Predictors of Time to Sputum Culture Conversion Among Drug-Resistant Tuberculosis Patients in Oromia Region Hospitals, Ethiopia

Introduction

Tuberculosis (TB) is an infectious disease caused by mycobacterium tuberculosis which can spread from person to person through the air.¹ Normally, TB is treatable and curable. However, people with TB can suffer from complications and death if they do not get appropriate treatment.¹ Globally, more than 1.7 billion people are infected by TB and about 10 million people became ill with TB in 2018.² The burden of TB varies from region to region but almost 90% of TB case occurs in 30 high TB burden countries.^2–5 Ethiopia is among the 30 high TB burden countries listed by the World Health Organization (WHO). In 2018, the incidence rate of TB was estimated to be 151 per 100,000 populations, and the incidence of multidrug-resistant TB (MDR-TB) or rifampicin-resistant (RR) was 1.4 per 100,000 people.²

MDR-TB occurs when the TB bacteria develop resistance to the two most effective first-line anti TB drugs, isoniazid and rifampicin.^6–8 Even though ending the TB epidemic by 2030 is among the health targets of the Sustainable Development Goal.⁹ Drug-resistant TB remains to be a serious public health problem throughout the world. In 2018, there were about 500,000 new cases of rifampicin-resistant TB of which 78% had MDR-TB. The three countries with the largest share of the global burden were India (27%), China (14%) and the Russian Federation (9%).^10–12 MDR-TB commonly develop in the course of TB treatment, and is most commonly due to incorrect or inadequate treatment, use of the wrong medications, not taking medication consistently or not completing full treatment course, and person to person transmission is also uncommon.^13–16

Evidence shows that MDR-TB is associated with high treatment costs, increased risk of adverse drug events, and poor treatment outcomes.^17–22 Culture conversion is one of the indicators of MDR-TB treatment success.²³ However, MDR-TB treatment success is affected by multiple factors such as HIV co-infection, presence of lung fibrosis and consolidations, presence of multiple drug resistance, type of treatment regimen.^24–28 Limited studies assessed the predictors of time to culture conversion among MDR-TB patients in Ethiopia, particularly in our study area. This study aimed to generate evidence on predictors of time to culture conversion among drug-resistant TB patients in Oromia regional state of Ethiopia.

Patients and Methods

Study Area, Period, Design, and Source Population

This study was conducted in Oromia regional state, Ethiopia. Oromia is the largest regional state in Ethiopia which covers 353, 690 square kilometers. According to the central statistical agency (CSA) report on the 2007 census, the region’s population size was 28,067,000 people.²⁹ There are 74 hospitals, 1360 health centers, and 6778 health posts in the region. Out of all hospitals in the region, only seventeen hospitals have started multi-drug-resistant tuberculosis (MDR-TB) treatment during this study period. All MDR-TB patients in the region referred to those hospitals to get the treatment. From those hospitals, we selected eight hospitals that have a five-year registry of MDR-TB patients, namely, Metu Karl hospital, Shanan Gibe hospital, Nekemte Hospital, Bishoftu hospital, Shashamane hospital, Adama hospital, Chiro hospital, and Dadar hospital. These hospitals have a separate unit for MDR-TB treatment, and all patients included in this study were drug-resistant TB patients.

Inclusion Criteria

All complete and initially culture-positive drug-resistant tuberculosis patients’ chart registered between November 2012 and December 2017 were included in the study.

Exclusion Criteria

Patient records that have incomplete data regarding the drug regimen followed, date of treatment initiation, date of treatment outcomes, and smear or culture results, and other clinical characteristics required by the data collection tool.

Diagnostic Techniques

GeneXpert MTB/RIF assay, line probe assay, or culture methods were used to diagnose drug resistance in all patients treated at the study hospitals..

Treatment of MDR-TB

All hospitals follow the national ministry of health standardized treatment protocol for the treatment of RR/MDR-TB. The Ethiopian Federal Ministry of Health adopted a standardized treatment regimen which consists of an 8-month intensive phase with a combination of pyrazinamide, capreomycin, levofloxacin, and prothionamide or ethionamide and cycloserine followed by a 12-month continuation phase with a combination of pyrazinamide, levofloxacin, prothionamide or ethionamide and cycloserine.³⁰ Most of the patients were admitted to the hospitals to follow the intensive phase of their treatment. They were discharged from the hospital once their smear and/or culture result converted to negative. Upon discharge, the patients continued their treatment at MDR-TB follow up clinics where daily direct observation treatments (DOTs) were given. The patients returned to their respective hospital outpatient MDR-TB follow up clinics monthly for evaluation. Sputum smears and cultures were collected and processed monthly for all inpatients and outpatients.

Dependent and Independent Variables

Time to sputum culture conversion was the dependent variable for this study. Censored was defined as: when culture result has not been converted for an individual. This includes when the patient stops the treatment even though the culture was positive, deceased before culture conversion, transferred out to another treatment site before culture conversion, and study time completion before culture conversion.

Data Collection Tools and Procedures

Semi-structured data collection tool was developed after reviewing different literature and client record/logbook.³¹ The tool contains variables on the outcome of interest that is time to smear and culture conversion, variables regarding socio-demographic characteristics, and clinical characteristics.

Data Quality Assurance

Data extraction tool was pretested on 15% of patients’ charts at Goba referral hospital hospital. Based on the finding of pre-test necessary amendments were made on the tool before the actual data collection. Data collectors and supervisors were recruited from the health professionals with clinical experience. Two days of training was given for data collectors and supervisors on the objectives of the study and how to use the data extraction tool. The completeness of the data was checked daily before leaving the facility.

Data Analysis

The collected data were first entered into EpiData V.3.1 and exported to SPSS V.20 for analysis. Descriptive statistics like median time to sputum smear and culture conversion were computed. Kaplan–Meier survival curve was used to illustrate the median time to culture conversion. The bivariate and multivariate Cox proportional hazard model was used to detect independent predictors of time to culture conversion. The adjusted hazard ratio with 95% confidence level was used to report the strength and presence of an association. Statistical significance was declared at p <0.05.

Ethical Statement

Ethical clearance was obtained from Madda Walabu University Ethical Review Committee. Upon the ethical approval, permission letter to conduct the study was submitted to the respective Clinical Director/Managers of the Hospitals. Tuberculosis clinic heads gave the consent for accessing and extracting data from records at each Hospital. Patient names and identification numbers were not extracted to ensure the confidentiality of patient information.

Operational Definitions

Sputum conversion: Is defined as two sets of consecutive negative smears and cultures, from samples collected at least 30 days apart. The date of collection for the first sample is considered as the date of conversion.

Multi-drug resistance: Resistance to at least both isoniazid and rifampicin

Rifampicin resistance (RR-TB): Resistance to rifampicin detected using phenotypic or genotypic methods, with or without resistance to other anti-TB drugs. It includes any resistance to rifampicin, whether mono-drug resistance, multi-drug resistance, poly-drug resistance, or extensive drug resistance.

New case: A patient who has received no or less than one month of anti-tuberculosis treatment.

Previously treated with First-line drugs: A patient who has received first-line anti-tuberculosis treatment for four weeks or more.

Relapse: A patient who was previously treated for TB and whose most recent treatment outcome was “cured” or “treatment completed”, and who is subsequently diagnosed with bacteriologically positive TB by sputum smear microscopy, GeneXpert MTB/RIF, or culture.

Treatment after being lost to follow-up: A patient after taking treatment for more than one month who returns to treatment, bacteriologically positive by sputum smear microscopy, GeneXpert MTB/RIF TB/RIF, or culture, following interruption of treatment for two or more consecutive months.

Treatment after failure of New TB regimen: A patient who has received a new regimen for TB and in whom treatment has failed. Failure is defined as sputum smear-positive at five months or later during treatment.

Treatment after failure of Retreatment regimen: A patient who has received a retreatment regimen for TB and in whom treatment has failed. Failure is defined as sputum smear-positive at five months or later during treatment.

Transfer in: A patient who has been transferred from another treatment initiation center to continue MDR-TB treatment.

Cured: Treatment completed according to national recommendation without evidence of failure and three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

Treatment completed: Treatment completed according to national recommendation without evidence of failure but no record that three or more consecutive cultures taken at least 30 days apart are negative after the intensive phase.

Treatment failure: Treatment was considered to be failed if two or more of five cultures in the final 12 months of therapy are positive or if any one of the final three cultures is positive.

Died: A patient who dies during TB treatment.

Results

Socio-Demographic Characteristics

A total of 228 drug-resistant tuberculosis patients with initial positive sputum culture were included in this analysis. The median age of the patients was 28 years (IQR: 22–32 years). Male accounts for 60% of the study participants. More than half (62%) of the patients were urban dwellers (Table 1).

Table 1 Socio-Demographic Characteristics of Drug-Resistant Tuberculosis Patients Following Treatment in Oromia Regional State Hospitals from 2012 to 2017, Oromia, Ethiopia

Clinical Characteristics of Study Participants

Out of 228 patients with initial culture positive result, 10% were new cases, about 16% relapse, about 48% were after the failure of retreatment with the first-line anti-TB regimen and 20% were failures after a new fist line anti-TB regimen. The diagnosis of drug resistance was made by GeneXpert MTB/RIF assay (79.4%), line probe assays (14.9%), or culture (5.7%). Regarding the drug-resistance, about 32% of the patients had drug susceptibility tests (DST) showing both isoniazid (INH) and rifampicin (RIF) resistance while 97.8% had rifampicin resistance. About 10% of study participants encountered adverse drug effects during treatment. Out of all study participants, about 5% had a history of smoking. Regarding the body mass index (BMI) of study participants, most (69%) of them had a BMI <18.5 kg/m² (Table 2).

Table 2 Clinical Characteristics of Drug-Resistant Tuberculosis Patients Following Treatment in Oromia Regional State Hospitals from 2012 to 2017, Oromia, Ethiopia

Time to Sputum Smear and Culture Conversion

The median time to sputum culture conversion to negative was 61 days with an inter-quartile range of 34–92 days. At the same time, the median time to sputum smear conversion was 34 days with an inter-quartile range of 28–54 days. The proportion of culture conversion at 2nd, 4th, and 6th months was 46.9%, 82.5%, and 89%, respectively. The proportion of smear conversion at 2nd, 4th, and 6th months was 81.6%, 94.5%, and 94.9%, respectively (Table 3).

Table 3 Time to Sputum Smear and Culture Conversion of Drug-Resistant Tuberculosis Patients Following Treatment in Oromia Regional State Hospitals from 2012 to 2017, Oromia, Ethiopia

Predictors of Time to Sputum Culture Conversion

Socio-demographic and clinical characteristics of patients were assessed for a possible difference in survival distribution using the Kaplan-Meier curve and Log rank tests. Patient characteristics like age, use of cotrimoxazole prophylaxis for HIV patients, body mass index, and chest-radiographic findings were found to have a significant difference in time to culture conversion (Table 4).

Table 4 Test of Equality of Survival Distribution Among Drug-Resistant Tuberculosis Patients Following Treatment in Oromia Regional State Hospitals from 2012 to 2017, Oromia, Ethiopia

In the final multivariate Cox-regression analysis, we found that the patient’s chest radiographic finding was a predictor of time to culture conversion. The culture conversion rate among patients with massive effusion was decreased by 60% (AHR: 0.4, 95% CI: 0.1–0.9) as compared to those with unitary lung cavitations. At the same time, the culture conversion rate among patients with abnormalities without cavitations decreased by 50% (AHR: 0.5, 95% CI: 0.2–0.9) when compared to those with unitary lung cavitations (Table 5).

Table 5 Predictors of Time to Culture Conversion Among Drug-Resistant Tuberculosis Patients Following Treatment in Oromia Regional State Hospitals from 2012 to 2017, Oromia, Ethiopia

Discussion

In the treatment of multidrug-resistant tuberculosis (MDR-TB) Sputum culture conversion is used as an indicator for the success of the treatment and used to guide the patient treatment regimen.^32,33 This study assessed predictors of time to culture conversion among Drug-resistant tuberculosis (DR-TB) patients attending their treatment in Oromia regional state hospitals, Ethiopia.

A total of 228 initially culture-positive DR-TB patients were included in this study. The median time to culture conversion was 61 days. This finding is comparable with studies conducted in the Amhara region (65 days)³⁴ and Gondar (72 days),³⁵ Latvia (60 days),²⁸ Peru (59 days),³⁶ and Indonesia (60 days).³⁷ The present study reported a shorter median time to culture conversion compared to studies conducted in China (159 days),³⁸ USA (93 days),³⁹ Delhi (91 days),⁴⁰ London (91 days).⁴¹ The median time to culture conversion in the present study is longer than the study conducted in Seoul (19 days),⁴² Germany (39 days),⁴³ and India (35 days).⁴⁴ The discrepancy in the median time to sputum culture conversion could be due to the reporting system of the time to conversion. Some studies used two consecutive negative culture results to report culture conversion, and others reported initial culture conversion to negative as well as re-conversion to a negative culture. This study used the first month in which the culture result turns negative to report the time to sputum conversion. The other possible source of the discrepancy could be factors such as the frequency with which sputum samples are tested (weekly vs monthly), resistance to additional drugs (which can vary by geographical region), and the availability of effective drugs. Some of the hospitals included in this study have no facility for culture testing so that they collect and send sputum to the other hospital this, in turn, might result in delayed reporting or sometimes missing of the result might have occurred.

This study found that 89% of DR-TB patient’s sputum culture converted to negative at 6 months of treatment initiation. This finding is in line with the study conducted in Gondar (88.6%),³⁵ India (87%),⁴⁵ South Africa (89%),⁴⁶ Peru (92.9%),³⁶ and China (90.5%).³⁸ On the other hand, the four-month sputum conversion rate in the current study found to be 82.5%. The four-month conversion rate is higher than the study conducted in Latvia (60%).²⁸ The two-month culture conversion rate in this study was 46.9% which is much lower than the study conducted in Seoul (90.1%)⁴² China (65.2%)⁴⁷ and Germany (61%),⁴³ but higher than reported finding from Chinese study (33.3%).³⁸ The difference in the culture conversion rate among different study sites might be related to a difference in treatment protocol followed in different sites, the difference in the study population, type of drug resistance, and the difference in the quality of reported data.

In this study patients in the age group, less than 18 years have shorter culture conversion time (p=0.004) compared to older ages. The previous study reported that as age increases the risk of TB drugs adverse outcome increases.⁴⁸ Furthermore, patients with baseline body mass index lower than 18 kg/m² had a long time to culture conversion than their counterparts. Similar previous studies reported that malnourished MDR-TB patients had longer conversion time.^35,40,49

In this study patient’s chest radiologic findings like lung cavitations, and massive effusion was found to affect the time to sputum culture conversion. In Cox regression analysis patients with massive effusion found to have less sputum culture conversion rate than those with unitary lung cavitations. When we compare the Kaplan Meier survival curve using a Log rank test, patients with unitary lung cavity had a shorter median time to culture conversion than those with bilateral lung cavitations, and massive effusion. Previous studies reported that patients with lung cavitations had delayed time to culture conversion.^34,50 This might be related to the fact that lung cavitations might hinder drug penetration and thus decrease the therapeutic efficacy of the drugs.

This study tried to assess the predictors of time to sputum culture conversion. Some of the strengths of this study were using data from eight hospitals and using five-year data. However, this study had limitations so that results from the study should be used with caution. Among the limitations, and the study used initial culture conversion to assess time to culture conversion, it does not assess the re-conversion of culture. The study used secondary data from hospital records so that limitations associated with secondary data might apply.

Conclusion

Chest radiographic findings such as massive effusion, abnormalities without cavitations, and uninterpreted findings were found to be predictors of time to sputum culture conversion. Patients with such characteristics have prolonged culture conversion time. Hence, they may need special attention during the treatment.