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Investigation of Seemingly Pathogen-Negative Diarrhoea

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Investigation of Seemingly Pathogen-Negative Diarrhoea 886 Gut, 1990,31, 886-889 Investigation of seemingly pathogen-negative diarrhoea in patients infected with HIV1 Gut: first published as 10.1136/gut.31.8.886 on 1 August 1990. Downloaded from G M Connolly, A Forbes, B G Gazzard Abstract Patients Thirty three consecutive patients infected by Thirty three consecutive male patients (median human immunodeficiency virus type 1 (HIV1) age 28 years; range 18-54) with serum antibodies with persistent diarrhoea which remained un- to HIVI and with undiagnosed diarrhoea were diagnosed after microbiological examination studied. All had passed more than three loose of six stool samples and rectal histology were stools daily for at least one month, with no investigated for malabsorption. All had xylose microbiological diagnosis established from rectal and Schilling tests, distal duodenal biopsy, histology and at least six stool examinations comprehensive barium studies, micro- performed in a microbiology laboratory biological examination of six further stool accustomed to the particular pathogens associ- samples, and repeat rectal histology. A micro- ated with this patient population. The CDC biological or histological diagnosis ofinfection criteria for full AIDS3 were fulfilled by 16 of the was made in 12 patients (multiple organisms in 33 patients at the time of presentation (group IV three). Cryptosporidia were identified on five C1 in each case); the remaining 17 (by definition) occasions, cytomegalovirus on four, Giardia had HIV disease group IV A. lamblia on two, and herpes simplex, Campy- lobacter jejuni, Salmonella enteritidis, and Entamoeba histolytica once each. No Methods organism was found when weight loss was less Daily stool volume (mean of three days) and than 5 kg or stool volume less than 400 ml/day estimated weight loss from usual premorbid (n=9). Pathogens were identified in nine of 13 weight (checked against ideal 'weight for height' patients (69%) with weight loss greater than 10 in cases of premorbid obesity or doubt) were kg and stool volume more than 800 ml/day. recorded. Upper gastrointestinal endoscopy for Barium studies were normal except for ileal distal duodenal biopsy, barium small bowel http://gut.bmj.com/ flocculation in two patients with cryptospori- follow through examination, and double contrast diosis. Evidence for malabsorption existed in barium enema were performed using standard 24 patients - impaired xylose absorption methods. (n= 19) and abnormal Schilling test (n=21). Of Serum concentrations of vitamin B- 12 and the patients with a severely abnormal Schilling serum and red cell folate concentrations were test, a pathogen was identified in 11 (79%) measured, and double labelled cobalt Schilling (including all five with cryptosporidia, and two tests carried out (normal greater than 11% on September 23, 2021 by guest. Protected copyright. of the patients with only moderate diarrhoea excreted). Xylose absorption testing (5 g) was and weight loss). A simple scoring system performed with assay of a five hour urine collec- based on degree of weight loss and Schilling tion (normal greater than 1-4 g excreted). test result may help to identify the HIV positive Sixfurtherstool sampleswere examined micro- patient with seemingly pathogen-negative biologically with special attention to oppor- diarrhoea in whom further investigations are tunistic pathogens; accordingly the modified likely to show a specific cause. Ziehl-Nielsen stain and use of both Lowenstein- Jensen and Kirchner media were used routinely as previously described.45 Diarrhoea is a common symptom in AIDS Rectal and duodenal histology were stained patients and occurs in up to 50% at some time with haematoxylin and eosin, and with Ziehl- during their illness.' In a proportion of patients Nielsen stain. Inclusion bodies and an inflam- no pathogenic cause of their diarrhoea is found, matory response were required for a histological and it has been hypothesised that direct human diagnosis of cytomegalovirus infecton. immunodeficiency virus type 1 (HIV1) infection Receiver operating characteristics curves6 of the gut mucosa leading to malabsorption may were constructed for each ofthe precisely quanti- be responsible.2 The frequency of finding a fiable parameters measured. Sensitivity, specifi- Departments of pathogen obviously increases with the number of and values were defined and Gastroenterology, city, predictive St Stephen's and tests performed but the clinician needs advice to calculated conventionally.7 Westminster Hospitals, decide when further investigation is unlikely to A scoring system based on Bayes' theorem' London yield diagnostic information. We prospectively was developed to assist early identification of G M Connolly A Forbes studied a group of 33 patients in whom no those in whom an infective aetiology for diar- B G Gazzard pathogen was detected despite examination of rhoea would eventually be found. Correspondence to: six stool samples and rectal biopsy specimen. Dr B G Gazzard, Department Further histo- of Gastroenterology, microbiological analysis, Westminster Hospital, pathology, and tests of malabsorption were Results Horseferry Road, London, to see was to SW1P 2AP. performed if it possible predict Stool volume varied from 300 ml to more than Accepted for publication which patients would benefit from these 3000 ml per 24 hours. Use of arbitrary cut off 5 October 1989 tests. points at 400 and 800 ml led to division of Investigation ofseeminglypathogen-negative diarrhoea inpatients infected with HIVI 887 Scattergram to show relation 0 Sensitivity, specificity, and positive predictive value (PPV) between xylose excretion, 0 -24 for each ofthe degrees ofabnormality ofthe parameters Schilling test result, and evaluated, with negative predictive value (NPV)for a normal 00 result (percentages in each case). final evidencefor or against Gut: first published as 10.1136/gut.31.8.886 on 1 August 1990. Downloaded from infective aetiology for 20 diarrhoea. Xylose results are 0 Sensitivity Specificity PPV NPV excretion in g/5/hour urine .16 collection and Schilling O" a* Weight loss: cm >5 kg 100 43 50 100 results are presented as the co >10 kg 75 90 64 - percentage ofradioisotope x 00 0 Abnormal xylose absorption 83 57 53 86 excretion; in both cases the 1-0' a n/ <50% normal lower limit 42 81 56 horizontal line marks the S. Abnormal Schilling test 92 52 52 92 lower end ofthe normall co <50% normal lower limit 92 86 79 1. 0 reference range. a 00 * 00 .0 oJ v-.. sr were identified. Weight loss of less than 5 kg Without With Without With therefore had a negative predictive value of 100% infection infection infection infection for an eventual microbiological diagnosis, whereas weight loss of greater than 10 kg had a patients between three approximately equal positive predictive value of 64% and a sensitivity sized groups: less than 400 ml, n=9; 400-800 ml, of 75% (Table). n=11; more than 800 ml, n=13. Similarly Abnormality of xylose absorption (whether or arbitrary cut off points for weight loss led to not severe), however, was less discriminatory - distribution of patients between three groups: an abnormal result had only a 53% positive less than 5 kg loss, n=9; 5-10 kg, n=10; more predictive value for a final microbiological diag- than 10 kg, n= 14. The groupings form natural nosis and a normal result only an 86% negative pairs and in all but one patient the stool volume predictive value. Severe abnormality of xylose grouping was 'equivalent' to that for weight loss. absorption had a specificity of 80% associated Serum B- 12 and folate and red cell folate with a sensitivity of only 42% (Table). The concentrations were normal in all patients. receiver operating characteristics curve con- Xylose excretion, however, was impaired in 19 structed from the xylose absorption data patients and in nine of these excretion was less indicated no better discrimination from any than 50% of the lower limit of normal (severely other given level of cut off. abnormal) (Figure). Unsurprisingly, the Schil- A microbiological diagnosis was made in only ling tests showed no evidence of intrinsic factor one patient with a normal Schilling test but of 14 deficiency, and both labels were detected at patients with a severely abnormal result, patho- similar radioconcentration: the mean of the two gens were found in 11 all five (including patients http://gut.bmj.com/ values for each patient was therefore used. In 21 with cryptosporidial infecton, and two patients patients abnormal values were detected and in 14 with only moderate weight loss and stool of these, mean values of less than 50% of the volume). A normal Schilling test therefore had a lower limit of normal were recorded (severely 92% negative predictive value for a final micro- abnormal). biological diagnosis. A severely abnormal Schil- Infection was finally shown in 12 patients ling test, however, had a sensitivity of92% and a (more than one organism in three): crypto- positive predictive value of 79% for subsequent sporidium, n=5; Giardia lamblia, n=2; Enta- microbiological diagnosis (Table). The receiver on September 23, 2021 by guest. Protected copyright. moeba histolytica, n=1; Campylobacter jejuni, operating characteristics curve for Schilling test n=1; Salmonella enteritidis, n=1; cytomegalo- results indicated that a cut offpoint at 50% ofthe virus, n=4; and herpes simplex virus, n=1. lower limit of normal (by chance) corresponded Diagnosis of cytomegalovirus was from biopsy to the best combination ofsensitivity and specifi- specimen alone. Diagnosis
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