Background: Tuberculosis remains a very common infectious disease in Democratic Republic of Congo (DRC). The resistance to drugs worsens the prognosis and the outcome of patients affected tuberculosis and increase their mortality. Objective: To identify factors associated with death among Multidrugs resistant tuberculosis (MDR/RR TB) patients referred to the referential hospital, Centre d’Excellence Damien (CEDA). Materials and Methods: A retrospective cohort study of patients attending health care to the Center CEDA, a referral center for management of MDR/RR-TB in DR Congo. This study included all MDR/RR-TB patients referred from February 1st, 2015 to February 29th, 2017. A multivariate COX regression was performed to identify factors associated with mortality in the target population. Kaplan Meier method described the survival of patients and the comparison of curves was performed by the test of log Rank. Results: 199 patients were included in our study. Male gender was predominant with a sex ratio of 1.3. The mean age of patients was 35.8 ± 13.9 years. Among them, 18 (15.1%) were died. The major complications were Chronicles pulmonary Heart failure (p = 0.035), Chronic respiratory insufficiency (p = 0.004), depression (p = 0.044), undernutrition (p = 0.033), alcohol addiction (p = 0.006) and high smoking (p = 0.019). In multivariated analysis, factors associated to the death were alcohol addiction (HRa = 12.64, 95% CI 2.36 - 14.55, p = 0.003), asthenia (HRa = 4.75, 95% CI 1.56 - 14.50, p < 0.001), pulmonary consolidation (HRa = 10.01 95% CI 2.34 - 12.86, p = 0.02), some chest X-ray abnormalities such as signs of pulmonary fibrosis (HR = 4.7, 95% CI 2.78 - 28.94, p = 0.002) and the Chronic respiratory insufficiency (HRa = 3.77, 95% CI 1.37 - 10.43, p = 0.010). Conclusion: The present retrospective cohort study revealed that structural and functional pulmonary alteration emerged as the main factors associated with mortality among MDR/RR TB patients in Kinshasa. National Tuberculosis Programs should take into account those parameters while defining mortality reduction strategy.
The infection of Mycobacterium tuberculosis (TB) remains one of top ten causes of death in the world, where resource-limited countries are most affected by the disease. The World Health Organization (WHO) has set an objective to reduce by 95% the absolute number of TB deaths in affected countries with ideal to reach this goal by 2035 [
The management of MDR/RR-TB cases in DRC has been based on the treatment and monitoring of diagnosed cases as ambulatory patients, this policy has been applied since the detection of first cases of MDR-TB in 1994 [
Previous studies have reported various factors that have been associated with increased mortality among TB patients [
In DRC, risk factors associated with TB mortality have not been well studied or only scarce information is available. With the increasing number of MDR/RR-TB cases reported in DRC, it has become crucial to identify the factors associated with MDR-TB occurrence and their consecutive mortality [
The study aimed to identify factors associated with mortality among MDR/RR-TB patients in Kinshasa in DRC.
We conducted a retrospective cohort study to identify risk factors of MDR/RR-TB mortality. Clinical records of MDR/RR-TB patients who were referred to The Kinshasa TB referral hospital CEDA during the period from February first, 2015 to February 29, 2017 were collected for this study purpose. Most of these patients were directly referred from the 35 health centers for diagnosis and ambulatory management of MDRTB patients (CSDT), these centers are found in different sites of Kinshasa (
All available files of MDR/RR-TB cases hospitalized in the CEDA during the period of our study window were enrolled. Cases of drug resistance other than MDR/RR-TB such as extensively drug-resistance TB (XDR-TB) and pre-XDR-TB were excluded from the current study. All MDR/RR-TB patients admitted in the CEDA were already under anti-tuberculosis treatment following the regimen recommended by the NTP of DRC. This regimen includes Kanamycin (Km), Moxifloxacin (Mfx), Prothionamide (Pfo), Clofazimin (Clz) Isoniazid (INH), Ethambutol (E) and Pyrazinamide (Z); the regimen covers a period of 9 months’ treatment and is divided in 2 rounds 4 km MfxPtoClz H E Z/5 MfxClz E Z.
For an objective interpretation of patients’ results, we have provided a conceptual definition to some terms used in this study:
・ Anemia not tolerated: when the Hemoglobin rate if less than 10 g/dl with tachycardia, shortness of breath and dizziness.
・ Asthma: When a patient had a known history of asthmatic disease or symptoms, wheezing and acute chest syndrome, with symptoms revolving with bronchodilator administration.
・ Asthenia: per WHO performance scale when the score is higher than 1.
・ Atelectasis: Chest X-ray showing hilar triangular opacity with diaphragmatic attraction [
・ Cavitary syndrome: radiographic images of pulmonary roundness, single or multiple, surrounded by an irregularly contoured wall, resulting from the destruction of the parenchyma of the lungs sometimes associated with a drainage bronchus [
・ Chronic pulmonary obstructive disease (COPD): when the spirometry Tiffeneau-Pinelli index is less than 70 (Tiffeneau-Pinelli < 70).
・ Chronic pulmonary heart disease: right ventricular pressure overload and dilatation of the right ventricle on echocardiography.
・ Chronic respiratory insufficiency: respiratory distress, clubbing, cyanosis, hypoxemia and/or hypercapnia, retracted and calcified pulmonary radiological image.
・ Coma: Loss of consciousness with a Glasgow Score of less than 10.
・ Death: irreversible cardiorespiratory arrest. Death certificate mentioning the date and time of death.
・ Depression: Hospital Anxiety and Depression Scale (HAD). Total > 11 with specialized opinion of the Neuro Psycho Pathological Center (CNPP) of Kinshasa [
・ Diabetes Mellitus: History of Diabetes, Fasting Glucose > 126 mg/dl twice with glycated hemoglobin > 6 IU/L.
・ Extensively drug resistance tuberculosis (XDR TB): This is a multidrug-resistant tuberculosis with fluoroquinolone resistance and resistance to at least one of three second-line injectable drugs (amikacin, capreomycin and kanamycin) [
・ Pre-Extensively Drug resistance tuberculosis (pre-XDR TB): This is a multi-drug resistant tuberculosis with fluoroquinolone resistance or resistance to at least one of the three second-line injectable drugs (amikacin, capreomycin and kanamycin) [
・ HIV: when two tests with different principles of detection of HIV Antibodies were positive, determine and unigold were used [
・ Hydropneumothorax: chest X-ray showing air and fluid in the pleural space.
・ Hypertension: Blood pressure > 140/90 mmHg and history of Hypertension.
・ Malaria: the diagnosis was made in the presence of a positive thick spot or a positive plasmodium falciparum rapid diagnostic test [
・ Multidrug-Resistant Tuberculosis (MDR-TB): it is a tuberculosis whose germ is resistant to the two major first line anti-tuberculosis drugs: isoniazid and rifampicin [
・ Pleural effusion syndrome: abolition of the transmission of vocal vibrations, abolition of vesicular murmur and fluid dullness [
・ Pulmonary consolidation: clinical and radiological signs of pulmonary consolidation [
・ Pulmonary embolism: Thrombus in the pulmonary artery was confirmed by computed Tomography pulmonary angiography [
・ Pulmonary fibrosis: Chest X-ray and thoracic Tomodensitometry with interstitial, retraction, calcifications and/or destroyed lung [
・ Rifampicin Resistant Tuberculosis (RR TB): This is a tuberculosis whose germ is resistant to rifampicin diagnosed by the phenotypic or genotypic method with or without resistance to other antituberculosis drugs [
・ Sepsis: Systolic blood pressure ≤ 100 mm Hg, Respiratory rate ≥ 22/min, Confusion, SOFA score increase of at least 2 points and/or positive blood culture [
・ Stroke: CT scan image showing cerebral infraction foci, cerebral edema, hematoma or an intracerebral hemorrhage.
・ Thrombophlebitis: venous doppler ultrasound of the lower extremities showing a thrombus [
・ Undernutrition: Body Mass Index (BMI) < 18 kg/m2 [
Data were input and analyzed using the statistical software SPSS 21 (IC Chicago).
Descriptive data were presented as mean with their standard deviations for normally distributed variables. Comparison between two groups was measured using t student test for continuous variables, Chi-square or F fisher tests were used to compare categorical variable data. Cox regression analysis was used to determine the predictors of mortality among MDR/RR-TB patients, reporting hazard ratio (HR) with a 95% confidence interval (CI). Kaplan-Meier survival analysis was applied to describe the survival rate between the date of admission in the hospital and the end-point, death (completed) or discharge of the patient (censored). Log-rank test was used to compare the survival curves between the two groups. Only curves with statistical significance were considered in this study, for a p < 0.05 data were considered as statistical significant.
One hundred nineteen patients with confirm MDR/RR-TB were admitted in the Damien Excellence Center during the study window time of our research. Most patients were male with a sex ratio of 1.3. The mean age of participant was 35.8 (13.9) years old. Eighteen patients (15.1%) died during their admission in the hospital. In addition, more than half of MDR/RR-TB (60.5%) patients were single, and patients without occupation were dominant with about a third of participants (35.3%) (
Information about symptoms, clinical signs and laboratory analysis were collected from patients’ file when available. Cough (74.8%) and dyspnea (64.7%) were the most frequents symptoms presented by the patients (
An increase of white blood cells count was observed in the group of patients who died during the admission time in hospital (
Variables | All n = 119 | Deceased n = 18 | Alive n = 101 | p |
---|---|---|---|---|
Age (years) | 35.8 ± 13.9 | 38.4 ± 19.3 | 35.4 ± 12.7 | 0.393 |
Sex n (%) | 0.460 | |||
Male | 68 (57.1) | 11 (61.1) | 57 (56.4) | |
Female | 51 (42.9) | 7 (38.9) | 44 (43.6) | |
Marital status n (%) | 0.585 | |||
Married | 41 (34.4) | 6 (33.3) | 35 (34.7) | |
Single | 72 (60.5) | 10 (55.6) | 62 (61.4) | |
Widow/widower | 6 (5.0) | 2 (11.1) | 4 (4.0) | |
Profession n (%) | 0.075 | |||
Student | 17 (14.3) | 5 (27.8) | 12 (11.9) | |
trader | 14 (11.8) | 1 (5.6) | 13 (12.9) | |
teacher | 3 (2.5) | 2 (11.1) | 1 (1.0) | |
Mechanic | 6 (5.0) | 1 (5.6) | 5 (5.0) | |
Carpenter | 7 (5.9) | 0 (0.0) | 7 (6.9) | |
Health worker | 5 (4.2) | 0 (0.0) | 5 (5.0) | |
No profession | 42 (35.3) | 7 (38.9) | 35 (34.7) | |
Freelancer | 25 (21.0) | 2 (11.1) | 23 (22.8) |
were the isolated bacteria in blood culture of five patients (
Information on complications and co-morbidity among MDR/RR-TB patients were collected to determine whether there was any pattern in the deceased group (
A univariate logistic regression was used to identify risk factors associated with mortality among MDR/RR-TB patients (
Variables | All n = 119 | Deceased n = 18 | Alive n = 101 | p |
---|---|---|---|---|
Number of of previous TB. | 0.942 | |||
1 n (%) | 44 (45.4) | 7 (46.7) | 37 (45.1) | |
2 n (%) | 36 (37.1) | 5 (33.3) | 31 (37.8) | |
≥3 n (%) | 17 (17.5) | 3 (20.0) | 14 (17.1) | |
Asthma. n (%) | 2 (1.7) | 0 (0.0) | 2 (2.0) | 0.719 |
HIV. n (%) | 11 (9.2) | 1 (5.6) | 10 (9.9) | 0.479 |
COPD. n (%) | 5 (4.2) | 1 (5.6) | 4 (4.0) | 0.566 |
Hypertension. n (%) | 3 (2.5) | 2 (11.1) | 1 (1.0) | 0.059 |
Tabac. n (%) Cannabis | 12 (10.1) 4 (3.4) | 4 (22.2) 2 (11.1) | 8 (7.9) 2 (2.0) | 0.082 0.108 |
Number of year pack | 11.7 ± 7.7 | 22.0 ± 6.8 | 9.6 ± 6.5 | 0.019 |
Alcohol. n (%) | 7 (5.9) | 3 (16.7) | 4 (4.0) | 0.006 |
Systolic blood pressure. mmHg | 98.3 ± 24.3 | 96.7 ± 26.7 | 98.6 ± 23.9 | 0.761 |
Diastolic blood pressure. mmHg | 63.9 ± 10.3 | 63.3 ± 14.6 | 64.0 ± 9.4 | 0.799 |
Cardiac frequency. bpm | 107.2 ± 20.6 | 110.9 ± 23.1 | 106.6 ± 20.3 | 0.427 |
Respiratory frequency.cpm | 31.3 ± 8.5 | 36.9 ± 10.1 | 30.5 ± 7.9 | 0.007 |
Temperature. ˚C | 36.8 ± 2.1 | 36.7 ± 0.9 | 36.9 ± 2.3 | 0.677 |
SaO2. % | 93.3 ± 7.5 | 89.6 ± 4.8 | 93.9 ± 7.7 | 0.045 |
BMI. kg/m2 | 16.8 ± 3.7 | 16.5 ± 4.7 | 16.9 ± 3.5 | 0.719 |
<15 | 36 (30.3) | 8 (44.4) | 28 (27.7) | |
15 - 17 | 35 (29.4) | 3 (16.7) | 32 (31.7) | |
17.1 - 18.4 | 17 (14.3) | 4 (22.2) | 13 (12.9) | |
18.5 - 24.9 | 26 (21.8) | 2 (11.1) | 24 (23.8) | |
Pulmonary consolidation. n (%) | 74 (62.2) | 4 (22.2) | 70 (69.3) | <0.001 |
Pleural effusion syndrome. n (%) | 2 (1.7) | 0 (0.0) | 2 (2.0) | 0.719 |
Pneumothorax. n (%) | 4 (3.4) | 0 (0.0) | 4 (4.0) | 0.514 |
Sibilant. n (%) | 4 (3.4) | 0 (0.0) | 4 (4.0) | 0.514 |
Coma. n (%) | 3 (2.5) | 1 (5.6) | 2 (2.0) | 0.391 |
Respiratory distress. n (%) | 32 (26.9) | 1 (5.6) | 31 (30.7) | 0.019 |
Variables | All n = 119 | Deceased n = 18 | Alive n = 101 | p |
---|---|---|---|---|
Hemoglobin. g/dl | 9.8 ± 2.2 | 9.2 ± 2.8 | 9.8 ± 2.1 | 0.310 |
white blood cell. elts/mm3 | 9543.8 ± 3893.9 | 12,743.8 ± 5129.6 | 9282.6 ± 3687.9 | 0.015 |
alv and interstitial sign. n (%) | 11 (93.3) | 18 (100.0) | 94 (93.0) | 0.018 |
Cavitarysyndrom. n (%) | 90 (75.6) | 13 (72.2) | 77 (76.2) | 0.459 |
Atelectasis. n (%) | 3 (2.5) | 0 (0.0) | 3 (3.0) | 0.609 |
Pulmonary Fibrosis. n (%) | 9 (7.6) | 3 (16.7) | 6 (5.9) | 0.013 |
Hydropneumothorax. n (%) Stroke n (%) Bloodculture positive n (%) | 6 (5.0) 2 (1.7) 5 (4.2) | 2 (11.1) 2 (11.1) 2 (11.1) | 4 (4.0) 0 (0) 3 (16.6) | 0.224 0.281 0.566 |
Variables | All n = 119 | Deceased n = 18 | Alive n = 101 | p |
---|---|---|---|---|
Undernutrition. n (%) | 71 (59.7) | 15 (83.3) | 56 (55.4) | 0.033 |
Anemia not tolerated. n (%) | 51 (42.8) | 10 (55.6) | 41 (40.6) | 0.178 |
ChronicResp insufficiency. n (%) | 21 (17.6) | 8 (44.4) | 13 (12.9) | 0.004 |
Malaria. n (%) | 20 (16.8) | 1 (5.6) | 19 (18.8) | 0.147 |
Sepsis. n (%) | 9 (7.6) | 3 (16.7) | 6 (5.9) | 0.136 |
Chronic pulmonary heart. n (%) | 7 (5.9) | 3 (16.7) | 4 (4.0) | 0.035 |
Diabetes Mellitus. n (%) | 7 (5.9) | 3 (16.7) | 4 (4.0) | 0.069 |
Depression. n (%) | 6 (5.0) | 3 (16.7) | 3 (3.0) | 0.044 |
Thrombophlebitis. n (%) | 3 (2.5) | 1 (5.6) | 2 (2.0) | 0.391 |
Coma. n (%) | 3 (2.5) | 2 (2.0) | 1 (5.6) | 0.391 |
Pulmonary embolism. n (%) | 2 (1.7) | 1 (5.6) | 1 (1.0) | 0.281 |
Variables | Univariate analysis | Multivariate analysis | ||
---|---|---|---|---|
p | HR (95% CI) | p | HRa (95% CI) | |
Chronic pulmonary heart | ||||
No | 1 | 1 | ||
Yes | 0.015 | 3.08 (1.89 - 10.66) | 0.465 | 1.72 (0.41 - 7.39) |
Asthenia | ||||
No | 1 | 1 | ||
Yes | <0.001 | 11.55 (4.44 - 30.02) | 0.006 | 4.75 (1.56 - 14.50) |
Alcohol | ||||
No | 1 | 1 | ||
Yes | 0.005 | 3.42 (1.99 - 11.84) | 0.003 | 12.64 (2.36 - 14.55) |
Pulmonary consolidation | ||||
No | 1 | 1 | ||
Yes | <0.001 | 7.27 (2.39 - 22.15) | 0.002 | 10.01 (2.34 - 12.86) |
Alveolar and interstitial image | ||||
No | 1 | 1 | ||
Yes | 0.011 | 4.23 (1.39 - 12.87) | 0.493 | 1.65 (0.39 - 6.89) |
Pulmonary Fibrosis | ||||
No | 1 | 1 | ||
Yes | 0.015 | 4.05 (1.17 - 14.01) | 0.006 | 3.74 (1.79 - 17.68) |
Undernutrition | ||||
No | 1 | 1 | ||
Yes | 0.037 | 2.76 (1.06 - 7.16) | 0.716 | 1.24 (0.38 - 4.04) |
Chronic pulmonary insufficiency | ||||
No | 1 | 1 | ||
Yes | 0.005 | 3.82 (1.51 - 9.69) | 0.010 | 3.77 (1.37 - 10.43) |
The probability of patients’ survival following MDR/RR-TB hospitalization was 88.2%, 87.4% and 84.9% respectively at 1, 2 and 3 months of cases management (
Since cough was the main symptoms at admission, we compared the survival rate between patient with or without patients (
All patients had received some medication depends on the cicrumstances of the case: Hypercaloric diet, oxygen therapy, antimalarial drugs, corticoid, antibiotique, bronchodilators, antiretroviral therapy, insulin therapy, anxiolytic, anticoagulant, thoracic drainage, hypertonic dextrose injection and antitubercular drugs were given.
Previous studies have reported various factors associated with mortality among TB patients [
In this study, sociodemographic parameters did not have any effect on the survival of TB patients unlike previously reported studies [
In this study, many clinical signs were found in association with patients’ death, these signs are related to a poor clinical evolution despite the specific anti TB therapy observed in ambulatory or out patient management. Some factors might explain this treatment failure, less compliance to treatment following side effects of medicines, inefficient directly observed treatment system (DOTS) or an inadequate TB regimen treatment, development of drug resistance other than MDR/RR-TB [
Severe anemia was observed among all MDR/RR-TB patients, and was associated with death among TB patients [
Radiographic lesions were associated with mortality among TB patients in our study, especially fibrosis and combined alveolar and interstital syndrome. In Niger, Piubello had observed extended radiographic lesions without fibrosis, and the outcome of patients was better if compared with this study [
Complications were significantly associated with cases of death in our study; these complications included a poor nutritional status, chronic pulmonary heartdisease, chronic respiratory insufficiency and depression. Other factors such anemia, HIV infection and diabetes mellitus have been reported in previous works [
Other associated morbidities such chronic obstructive bronchopneumonia, asthma, sepsis, malaria and thromboembolic pathologies were rather associated with increased morbidity than mortality of MDR/RR-TB patients (
Five factors were associated with mortality in a multivariate analysis (
Depression and smoking have been reported as factors associated with high mortality among TB patients [
The survival rate of hospital-admitted patients was influenced by the presence of lung fibrosis, and Ralph et al. have reported similar results [
The current study has targeted only patients admitted in a referral hospital with MDR/RR-TB with a limited number of patients during the study window’s time. A future study should integrate treatment outcomes of at a large scale of TB patients to increase the statistical power. Despite the limited number of subjects, this study could identify factors associated with poor outcomes of out-patient’s management of MDR/RR-TB cases in Kinshasa, including the associated complications and co-morbidities.
Mortality among MDR/RR-TB patients in DRC can be reduced by an effective control of alcohol addiction, an improvement of nutritional status of patients with an appropriated dietetic regimen, early detection of drug resistance and appropriated management of diagnosed cases without delay to prevent irreversible complications. HIV infection, depression, chronic pulmonary heart disease and diabetes mellitus are potential co-morbidities susceptible to affect the outcome of MDR/RR-TB management, and should not be neglected to improve the life quality of patients. The national program against tuberculosis should include the management these risk factors in the strategic plans to reduce mortality.
The authors are grateful to Action Damien Foundation for the financial management of hospitalized patients and gratefully thank to professor Yombodan Justin Kalenda of Nagasaki University and to Doctor Nkodila Aliocha for statistical and critical analysis.
This work received no financial assistance from any funding agency in the public, commercial, or non-profit sectors.
The authors declare that they do not have any financial interest with the information contained in this paper.
The study protocol was approved by the ethical committee of the School of public health of the University of Kinshasa.
Kashongwe, M.I., Mbulula, L., Umba, P., Lepira, F.B., Kaswa, M. and Kashongwe, Z.M. (2017) Factors Associated with Mortality among Multidrug Resistant Tuberculosis MDR/RR-TB Patients in Democratic Republic of Congo. Journal of Tuberculosis Research, 5, 276-291. https://doi.org/10.4236/jtr.2017.54029