Delay in the diagnosis and treatment of pulmonary tuberculosis in Uzbekistan: a cross-sectional study

Between August 2013 and January 2014, we conducted a cross-sectional study among newly diagnosed pulmonary TB patients in two cities of Uzbekistan, Tashkent and Nukus. In Tashkent, the study was conducted at the Republican Specialized Scientific and Practical Medical Centre for Phthisiology and Pulmonology providing treatment to patients from across the country. In Nukus, the main city of the Autonomous Republic of Karakalpakstan, two hospitals and one dispensary were chosen as study settings.

We reviewed the TB Electronic Surveillance Case-based Management System (ESCM) database of all cases of culture-confirmed pulmonary TB registered in the selected facilities from August 2013 to January 2014. Paper-based inpatient and outpatient medical cards from adult patients (aged ≥15 years) were reviewed and all patients with newly diagnosed pulmonary TB were included in the study. We excluded those with recurrent TB.

The patients were interviewed using an adapted and slightly modified version of the WHO questionnaire developed for the assessment of TB diagnostic and treatment delay [7]. The questionnaire was pre-tested and administered by trained doctors and health workers. All interviews were performed in the Uzbek, Karakalpak or Russian language.

Verbally informed consent was obtained from patients prior to inclusion in the survey, and the study was approved by the Ethical Committee of Charles University in Prague, the Ministry of Health of the Republic of Karakalpakstan, and the Ethical Committee of the Republican Specialized Scientific and Practical Medical Centre for Phthisiology and Pulmonology.

Patients were considered to have pulmonary TB on the basis of clinical, pathological and radiological findings confirmed bacteriologically and histologically. The time between onset of respiratory symptoms and initiation of anti-TB treatment was assessed and delays were divided into three types. Patient delay was measured in days from the first onset of any TB symptom (e.g., cough, fever, weight loss, or night sweats) until the first presentation to the healthcare system (not necessarily a TB facility). Patient delays were allowed to be negative, indicating the situation in which regular healthcare visits detected TB infection before onset of symptoms. Healthcare delay was measured as the number of days from first presentation to the healthcare system until the start of TB treatment. Total delay was calculated as patient delay plus healthcare delay (and thus may also take negative values). Comorbidity was defined as underlying cardiovascular, gastrointestinal, pulmonary, immunologic or malignant disease. Self-medication was defined as use of any medication not prescribed by a healthcare professional. Antibiotics and other medications are available at pharmacies in Uzbekistan over-the-counter and without a prescription.

Analysis of sputum samples for smear microscopy, culture, drug-susceptibility testing (DST) and real-time PCR (Xpert MTB system) were conducted as per international guidelines [8]-[10] at the National Reference laboratory in Tashkent and at the Mycobacterial Laboratory in Nukus. Preliminary confirmation of acid-fast bacilli (AFBs) was performed using Ziehl-Neelsen staining while culturing was done using Lowenstein-Jensen medium. AFB strains were classified according to the WHO/International Union against Tuberculosis and Lung Disease scale: 1+ (10-99 AFBs per 100 fields), 2+ (1-10 AFBs per individual field), 3+ (10-100 AFBs per individual field), and 4+ (>100 AFBs per individual field) [11]. The BACTEC MGIT 960 system, based on the critical concentration method, was used for determining susceptibility to first-line drugs. DST for second line drugs was performed using the agar proportion method in Lowenstein-Jensen medium. Provider-initiated HIV testing is routinely recommended for all patients presenting with symptoms and signs of TB and TB diagnosed patients [12],[13]. MDR-TB and HIV-associated TB sputum samples were analysed using real-time PCR Xpert MTB assay.

The questionnaire included sociodemographic characteristics, risk factors of TB, comorbidity, and TB knowledge and attitudes. Follow-up data included history of TB treatment, such as a detailed description of diagnostic investigation process, first symptoms perceived by the patient, and health seeking actions. The patients were also asked to complete a number of questions measuring psychosocial aspects, for example, feeling ashamed about having TB, fear of social isolation and stigma. In addition, patient medical cards were reviewed for TB diagnostic information, such as date of diagnosis, date of treatment initiation, and laboratory results.

Univariable and multivariable logistic regression analysis was used to evaluate risk factors for patient, healthcare and total delays, which were dichotomised into delay versus non-delay. Following studies in comparable countries (e.g. Rabin et al. [14]), median delays were used as a cut-off. Variables included in the multivariable model were chosen according to the strategy of purposeful selection [15] based on behavioural and biological plausibility as well as statistical (p ≤ 0.2) criteria. The regression outcome was given by the estimated (adjusted) odds ratios and the corresponding 95% confidence intervals. Hypothesis tests for regression coefficients (Wald tests) were performed and expressed with p values at the significance level α = 0.05. PASW statistical software was used for all analyses (IBM Corporation, Armonk, NY, USA, version 18.0).

Knowledge and stigma were measured using scoring systems. For stigma, the responses to the corresponding questions were marked on a five-point scale (1, strongly agree; 2, agree; 3, no opinion; 4, disagree; and 5, strongly disagree), with a low score corresponding to a high degree of stigma (except for the question "Do you feel you can talk to others about your TB" where the score was first reversed before addition to its domain). The mean percentage score for stigma was calculated as 100 times the sum of scores obtained divided by the maximum scores that could be obtained. This resulted in a Cronbach α value of 0.655 in cases for which all 10 stigma questions were answered (unmarried/single patients) and 0.621 in cases for which the last stigma question was unanswered. Knowledge was computed in a less straightforward way to reflect the different degrees of difficulty for the individual questions. For questions about knowledge, contagiosity and curability of TB, the wrong answer resulted in a score of 0 and the right answer in a score of 1, except for the question of whether TB is contagious, which received a score of 2. The right answer to the question about the means of transmission resulted in a score of 3, and all other answers resulted in a score of 1. For the question about common symptoms of pulmonary TB, the score was defined as the number of marked symptoms divided by six (the total number of displayed symptoms). This gave a Cronbach α value of 0.545 for the five knowledge-related items.

We assessed 600 newly diagnosed pulmonary TB cases that were confirmed bacteriologically. Fifty of these showed TB recurrence, and 12 patients refused to participate due to poor clinical conditions. The final sample comprised 538 patients, 243 from Karakalpakstan, 179 from Tashkent, and 116 representing all 12 provinces of Uzbekistan. The characteristics of these patients are summarised in Table 1. The mean age was 40 years and there was no significant gender difference in notified TB cases. The number of cases was, however, slightly higher in men than in women. The prevalence rate was highest in men aged 25-35 years. Of the 538 patients, 231 (42.9%) practiced self-medication or consulted pharmacists with the onset of respiratory symptoms and 124 patients (54.0%) self-treated with antibiotics. The proportion of MDR-TB among new TB cases was 41% and occurred predominantly in Karakalpakstan. No cases of XDR-TB were observed among our patients.

The median patient delay for all patients included in the study was 27 days [interquartile range (IQR), 6-62 days]. Delay was significantly longer in patients who abused alcohol, were HIV positive, and had specific TB symptoms of persistent cough and loss of weight (Table 2). Additionally, patients with positive sputum smear results and those who self-medicated, ordinarily with antibiotics, had longer diagnostic delay. The first healthcare provider consulted (pharmacies, private or district outpatient clinics, ambulance services) and time to reach the nearest health care facility or facility providing TB treatment were significantly associated with longer delay.

The median health system delay of 7 days (IQR, 1-32 days) seemed to be insignificant (Table 2). The health system delay was associated with younger age, unemployment, or labour migration, for those who had recently worked abroad (p = 0.001 and p = 0.02, respectively). Being a health care worker was a strong risk factor (p = 0.01) for health system delay, but could not be fully assessed since there were only eight (1.5%) healthcare workers and all of them had delayed diagnosis. Furthermore, patients who had longer health system delay also were HIV-positive, stigmatised by TB disease, and prescribed antimicrobials.

The median total delay was nearly 2 months (50 days, IQR, 22-92 days), and 228 of 538 patients (42%) experienced a delay of ≥3 months. Patients with a cough, loss of weight, who self-medicated, were prescribed anti-TB medications by non-TB physicians, from distant location to healthcare facility, or facility providing TB treatment experienced longer delays in the diagnosis and treatment of TB.

Further multivariate analysis revealed that self-medication and initial consultation with a private facility predicted long patient delay, while administration of antimicrobial therapy as well as seeking care at private clinics were risk factors for health system delay (Table 3). Cough, self-medication, and private and primary healthcare facilities were associated with long total delay.

Untreated MDR-TB is highly contagious; therefore, we defined the extent of delay and evaluated risk factors among patients with and without MDR-TB. Among MDR-TB patients, there was a slightly longer median patient delay of 36 days, healthcare delay was 8 days, and total delay was 47 days. There were no differences between the two groups for predictors of diagnostic delay. However, high social stigma prevailed in patients with MDR-TB (odds ratio 1.39, 95% confidence interval 0.74-2.62).