence, Rwanda, the specificity was found to be high (9 1 YO)but the sensitivity low (only 44%),and hence the positive predictive value of chronic diarrhea for AIDS was just 47% (7). The corresponding figures for weight loss equivalent to > 1OYo of usual body weight were 54% and 68%, with a positive predictive value of only 21%. The reason why diarrheal disease was not predictive of HIV was the high rate for diarrheal diseases in the children without AIDS. Thus, the only useful predictive clinical findings in this population were respiratory distress due to acute lower respiratory tract infections and generalized lymphadenopathy. The purpose of this paper is to review the available data on persistent diarrhea and HIV infection in adults, to present some preliminary prospective data from a study now being carried out in Kinshasa, Zaire, and to highlight the importance of HIV infection in determining the outcome ofdiarrhea, whether acute or persistent.
Persistent diarrhea in adult aids patients Official note of an increase in the prevalence of persistent diarrhea, severe weight loss, fever, malaise, weakness and death in Ugandan adults was first recorded by the Ugandan Ministry of Health in 1982 although i t was not published in the international medical literature until 1985 (8). In 1982 the syndrome was already known to the local population, who called it “Slim” disease because of the prominence of diarrhea and wasting. Within a year of this, Slim disease was shown to be associated with infection with HIV. In contrast to the industrialized countries, where attention to HIV infection was focused by the sharp increase in opportunistic respiratory infections, primarily Pneumocystis carinii, and Kaposi’s sarcoma, the principal problem in Africa and Caribbean countries such as Haiti seemed to be an “enteropathic” variant of AIDS, consisting of the triad of wasting, chronic diarrhea, and fever (9, 10). In Zaire, for example, Colebunders et al. reported that 4o‘X of AIDS patients presenting to a large city hospital in Kinshasa complained of chronic diarrhea and wasting ( 1 1). As a result, chronic diarrhea, defined as more than 30 days with diarrhea in the previous two months, and weight loss greater than 10% of normal body weight, were included in the criteria for the World Health Organization case definition of AIDS in Africa (12). Shortly thereafter, the specificity and sensitivity of this definition were validated (1 3). Chronic diarrhea is now one of
ACTA PRDIATR SUPPL 381 (1992)
the criteria used for clinical staging of HIV infection, and its presence in a patient with other manifestations of AIDS is considered to indicate at least clinical stage 3 by the World Health Organization (14). Intestinal manifestations of AIDS occur in all parts of the intestinal tract, from the mouth to the anus (15). Oral infection with Candida albicans is an exceedingly common event in AIDS, even in the early stages of clinical illness. Esophagitis with dysphagia and odynophagia is common and often due to Candida spp., but may be caused by cytomegalovirus or the Herpes simplex virus as well. The chronic diarrhea of AIDS may vary from an acute large volume watery secretory-like process with dehydration, to a more indolent malabsorptive presentation with frequent bulky stools, steatorrhea, and progressive weight loss. Proctitis, with anorectal pain, tenesmus and bloody mucoid discharge are all too familiar problems for clinicians caring for patients with Herpes simplex rectal infection. Loss of anal sphincter tone in such individuals also contributes to fecal incontinence, and patients may pass soft stool continuously during the entire day, representing a major problem for nursing care.
Microbiologic studies Systematic prospective studies of etiology of the chronic diarrhea in adult AIDS patients have not been reported. In the published collections of patients presenting with this symptom, however, a paucity of classical bacterial pathogens has been noted. About one-third of cases have been infected with the protozoan pathogens Cryptosporidium parvum or Isospora belli. In one series of patients in London with watery diarrhea, excluding those with cryptosporidiosis, the most common pathogen was Mycobacterium avium-intracellulare ( 16). When a group of 33 consecutive patients with previously undiagnosed persistent diarrhea were evaluated by the same investigators, an agent was found in 12, all of whom had stool volumes greater than 400 ml day and weight loss greater than 5 kg (17). Diagnostic success rose to 69% among patients with stool volume above 800 ml/day and weight loss greater than 10% of usual body weight, the two most common agents being Cryptosporidium and cytomegalovirus. Patients with persistent colitis and proctitis often are found to be infected with Herpes simplex and/or cytomegalovirus. Although one report from Australia suggested that common childhood enteric viruses were found in homosexual male AIDS patients with diarrhea ( 1 8), others have not been able to show any association in similar populations in the United States (19). In preliminary studies in Kinshasa, Zaire, these viruses were not found more frequently by our group in HIV+ compared to HIV- adults admitted to internal medicine wards (20), although 21% of the total population had a virus identified in the stool. Thus, while these enteric viruses
Persistent diarrhea in AIDS
ACTA PRDIATR SUPPL 381 (1992)
Table 1. Persistent diarrhea in HIV+ and HIV- infants.
HIV serology Mother
+ +-
Infant
Number
+
35
-
I55
-
I 86
Child-years observed (CY)
P D cases (No.)
PDjlOO CY
21 83 98
4 9 3
19.0*
* Significant difference between
+ / + and - /
~
10.8 3.0
groups ( p = 0.02).
Table 2. Recurrent diarrhea (RD) in HIV+ and HIV- infants.
HIV serology Mother
+ +-
Infant
Number
+
35
-
I55 I 86
-
Child-years observed (CY)
R D cases (No.)
RDjlW CY
21 83 98
24 49 49
I l6*
*Significant difference between
+/+ and - / -
51 49
groups ( p = O . O I ) .
are circulating among adults, their clinical significance is as yet unknown. It is not always (or even often) clear that an agent found in stool is responsible for clinical illness. For some agents, the most convincing data may be therapeutic response. However, since no effective therapy for cryptosporidiosis has been reported to date (except for preliminary evidence suggesting that oral therapy with hyperimmune anti-Cryptosporidium bovine colostrum may be ofclinical use in some patients (21)), it is difficult to be certain that this organism is a pathogen causing disease in individual cases, especially when only small numbers of the parasite are present in the stool. More invasive examination of patients without defined etiologic agents often reveals microsporidiosis (Enterocytozoon bieneusi) infection. However, as this diagnosis currently is dependent on electron microscopic examination of biopsy specimens from the proximal small bowel, it is no doubt underdiagnosed (22). The inability to treat these patients precludes a firm conclusion that mirosporidium infection is the cause of their clinical manifestations.
Pilot study of acute and persistent diarrhea in Zairean infants with and without HIV infections We have recently initiated a pilot study of diarrhea and HIV infection in cohorts of babies born of HIV+ and HIV- mothers in Kinshasa, Zaire. The intent of this preliminary study was to assess the likely impact of HIV
47
on progression of acute diarrhea to persistent diarrhea, using as the definition of chronicity the presence of three or more stools per day for > 14 days; 402 infants have been followed thus far and observed for six months. The cohort includes 190 infants born to HIV+ mothers, of whom 35 have already been documented to be HIV+. There were 269 observed episodes of acute diarrhea in the whole group during the six months of observation. The mean duration of acute episodes was five days. Routine culture for classical enteric bacteria and microscopic examination for parasites were rather unrewarding, as only 10% had possible pathogens identified. Studies are underway to determine the presence of various pathogenic E. coli by gene probes for virulence factors, and to define the presence of enteric viruses in these subjects. In 20% of the episodes, yeasts were found to be plentiful on microscopic examination of the stool, although the significance of this is uncertain. Six deaths occurred among this group. Sixteen (5%) of the 269 acute episodes of diarrhea became persistent (Table 1). Infants with persistent diarrhea (PD) were slightly older than the acute diarrhea group (mean age 8.2 months vs 7.3 months), with a mean duration of illness of 20 days. The PD rate in HIV+ infants was more than six times greater than that for infants born of HIV seronegative mothers. Interestingly, the PD rate for HIV- infants born of HIV+ mothers was intermediate between the HIV+ infants from HIV+ mothers and the true controls born of HIVmothers. This finding is consistent with previous data from Kinshasa (1). Three of four babies who died with PD were HIV+ ( p =0.003). The cohort infants have also been examined for recurrent diarrhea episodes (Table 2). Preliminary data suggest that HIV+ infants are also at significantly greater risk of developing recurrent diarrhea (defined as diarrhea occurring after seven or more symptom-free days) compared to HIV- babies born to either HIV+ or HIV- mothers (relative risk, RR=2.3). A large number of potential risk factors for PD were sought by questionnaire in this population. No association was seen with breast feeding prior to or during the episode, water source, formula preparation, use of boiled water, handwashing, number of household members or number of infants under five, domestic animals, antecedant malaria, respiratory infections or measles, or therapy with antimicrobials, antidiarrheals, the use of oral rehydration solutions, or traditional medicine use. Rather, HIV infection appeared to be the only risk factor encountered. The differences already detected in morbidity and mortality between HIV+ and HIV- babies associated with acute, persistent, and recurrent diarrhea can be expected to increase as these infants are followed further and become more immunosuppressed, and as maternal morbidity and mortality affects parents' ability to provide general care. It seems inevitable that HIV infection will emerge as an important confounding
48
GT Keusch et al
factor in PD episodes and outcome in populations in which HIV infection is prevalent among women of child-bearing age. From the limited data available thus far, acute and persistent diarrhea accounted for 50% of all deaths during the short period of follow-up, and it is highly likely that the prediction that HIV will have a major and adverse impact on child survival will be fulfilled. Acknowledgemenu.-Supported by Grant No. PO- 1 AI-26698, International Collaboration in AIDS Research, from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
References I . Gottlieb MS, Groopman JE, Weinstein WM. Fahey JL. Detels R. The acquired immunodeficiency syndrome. Ann Intern Med 1983;99:208-20 2. Ryder RW, Nsa W, Hassig S, Behets F, Rayfield M, Ebungola B, et al. Perinatal transmission of the human immunodeficiency virus type 1 to infants of seropositive women in Zaire. New Engl J Med 1989;320:1637-42 3. Mayala M, Manzila T, Kabagabo U, Matela B, Zola B. Binyingo E, et al. Morbidite et mortalite au cows des 3 premiere annees de vew chez 464 enfants nes des meres seropositives au Zaire. Abstr. TOD I . Fifth International Conference on AIDS in Africa, 10-12 October 1990, Kinshasa, Zaire. p. 168 4. Kamenga M. DaSilva M, Muniaka K, Matela B, Batter V, Ryder R. AIDS orphans in Kinshasa, Zaire. Abstr ThD 127 Fifth International Conference on AIDS in Africa, 10-12 October 1990, Kinshasa, Zaire. p. 5. Malek ANA, Mukelabai K, Nyumbu M, Nyaywa S, Iuo N. Paediatric HIV disease: a 3-year prospective study. Abstr SB 30 Sixth International Conference on AIDS, 20-23 June 1990, San Francisco, CA. Vol. 3, p. 103 6. Fleming AF. Opportunistic infections in AIDS in developed and developing countries. Trans Roy SOCTrop Med Hyg 1990; 84 (Suppl 1): 1-6 7. Lepage P, van de Perre P, Dabis F. Commenges D. Orbinski J, Hitimana DG, et al. Evaluation and simplification of the World
ACTA PRDIATR SUPPL 381 (1992)
Health Organization clinical case definition for paediatric AIDS. AIDS 1989;3:221-5 8. Serwadda D, Mugerwa RD, Sewankambo NK, Lwegaba A, Carswell JW, Kirya GB, et al. Slim disease: a new disease in Uganda and its association with HTLV-Ill infection. Lancet 1985;2:849-52 9. Biggar RJ. The AIDS problem in Africa. Lancet 1986;1:79-83 10. Malebranche R, Arnoux C, Guerin JM, Pierre GD, Laroche AC, Pean-Guichard C, et al. Acquired immunodeficiency syndrome with severe gastro-intestinal manifestations in Haiti. Lancet 1983;2:873-8 11. Colebunders R, Francis H, Mann J, Bila K, Izaley L, Kimputu L, et al. Persistent diarrhea strongly associated with HIV infection in Kinshasa, Zaire. Am J Gastroenterol 1987;82:859-64 12. World Health Organization. Acquired immunodeficiency syndrome (AIDS). Wkly Epidemiol Rec 1986;61:69-73 3. Colebunders R, Mann JM, Francis H, Bila K, Izaley L, Kakonde N, et al. Evaluation of a clinical case-definition of acquired immunodeficiency syndrome in Africa. Lancet 1987;1:492-4 1. World Health Organization. Proposed clinical staging system for HIV infection and disease. Wkly Epidemiol Rec 1990;29:222 5. Keusch GT, Farthing MJG. Nutritional aspects of AIDS. Annu Rev Nutr 1990;10:475-501 16. Connolly GM, Shanson D, Hawkins DA, Harcourt Webster JN, Gazzard BG. Non-cryptosporidial diarrhoea in human irnrnunodeficiency virus (HIV) infected patients. Gut 1989;30:195-200 17. Connolly GM, Forbes A, Gassard BG. Investigation ofseemingly pathogen-negative diarrhoea in patients infected with HIV 1. Gut l990;3 l:886-9 18. Cunningham AL, Grohman GS, Harkness J, Law C, Marriott D, Tindall B, et al. Gastrointestinal viral infections in homosexual men who were symptomatic and seropositive for human immunodeficiency virus. J Infect Dis 1988;158:386-91 19. Kaljot KT, Ling JP, Gold JM Laughon BE, Bartlett JG, Kotlet DP, et al. Prevalence of acute enteric viral pathogens in acquired immunodeficiency syndrome patients with diarrhea. Gastroenterology 1989;97:1031-2 20. Thea DM, Glass R, Perriens J, Ngoy B, Kapita B, Atido U, et al. Lack of significant enteric viral shedding among African AIDS paients. Abstr FPB 42. Fifth International Conference on AIDS in Africa, 10-12 October 1990, Kinshasa, Zaire. p. 280 21. Nord J, Ma P, DiJohn D, Tzipori S, Tacket CO. Treatment with bovine hyperimmune colostrum of cryptosporidial diarrhea in AIDS patients. AIDS 1990;4:581-4 22. Orenstein JM, Chiang J, Steinberg W, Smith PD, Rotterdam H, Kotler DP. Intestinal microsporidiosis as a cause of diarrhea in human immunodeficiency virus-infected patients: a report of 20 cases. Hum Path 1990;21:475-81
Persistent diarrhea associated with AIDS G T Keusch, DM Thea, M Kamenga, K Kakanda, M Mbala, C Brown and F Davachi [CAR Unit, Projet SIDA. and Department of Pediatrics, Mama Yemo Hospital, Kinshasa, Zaire: Division of Geographic Medicine and Infectious Diseases, Tufts-New England Medical Center, Boston, MA
Keusch GT, Thea DM, Kamenga M, Kakanda K, Mbala M, Brown C, Davachi F. Persistent diarrhea associated with AIDS. Acta PEdiatr 1992;(suppl 381):45-8. Stockholm. ISSN 0803-5326 Chronic diarrhea and wasting are very common manifestations of AIDS in adults in developing countries. Etiologic studies show that protozoa (including Cryptosporidium parvum, Isospora belli, and Enterocytozoon bieniusi) and Mycobacterium avium-intracellulara are the most frequently identified pathogens. Limited data in children suggest that common enteric pathogens are equally as likely in HIV+ and HIV- babies. Preliminary analysis of an ongoing longitudinal study of 469 babies born to mothers with known HIV serostatus in Kinshasa, Zaire, reveals progression of acute to persistent diarrhea is six times greater in HIV+ compared to HIV- babies, and 3.5 times greater in HIV- babies born of HIV+ mothers in comparison to HIV- babies with HIV- mothers. HIV+ babies were also at greater risk than HIV- babies to have recurrent episodes of diarrhea (RR=2.3). Fifty percent of the deaths were due to acute or persistent diarrhea, and were strongly associated with HIV infection. Efforts to improve child survival in AIDS infected populations will need to address HIV infections in both mothers and infants. 0 Acute diarrhea, AIDS, HIV infection, malnutrition. perinatal AIDS, persistent diarrhea. wasting syndrome GT Keusch, Department of Medicine, New England Medical Center, 750 Washington Street, Box 041. Boston, M A 02111. USA
Although persistent diarrhea was recognized as a complication in adult AIDS patients early in the course of the epidemic (l), there are still few published data on the possible interactions of perinatally acquired HIV infection and enteric pathogens. Hence, the extent of diarheal disease morbidity and mortality in young AIDS babies remains unclear. However, based on the tremendous impact of HIV on diarrheal disease and wasting in adults, especially in Africa, we might predict that a similar or even exaggerated effect would occur in infants and children, who are so susceptible to diarrheal diseases even in the absence of HIV infection. A large, well controlled perinatal HIV transmission study carried out in Zaire by Ryder et al. (2) evaluated mortality rates and reported causes of death in HIV infected and non-infected infants. Subjects were selected from cohorts enrolled at birth from mothers with known HIV serology. Neonatal deaths in infants born of HIV+ mothers were increased three-fold compared to those born of HIV- mothers, with prematurity accounting for nearly two-thirds of the fatal outcomes. During the remainder of the first year of life, however, mortality was increased five-fold in those born of HIV+ mothers. Diarrhea was the second leading listed cause of death after AIDS itself, and accounted for approximately 50% of the potentially preventable deaths in all infants, whether born of HIV+ or HIV- mothers. A preliminary analysis of the second and third year
mortality in these cohorts suggests that diarrheal disease becomes the leading preventable cause of death in the babies born of HIV+ mothers, especially in infants with serologically documented HIV infection (3). It is of both considerable interest and importance that mortality rates in HIV- children born of HIV+ mothers appeared to be intermediate between that of the HIV+ children and the offspring of HIV seronegative mothers. One interpretation of this finding is that it may represent a consequence of an impaired ability of AIDS parents to care for their children. If so, the implication of this is that programs to improve child survival in regions with high HIV prevalence may need to target resources to adult AIDS patients as well. This is because appropriate care to reduce adult AIDS morbidity and delay death will permit parents with AIDS to continue to care for their infants, at least through the most vulnerable first few years of life. These children are at great risk of becoming early AIDS orphans (4),a growing and serious problem in areas of the world where underdevelopment, poverty and rising prevalence of HIV infections occur together. This is extremely important, since only around one-quarter to one-third of the babies born of HIV+ mothers will themselves develop HIV infection and AIDS (2). Diarrheal disease appears to be extremely prevalent in young children with AIDS. In a preliminary report of a study from Zambia, 192 of 198 (97%) HIV seropositive
46 GTKeusch el a/.
children, most 1-2 years of age, had a diarrheal illness at presentation or during follow-up, with severe malnutrition in 172 (87%) (5). In another study from Zambia, 44% of children under two presented with chronic watery diarrhea, compared to 18% of children 2-14 years of age, and 28% of those 15 years and older (6). However, when the predictive value of chronic diarrhea for HIV was evaluated in hospitalized young children in another Central African country with high rates of HIV seroprevalence, Rwanda, the specificity was found to be high (9 1 YO)but the sensitivity low (only 44%),and hence the positive predictive value of chronic diarrhea for AIDS was just 47% (7). The corresponding figures for weight loss equivalent to > 1OYo of usual body weight were 54% and 68%, with a positive predictive value of only 21%. The reason why diarrheal disease was not predictive of HIV was the high rate for diarrheal diseases in the children without AIDS. Thus, the only useful predictive clinical findings in this population were respiratory distress due to acute lower respiratory tract infections and generalized lymphadenopathy. The purpose of this paper is to review the available data on persistent diarrhea and HIV infection in adults, to present some preliminary prospective data from a study now being carried out in Kinshasa, Zaire, and to highlight the importance of HIV infection in determining the outcome ofdiarrhea, whether acute or persistent.
Persistent diarrhea in adult aids patients Official note of an increase in the prevalence of persistent diarrhea, severe weight loss, fever, malaise, weakness and death in Ugandan adults was first recorded by the Ugandan Ministry of Health in 1982 although i t was not published in the international medical literature until 1985 (8). In 1982 the syndrome was already known to the local population, who called it “Slim” disease because of the prominence of diarrhea and wasting. Within a year of this, Slim disease was shown to be associated with infection with HIV. In contrast to the industrialized countries, where attention to HIV infection was focused by the sharp increase in opportunistic respiratory infections, primarily Pneumocystis carinii, and Kaposi’s sarcoma, the principal problem in Africa and Caribbean countries such as Haiti seemed to be an “enteropathic” variant of AIDS, consisting of the triad of wasting, chronic diarrhea, and fever (9, 10). In Zaire, for example, Colebunders et al. reported that 4o‘X of AIDS patients presenting to a large city hospital in Kinshasa complained of chronic diarrhea and wasting ( 1 1). As a result, chronic diarrhea, defined as more than 30 days with diarrhea in the previous two months, and weight loss greater than 10% of normal body weight, were included in the criteria for the World Health Organization case definition of AIDS in Africa (12). Shortly thereafter, the specificity and sensitivity of this definition were validated (1 3). Chronic diarrhea is now one of
ACTA PRDIATR SUPPL 381 (1992)
the criteria used for clinical staging of HIV infection, and its presence in a patient with other manifestations of AIDS is considered to indicate at least clinical stage 3 by the World Health Organization (14). Intestinal manifestations of AIDS occur in all parts of the intestinal tract, from the mouth to the anus (15). Oral infection with Candida albicans is an exceedingly common event in AIDS, even in the early stages of clinical illness. Esophagitis with dysphagia and odynophagia is common and often due to Candida spp., but may be caused by cytomegalovirus or the Herpes simplex virus as well. The chronic diarrhea of AIDS may vary from an acute large volume watery secretory-like process with dehydration, to a more indolent malabsorptive presentation with frequent bulky stools, steatorrhea, and progressive weight loss. Proctitis, with anorectal pain, tenesmus and bloody mucoid discharge are all too familiar problems for clinicians caring for patients with Herpes simplex rectal infection. Loss of anal sphincter tone in such individuals also contributes to fecal incontinence, and patients may pass soft stool continuously during the entire day, representing a major problem for nursing care.
Microbiologic studies Systematic prospective studies of etiology of the chronic diarrhea in adult AIDS patients have not been reported. In the published collections of patients presenting with this symptom, however, a paucity of classical bacterial pathogens has been noted. About one-third of cases have been infected with the protozoan pathogens Cryptosporidium parvum or Isospora belli. In one series of patients in London with watery diarrhea, excluding those with cryptosporidiosis, the most common pathogen was Mycobacterium avium-intracellulare ( 16). When a group of 33 consecutive patients with previously undiagnosed persistent diarrhea were evaluated by the same investigators, an agent was found in 12, all of whom had stool volumes greater than 400 ml day and weight loss greater than 5 kg (17). Diagnostic success rose to 69% among patients with stool volume above 800 ml/day and weight loss greater than 10% of usual body weight, the two most common agents being Cryptosporidium and cytomegalovirus. Patients with persistent colitis and proctitis often are found to be infected with Herpes simplex and/or cytomegalovirus. Although one report from Australia suggested that common childhood enteric viruses were found in homosexual male AIDS patients with diarrhea ( 1 8), others have not been able to show any association in similar populations in the United States (19). In preliminary studies in Kinshasa, Zaire, these viruses were not found more frequently by our group in HIV+ compared to HIV- adults admitted to internal medicine wards (20), although 21% of the total population had a virus identified in the stool. Thus, while these enteric viruses
Persistent diarrhea in AIDS
ACTA PRDIATR SUPPL 381 (1992)
Table 1. Persistent diarrhea in HIV+ and HIV- infants.
HIV serology Mother
+ +-
Infant
Number
+
35
-
I55
-
I 86
Child-years observed (CY)
P D cases (No.)
PDjlOO CY
21 83 98
4 9 3
19.0*
* Significant difference between
+ / + and - /
~
10.8 3.0
groups ( p = 0.02).
Table 2. Recurrent diarrhea (RD) in HIV+ and HIV- infants.
HIV serology Mother
+ +-
Infant
Number
+
35
-
I55 I 86
-
Child-years observed (CY)
R D cases (No.)
RDjlW CY
21 83 98
24 49 49
I l6*
*Significant difference between
+/+ and - / -
51 49
groups ( p = O . O I ) .
are circulating among adults, their clinical significance is as yet unknown. It is not always (or even often) clear that an agent found in stool is responsible for clinical illness. For some agents, the most convincing data may be therapeutic response. However, since no effective therapy for cryptosporidiosis has been reported to date (except for preliminary evidence suggesting that oral therapy with hyperimmune anti-Cryptosporidium bovine colostrum may be ofclinical use in some patients (21)), it is difficult to be certain that this organism is a pathogen causing disease in individual cases, especially when only small numbers of the parasite are present in the stool. More invasive examination of patients without defined etiologic agents often reveals microsporidiosis (Enterocytozoon bieneusi) infection. However, as this diagnosis currently is dependent on electron microscopic examination of biopsy specimens from the proximal small bowel, it is no doubt underdiagnosed (22). The inability to treat these patients precludes a firm conclusion that mirosporidium infection is the cause of their clinical manifestations.
Pilot study of acute and persistent diarrhea in Zairean infants with and without HIV infections We have recently initiated a pilot study of diarrhea and HIV infection in cohorts of babies born of HIV+ and HIV- mothers in Kinshasa, Zaire. The intent of this preliminary study was to assess the likely impact of HIV
47
on progression of acute diarrhea to persistent diarrhea, using as the definition of chronicity the presence of three or more stools per day for > 14 days; 402 infants have been followed thus far and observed for six months. The cohort includes 190 infants born to HIV+ mothers, of whom 35 have already been documented to be HIV+. There were 269 observed episodes of acute diarrhea in the whole group during the six months of observation. The mean duration of acute episodes was five days. Routine culture for classical enteric bacteria and microscopic examination for parasites were rather unrewarding, as only 10% had possible pathogens identified. Studies are underway to determine the presence of various pathogenic E. coli by gene probes for virulence factors, and to define the presence of enteric viruses in these subjects. In 20% of the episodes, yeasts were found to be plentiful on microscopic examination of the stool, although the significance of this is uncertain. Six deaths occurred among this group. Sixteen (5%) of the 269 acute episodes of diarrhea became persistent (Table 1). Infants with persistent diarrhea (PD) were slightly older than the acute diarrhea group (mean age 8.2 months vs 7.3 months), with a mean duration of illness of 20 days. The PD rate in HIV+ infants was more than six times greater than that for infants born of HIV seronegative mothers. Interestingly, the PD rate for HIV- infants born of HIV+ mothers was intermediate between the HIV+ infants from HIV+ mothers and the true controls born of HIVmothers. This finding is consistent with previous data from Kinshasa (1). Three of four babies who died with PD were HIV+ ( p =0.003). The cohort infants have also been examined for recurrent diarrhea episodes (Table 2). Preliminary data suggest that HIV+ infants are also at significantly greater risk of developing recurrent diarrhea (defined as diarrhea occurring after seven or more symptom-free days) compared to HIV- babies born to either HIV+ or HIV- mothers (relative risk, RR=2.3). A large number of potential risk factors for PD were sought by questionnaire in this population. No association was seen with breast feeding prior to or during the episode, water source, formula preparation, use of boiled water, handwashing, number of household members or number of infants under five, domestic animals, antecedant malaria, respiratory infections or measles, or therapy with antimicrobials, antidiarrheals, the use of oral rehydration solutions, or traditional medicine use. Rather, HIV infection appeared to be the only risk factor encountered. The differences already detected in morbidity and mortality between HIV+ and HIV- babies associated with acute, persistent, and recurrent diarrhea can be expected to increase as these infants are followed further and become more immunosuppressed, and as maternal morbidity and mortality affects parents' ability to provide general care. It seems inevitable that HIV infection will emerge as an important confounding
48
GT Keusch et al
factor in PD episodes and outcome in populations in which HIV infection is prevalent among women of child-bearing age. From the limited data available thus far, acute and persistent diarrhea accounted for 50% of all deaths during the short period of follow-up, and it is highly likely that the prediction that HIV will have a major and adverse impact on child survival will be fulfilled. Acknowledgemenu.-Supported by Grant No. PO- 1 AI-26698, International Collaboration in AIDS Research, from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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