Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: a randomized controlled trial in Ethiopia.

OBJECTIVE: Immunotherapy using vitamin D (vitD3 ) and phenylbutyrate (PBA) may support standard drug regimens used to treat infectious diseases. We investigated if vitD3 + PBA enhanced clinical recovery from pulmonary tuberculosis (TB). METHODS: A randomized controlled trial was conducted in Addis Ababa, Ethiopia. Patients with smear-positive or smear-negative TB received daily oral supplementation with 5000 IU vitD3 and 2 × 500 mg PBA or placebo for 16 weeks, together with 6-month chemotherapy. Primary end-point: reduction of a clinical composite TB score at week 8 compared with baseline using modified intention-to-treat (mITT, n = 348) and per-protocol (n = 296) analyses. Secondary end-points: primary and modified TB scores (week 0, 4, 8, 16, 24), sputum conversion, radiological findings and plasma 25(OH)D3 concentrations. RESULTS: Most subjects had low baseline plasma 25(OH)D3 levels that increased gradually in the vitD3 + PBA group compared with placebo (P < 0.0001) from week 0 to 16 (mean 34.7 vs. 127.4 nmol L-1 ). In the adjusted mITT analysis, the primary TB score was significantly reduced in the intervention group at week 8 (-0.52, 95% CI -0.93, -0.10; P = 0.015) while the modified TB score was reduced at week 8 (-0.58, 95% CI -1.02, -0.14; P = 0.01) and 16 (-0.34, 95% CI -0.64, -0.03; P = 0.03). VitD3 + PBA had no effect on longitudinal sputum-smear conversion (P = 0.98). Clinical adverse events were more common in the placebo group (24.3%) compared with the vitD3 + PBA group (12.6%). CONCLUSION: Daily supplementation with vitD3 + PBA may ameliorate clinical TB symptoms and disease-specific complications, while the intervention had no effect on bacterial clearance in sputum.

Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients.

We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4ß-hydroxycholesterol/cholesterol (4ß-OHC/Chol) as a marker for CYP3A induction. Plasma 4ß-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy-naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4ß-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4ß-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4ß-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure.

High plasma efavirenz level and CYP2B6*6 are associated with efavirenz-based HAART-induced liver injury in the treatment of naïve HIV patients from Ethiopia: a prospective cohort study.

The objective of this study was to assess the incidence, timing and identify pharmacogenetic, efavirenz (EFV) pharmacokinetic and biochemical predictors of EFV-based antiretroviral therapy (ART) drug-induced liver injury (DILI). ART-naïve HIV patients (n = 285) were prospectively enrolled. Pretreatment laboratory evaluations included hepatitis B surface antigen and C antibody, CD4 count and viral load. Liver tests were done at baseline, 1st, 2nd, 4th, 8th, 12th, 24th and 48th weeks during ART. Plasma EFV and 8-hydroxyefvairenz concentration was determined at week 4 using liquid chromatography-mass spectrometry. CYP2B6, CYP3A5, ABCB1 3435C/T and UGT2B7*2 genotyping was done using Taqman genotyping assay. Data were analyzed using survival analysis and Cox proportional hazards model. The incidence of DILI was 15.7% or 27.9 per 100 person-years and that of severe injury was 3.4% or 6.13 per 100 person-years. The median time for the development of DILI and severe injury was 2 and 4 weeks after initiation of ART, respectively. There was significant association of DILI with lower baseline platelet, albumin, log plasma viral load and CD4 count (P = 0.031, 0.037, 0.06 and 0.019, respectively). Elevated baseline alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, plasma EFV level and CYP2B6*6 were good predictors for the development of DILI (P = 0.03, 0.01, 0.016, 0.017 and 0.04, respectively). We report for the first time CYP2B6*6 as a putative genetic marker and high plasma EFV concentration as intermediate biomarker for vulnerability to EFV-induced liver injury in HIV patients. CYP2B6 genotyping and/or regular monitoring of EFV and lever enzymes level during early therapy is advised for early diagnosis and management of DILI.

Evaluation of Toluidine Blue O staining for the diagnosis of Pneumocystis jiroveci in expectorated sputum sample and bronchoalveolar lavage from HIV-infected patients in a tertiary care referral center in Ethiopia.

BACKGROUND: Pneumocystis pneumonia (PCP) is becoming increasingly recognized in sub-Saharan Africa. The currently recommended diagnostic methods using induced sputum (IS) and bronchoalveolar lavage (BAL) are neither technically feasible nor affordable for a wider clinical use in developing countries. Therefore, there is a need for a simple and affordable diagnostic test. METHODS: The yield of Toluidine Blue O (TBO) stain, immunofluorescence (IF), and polymerase chain reaction (PCR) for the diagnosis of Pneumocystis jiroveci were compared in 78 expectorated sputum and 118 BAL samples of 131 HIV-infected patients presenting with atypical chest X-ray and sputum smear-negative for acid-fast bacilli. RESULTS: A total of 56 (42.7%) patients tested positive for P. jiroveci by PCR, 39 (29.4%) by IF, and 28 (21.4%) by TBO stain. The sensitivity of TBO as compared to IF and PCR was 71.4% and 34.5% in expectorated sputum and 68% and 41.5% in BAL samples, respectively, with a specificity approaching 100% in both. The sputum PCR showed high concordance rate with BAL PCR. The sensitivity and specificity of sputum PCR as compared to BALPCR was 78.9% and 89%, respectively. In both TBO and IF positive BAL samples, majority were from patients who could not produce sputum (p<0.001). The density of P. jiroveci clusters in BAL samples did not correlate with prior co-trimoxazole use, immunologic status of the patient or overall mortality. CONCLUSION: Compared to IF, TBO staining has an acceptable sensitivity and very high specificity both in expectorated sputum and BAL samples. Expectorated sputum is, therefore, the most practical specimen and TBO staining an inexpensive diagnostic method to be recommended for high-HIV, resource-constrained settings. Bronchoscopy for the diagnosis of PCP is often not required for patients who can produce sputum. For patients who cannot produce sputum, however, the cost and efficacy of TBO in IS sample needs to be investigated in resource-poor countries.

The relationship between disease pattern and disease burden by chest radiography, M. tuberculosis Load, and HIV status in patients with pulmonary tuberculosis in Addis Ababa.

BACKGROUND: We evaluated the impact of HIV coinfection on the chest radiographic pattern and extent of disease and its relation to the load of Mycobacterium tuberculosis in Ethiopian out-patients with pulmonary tuberculosis. PATIENTS AND METHODS: A total of 168 patients with cultureverified pulmonary tuberculosis had their chest X-rays (CXR) reviewed for the site, pattern, and extent of disease and the findings were correlated to (a) the mycobacterial culture count and bacillus load after sputum concentration and (b) the HIV status of the patients. RESULTS: HIV-positive patients were less likely to have cavitary disease (p < 0.001) and more likely to have pleural effusion (p = 0.08), miliary (p < 0.05), and interstitial (p < 0.01) patterns. A total of 15 (9.2%) patients had normal chest X-rays. HIV-infected patients had a CXR classified as normal or with minimal involvement (p = 0.059) and a reduced mycobacterial colony count (p = 0.002) compared to HIV-negative patients. Middle and lower lung involvement were more common in HIV-positive patients. CONCLUSION: CXR findings in the setting of an underlying HIV infection tend to be more atypical and could present as either normal or with minimal involvement. In general, HIV-positive patients had lower colony count of M. tuberculosis than HIV-negative patients. Of particular interest is the finding of a large number of normal chest X-rays in HIV-infected patients. With the rising incidence of both tuberculosis and HIV infection in Ethiopia, the finding of a normal chest X-ray and a negative smear poses a challenge for the diagnosis of pulmonary tuberculosis.

Causes and clinical characteristics of chronic cor-pulmonale in Ethiopia.

OBJECTIVE: To determine the clinical characteristics and underlying causes of chronic cor-pulmonale in Ethiopian patients. DESIGN: A hospital based cross-sectional study. SETTING: Tikur Anbessa Hospital, a large referral hospital in Addis Ababa, Ethiopia. SUBJECTS: Fourty two consecutive patients referred to the chest clinic of Tikur Anbessa Hospital, Addis Ababa, Ethiopia. RESULTS: Bronchial asthma (36%), chronic fibrocavitary tuberculosis (31%) and chronic bronchitis/emphysema (33%) were the most frequent underlying causes and occurred either singly or in combination in 36(86%) of patients. Interstitial lung disease occurred in five (11.9%) patients. Right-sided heart failure and cyanosis were the most common clinical presentations. Secondary polycythemia was noted in 32 of 40 patients (80%). The role of pulmonary vascular diseases including pulmonary schistosomiasis as a cause of pulmonary heart disease could not be ascertained but appeared to be insignificant. CONCLUSION: Chronic persistent asthma is a frequent underlying cause of chronic obstructive pulmonary disease and chronic cor-pulmonale compared to smoking related chronic bronchitis/emphysema in Ethiopia. The preventive strategy of chronic cor-pulmonale includes optimal treatment of bronchial asthma, early diagnosis and effective treatment of tuberculosis and health education to avoid cigarette smoking.

Circulating TNF-alpha, TGF-beta, and IL-10 in tuberculosis patients and healthy contacts.

Levels of tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and interleukin (IL)-10 in plasma of pulmonary tuberculosis (TB) patients and healthy contacts and plasma and pleural fluid of patients with tuberculous pleuritis were examined by enzyme immunoassay. Plasma TNF-alpha and IL-10 were elevated to significant levels in healthy contacts. High levels of TGF-beta and IL-10 were also detected in plasma from TB patients and healthy contacts. Pleural fluid contained all three cytokines with the level of IL-10 being highest followed by TGF-beta and TNF-alpha. Plasma of tuberculous pleuritis patients also had detectable levels of the three cytokines. Increased levels of TNF-alpha in plasma of contacts and to some extent pleural fluid of pleuritis patients, is perhaps to limit the infection, while elevated IL-10 in plasma of TB patients and contacts and pleural fluid would perhaps modulate excess proinflammation. Elevated TGF-beta in TB patients suggests its role in the immunopathogenesis.

Sputum concentration improves diagnosis of tuberculosis in a setting with a high prevalence of HIV.

Sputum microscopy for acid-fast bacilli (AFB), although relatively insensitive, is still the cornerstone of tuberculosis (TB) diagnosis in the developing world. Its diagnostic value has been eroded owing to the increasing number of HIV-related smear-negative pulmonary TB cases. Concentration of sputum by centrifugation after liquefaction with sodium hypochlorite is a possible means of increasing the sensitivity of direct microscopy. This procedure has been studied recently in developing countries although with conflicting results. The aim of our study, performed in 1996 in Addis Ababa, Ethiopia, was to evaluate the sensitivity of the concentration method in a large cohort of consecutive patients with suspected pulmonary TB. We show that the overall sensitivity increased from 54.2% using conventional direct microscopy to 63.1% after concentration (P < 0x0015). In HIV-positive patients, sensitivity increased from 38.5% before to 50.0% after concentration (P < 0x0034). The significant increase in yield of AFB in HIV-positive patients suggests that this method has a place in routine diagnosis of pulmonary TB in countries with a high prevalence of HIV.

Prevalence and clinical features of tuberculosis in Ethiopian diabetic patients.

OBJECTIVE: To determine the prevalence and clinical characteristics of tuberculosis (TB) in diabetic patients. DESIGN: This study was a cross-sectional survey based on the retrospective analysis of data on tuberculosis in diabetic patients. SETTINGS: The study was conducted at Endocrinology and Metabolism Unit of the Department of Internal Medicine, Faculty of Medicine, Addis Ababa, Ethiopia. SUBJECTS: Seventy-eight cases of tuberculosis among 1352 diabetic patients were included from September 1989 to 1996. MAIN OUTCOME MEASURES: Clinical evaluation, chest x-ray, acid fast bacilli (AFB) in sputum or measures tissue and histopathologic characteristic of biopsy specimens. RESULTS: Seventy-eight cases of TB were identified among 1352 diabetic patients giving a prevalence of 5.8%. Among 1352 diabetic patients, 713 (52.7%) were males, 639 (43.3%) were females, 619 (45.8%) were IDDM and 733 (54.2%) were NIDDM. The mean age of the 71 TB patients whose records could be retrieved was 34.0 +/- 11.9 years, 42(59%) were males, 29 (41%) were females. Fifty-four (76.1%) were IDDM and 17(23.9%) were NIDDM, 17 of the IDDM had clinical characteristics of malnutrition-related diabetes mellitus (MRDM), 36 (56%) of 71 patients were admitted for management. The three most common symptoms of tuberculosis were fever (80.5%), sweating (80.4%) and cough (70.5%). Twenty six (36.6%) of 71 cases were positive for AFB and six (8.5%) were seropositive for HIV. Fifty-six (78.9%) had pulmonary,eight (11.2%) had extrapulmonary and seven(9.8%) had disseminated TB. Forty-eight of 53 abnormal chest x-ray showed unilateral involvement. Thirty-eight of 41 (53.6%) had completed TB treatment, relapse occurred in seven (9.8%), eight (11.2%) are currently on treatment, 13 (18.3%) were lost to follow up, four (5.6%) defaulted and three (4.2%) died. The relative risk of developing TB in IDDM and NIDDM patients was being 26 times and seven times than the general population respectively. CONCLUSION: The prevalence of tuberculosis in the diabetic population is high and this warrants a prospective study to determine association between pulmonary tuberculosis and diabetes.

PIP: This retrospective, cross-sectional analysis examines the prevalence and clinical characteristics of tuberculosis (TB) in Ethiopian diabetic patients. Using the records of 1352 patients seen at the Endocrinology and Metabolism Unit of the Department of Internal Medicine, Faculty of Medicine, Addis Ababa, Ethiopia, 78 cases (5.8%) of TB were identified. Diagnosis of the disease includes clinical evaluations, chest x-ray, and detection of acid-fast bacilli (AFB) in the sputum or measures tissue and histopathologic characteristics of biopsy specimens. Prevalence was 52.7% among males, 54.25% among those with non-insulin-dependent diabetes mellitus (NIDDM), 47.3% among females, and 45.8% among those with insulin-dependent diabetes mellitus (IDDM). The mean age of 71 patients with TB was 34 +or- 19 years (14-85 years); 76.0% were IDDM and 23.9% were NIDDM patients. 17 of the IDDM patients also had clinical characteristics similar to those of malnutrition-related diabetes mellitus. The most frequent symptoms of TB included fever (80.5%), sweating (80.5%), and cough (76%); 78.9% of patients suffered from pulmonary, 11.2% from extrapulmonary, and 9.9% from disseminated TB. On the other hand, chest X-ray reports revealed that 48 of the patients had unilateral or multiple lobe involvement and 5 had bilateral involvement. Of the 71 patients, 38 were able to complete antituberculosis treatment, 4 patients defaulted, 7 had relapse, 6 were still in treatment, 13 were lost to follow-up, and 3 died. In conclusion, this study confirmed the 26- and 7-fold risk of developing TB among IDDM and NIDDM patients, respectively.

Effects of HIV co-infection and chemotherapy on the urinary levels of nitric oxide metabolites in patients with pulmonary tuberculosis.

The presence of nitric oxide (NO) and its role as a factor in host defence against intracellular pathogens in human macrophages is controversial. We measured the metabolites of NO (nitrite (NO2-) and nitrate (NO3-)) in urine from Ethiopian patients suffering from tuberculosis. The urinary level of NO2-/NO3- in a group of healthy Ethiopians was 1020+/-471 microM (n = 22). Untreated HIV negative patients with active pulmonary tuberculosis (1574+/-588 microM, p<0.01, n = 12) and household contacts to tuberculosis patients (1949+/-812 microM, p = 0.006, n = 7) had significantly higher levels of urinary NO2-/NO3- than the control group. Untreated HIV positive patients with pulmonary tuberculosis did not have increased levels of urinary NO2-/NO3- (1101+/-614 microM, n = 6). Some of the HIV negative untreated patients with pulmonary tuberculosis (1710+/-519 microM, n = 6) were followed up after treatment and showed a reduction in the levels of urinary NO2-/NO3- 1 week after treatment (945+/-599 microM, p<0.05). We conclude that HIV negative patients with active pulmonary tuberculosis have increased urinary levels of nitric oxide metabolites with a reduction following specific anti-tuberculous chemotherapy.

Pulmonary hydatid cyst as a cause of recurrent haemoptysis and responding to treatment with albendazole.

A 28 year old Ethiopian male who presented with recurrent haemoptysis, fever, and multiple well defined masses on a chest x-ray and subsequently responded to treatment with albendazole is reported. Complete remission of the symptoms and improvement of chest x-ray findings was attained within 2 months of initiation of treatment. The unusual presentation of pulmonary hydatid cyst and the response to pharmacotherapy is briefly reviewed.

Hypertrophic pulmonary osteoarthropathy in pulmonary metastasis--a case report.

Hypertrophic pulmonary Osteoarthropathy is most commonly encountered in association with bronchogenic carcinoma and tumours of the pleura. Its association with pulmonary metastasis from extrathoracic neoplasms is rare. We report a 33 years old male Ethiopian who presented with Cannon ball lesions, clubbing of the digits, periostitis, gynaecomastia, acromegalic features and bilateral knee arthritis. Related literature is briefly reviewed.

Bilateral pulmonary aspergilloma: case report.

Bilateral pulmonary aspergilloma colonising an old tuberculous cavity and a pyogenic lung abscess in a 25-year old Ethiopian lady is reported. The diagnosis was based on the findings of a rounded density with typical air crescent sign on a chest x-ray and isolation of Aspergillus species from a bronchoscopic aspirate. Despite the high prevalence of cavity pulmonary tuberculosis, pulmonary aspergilloma is rarely reported from this and other African countries and the likely reasons for this are discussed.

Community acquired pneumonia in adults in Addis Ababa: etiologic agents and the impact of HIV infection.

SETTING: Black Lion Hospital, a tertiary care referral hospital in Addis Ababa, Ethiopia. OBJECTIVE: To determine the prevalence of HIV infection in patients with Community Acquired Pneumonia (CAP) and compare the etiologic agents, clinical and radiographic presentation and outcome of the disease in HIV positive and negative patients. DESIGN: A hospital based prospective study on 110 adult patients consecutively coming to Black Lion Hospital between August 1987 and July 1989. RESULTS: 8% of patients with pneumonia versus 2.4% for the general population (P < 0.05) were seropositive for HIV-I. Streptococcus pneumoniae was the most common offending pathogen. HIV positive patients were more likely to be male, young and of urban residence. They had fewer chills, increased bilateral and multilobar lung involvement, frequent association with pulmonary tuberculosis and recurrent chest infiltrate. CONCLUSION: The incidence of Community Acquired Pneumonia in patients with HIV infection is likely to increase with the rapid rise in HIV infection. Future studies should therefore look further into (a) the pattern of etiologic agents, (b) unusual clinical patterns which may help set criteria for screening for HIV infection, and (c) the use of pneumococcal vaccine in selected groups of patients.

The value of sputum gram stain in the diagnosis of pneumococcal pneumonia.

The utility of sputum Gram stain in identifying Gram positive diplococci and other bacteria was studied in 39 patients with community acquired pneumonia (CAP). The results of the Gram stain of the sputum were compared to the Gram stain of the lung aspirate (LA). Of 28 patients whose LA smear showed Gram positive diplococci, 26 (95%) had the same organisms, either exclusively or predominantly, in their sputum. One patient had Gram negative rods both in the sputum and lung aspirate. Seventy-one per cent of patients with positive LA stain versus 50% with negative LA stain had taken antimicrobials for less than 36 hours prior to coming to hospital. We conclude that sputum Gram stain is a sensitive method for the diagnosis of pneumococcal pneumonia and is unaffected by a short period of prior antimicrobial treatment.

The etiology of community acquired pneumonia in adults in Addis Ababa.

Over a two year period, we prospectively studied 110 adult patients with Community Acquired Pneumonia (CAP) who presented to the Black Lion Hospital, Addis Ababa, Ethiopia. Pneumococcal infection was diagnosed in 41% by the detection of pneumococcal antigen in sputum and other biologic fluids; in 72% by Gram stain of Lung Aspirate (LA) and in 67.5% by Gram stain of sputum. Blood and Lung Aspirate culture grew Streptococcus Pneumoniae in 4 cases (6%), Staphylococcus Aureus in 4 (6%), Enterobacteriacae in 3(5%), Pseudomonas, Klebsiella Pneumoniae and Strep. Viridans in one case each. Other non-bacterial causes included Mycoplasma Pneumoniae in 4 (4%) Influenza A in 4 (4%), Influenza B in 3 (3%) and Psittacosis/LGV in a 4 (4%). There was no case of Legionnaires disease. 39% had taken treatment before coming to hospital. The mortality was 11%. The study showed that antibiotic treatment during the preceding 36 hours did not affect the outcome of the Gram stain.

Community acquired pneumonia in adults in Addis Abeba: etiologic agents, clinical and radiographic presentation.

We prospectively studied 110 adult patients coming to Black Lion Hospital between August 1987 and July 1989 with community acquired pneumonia (CAP) for various etiologic agents and clinical and radiographic presentation. Streptococcus pneumoniae was the most common offending pathogen in 72% and 67.5% from sputum and lung aspirate (LA) Gram stain respectively, and in 41% by pneumococcal serotyping of sputum. Blood and LA culture grew Streptococcus pneumoniae in 4 (6%), Staphylococcus aureus in 4 (6%), Enterobacteriaceae in (3%), Pseudomonas, Klebsiella and Streptococcus viridans in one case each. Non-bacterial pathogens included Mycoplasma pneumoniae in 3 (3%), Influenza A in 4 (4%), Influenza B in 3 (3%) and psittacosis/LGV in 4 (4%). Fever, cough, chest pain, tachypnea and coarse crepitations/bronchial breathing were the most common presenting signs and symptoms. Thirty per cent had associated diarrhoea and vomiting initially and 9% had altered state of consciousness at admission. Six patients came in a state of shock. Thirty-nine per cent had underlying illnesses. Ninety-three per cent had either segmental or lobar consolidation. Parapneumonic effusion occurred in 14%. The mortality was 11%. Tachypnea, the presence of underlying illness, altered state of consciousness, extreme leucocytosis and the presence of bilateral and multilobar lung involvement were found to be signs of poor prognosis. Our finding is similar to those from other African countries, except that we are reporting psittacosis/LGV for the first time in Africa.