Epiregulin (EREG) and human V-ATPase (TCIRG1): genetic variation, ethnicity and pulmonary tuberculosis susceptibility in Guinea-Bissau and The Gambia.

We analyzed two West African samples (Guinea-Bissau: n=289 cases and 322 controls; The Gambia: n=240 cases and 248 controls) to evaluate single-nucleotide polymorphisms (SNPs) in Epiregulin (EREG) and V-ATPase (T-cell immune regulator 1 (TCIRG1)) using single and multilocus analyses to determine whether previously described associations with pulmonary tuberculosis (PTB) in Vietnamese and Italians would replicate in African populations. We did not detect any significant single locus or haplotype associations in either sample. We also performed exploratory pairwise interaction analyses using Visualization of Statistical Epistasis Networks (ViSEN), a novel method to detect only interactions among multiple variables, to elucidate possible interaction effects between SNPs and demographic factors. Although we found no strong evidence of marginal effects, there were several significant pairwise interactions that were identified in either the Guinea-Bissau or the Gambian samples, two of which replicated across populations. Our results indicate that the effects of EREG and TCIRG1 variants on PTB susceptibility, to the extent that they exist, are dependent on gene-gene interactions in West African populations as detected with ViSEN. In addition, epistatic effects are likely to be influenced by inter- and intra-population differences in genetic or environmental context and/or the mycobacterial lineages causing disease.

A structured 2-week follow-up visit in the cascade of care for TB increases case detection.

Delayed detection in TB due to structural and diagnostic shortcomings is pivotal for disease transmission, morbidity and mortality. We investigated whether an inclusive screening, followed by a structured clinical follow-up (FU) could improve case-finding.Patients were recruited from health centres in Bissau, Guinea-Bissau, and Gondar, Ethiopia. A routine FU was done at Week 2. If persisting symptoms were found, patients were investigated using chest X-ray (CXR) and Xpert® MTB/RIF, followed by a medical consultation. The main outcome were additional TB patients diagnosed by applying the FU strategy.Of 3,571 adults, 3,285 (95%) were examined at Week 2 FU, where 2,491 (72%) were asymptomatic. Screening patients presenting with cough >2 weeks alone contributed to the diagnosis of 93 patients (45% of all patients diagnosed here), whereas a TBscore >3 increased this by 18 (9%); adding a Week 2 FU yielded an additional 94 (46%) patients. Among the 794 (24%) with persisting symptoms, 25 were diagnosed using Xpert and 69 at clinical FU, which constituted 46% (94/205) of the total TB patients diagnosed.A Week 2 FU visit, which can be nested into routine healthcare, increased the diagnosis of TB patients by two-fold and avoids diagnostic gaps in the cascade-of-care..

Hypertension is associated with increased mortality in patients with tuberculosis in Guinea-Bissau.

OBJECTIVES: Tuberculosis (TB) is associated with a number of non-communicable co-morbidities, which can complicate treatment and impair outcome. The aim of this study was to assess the impact of hypertension on disease severity, treatment outcome and survival in a cohort of patients with TB. METHODS: A retrospective cohort study was conducted in Guinea-Bissau. Patients newly diagnosed with TB between November 2003 and June 2016 were included. Hypertension was defined as blood pressure ≥140/90 mmHg. Disease severity was assessed using the Bandim TBscore. Survival was assessed at the end of treatment and 2 years after treatment initiation. RESULTS: In total, 1544 patients were included in this study. Hypertension was present in 12.8% of patients at inclusion. Patients with hypertension had slightly less severe TB, but were less likely to have a successful treatment outcome and had 64% higher mortality at 2-year follow-up (adjusted hazard ratio 1.64, 95% confidence interval 1.15-2.34). Mortality rates were highest in hypertensive female patients and patients aged ≥ 45 years. CONCLUSION: Patients with high blood pressure at the start of TB treatment had a higher mortality rate at 2-year follow-up. Mortality rates were highest in hypertensive females and patients aged ≥ 45 years.

Low prevalence of malnourishment among household contacts of patients with tuberculosis in Guinea-Bissau.

SETTING: An urban demographic surveillance site in Bissau, the capital of Guinea-Bissau, West Africa.BACKGROUND We hypothesised that if previous malnutrition plays a part in acquiring active tuberculosis (TB) disease, households of TB cases would have a higher prevalence of malnutrition than those of healthy controls. DESIGN: A cross-sectional study comparing nutritional and socio-economic status of all newly diagnosed patients with TB in 2014 with household contacts (persons residing in the household of TB cases) and random controls. Exclusion criteria were extra-pulmonary TB, age <15 years and pregnancy. RESULTS: Prevalence of malnutrition was 5% in household contacts and healthy controls, and 51% in patients with TB. Patients with TB had 22% (95%CI 19-25) lower body weight, 22% (95%CI 20-25) lower body mass index and 22% (95%CI 19-24) lower mid-upper arm circumference than healthy controls (P < 0.001); household contacts and healthy controls were comparable for all measures. The socio-economic status of households with TB cases was lower. CONCLUSIONS: We did not find a higher prevalence of malnourishment in households with TB cases. This finding did not support the hypothesis that malnourishment was an important causative factor for the development of active TB among patients in this study.

Tuberculosis case finding and mortality prediction: added value of the clinical TBscore and biomarker suPAR.

SETTING: A suburban area of Bissau, the capital of Guinea-Bissau; the study was conducted among presumptive pulmonary tuberculosis (prePTB) patients seeking medical care for signs and symptoms suggestive of PTB. OBJECTIVE: To determine if a clinical TB score and a biomarker suPAR (soluble urokinase plasminogen activator receptor) have separate and composite ability to predict PTB diagnosis and mortality in prePTB patients. DESIGN: Observational prospective follow-up study conducted from August 2010 to August 2012. RESULTS: We included 1011 prePTB patients (mean age 34 years, 95%CI 33-35); 55% (n = 559) were female and 161 (16%) had human immunodeficiency virus (HIV) infection. Of all included patients, 10% (n = 101) were diagnosed with PTB. Mortality during follow-up was 5% (n = 48), with a mean survival time of 158 days (95%CI 27-289) in prePTB patients diagnosed with PTB vs. 144 days (95%CI 109-178) in those not diagnosed with PTB (P = 0.774). After adjusting for HIV status and age, the best separate predictor was suPAR 5 ng/ml, with a hazard ratio (HR) of 4.6 (95%CI 2.1-9.9) for mortality and 6.7 (95%CI 4.0-11.2) for TB diagnosis. All patients who died had a TBscore II + suPAR 7; the HR of the composite score for subsequent PTB diagnosis was 33.0 (95%CI 4.6-236.6). CONCLUSION: The proposed composite score of suPAR + TBscore II 7 can improve TB case finding and clinical monitoring.

Impact of HIV-1, HIV-2, and HIV-1+2 dual infection on the outcome of tuberculosis.

BACKGROUND: HIV-1 infection has been shown to impact the outcome of patients with tuberculosis (TB), but data regarding the impact of HIV-2 on TB outcomes are limited. The aim of this study was to assess the impact of HIV types on mortality among TB patients in Guinea-Bissau and to examine the predictive ability of the TBscoreII, a clinical score used to assess disease severity. METHODS: In a prospective follow-up study, we examined the prevalence of HIV-1, HIV-2, and HIV-1+2 co-infection in TB patients in Guinea-Bissau, and the impact on outcomes at 12 months of follow-up. We included all adult TB patients in an observational TB cohort at the Bandim Health Project (BHP) in Guinea-Bissau between 2003 and 2013 and assessed survival status at 12 months after the start of treatment. RESULTS: A total 1312 patients were included; 499 (38%) were female (male/female ratio 1.6). Three hundred and seventy-nine patients were HIV-infected: 241 had HIV-1, 93 had HIV-2, and 45 were HIV-1+2 dual infected. The HIV type-associated risk of TB was 6-fold higher for HIV-1, 7-fold higher for HIV-1+2 dual infection, and 2-fold higher for HIV-2 compared with the HIV-uninfected. Of the patients included, 144 (11%) died, 62 (12%) among females and 82 (9%) among males (hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.64-1.30; p=0.596). Compared to male patients, female patients were younger (1 year younger, 95% CI 0.5-2; p=0.04), reported a longer duration of symptoms (14 days longer, 95% CI 4-25; p=0.003), and had a higher TBscoreII (0.5 points more, 95% CI 0.3-0.7; p<0.001). More females than males were HIV-infected (36% vs. 25%; p<0.001) and more females had a body mass index (BMI) <15 kg/m(2) (11% vs. 6%; p<0.001) and a mid upper arm circumference (MUAC) <200 mm (13% vs. 7%; p < 0.001). HIV infection increased the mortality risk, with HIV-1 infection displaying the highest HR (5.0, 95% CI 3.5-7.1), followed by HIV-1+2 (HR 4.2, 95% CI 2.2-7.8) and HIV-2 (HR 2.1, 95% CI 1.2-3.8). A TBscoreII ≥4 was associated with increased mortality (HR 2.2, 95% CI 1.5-3.1). Significantly increased HRs were found for signs of wasting; a BMI <18 kg/m(2) was associated with a HR of 1.8 (95% CI 1.3-2.6) and a MUAC <220 mm with a HR of 3.8 (95% CI 2.7-5.2). CONCLUSION: The HIV type-associated risk of TB was much higher for HIV-1 patients and higher but less so for HIV-2 patients, compared with the HIV-uninfected. Clinical severity at presentation was also higher for HIV-infected patients, although less so for HIV-2-infected patients, and all HIV-infected patients had a poorer outcome than the uninfected; mortality was 4-5-fold higher for HIV-1 and dually infected patients and two-fold higher for HIV-2-infected patients. These differences between HIV types did not disappear after adjusting for CD4 count.

The serum level of soluble urokinase receptor is elevated in tuberculosis patients and predicts mortality during treatment: a community study from Guinea-Bissau.

OBJECTIVE: To investigate whether the serum level of soluble urokinase plasminogen activator receptor (suPAR) carries prognostic information in individuals infected with Mycobacterium tuberculosis. DESIGN: suPAR was measured by ELISA in 262 individuals at the time of enrolment into a cohort based on suspicion of active tuberculosis and in 101 individuals after 8 months of follow-up. RESULTS: The suPAR levels were elevated in patients with active TB compared to TB-negative individuals (P < 0.001). suPAR levels were highest in patients positive for TB on direct microscopy (n = 84, median suPAR 3.17 ng/ml, P < 0.001), followed by patients negative on direct microscopy but culture positive (n = 35, median suPAR 2.41 ng/ml, P = 0.005) and by patients diagnosed on clinical grounds (n = 63, median suPAR 2.13 ng/ml, P = 0.06) compared to 64 TB-negative individuals (median suPAR 1.73 ng/ml). During the 8-month treatment period, 23 TB cases died. In a multivariate Cox model controlling for HIV status, age, sex, CD4 count and type of TB diagnosis, the mortality increase per ng suPAR was 1.25 (95%CI 1.12-1.40). After treatment, suPAR levels had decreased to the levels of TB-negative individuals. CONCLUSIONS: suPAR levels are elevated in TB patients and associated with mortality. Furthermore, suPAR may be a potential marker of treatment efficacy.

Can tuberculosis case finding among health-care seeking adults be improved? Observations from Bissau.

SETTING: The Bandim Health Project study area in Bissau, Guinea-Bissau. OBJECTIVE: To assess the potential usefulness of predictors (elsewhere applied) and clinical scores (TBscore and TBscore II) based on signs and symptoms typical of tuberculosis (TB) in case finding. DESIGN: Observational prospective cohort study of patients with signs and symptoms suggestive of pulmonary TB (PTB) from 2010 to 2012. RESULTS: We included 1089 PTB suspects with a mean age of 34 years (95%CI 33-35); human immunodeficiency virus (HIV) prevalence was 15.1%. PTB was diagnosed in 107 suspects (76.4% sputum smear-positive, 25.2% HIV-infected). Cough > 2 weeks had the highest diagnostic ability (area under the receiver operating characteristic curve [AUC] 0.66, 95%CI 0.62-0.71), while TBscore < 3 best excluded PTB (negative likelihood ratio [LR-] 0.3) when HIV status was not known. TBscore II ≥ 3 had the highest diagnostic ability in HIV-infected PTB suspects (AUC 0.62, 95%CI 0.53-0.72), while the absence of self-reported weight loss best excluded PTB (LR- 0.2). Cough > 2 weeks as a trigger for smear microscopy missed 32.1% of smear-positive PTB cases. CONCLUSION: Case finding could be improved by screening symptomatic adults for cough and/or weight loss using TBscore II as the trigger for smear microscopy. To suspect PTB only in patients with cough > 2 weeks (non-HIV-infected) or with current cough, fever, weight loss or night sweats (HIV-infected) was not effective in patients whose HIV status was unknown at first visit.

Adherence to isoniazid preventive therapy in children exposed to tuberculosis: a prospective study from Guinea-Bissau.

OBJECTIVE: To assess adherence to isoniazid preventive therapy (IPT) in children exposed to adult pulmonary tuberculosis (TB) at home. METHODS: Children were enrolled on IPT if they were aged ≤ 5 years or 5-15 years and presented a tuberculin skin test induration of ≥ 10 mm. Children were included from the demographic surveillance system of the Bandim Health Project in Bissau, Guinea-Bissau. The main outcome measures were adherence, completion rates and side effects during 9 months of IPT. The main outcome was 6 consecutive months of at least 80% adherence. RESULTS: A total of 2631 children were identified as contacts of adult TB cases. Among the children identified, 1895 (72%) were evaluated for eligibility for IPT, and 820 were enrolled in the study: 609 were aged ≤ 5 years and 211 aged 5-15 years. A total of 79% of the prescribed doses were taken, with 65% of the children taking > 80% of their doses. In all, 51% completed more than 6 consecutive months of IPT. CONCLUSION: Overall adherence to IPT was better than previously reported from TB-endemic areas, with 76% of the children completing at least 6 months of treatment, with more than 80% adherence.

Clinical predictors for death in HIV-positive and HIV-negative tuberculosis patients in Guinea-Bissau.

OBJECT: To assess easily monitored predictors for tuberculosis mortality. DESIGN: Risk factors for tuberculosis mortality were assessed during the 8-month treatment in 440 men and 269 women diagnosed with confirmed or presumed intrathoracic tuberculosis included prospectively in Guinea-Bissau from May 1996 to April 2001. A civil war occurred in the study area from June 1998 to May 1999. RESULTS: 12% were HIV-1 positive, 16% HIV-2 positive and 7% were HIV dually infected. Case fatality rates for HIV positive were higher during (35% [22/63]) and after the war (29% [27/92]) compared to before the war (17% [15/88]). The war did not have an effect on the case fatality rate in HIV negative (10% [13/135] before the war). HIV-1-infected patients had higher mortality than HIV-2 infected, mortality rate ratio (MRR) = 2.28 (95% confidence interval 1.17-4.46). Men had higher mortality than women but only among the HIV negative (MRR = 2.09 [0.95-4.59]). Hence, the negative impact of HIV infection on mortality was stronger in women (MRR = 6.51 [2.98-14.2]) than in men (MRR = 2.64 [1.67-4.17]) (test of homogeneity, p = 0.051). Anergy to tuberculin was associated with death in HIV positive (MRR = 2.77 [1.38-5.54]) but not in HIV negative (MRR = 1.14 [0.52-2.53]). Signs of immune deficiency, such as oral candida infection or leukoplakia (MRR = 4.25 [1.92-9.44]) and diarrhea (MRR = 2.15 [1.29-3.58] was associated with mortality in HIV positive. Tendencies were similar among HIV negative. HIV-positive relapse cases were at increased risk of dying (MRR = 2.42 [1.10-5.34]). Malnutrition, measured through mid-upper arm circumference (MUAC), increased the risk of death. CONCLUSION: Easily monitored predictors for mortality in tuberculosis patients include clinical signs of immune deficiency and low MUAC.

Tuberculosis mortality during a civil war in Guinea-Bissau.

CONTEXT: Tuberculosis (TB) is an increasing global problem, despite effective drug therapies. Access to TB therapy during conflict situations has not been studied. OBJECTIVE: To determine the effect of irregular TB treatment due to an armed conflict in Guinea-Bissau, West Africa. DESIGN, SETTING, AND PATIENTS: Ongoing retrospective cohort study conducted in the capital city of Bissau among 101 patients with TB who received irregular or no treatment during the civil war (war cohort; June 7-December 6, 1998) and 108 patients with TB who received treatment 12 months earlier (peace cohort; June 7-December 6, 1997) and comparison of an additional 42 patients who had completed treatment before June 6, 1998, and 69 patients who had completed treatment before June 6, 1997. MAIN OUTCOME MEASURE: Mortality rates, compared by irregular (war cohort) vs regular (peace cohort) access to treatment, by intensive vs continuation phase of treatment, and by those who had previously completed treatment for TB. RESULTS: Irregular treatment was associated with an increased mortality rate among patients with TB. The mortality rate ratio (MR) was 3.12 (95% confidence interval [CI], 1.20-8.12) in the war cohort, adjusting for age, sex, human immunodeficiency virus (HIV) infection, residence, and length of treatment. Each additional week of treatment before the war started increased probability of survival by 5% (95% CI, 0%-10%). In the intensive phase of treatment, the adjusted MR was 3.30 (95% CI, 1.04-10.50) and in the continuation phase it was 2.26 (95% CI, 0.33-15.34). Increased mortality among the war cohort was most marked in HIV-positive patients, who had an adjusted MR of 8.19 (95% CI, 1.62-41.25). Mortality was not increased in HIV-positive or HIV-negative patients who had completed TB treatment when the war started. CONCLUSIONS: Interruption of treatment had a profound impact on mortality among patients with TB during the war in Guinea-Bissau. Regular treatment for TB was associated with significantly improved survival for HIV-infected individuals. In emergencies, it is crucial to ensure availability of TB drugs.