The quality of tuberculosis diagnosis in districts of Tigray region of northern Ethiopia

Mengiste M Mesfin1; Tesfay W Tasew2 and Madeley J Richard1 Abstract Background: Low detection of smear-positive and over-diagnosis of smear-negative Pulmonary Tuberculosis (PTB) are major problems in Ethiopia. Non-adherence to diagnostic guidelines could be contributing to the poor detection of tuberculosis. Objective: To assess the quality of diagnosis based on the national tuberculosis guidelines. Methods: A retrospective diagnostic audit was made in eight districts among patients aged 15 years that were on TB treatment between 12/10/2001 and 15/05/2002. A team of three physicians reviewed patient charts, sputum microscopy and radiograph registers to assess diagnostic criteria used to each patient. Results: A total of 237 patients were reviewed: 42 were smear-positive, 101 were smear-negative PTB and 94 were extra-pulmonary tuberculosis. The diagnosis was considered correct in 33 of the 42 smear-positive PTB patients and incorrect in 9 patients. Of 101 smear-negative PTB patients, 31 (31%) were diagnosed as per the national diagnostic guideline. In more than half of patients treated for lymph node tuberculosis their diagnosis was inconsistent with the national diagnostic guideline. Conclusion: Non-adherence to the national guidelines is a major problem in district hospitals. This calls for action to promote clinicians' adherence to the national diagnostic guidelines. [Ethiop.J.Health Dev. 2005;19:13-20] Background Tuberculosis (TB) is the second leading cause of death after HIV/AIDS worldwide. There were an estimated 8-9 million new cases of TB of which 3-4 million were sputum-smear positive (1). The incidence of TB in Africa is strongly associated with prevalence of HIV infection (2). Globally, it was estimated that 11% of new adult TB cases in the year 2000 were infected with HIV, and 38% of those were from sub-Saharan Africa. Directly Observed Treatment-Short course (DOTS) of TB is the World Health Organization (WHO) recommended control strategy adopted by most countries. The strategy stipulates passive detection of Pulmonary Tuberculosis (PTB) cases primarily using sputumsmear microscopy. The WHO's global target is to detect 70% of new sputum-smear positive PTB cases (3). However, only 32% of the estimated new smearpositive PTB cases were detected worldwide under DOTS programmes (4). Ethiopia is still among the countries with the highest tuberculosis burden despite the expansion of DOTS in public health institutions during the past decade. Direct microscopy of sputum-smear using the Ziehl-Neelsen method is the only means to diagnose PTB in Ethiopia (5). Two diagnostic algorithms developed by the National Tuberculosis and Leprosy control program (NTLC) are used to detect PTB and lymph node TB (6). Other diagnostic services such as Mycobacterial cultures and pathological services are not available for routine purposes and as a result the NTLC advocates adherence to the two diagnostic algorithms. The diagnosis of smear-negative PTB primarily relies on patients' clinical conditions, response to broad spectrum antibiotics and chest radiographic evidences. Despite the 90% DOTS coverage in public health institutions, detection of smearpositive PTB was by far lower than the global targets, and the proportion of smear-negative PTB (68%) was disproportionately high (7). Detection of smear-positive PTB increased from 20% in 1995 to 30% in 2002 mainly because of increasing health service coverage (7). Low detection of smearpositive PTB, the higher proportion of sputumsmear negative PTB and Extra-Pulmonary Tuberculosis (EPTB) cases have posed major challenges to tuberculosis control over the years. High prevalence of Human Immunodeficiency Virus (HIV), poor quality of diagnosis using sputum-smear microscopic and a lack of diagnostic facilities to detect other causes of pulmonary diseases mimicking PTB were thought to be the cause of the high smear-negative PTB detection (8-

______________________________________________________________________________________ 1 University of Nottingham, Division of Epidemiology and Public Health, United Kingdom; 2Tigray Regional Health Bureau, Correspondence to Dr. Mengiste Mesfin P.O.Box 7, Mekelle, Ethiopia, E-mail: melesmarye@yahoo.com

14 Ethiop.J.Health Dev. ______________________________________________________________________________________ 10). A few studies investigated the causes for high smear-negative PTB diagnosis in Ethiopia. Clinicians' non-adherence to diagnostic algorithms and the high prevalence of HIV-TB co-infection coupled with the absence of diagnostic tools to identify other HIV-related pulmonary infections were thought to be responsible for the high detection of smear-negative PTB in Ethiopia (11, 12). Improving clinicians' adherence to the national tuberculosis diagnostic guidelines was found to increase detection of smear-positive PTB from 48% to 65% in Ethiopia (11). In Tigray, the proportion of smear-positive PTB patients remained below 20% despite continued efforts to improve the quality of diagnosis in hospitals where 95% of tuberculosis cases are diagnosed. Inconsistent use of the NTLP diagnostic guidelines was observed in most hospitals of Tigray region. However, the extent of clinicians' adherence to the national diagnostic guidelines was not assessed by formal studies. This retrospective audit of patients who were on TB treatment was made to assess the quality of tuberculosis diagnosis based on the national diagnostic guidelines in eight districts of Tigray region. Methods A retrospective diagnostic audit of tuberculosis was made in eight districts of Tigray region of northern Ethiopia. An audit of diagnosis was made in the 16 tuberculosis diagnostic centers (8 hospitals and 8 health centers) of the study districts (see background of study areas). From the district tuberculosis registers, all new patients 15 years of age on TB treatment from 12/10/2001 to 15/05/2002 were included. At the time of the study, there were 834 patients on TB treatment and of these 295 were in the intensive phase. All patients who were diagnosed in the study districts and in their intensive phase of TB treatment were included (n=237). A team of three physicians reviewed patient charts, laboratory sputum registers, radiograph registers and tuberculosis treatment unit registers in order to determine the diagnostic criteria used for each patient to which he/she was put on the category of tuberculosis treatment. A structured form was used to collect data. Based on the documented clinical and laboratory evidences, the diagnosis of each patient was compared with the diagnostic criteria set by the National Tuberculosis and Leprosy Control Program of Ethiopia. The following diagnostic criteria were used to classify tuberculous diseases (6). A smear-positive pulmonary TB patient: a patient with at least two initial sputum smear positive by direct microscopy, or one initial smear examination positive and culture positive, or one initial sputum-smear positive and radiographic abnormalities consistent with active TB as determined by a clinician. A smear-negative pulmonary TB patient: a patient with 3 initial negative smear results for Acid Fast Bacillus (AFB), and no response to a course of broad-spectrum antibiotics, and 3 repeat negative smears for AFB, and radiological abnormalities consistent with PTB, and clinicians decision to treat the patient with anti-tuberculosis drugs, or a patient with 3 initial negative smears for AFB but positive by culture. An EPTB patient other than lymph node TB is diagnosed when there is strong clinical evidence consistent with active EPTB and the decision by a clinician to treat with a full course of anti-TB drugs, or TB in organs other than the lungs proven by one culture positive specimen from an extra-pulmonary site or histo-pathological evidence from a biopsy. A patient with lymph node TB: a patient with consistent signs/symptoms of tuberculosis, and no clinical response or worsening of illness following a trial of treatment with broadspectrum antibiotics. Data entry and analysis was conducted with SPSS for personal computers (SPSS version 10 for Windows). Descriptive statistics were computed for categorical and continuous variables. Ethical clearance was obtained from the Tigray Regional Ethical Committee for Health Research. Results A diagnostic audit was made for 237 patients aged 15 years and above who were in the intensive phase of tuberculosis treatment. Most (94%) were diagnosed in district hospitals, 122 (51.5%) were female, 131 (55.3%) were married and 131 (56.1%) were rural residents. The median age of patients was 34 years. Of the total patients assessed, 42 (17.7%) were diagnosed as smear-positive pulmonary tuberculosis, 101 (42.6%) were smear negative PTB and 94 (39.7%) were EPTB. Of the 42 smear-positive pulmonary patients, 31 had at least 2 initial smears positive for AFB while two patients had at least one initial and one repeat positive sputum-smears following treatment with broad-spectrum antibiotics. Among patients who Ethiop.J.Health Dev. 2005;19(Special Issue)

The quality of tuberculosis diagnosis in districts of Tigray region of northern Ethiopia 15 ______________________________________________________________________________________ were diagnosed as smear-positive PTB, 33 (78.6%) were properly diagnosed (2 or more sputum-smears positive for AFB), 8 (19%) were diagnosed without any documented evidence while one patient was put on anti-TB drugs after a trial of treatment with broad spectrum antibiotics (Table 1).

Table 1: Audit of diagnosis among smear-positive pulmonary patients in Tigray region, northern Ethiopia Diagnostic criteria Number (%) Correct diagnostic criteria used: Cases with at least 2 initial positive sputum smears 31 (73.8) Cases with at least 1 initial and 1 repeat positive sputum smears 2 (4.8) Incorrect criteria or no evidence for diagnosis: Cases diagnosed based on a trial of antibiotics treatment only Cases with no documented sputum-smear results Total cases evaluated 1 (2.4) 8 (19) 42 (100)

The diagnosis of smear-negative PTB was considered correct in 3 patients based on the national tuberculosis diagnostic criteria (3 initial negative smears for AFB followed by a trial of treatment with broad-spectrum antibiotics; and 3 repeat negative smears and chest radiograph findings consistent with pulmonary tuberculosis disease). For 28 of 101 (27.7%) smear-negative patients, the diagnosis was also considered correct by the review team. In 22 (22.2%) patients, smear-

negative pulmonary diagnosis was made based on 3 initial negative smears and chest radiographic features while 8 (7.9%) were diagnosed based on 3 initial negative smears for AFB. Only chest radiographic evidences were used in 7 (6.9%) patients while 6 were put on TB treatment without any documented evidences to substantiate their diagnosis. Two patients with 3 initial smears positive for AFB were put on anti-TB drugs as smear negative PTB (Table 2).

Table 2: Results of diagnostic review among patients treated as smear-negative PTB in Tigray, northern Ethiopia 1 Number and types of diagnostic criteria Number of cases (%) All 4 diagnostic criteria used: 3 initial smears negative + no response to antibiotics + 3 repeat smears negative + chest x-ray findings 3 (3) Three of the 4 diagnostic criteria used: 3 initial smears negative + no response to a trial of antibiotics + chest x-ray findings 28 (27.7) Two of the 4 diagnostic criteria used: 3 initial smears negative + no clinical response to a trial of broad-spectrum antibiotics 3 initial smears negative + chest x-ray findings No clinical response to a trial of broad-spectrum antibiotics + chest x-ray findings One of the 4 diagnostic criteria used: 3 initial smears negative for AFB Chest x-ray findings No clinical response to a broad-spectrum antibiotics No evidence/miss-classification of disease: No documented supportive evidence of the diagnosis 2 initial smears positive but treated as smear-negative PTB 1 + Indicates column percentage. Indicates plus 14 (13.9) 22 (21.7) 9 (8.9)

8 (7.9) 7 (6.9) 2 (2) 6 (5.9) 2 (2)

Assessment regarding the investigations and procedures used to reach smear-negative PTB diagnosis was made. Of the 99 patients with presumed smear-negative PTB diagnosis, 3 initial smears was not made in 24 (24.2%), 43(43.4%) were not tried on broad-spectrum antibiotics, only 5 had repeat sputum-smear, 32(32.3%) had no chest radiographic evidences and no investigations were made in 6 patients (Table 3).

The quality of EPTB diagnosis was assessed based on whether patients had consistent signs/symptoms of tuberculosis and lack of clinical response to treatment with broad-spectrum antibiotics. Of the EPTB patients who were on treatment, 63(67%) were lymph node TB mainly located in the cervical areas and the remaining 31(23%) were in other anatomical sites (Table 4). All patients diagnosed as lymph node tuberculosis had no documented Ethiop.J.Health Dev. 2005;19(Special Issue)

16 Ethiop.J.Health Dev. ______________________________________________________________________________________ evidence of clinical signs and symptoms consistent with active PTB disease. Of the 94 EPTB patients, 50(53.2%) were treated with broad-spectrum antibiotics while 42 (44.7%) were not. In 32 of 63 lymph node TB patients (50.8%) worsening or the absence of a clinical response to broad-spectrum antibiotics treatment was documented while the remaining 31(49.2%) were put on anti-TB drugs without trial of treatment. Thirteen patients with involvement of organs other than lymph nodes were put on anti-tuberculous drugs without a trial of treatment with broad-spectrum antibiotics and 18(50.1%) had worsening or no clinical response to broad-spectrum antibiotics treatment.

Table 3: Assessment of diagnostic tools used in patients with smear-negative PTB diagnosis in Tigray, northern Ethiopia 1 Type of investigations/tools used Number of patients (%) Three initial negative sputum-smear for AFB 75 (75.8) A trial of treatment with a broad spectrum antibiotics 56 (56.6) Three repeat negative sputum-smears for AFB 5 (5.1) 2 Chest x-ray consistent with PTB 67 (67.7) 3 Only treated based on clinical features 6 (6.1)
1

Row percentages were calculated from 99 patients (2 smear-positive PTB patients who were treated as smear-negative PTB were excluded). 2 Chest x-ray reading was not made by a radiologist. 3 No evidence of investigations was found by review of relevant documents.

Table 4: Anatomical sites of involvement in patients with extra-pulmonary tuberculosis diagnosis in Tigray, northern Ethiopia Location and diagnosis Lymph node TB Soft tissue abscess Bone and skin TB Peritoneal TB Multiple organ involvement TB orchitis Empyma TB pericarditis Total evaluated Number (%) 63 (67) 5 (5.3) 12 (13.9) 6 (6.4) 4 (4.2) 2 (2.1) 1 (1.1) 1 (1.1) 94

than reports from elsewhere (13, 14). Patients with presumed sputum-smear negative diagnosis accounted for 101 (42.6%) of all TB and 70.6% PTB diagnoses. These findings clearly indicate that the chance of tuberculosis transmission could be high because of suboptimal detection of sputum smear positive PTB cases in Tigray. The increases in smear-negative PTB diagnosis in Ethiopia could be attributed to several factors: nonadherence to diagnostic algorithm, poor quality of sputum-microscopy and HIV-TB co-infection. We found that non-adherence to the national diagnostic algorithm is a common problem in hospitals, contributing to the over-diagnosis of smear-negative PTB in the study districts. Of the 101 smearnegative PTB patients, only 3 were diagnosed as per the national diagnostic criteria. The diagnosis of 28 smear-negative PTB patients who satisfied 3 of the 4 diagnostic criteria but with no repeat sputumsmears were examined was also considered correct for the following reasons. First, most patients sought health care after 2-3 months of onset of constitutional symptoms in the study districts as elsewhere in Ethiopia (15, 16). Consequently, these patients present with severe forms of illness; and the yield of repeat sputum-microscopy would be insignificant irrespective of their HIV status if the first three initial sputum-smears were negative (1720). Examination of repeat sputum-smears was reported to produce a higher cumulative detection of PTB among patients with HIV co-infection when 3 Ethiop.J.Health Dev. 2005;19(Special Issue)

Discussion The primary target of DOTS strategy is to at least detect those 70% of smear-positive PTB cases who are the major sources of tuberculosis transmission. Accurate diagnosis of pulmonary tuberculosis is therefore a cornerstone of tuberculosis control. Low detection of smear positive and over diagnosis of smear negative PTB has been a relentless problem over the years in Ethiopia. In this study, smear-positive pulmonary patients diagnosed as per the diagnostic criteria represented 13.9% of all forms of tuberculosis patients and 24.6% of pulmonary tuberculosis cases. The detection of smear-positive PTB among all forms of new TB was twice lower than the proportion reported for Ethiopia in the year 2002 (4). On the other hand, the proportion of patients with smear-negative PTB diagnosis was found to be disproportionately higher

The quality of tuberculosis diagnosis in districts of Tigray region of northern Ethiopia 17 ______________________________________________________________________________________ or greater samples were examined (21), but its relative efficiency in PTB diagnosis is not established in Ethiopia. Second, because of the high chance of losing suspected patients as a result of prolonged diagnostic delay, studies recommend that two or three initial sputum-smears for AFB should be made for PTB diagnosis (17, 18). In this study, because of the clinical conditions at presentation and/or the cost of prolonged stay for patients from the rural areas, repeat sputum-smear examination was not made for 95.9% of those with presumed smear negative PTB diagnosis. We therefore inferred that the impact of not having repeated sputum-smear microscopic exam to the observed over-diagnosis of smear-negative PTB would be insignificant. Based on our assessment, the diagnosis of smear-negative PTB was considered incorrect in 68 of 99 patients (68.7%) when repeat smear sputum is excluded as a diagnostic criterion (3 initial negative sputumsmears, no response to a broad-spectrum antibiotics and chest x-ray evidence) and 2 smear-positive patients were treated as smear-negative PTB. Poor quality (under-reading) and examination of a suboptimal number of sputum-smears could partly be contributing to the high diagnosis of smearnegative PTB diagnosis (9). In this study, 24 of 99 patients (24.2%) were treated as smear-negative PTB without AFB sputum-microscopic examination. Thus, miss-diagnosis is highly likely to occur among patients in whom the diagnosis of PTB was made without sputum-smear examination because of the low diagnostic specificity of clinical signs and/or radiographic findings particularly in HIV-high burden countries like Ethiopia (22, 23). Consistent with our conclusion, a similar study in Malawi documented a relatively higher case detection rate (59%) among PTB suspects with three sputum-smears examination (24). In countries with high burden of HIV, an increase in smear negative PTB diagnosis was attributed to HIV co-infection. Other HIV-related pulmonary diseases that clinically resemble PTB were found to increase the diagnosis of smear-negative in resource poor countries like Ethiopia (12) and other African countries (10, 25) where other diagnostic facilities are unavailable. However, most HIV-infected PTB patients are sputum-smear positive in most African countries (26, 27). Over-diagnosis of smearnegative PTB in this study therefore cannot only be explained by the high occurrence of HIV coinfection, although the proportion of patients who are smear-negative is greater among HIV-infected than HIV-negative tuberculosis patients (28). In this study, EPTB diagnosis accounted for 39.7% of all tuberculosis patients and this figure was found to be higher than in a previous report (29). Because of the lack of Mycobacterium tuberculosis culture and pathological services in Ethiopia, the diagnosis of lymph node TB mainly relies on patients' clinical features, their response to treatment trials with broad spectrum antibiotics and physicians' decision to treat with a full course of anti-TB therapy. Assessment using the diagnostic algorithm revealed that 31 of the 63 patients with enlarged lymph nodes were treated with anti-tuberculous drugs without a trial of treatment using broad- spectrum antibiotics. This indicates that in nearly half of patients with enlarged lymph node the national diagnostic algorithm was not adhered to by clinicians and that their decision to treat depended solely on clinical judgments. The national diagnostic algorithm in use for suspects with enlarged lymph nodes is intended to exclude other illnesses with similar clinical features despite the fact that the exact causes are not known. However, the results of a recent pathological investigation (Fine needle aspiration) in the study districts among patients with an enlarged lymph node who failed to respond to broad-spectrum antibiotics indicated that 66.7% were tuberculosis while 33.3% were other conditions (30). These findings revealed that even after a trial of antibiotic treatment more than a quarter of suspects would be miss-diagnosed as tuberculosis, and over-diagnosis of lymph node TB would be more common if clinicians do not adhere to the diagnostic algorithm. The other explanation for the increased proportion of EPTB could be due to the high HIV prevalence in Ethiopia. Elsewhere HIV infection was attributed to increases in lymph node TB (31). However, because of the diagnostic criteria for lymph node TB relies exclusively on patients' clinical features and their response to a broadspectrum antibiotics, it is assumed that there might not be a significant difference in detection rates among those suspected with or without HIV. In this study, EPTB patients other than lymph node were diagnosed based on their clinical features and Ethiop.J.Health Dev. 2005;19(Special Issue)

18 Ethiop.J.Health Dev. ______________________________________________________________________________________ clinicians' decision to treat with TB treatment. The common extra-pulmonary sites of involvement were typical for HIV-high burden countries (32). Because of the scarcity of diagnostic facilities to confirm TB diagnosis and the absence of working diagnostic criteria to compare with, we are not certain to comment about the quality of diagnosis in those cases. However, in the absence of diagnostic facilities, it is apparent that some of these patients could be miss-diagnosed. The institution of proper documentation of TB health information that would enable to evaluate detection and treatment outcomes of tuberculosis patients is essential (33). However, 16 of 237 patients (6.8%) were put on treatment without any documented evidence and 2 smear-positive PTB patients were treated as smear-negative PTB. These problems could be attributed to the poor quality of supervision by district TB/leprosy officers. If patients are improperly classified to different disease categories, they will receive inappropriate anti-TB drug regimens. We strongly ascribed that clinicians' poor adherence to the national diagnostic guidelines is contributing to the increasing detection of smear-negative PTB and EPTB in the study districts. A previous study in Ethiopia has shown increases in the detection of sputum-smear positive PTB by improving adherence to the national diagnostic algorithm (11). In many African countries where other diagnostic tools are unavailable and HIV-TB co-infection is high, the use of rigorous diagnostic algorithms is recommended to improve detection of PTB (12, 34, 35). Nevertheless, the diagnostic algorithm used for PTB screening in Ethiopia was reported to be less sensitive and specific among HIV-infected suspects, and the inclusion of patients' HIV-status as part of the diagnostic work-up was recommended (12). Hence, it can not be concluded with certainty that strict adherence to the national diagnostic algorithm leads to optimum detection of PTB particularly when the quality of sputum-microscopy is poor in the diagnostic institutions (health centers and hospitals). We therefore recommend studies to be conducted on the relative contribution of poor quality of sputum-microscopy and HIV co-infection on PTB diagnosis. Strategies that increase clinicians' adherence to diagnostic guidelines need to be identified to in order to improve the quality of tuberculosis diagnosis. The institution of diagnostic internal quality control in district hospitals and joint evaluation TB control activities with clinicians might create ownership and accountability to improve quality of tuberculosis diagnosis in Ethiopia. References 1. Corbett EL, Watt CJ, Walker N, et al. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163: 1009-21. 2. Corbett EL, Steketee RW, ter Kuile FO, Latif AS, Kamali A, Hayes RJ. HIV/AIDS and the control of other infectious diseases in Africa. Lancet 2002; 359: 2177-87. 3. World Health Organization. 44th World Health Assembly (WHA/1991/REC/1); supplemented by 53rd World Health Assembly, Report by the Director General, Provisional Agenda Item 12.1, A53/5; May 5, 2000. 4. World Health Organization. Global tuberculosis control: surveillance, planning, financing, WHO Report 2003 (WHO/CDC/TB/2003.316). Geneva: WHO, 2003. 5. Enarson DA, Rieder HL, Arnadottir T, Treucq A. Management of tuberculosis: a guild for low-income countries, 5th edn. Paris: International Union against Tuberculosis and Lung Disease, 2000: 1-89. 6. Ministry of Health. Manual of the National Tuberculosis and Leprosy Control Program. 1997: Addis Ababa, Ethiopia. 7. World Health Organization. Global tuberculosis control: surveillance, planning, financing. WHO Report 2002(WHO/TB/ 2002.295). Geneva: WHO, 2002. 8. Hargreaves NJ, Kadzakumanja O, Phiri S, Nyangulu DS, Salaniponi FM, Harries AD, Squire SB. What causes smear-negative pulmonary tuberculosis in Malawi, an area of high HIV sero-prevalence? Int J Tuberc Lung Dis 2001; 5(2): 113-22. 9. Hawken MP, Muhindi DW, Chakaya JM, Bhatt SM, Ng'ang'a LW, Porter JD. Under-diagnosis of smear-positive pulmonary tuberculosis in Nairobi, Kenya. Int J Tuberc Lung Dis 2001; 5(4): 360-3. 10. Lockman S, Hone N, Kenyon TA, et al. Etiology of pulmonary infections in predominantly HIV-infected adults with Ethiop.J.Health Dev. 2005;19(Special Issue)

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