Factors influencing the length of hospital stays during the intensive phase of multidrug-resistant tuberculosis treatment at Amhara Regional State hospitals, Ethiopia: A retrospective follow up study

Abstract

Background: The length of hospital stay is the duration of hospitalization and reflects disease severity and resource utilization indirectly. Generally, tuberculosis considered as an ambulatory disease able to be treated at DOTs clinics, however, hospitalization remains an important component for clinical stabilization of patients. Hence, this study aimed to identify factors influencing the length of hospital stay during the intensive phase of multidrug-resistant tuberculosis treatment at Amhara Regional State hospitals, Ethiopia.

Methods: An institution-based retrospective follow-up study was conducted at three hospitals, namely the University of Gondar comprehensive specialized, Borumeda, and Debremarkos referral from September 2010 to December 2016 (n=432). Data were extracted from hospital admission/discharge logbooks and individual patient medical charts. Logistic regression analysis was used to identify factors associated with longer hospital stays during the intensive phase of multidrug-resistant tuberculosis treatment.

Result: Most patients (93.5%) had a pulmonary form of multidrug-resistant tuberculosis and 26.2% had /TB/HIV co-infections. The median length of hospital stay was 62 (interquartile range 36 to 100) days. The pulmonary form of tuberculosis (Adjusted odds ratio [AOR], 3.47, 95% confidence interval [CI]; 1.31 to 9.16), functional status of bedridden (AOR= 2.88, 95%CI; 1.29 to 6.43), and reported adverse drug effects (AOR=2.11, 95%CI; 1.35 to 3.30) were significant predictors of extended hospital stays.

Conclusion: The study revealed that the length of hospital-stay differed significantly between the hospitals. The pulmonary form of tuberculosis decreased functional status at admission and reported adverse drug reactions were determinants of longer hospital stays. This underscores the importance of early case detection and prompt treatment of adverse drug effects.

Background

Tuberculosis is the leading cause of mortality and morbidity and an increased concern for global health [1-3]. The emergence of drug-resistant strains of Mycobacterium tuberculosis further complicated tuberculosis treatment and control efforts worldwide [4]. According to the 2016 World Health Organization (WHO) report, there were about 600,000 multi-drug resistant tuberculosis (MDRTB) cases and 250,000 MDRTB related deaths each year globally [5]. Thirty high burden countries carry more than 85% of the world’s drug-resistant tuberculosis (DRTB) cases [5]. Ethiopia is the third among high burden countries in Africa with an estimated 2,100 MDRTB cases annually [6]. Besides, the magnitude of susceptible TB was estimated to be 88.5 per 100,000 population and ranked 11^th and 3^rd from the world and Africa, respectively, according to the global TB report of 2016 [5].

Treatment of drug-resistant tuberculosis is longer and usually lasts 18 to 24 months and successful treatment outcomes remained around 50% [7]. The standard drug-resistant treatment regimen is a treatment protocol designed based on data from population-based drug-resistance surveys about tuberculosis medications used to treat DRTB patients in the absence of individual drug susceptibility tests. Thus, all patients in the same group received the same regimen as per national guidance and widely approached in Ethiopia [8, 9].

The intensive phase of drug-resistant TB, the first 8-12 months, is the period in which patients suffer from critical disease conditions and drug side effects [10, 11]. Moreover, has life-threatening adverse drug effects of second-line anti-TB medications led to more frequent and prolonged hospitalizations during this phase of the treatment [12, 13]. In the initial phase, all the efforts are directed to ensure that patients are both clinically stable and adherent to SLDs; hence, the role of the clinical team at hospitals is more intensive to provide the necessary clinical, adherence and social support arrangements to enables the patient to be fit enough to be followed at DOTs clinic.

Length of hospital stay (LOS) refers to the duration of hospitalization [14, 15]. It reflects several aspects of hospital care including the complexity of the case, the efficiency of hospital care, and the nature of hospital policies on admission and discharge [14]. The length of hospital stays can also be used as an indirect estimator of resource utilization and efficiency within the settings of a hospital and has direct implications for overall healthcare planning and policy [4, 8, 16]. Prolonged hospital stay in the treatment of DRTB affects the efficiency of the hospital by increasing resource utilization like increased bed occupancies, frequent physician visits, compromise the quality of care, and create long waiting lists for admission and treatment [4, 15, 17-19]. A study in South Africa revealed that the mean cost per MDRTB patient was 17,164 USD, of which 95% were hospitalization costs (buildings, staff, etc.) [16]. Also, in-hospital patient management associated with an increased risk of nosocomial infection transmission that affects the quality of care and treatment outcome [20].

 Globally, the reported median length of hospital stay was 90 days in high burden MDR countries during the treatment [21]. African countries are characterized by a high burden of drug-resistant tuberculosis and inefficient and inadequate health care facilities for the treatment of the disease. Findings from South Africa showed a LOS median of 144 days [22] and those Nigeria 135 days [7]. Patient functional status, co-morbidities, extensive lung damage, and adverse drug effects were determinants of prolonged hospital stay in the course of MDRTB treatment [2, 10, 22-25].

Concerning health facility availability and efficiency, the WHO recommends a conditional ambulatory model of care in the standard treatment of drug-resistant tuberculosis [26, 27]. Although Ethiopia is one of the high MDRTB burden countries, there have been only limited health facilities providing MDRTB treatments with scarce evidence on length of hospital stay and associated factors during the treatment.

Therefore, this study aimed to determine the length of hospital stay and its predictors during the intensive phase of MDRTB treatment. The study could be of paramount importance to clinicians and hospital administrators for more efficient planning of drug-resistant tuberculosis treatment programs and resource allocations.

Methods

Study design, area and period

An institution-based retrospective study was conducted at the University of Gondar comprehensive specialized and Borumeda and Debremarkos referral hospitals from September 2016 to December 2016. In the Amhara region, there are nine drug-resistant tuberculosis treatment initiating centers. The hospitals were selected because they were located in the main cities of the region and covered more than 85% of the services. The remaining six centers included recently were located in the districts with a major purpose of supporting the three main TICs (hospitals) mentioned above as referrals for outpatient follow-ups and enhancing the accessibility of health services (Figure1). Stable clinical conditions, satisfactory adherence to post-discharge follow-up at DOTs clinic, and sputum culture conversion were criteria used to discharge patients from the hospitals.

The laboratory tests like GeneXpert MTB/RIF Assay (GeneXpert® System – Cepheid), Line probe Assay (LPA), liquid culture (MGIT), and solid culture medium (LJ standard medium) were methods of diagnosis to confirm drug-resistant tuberculosis for the first-line anti-TB drugs. During the data collection, time sensitivity tests for the second-line drugs were not available and all LPA tests were for first-line drugs. The sputum sample referral and laboratory result communication made through the postal office between reference laboratories and district health facilities to improve the accessibility of services [28]. After the patient diagnosed to have the diease refered to thses hospitals for treatment initation and follow-ups.

Population and sample

Patients who were admitted and discharged from the selected hospitals during the initial phase of MDRTB treatment were the study population. The ingle population proportion formula with the assumptions of 50% of patients experience longer hospital stay, 5% level of precision, and a 10% contingency rate for those who do not have treatment outcome/discharge information was used to determine the final sample of 422. A total of 490 multidrug-resistant tuberculosis patients were enrolled for DRTB treatment in the three hospitals from September 2010 to December 2016, and we included 432 patients who fulfilled the inclusion criteria. However, Fifty-eight patients were excluded owing to incomplete data, death during treatment, and transfer before completing the intensive phase.

Data collection procedures

Data available on patient records were examined and the appropriate extraction format was prepared in English. Six data collectors and supervisors (nurses and health officers) were recruited. A two day training was given on research objectives and on how to review documents as per the data extraction format before the process. Before data collection, records were identified by their medical registration numbers. The trained collectors reviewed and extracted data from patient charts and hospital admission/discharge logbooks using the checklists.

Variables of the study

The dependent variable was the length of hospital stays in days from the date of admission to discharge. The length of hospital stays (LOS) refers to the duration of stays in days from the date of admission to the date of discharge under the initial phase of MDRTB treatment with zero days of stay for a patient with less than 24 hours of ward stay. When the patient stays admitted for more than a median cut off point, LOS ≥62 days considered as prolonged hospital stays, whereas socio-demographic characteristics (sex, age, residence, housing condition, educational status, marital status), behavioral factors (smoking, alcohol use, khat chewing), and clinical characteristics (TB/HIV co-infection, registration group, a form of TB, presence of chronic diseases, adverse drug effects, radiological findings, treatment delay, baseline BMI, and functional status) were the independent variables.

Multidrug-resistant tuberculosis is defined as tuberculosis that is resistant to the first-line drugs isoniazid and rifampicin, or when an individual is resistant only to rifampicin and treated as multi-drug resistant. A previously treated case was defined as a patient who was treated for TB for one month or more. A patient who had less than <18.5 kg/m² body mass index was classified as underweight, whereas a patient who had ≥18.5kg/m² body mass index was classified as normal BMI. Treatment initiating centers (TIC) are health facilities selected by the TB program to provide patient care and treatment services from the time of DRTB diagnosis and throughout treatment with SLDs.

Data analysis

Data were entered into EPI info version 7 and analyzed using Stata version 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). Descriptive statistics, such as percentages and medians with interquartile range (IQR) were used to summarize categorical and continuous variables, respectively.

Based on their LOS, patients were dichotomized using the median value, <62 days (0) vs. 62 or more (1). The median of 62 days was used to categorize the patient’s length of hospital stay in two because there is no standardized cutoff point from previous studies. Logistic regression was used to identify factors associated with longer (62 or more days of hospital stay) during the intensive phase of MDRTB treatment. Odds ratio (OR) with 95% confidence intervals (CI) was computed to assess the associations between socio-demographic and clinical factors and the LOS.

Result

Baseline socio-demographic characteristics

A total of 490 patients enrolled on MDRTB treatment in the three hospitals. Fifty-eight patients were excluded owing to incomplete data, treatment initiated in an ambulatory model, death during treatment, and transfer before completing the intensive phase. A total of 432 patients were included in the final analysis.

Most of the admission/discharge 61.1%) were at the University of Gondar comprehensive specialized hospital, followed by Borumeda (28.2%) and the rest at Debremarkos referral hospital.

 More than half (57.4 %) of the patients were male with the median age was 29 (IQR, 22 to 40 years), and 64.4% of them were aged below 34 years. Of the participants, 43.1% and 34.3% were married and single, respectively; 56.9% had some primary and above educational status, while rural dwellers constituted 52.8% of the respondents. As far as substance use was concerned, 19%, 12.7%, and 8.3% drunk alcohol smoked cigarettes and chewed khat, respectively (Table 1).

Clinical characteristics

The pulmonary form of MDRTB accounted for 93.5% while the rest were extra pulmonary forms. One-fourth (26.2 %) of the MDRTB patients 93.8% of whom were on ART had TB/HIV co-infections. One or more medical co-morbidities reported, involved 9.5% of the participants, of whom 2.8% had diabetes mellitus. One or more radiological abnormalities were seen in 71.3% of the patients. The most common radiological findings included 42.2% cavitation, 26.6% infiltration, and 24.7% chronic changes, like fibrosis. Out of the total patients, 71.1% had at least one adverse drug effect with gastro-intestinal upset, (81.5%) and electrolyte disturbance (33.6%), the most common side effects. Fifteen patients underwent surgery for tuberculosis related problems (Table 1).

Line probe assay (LPA) (45.6%) and GeneXpert (46.7%) were the most commonly used diagnostic methods for confirmation of drug resistance TB. Concerning the TB resistance pattern, 96.3% of the patients had confirmatory drug resistance test results, 96% resistant to Rifampicin, and 45.6% to Isoniazid. Moreover, 8.3% of the patients were resistant to all first-line anti-TB drugs. The median time to start anti TB medication was 10 (IQR of 3 to 72) days and 70% of patients initiated treatment with 30 days of diagnosis (Table 2).

Length of in-hospital stay (LOS)

The median length of hospital stay during the intensive phase of MDRTB treatment was 62(IQR, 36 to100) with the mean (SD) of 76.7 (±57.8) days. The median length of hospital stay for each treatment center at the University of Gondar hospital was 59.5 (IQR, 34 to 100 days), Borumeda 72 (IQR, 47 to 111 days), and Debremarkos referral hospital 39.5 (IQR, 24 to76 days). Two hundred seventeen (50.7%) patients with a 95%CI (45.4. to 55.0) were hospitalized for longer than 62 days during the intensive phase of the MDRTB treatment. Detail description of the length of hospital stays by socio-demographic and clinical characteristics presented on table 3. In addition, the median length of hospitals stays per annum presented using line graph on Figure 2

Factors associated with a prolonged hospital stay

The binary logistic regression model was fitted to identify factors associated with prolonged hospital stays (≥62 days). The pulmonary form of TB, bedridden functional status, and adverse drug effects was significantly associated with longer hospital stays at a p-value of 0.05 in the multivariable analysis. Thus, patients who had a pulmonary form of drug-resistant tuberculosis, the odds of prolonged hospital stay was 3.47 times higher compared to extra pulmonary cases (AOR=3.47, 95%CI: 1.35 to 3.30). Similarly, patients who had a functional status of bedridden at admission had 2.88 times higher odds of prolonged hospital stays compared to those who had working functional status (AOR= 2.88, 95% CI: 1.29 6.43). Likewise, patients who had reports of adverse drug effects were 2.11 times more likely to have longer hospital stays compared to those who didn’t have such adverse drug events (AOR=2.11, 95%CI: 1.35 3.30) (Table 4).

Discussion

In this study, the median length of hospital stay was 62 (IQR, 36to 100) days. Bedridden functional status, a pulmonary form of TB, and adverse drug effects were factors associated with prolonged hospital stays (≥ 62 days).

 The length of hospital-stay also differed significantly between the hospitals, ranging from 39.5 days at Debremarkos referral hospital to 72.5 days at Bourmeda. The possible reasons might be the lack of consistent discharge criteria and professional expertise differences among hospitals. Also, the median length of hospital stay was explored per annum and differences were observed from a median of 94 days in 2012 to 60 days in 2015. The possible explanations might be better patient management experience in the later time, the use of new treatment approaches, and early case detection through active surveillance before critical conditions happened might contribute to cutting LOS [29].

The median length of hospital stay in this work was shorter than the WHO 2014 global TB report of 90 days [21], South Africa centralized hospital of 144 days [22], South Africa community-based sites of 143 days [22], and Canada Ontario of 82 days [30]. This might be due to differences in the health care system, the clinical condition of the patients like the severity of the disease, and the presence of co-morbidities, like HIV. However, the median length of hospital stay of this attempt was longer than that of a study conducted in San Francisco (14 days) [12]. The possible reasons might be differences in treatment approaches. In the San Francisco study, MDRTB treatment was provided through outpatient follow-ups, which decreased the length of hospital stays in the course of treatments.

Thus, patients who had the pulmonary form of tuberculosis associated with longer hospital stay compared to extra pulmonary cases. The pulmonary form of the disease is clinically more symptomatic and associated with severe illnesses which might be associated with longer hospital stays. Also, pulmonary TB is more public health concern for transmission of bacilli to others. Thus, pulmonary TB patients came from congregated settings like university dormitories and prisons usually stayed isolated in hospitals until the patient had two consecutive negative sputum culture result.

Moreover, the admissions of tuberculosis patients during the infectiousness period are highly important for isolation, especially for patients who come from congregated settings, such as university dormitories [31], prisons and refugee camps where the risk of transmission is high. Before the revision of DR-TB treatment protocol, smear and culture-positive pulmonary drug-resistant tuberculosis patients stayed admitted until their sputum result was converted to negative, perhaps contributing to longer hospital stays of a pulmonary form of TB sufferers [13, 27].

Similarly, Patients who had bedridden functional status at admission associated with three times higher odds of longer hospital stays compared to patients who had working functional status. This may be because patients with debilitating clinical conditions and altered functional status might have delayed clinical and treatment responses. Also, patients with low functional status have comorbidities, like HIV co-infection, which causes advanced diseases that require longer physician monitoring [14]. As shown on the table 3 the median length of hospital stay for working and bedridden functional status was 32 and 95 days, respectively, ultimately increased resource utilization and hospital bed occupancies.

 Likewise, patients who reported having one or more adverse drug effects were two times more likely to stay longer at hospitals compared to those free form adverse drug effects. This finding is in line with those of studies conducted in Iran and Uzbekistan [32, 33]. Second-line anti-TB drugs are often more toxic and less effective and some of the adverse drug effects are life-threatening and occult to detect; hence, more frequent and close follow up is mandatory for early detection and prompt treatment. As shown on the table 3 adverse drug effects like neuropathy, ototoxicity, and electrolyte disturbance the median LOS was 78, 77.5, and 74 days respectively. These toxicities are life-threatening and require close monitoring and follow up until improvements. Early anticipation and detection of adverse drug effects could reduce unnecessary prolonged hospital stays and saves the cost of treatment [34].

This study has implications for patients, health care workers, public health experts, and health system administrators and national tuberculosis programs as well to design efficient drug-resistant tuberculosis treatment protocol. In addition, factors identified like bedridden functional status and adverse drug effects suggest the importance of early case detection and anticipated adverse events of SLD to reduce prolonged hospital stays that make health facilities more efficient. Furthermore, the findings of this study also helpful for evidence-based planning and resource allocation.

Limitation of the study

Since data from this retrospective review were collected from secondary sources, some important predictors, like adherence and health facility characteristics, which had significant associations with the length of hospital stay in other studies were missing in the treatment of patients at the centers. In addition, baseline sputum culture and treatment outcome of some of the patents had unknown status due to poor documentation and patient file keeping. There were consistent no discharge criteria for inpatient management of DRTB and standard cut off point for the length of hospital stay and might introduce misclassification of participants.

Conclusion

The length of hospital-stay also differed significantly between the hospitals. Decreased functional status at admission, the pulmonary form of tuberculosis, and reported adverse drug effects were determinants of longer hospital stays. This underscores the importance of early case detection and prompt treatment of adverse drug effects.

Declarations

Ethical approval and consent to participate

Ethical clearance was obtained from the Institutional Review Board of the Institute of Public Health, College of Medicine and Health Sciences, the University of Gondar (Ref/no- IPH/2493). A letter of permission was obtained from the Amhara Regional State Health Bureau for Borumeda and Debremarkos referral hospitals (Ref/no H/R/T/T1/638/09).

Consent for publication

Not applicable

Availability of data and material

Data is available from the corresponding author upon request. Because the data contains sensitive issues in the data set.

Competing interests

The authors declare that they have no competing interests

Funding

The study was funded by the University of Gondar, Ethiopia. The funder has no role in study design, data collection, and analysis, interpretation of data, the decision to publish, or preparation of the manuscript.

Authors' contributions

KST, GA, and YAB participated to design the study, performed data analysis, visualization, validation of the whole work, and prepared the manuscript. KST took part in funding acquisition, data collection, supervision and software, and other resources. All authors read and approved the final manuscript.

Acknowledgments

We are thankful to data collectors, supervisors, and radiographers, hospital administrators of the University of Gondar Comprehensive Specialized Hospital, Borumeda Hospital, and Debremarkos Referral hospitals.

Abbreviations

ADR: Adverse Drug Reaction , ART: Anti Retro viral Therapy, BMI: Body ,Mass Index, DRTB: Drug Resistance Tuberculosis, DST: Drug Susceptibility Test, FLD: First Line Drug, GHC: Global Health Committee, HIV: Human Immune deficiency  Virus, IQR: Inter Quartile Range, IRR: Incidence Rate Ratio, LOS: Length Of hospital Stay, LPA: Line Probe Assay, MDRTB: Multi Drug Resistance Tuberculosis, MTB/RIF: Mycobacterium Tubercle Bacilli/Refampicine, SLD: Second Line Drug, TB: Tuberculosis, TIC: Treatment Initiating Center, WHO: World Health Organization, XDRTB: Extensive Drug Resistance Tuberculosis

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Tables

Table 1: Socio-demographic and clinical characteristics of drug-resistant tuberculosis patients in Amhara region hospitals (n=432)

Table 2: Treatment outcome, median time to initiate treatment and length of hospitals stay by hospitals 

Table 3: Median length of hospital stay per clinical and socio-demographic characteristics of patients (n=432) 

Table 4: Binary logistic regression analysis to identify factors associated with prolonged hospital stays among drug resistant tuberculosis patients in Amhara region (n=432)