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Etiology of Chronic Diarrhea in Antiretroviral-Naive Patients with HIV Infection Admitted to Norodom Sihanouk Hospital, Phnom Penh, Cambodia

  1. Senya Chhin1,
  2. Joseph I. Harwell3,
  3. Joanna D. Bell7,
  4. Gregory Rozycki8,
  5. Tom Ellman2,
  6. J. Mark Barnett4,
  7. Honorine Ward9,
  8. Steven E. Reinert6, and
  9. David Pugatch5
  1. 1Department of Infectious Diseases, Preah Bat Norodom Sihanouk Hospital, Phnom Penh, Cambodia
  2. 2Médecins Sans Frontiéres, London, United Kingdom
  3. 3Division of Infectious Diseases, Department of Medicine, Brown Medical School, Providence, Rhode Island
  4. 4Division of Hematology and Oncology, Department of Medicine, Brown Medical School, Providence, Rhode Island
  5. 5Division of Pediatric Infectious Diseases, Department of Pediatrics, Brown Medical School, Providence, Rhode Island
  6. 6Lifespan Information Services, Rhode Island Hospital, Providence, Rhode Island, and Division of Infectious Diseases and HIV/AIDS Medicine, Department of Medicine, Drexel University College of Medicine, Providence, Rhode Island
  7. 7Division of Infectious Diseases and HIV/AIDS Medicine, Department of Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania
  8. 8Department of Pediatrics, Kaiser Permanente Hospital, Hayward, California
  9. 9Division of Geographic Medicine and Infectious Diseases, Department of Medicine, Tufts-New England Medical Center, Boston, Massachusetts
  1. Reprints or correspondence: Dr. Joanna D. Bell, Drexel University College of Medicine, Div. of Infectious Diseases and HIV/AIDS Medicine, 1427 Vine St. 5th Fl., Philadelphia, PA 19102 (jbell{at}drexelmed.edu).
 
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Abstract

Background. Although both human immunodeficiency virus (HIV) infection and diarrhea are considerable problems in Cambodia, there have not been any studies to determine the history, clinical presentation, and etiology of chronic diarrhea in patients with HIV infection in Cambodia. In this article, we present a case-control study involving 40 HIV-infected patients with chronic diarrhea and 40 HIV-infected patients without diarrhea.

Methods. Clinical, demographic, and laboratory data were collected. Stool samples were examined for parasites, including Cryptosporidium species (by partial acid-fast stain), bacterial pathogens, and rotavirus. Samples from 10 case patients and 10 control subjects were also analyzed for Cryptosporidium species by polymerase chain reaction-restriction fragment-length polymorphism.

Results. The median CD4+ cell count was 11.5 cells/mm3. A potential pathogen was found in 30 case patients (75%) and 29 control subjects (72.5%). Cryptosporidium was the most common pathogen, present in 16 case patients (40%) and 20 control subjects (53.3%). The presence of Cryptosporidium was confirmed by polymerase chain reaction-restriction fragment-length polymorphism, with a prevalence of 40% in each of the 2 groups of 10 subjects who were enrolled for Cryptosporidium evaluation.

Conclusions. Subjects in this cohort had severe immunosuppression. The prevalence of pathogens, including Cryptosporidium, was extremely high but did not differ significantly between the case patients with diarrhea and the control subjects without diarrhea. Further studies are needed to examine factors associated with Cryptosporidium carriage and the natural history of asymptomatic infection.

Chronic diarrhea in patients with HIV infection is an independent marker of poor prognosis [1–3]. This condition has a profound effect on morbidity and mortality in developing nations, where diarrhea occurs in up to 90% of HIV-infected individuals [4]. Findings from studies in both industrialized and developing nations have shown that prevalence rates for specific pathogens vary among geographic locations [2, 5, 6]. In addition, 30%–60% of patients will have no identifiable cause of diarrhea after exhaustive laboratory examinations. In developing nations, these numbers may be higher, in part because of the lack of funding or technology needed for complete investigations [7, 8].

Cambodia has one of the highest prevalence rates for HIV infection in southeast Asia, yet little is known about the course of HIV infection in that country. Current estimates are that ∼2% of the general population is infected with HIV [9]. Recent research from the largest AIDS center in the country, located in Phnom Penh, Cambodia, shows that chronic diarrhea is the most common complication among hospitalized patients with HIV infection, occurring in >40% of patients [10]. However, the cause of diarrhea among this patient population has not been studied.

In January 2001, we conducted an initial study to determine the history, clinical presentation, and etiology of diarrhea for 30 HIV-infected patients with chronic diarrhea and 30 patients without diarrhea who had been admitted to a Cambodian AIDS hospital. We enrolled 20 additional HIV-infected patients, 10 with diarrhea and 10 without diarrhea, to develop preliminary data on the role of Cryptosporidium in these patients.

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Materials and Methods

Study site and population. Preah Bat Norodom Sihanouk Hospital is a 500-bed hospital located in Phnom Penh, Cambodia. The Infectious Disease Department acts as the largest referral center for patients with HIV/AIDS in the entire country, admitting nearly 800 patients annually. At the time that this study was conducted, antiretroviral therapy was not yet widely available in Cambodia, and no subject enrolled in the study was receiving it.

From January 2001 to April 2001, we prospectively enrolled 30 consecutive HIV-infected adults who met the World Health Organization and Cambodian Ministry of Health definition for chronic diarrhea, defined as >3 loose stools per day for 30 or more days in a constant or intermittent pattern. Thirty HIV-infected patients with no history of loose stools in at least the 14 days before hospital admission were enrolled in an unmatched control group.

In addition, 21 patients were later enrolled for the preliminarily evaluation of the role of Cryptosporidium species in chronic diarrhea using molecular methods; 11 case patients had chronic diarrhea, and 10 patients were in the control group. The study research protocol was reviewed and approved by the ethical review boards at both Preah Bat Norodom Sihanouk Hospital and Brown University in Providence, Rhode Island.

Data collection. Using a standardized questionnaire, data were collected regarding age, sex, occupation, marital status, residence, suspected mode of HIV acquisition, self-reported weight loss, and clinical features of diarrhea. Each patient underwent a physical evaluation that included measuring body mass index, mid-arm circumference, and percentage of body fat calculated from skin-fold caliper measurements. At the time of enrollment, a blood sample was obtained from each patient for a complete blood count with differential CD4+ and CD8+ T lymphocyte counts, as well as HIV-1 load (measured by PCR). For those patients who did not already have recorded test results for HIV infection, an ELISA and confirming agglutination test were performed. Markers of wasting and HIV-1 load were not measured for the 21 subjects enrolled for Cryptosporidium evaluation.

Laboratory methods. Two fresh stool samples were collected from each subject. A standard stool ova and parasite examination was performed, as well as a Gram stain for bacteria and cells. A modified trichrome stain with a high concentration of chromotrope 2R (modified Weber stain) for Microsporidia species was performed. Cryptosporidium, Cyclospora, and acid-fast bacilli were detected using a modified Ziehl-Neelsen stain. Strongyloides species were cultured using the Harada-Mori method. Stool cultures specific for bacterial pathogens were performed, including cultures for Mycobacterium on Löwenstein-Jensen agar, Salmonella and Shigella on Hektoen enteric agar and Salmonella-Shigella agar, Escherichia coli on eosin-methylene blue lactose saccharose agar, and Yersinia species on cefsulodine-irgasan-novobiocin agar (incubated at 30°C). For confirmation of genus, samples were plated on Skirrow agar and incubated at 42°C. To confirm the genus of Campylobacter species, samples were plated on Skirrow agar and incubated with Gram stain and catalase and oxidase tests only; for confirmation of Vibrio species, samples were incubated with thiosulfate citrate bile salts sucrose agar; and for confirmation of yeasts, samples were incubated with Sabouraud chloramphenicol culture. Stool samples were also checked for rotavirus using the Slidex Rota Kit 2 latex agglutination kit (BioMérieux), and Clostridium difficile-associated colitis was diagnosed on the basis of the presence of C. difficile toxin A in stool samples (Oxoid Toxin Detection Kit; Sykehuset Asker og Bærum).

All laboratory tests were performed at the Pasteur Institute of Cambodia (Phnom Penh, Cambodia). The stool specimens from the Cryptosporidium evaluation group were collected and analyzed for pathogens in the manner described above. In addition, each specimen was divided into 2 parts and sent in equal volume to the Pasteur Institute of Cambodia and Tufts New England Medical Center (Boston, MA). The stool specimens were preserved in potassium dichromate before being shipped to Boston for Cryptosporidium detection by PCR-restriction fragment-length polymorphism (RFLP), which is a more sensitive method for detection of Cryptosporidium species and is generally considered to be the gold standard for diagnosis. DNA was isolated from fecal samples, as described elsewhere [11]. PCR-RFLP at the small subunit rRNA locus was performed to determine Cryptosporidium species and genotype. A nested PCR was performed using primers and conditions described elsewhere [12]. PCR products were digested separately with SspI and VspI at 37°C for 1 h for species determination and genotype determination, respectively, and the products resolved on 2% agarose gel plates and were visualized with ethidium bromide staining.

Statistical analysis. The data from the subjects enrolled in the Cryptosporidium evaluation group were combined with the data from the case-control study subjects for analysis of the pathogens found in the stool samples and CD4+ cell count. For comparing patient characteristics between the case and control groups, we used the independent-samples t test (with adjustment for unequal variance where appropriate), the Wilcoxon rank-sum test (for variables with non-normal distributions), and the χ2 test. For comparing percent values, the χ2 test was used, except for contingency tables where expected cell counts were <5 cells/mm3, in which instance, we employed Fisher's exact test. We used an α probability of 0.05 as the threshold for statistical significance in 2-tailed comparisons. Values are presented as means ± SDs throughout. Median values are presented with the first and third quartiles. All analyses were performed using Stata software, version 8 (Stata).

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Results

In all, 33 HIV-infected patients with chronic diarrhea and 31 HIV-infected patients with no history of loose stool for ⩾14 days before the study began were offered enrollment into the study. One case patient in the diarrhea group was excluded, because his first stool sample was formed. Another case patient from this group was excluded, because he was unable to produce a stool sample. A third case patient with chronic diarrhea died before specimen collection. In the control group, 1 patient was excluded because his first stool specimen was watery. All patients had at least 1 stool sample sent to the laboratory for examination, and 55 (92%) of 60 patients had a second stool sample examined.

Twenty-one patients were enrolled in the study for Cryptosporidium evaluation; 1 patient was discharged from the hospital before providing a stool specimen. Twenty patients had their stool samples analyzed (10 patients who had diarrhea and 10 who did not). A total of 18 patients provided 2 stool samples each. Results of testing among these patients are included with the results for the case and control patients, as presented in tables 1 and 2.

Table 1
Table 1

Etiology and prevalence of pathogens identified in stool samples of 80 patients with HIV infection.

Table 2
Table 2

Data for the patients with and without chronic diarrhea enrolled for Cryptosporidium evaluation.

Demographic and laboratory characteristics are presented in table 3. There were no significant differences between the 2 groups in age, sex, country of origin, current place of residence, and marital status. Patients without chronic diarrhea were more likely to report that they were uncertain of how they acquired HIV infection than were patients with chronic diarrhea (P < .001). The median CD4+ cell count of the 80-patient cohort was 11.5 cells/mm3 (interquartile range, 4–28.5 cells/mm3). The median CD4+ cell count of subjects with chronic diarrhea was lower than that of patients in the control group (6 vs. 14 cells/mm3; P = .05). There was no statistically significant difference in plasma viral load between the 2 groups.

Table 3
Table 3

Demographic characteristics, risk factors, CD4+ cell counts, and plasma HIV loads of HIV-infected patients with and without chronic diarrhea.

Patients with chronic diarrhea exhibited a lower mean body mass index (P = .04) and mid-arm circumference (P = .03) than patients without diarrhea. Both groups of patients reported significant weight loss, with an “estimated weight loss” (defined as their reported “normal” weight minus weight at time of enrollment) of 13.52 kg (±6.24 kg) among those enrolled with chronic diarrhea and 10.40 kg (±5.61 kg) among those without diarrhea (P = .13). Patients with chronic diarrhea more commonly complained of abdominal pain (P < .001), odynophagia (P = .03), and feeling weak upon standing (P = .03) (table 4).

Table 4
Table 4

Clinical findings for HIV-infected patients with and without chronic diarrhea.

Laboratory analysis of fecal material revealed that patients with a history of prolonged diarrhea were more likely than control subjects to have fecal leukocytes (50% of patients vs. 12.5% of patients; P < .001), RBCs in their stool samples (22.5% vs. 7.5%; P = .06), and mucus visible in stool on light microscopic examination (40% vs. 12.5%; P = .005) (table 1). Stool samples from both groups were examined, and a potential pathogen was found in 30 (75%) of 40 patients with chronic diarrhea and in 29 (72.5%) of 40 control subjects. Thirteen patients (32.5%) in the chronic diarrhea group had ⩾2 pathogens found, and 14 (35%) without diarrhea had ⩾2 pathogens found. Cryptosporidium was the most commonly found pathogen overall, present in the stool of 16 (40%) of 40 patients with chronic diarrhea and 20 (50%) of 40 patients without diarrhea (P = .37). CD4+ cell counts were not significantly different between symptomatic Cryptosporidium carriers (mean CD4+ cell count, 6 cells/mm3) and asymptomatic Cryptosporidium carriers (mean CD4+ cell count, 19.5 cells/mm3; P = .1).

Other pathogens isolated are listed in table 1. of note, 23 (57.5%) of 40 case patients had acid-fast bacilli detected in their stool samples, as did 17 (42.5%) of 40 control subjects (P = .18). Microsporidia species were not identified in the stool samples of any patient in either group.

Data from the 20 subjects enrolled for Cryptosporidium evaluation revealed that, for 4 subjects in the chronic diarrhea group, PCR-RFLP results were positive for Cryptosporidium hominis, previously known as Cryptosporidium parvum human genotype 1. There were also 4 patients in the non-diarrhea group whose test results were positive for C. hominis, and 1 of these patients had a coinfection with C. parvum, as well. The CD4+ cell count of the patient whose test results were positive for C. parvum was 195 cells/mm3. There were 2 patients whose samples were positive for Cryptosporidium by modified Ziehl stain, performed in Cambodia, but the samples were negative by PCR-RFLP, performed in Boston. These patients' results were regarded as false positive. Data for the Cryptosporidium follow-up study is presented in table 2, showing detection by test type.

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Discussion

Among patients with HIV infection, chronic diarrhea is associated with a decrease in quality of life and is an independent predictor of poor prognosis [1, 2, 13]. This study of 40 HIV-infected case patients with chronic diarrhea and 40 HIV-infected control subjects without diarrhea is the first of its kind in Cambodia. We identified a high prevalence of potential pathogens in HIV-infected patients in Cambodia and illustrated trends in markers of nutritional status.

One of the most striking findings was the profound immunosuppression of both the patients with chronic diarrhea and those without. In all, 75 subjects (>90%) enrolled in this study had CD4+ cell counts <200 cells/mm3. In addition, every subject met the Centers for Disease Control and Prevention criteria for AIDS. The 5 patients with CD4+ cell counts >200 cells/mm3 had AIDS-defining opportunistic infections. Obviously, low CD4+ cell counts put these patients at increased risk for acquiring opportunistic infections, and within the context of diarrhea, lower CD4+ cell counts have been shown to predict longer and more protracted bouts of Cryptosporidium-associated diarrhea [14].

We also found that the prevalence of enteric pathogens in the stool did not differ significantly between patients who experienced chronic diarrhea and patients who did not. This result is in agreement with the outcomes from one study in Thailand in which the rate of identification of pathogens was consistent between patients with and without diarrhea [8]. Cryptosporidium was the most frequent pathogen found in the stool samples of our study subjects. This is consistent with at least 4 other reports from Thailand, in which the infection rate for Cryptosporidium was among the highest of the infection rates of the various infectious agents [6, 15–17]. Most interesting was the fact that subjects in the control group of our study were at least as likely to have Cryptosporidium infection (53% of patients) as were patients with chronic diarrhea (40% of patients). The above data were supported by our follow-up study, in which stool samples were specifically analyzed for the presence of Cryptosporidium by PCR-RFLP (table 2). A larger study using more sensitive methods is needed to confirm these preliminary findings.

Asymptomatic shedding of Cryptosporidium among immunocompetent individuals has frequently been described, particularly in populations with a high prevalence of infection with and carriage of pathogens, such as preschools and areas with poor sanitation, overcrowding, and contaminated water supplies [18–20]. However, asymptomatic carriage of Cryptosporidium in HIV-infected patients is not widely reported. Recent studies do document populations of patients with HIV infection or patients who otherwise experience immunosuppression who shed Cryptosporidium in stool but do not complain of diarrhea [21]. A prospective study in Switzerland found Cryptosporidium in the stool samples of 0.7% of HIV-infected subjects without diarrhea [2]. Also, a study from 1995 showed a 22% rate of asymptomatic carriage among immunodeficient children, including 2 HIV-infected individuals [22]. Even more compelling is a study from India involving injection drug users with HIV infection who had an asymptomatic Cryptosporidium carriage rate of 94.4% [23]. In another study involving HIV-infected injection drug users from Malaysia, the prevalence of asymptomatic Cryptosporidium carriage was 23%. The CD4+ cell counts were not measured for these patients, and it was noted that they had no overt clinical evidence of AIDS [24]. Two similarly designed studies, one from Malawi and the other from Peru, involving HIV-infected patients found significantly lower rates of Cryptosporidium carriage among those without diarrhea [25, 26]. In the Peruvian study, the CD4+ cell counts of patients with evidence of Cryptosporidium infection or carriage were the lowest in the study [26].

The high carriage rate found in our study in Cambodia may be, in part, a reflection of poor sanitation and contaminated water supply, conditions which are widespread throughout the country. Although detailed data regarding potential sources of exposure, such as contaminated water, were not collected during this study, it should be noted that 22 (37%) of 60 patients were from provincial sites where hygiene conditions are universally poor. Differences between groups with regard to environmental exposure to Cryptosporidium could certainly have affected our results. In addition, although the follow-up study was small, it is important to note the finding of 2 distinct genotypes of Cryptosporidium in 1 of the control subjects. C. parvum and C. hominis are the main causes of human cryptosporidiosis. C. hominis is found almost exclusively in humans, and C. parvum is found in domestic livestock, wild animals, and humans [27]. There is thought to be geographic variation in the distribution of Cryptosporidium. C. hominis infection accounts for the majority of cases of Cryptosporidium infection in the United States and Australia, and C. parvum infection seems to be more prevalent in Europe [28]. Studies from Thailand have indicated that C. hominis is the dominant genotype that causes human cryptosporidiosis; however, zoonotic species of Cryptosporidium have been observed in HIV-infected patients with diarrhea [29]. One study by Gatei et al. [30] showed extensive genotypic heterogeneity among Cryptosporidium isolates.

Other potential pathogens affecting our subjects include Entamoeba histolytica, Strongyloides stercoralis, and hookworm species. The presence of multiple potential enteric pathogens in stool samples was common in both groups. Two or more pathogens were found in 13 stool samples (32.5%) from patients with diarrhea and in 14 stool samples (35%) from control patients. High rates of recovery of multiple enteric pathogens were found in other similar studies [2, 5, 6].

As in other studies, we were not able to find an etiology for all cases of diarrhea [31]. This could be partly because of the limitations of laboratory testing, particularly for pathogens such as cytomegalovirus, which is not routinely tested for on simple stool examination [32]. Similarly, the significance of the presence of acid-fast bacilli in 23 case patients (57.5%) and 17 (42.5%) of 40 control subjects was difficult to interpret [33]. The laboratory scientists in Cambodia were unable to discern between atypical mycobacteria and Mycobacterium tuberculosis. In addition, our inability to identify Microsporidia in the stool of any patient is inconsistent with studies done in both developing and developed nations, where this pathogen is responsible for the majority of chronic diarrhea and wasting observed [34, 35]. It is highly possible that laboratory error was responsible for this inability because of the difficulty of identifying Microsporidia without the aid of electron microcopy or molecular methods [36]. Other potential causes of diarrhea among patients with pathogen-negative chronic diarrhea include HIV-induced enteropathy [31] and fat malabsorption [37, 38]. Finally, no specific assays were performed to identify pathogenic strains of Escherichia coli, such as enteroadherent E. coli.

A potential bias for this study is the fact that Preah Bat Norodom Sihanouk Hospital is a large referral center, and therefore, results from that hospital may not be generalizable to other populations in Cambodia. The fact that this is a hospital-based cohort likely accounted for the equal level of immunosuppression seen between the 2 groups.

In summary, a high prevalence of potential pathogens was found among Cambodian patients with HIV infection with and without chronic diarrhea, including an asymptomatic Cryptosporidium carriage rate of 50%. This high rate of carriage, along with the profound immunosuppression in the majority of subjects enrolled in this study, may increase patients' risk of developing symptomatic disease. This is particularly important in Cambodia, where health problems associated with poverty and poor sanitation are significant. Further studies are needed to examine the factors associated with the high rate of Cryptosporidium carriage, whether asymptomatic carriers experience progression to symptomatic disease, the immunologic correlates of disease (including mucosal antibody production), and the impact of HAART on the clinical course of these patients.

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Acknowledgments

Financial support. The Fogarty International Center and the US National Institutes of Health program of international training related to HIV/AIDS (grant 7 D43 TW00237).

Potential conflicts of interest. All authors: no conflicts.

  • Received December 6, 2005.
  • Accepted June 8, 2006.
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  1. Clin Infect Dis. (2006) 43 (7): 925-932. doi: 10.1086/507531
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