Jamal Eddine Bourkadi

Genetic diversity of TLR2, TLR4, and VDR loci and pulmonary tuberculosis in Moroccan patients

INTRODUCTION Toll-like receptors (TLRs) 2, 4, and the vitamin D receptor (VDR) are central components of the innate and adaptive immunity against Mycobacterium tuberculosis (Mtb). TLR2, TLR4, and VDR polymorphisms were previously associated with tuberculosis (TB) and were here investigated as candidates for pulmonary TB (PTB) susceptibility in a Moroccan population group. METHODOLOGY Genomic DNA from 343 PTB patients and 203 healthy controls were analyzed for 12 single nucleotide polymorphisms (SNPs) located in TLR2, TLR4, and VDR genes using polymerase chain reaction-based restriction fragment length polymorphism and TaqMan SNP genotyping assays. RESULTS The TLR2 +597 CT genotype was associated with protection against PTB (corrected p [pc] = 0.04; odds ratio (OR) = 0.65; 95% confidence interval (CI) = 0.45 - 0.94), and the TLR4 +7263 C allele was significantly associated with PTB susceptibility (pc = 0.04; OR = 1.63; CI = 1.06 - 2.57). The VDR [f,b,a,T] haplotype was found to confer protection (pc < 0.00001; OR = 0.18; CI = 0.09 - 0.35), while the TLR2 [-16934T,+597C,+1349T] haplotype seemed to be at risk (p = 0.03; OR = 1.52; CI = 1.01 - 2.30), but statistical significance was not reached. Finally, cross-analysis between polymorphisms of the three studied genes revealed significant interaction between TLR2 +597 and TLR4 +4434 SNPs towards protection against PTB (pc = 0.036), suggesting that the functionally relevant TLR4 +4434 SNP may act synergistically with TLR2 SNPs. CONCLUSIONS TLR2 and TLR4 interaction and a specific VDR haplotype influence protection against PTB in Moroccans patients.

Treatment Default amongst Patients with Tuberculosis in Urban Morocco: Predicting and Explaining Default and Post-Default Sputum Smear and Drug Susceptibility Results

Setting Public tuberculosis (TB) clinics in urban Morocco. Objective Explore risk factors for TB treatment default and develop a prediction tool. Assess consequences of default, specifically risk for transmission or development of drug resistance. Design Case-control study comparing patients who defaulted from TB treatment and patients who completed it using quantitative methods and open-ended questions. Results were interpreted in light of health professionals’ perspectives from a parallel study. A predictive model and simple tool to identify patients at high risk of default were developed. Sputum from cases with pulmonary TB was collected for smear and drug susceptibility testing. Results 91 cases and 186 controls enrolled. Independent risk factors for default included current smoking, retreatment, work interference with adherence, daily directly observed therapy, side effects, quick symptom resolution, and not knowing one’s treatment duration. Age >50 years, never smoking, and having friends who knew one’s diagnosis were protective. A simple scoring tool incorporating these factors was 82.4% sensitive and 87.6% specific for predicting default in this population. Clinicians and patients described additional contributors to default and suggested locally-relevant intervention targets. Among 89 cases with pulmonary TB, 71% had sputum that was smear positive for TB. Drug resistance was rare. Conclusion The causes of default from TB treatment were explored through synthesis of qualitative and quantitative data from patients and health professionals. A scoring tool with high sensitivity and specificity to predict default was developed. Prospective evaluation of this tool coupled with targeted interventions based on our findings is warranted. Of note, the risk of TB transmission from patients who default treatment to others is likely to be high. The commonly-feared risk of drug resistance, though, may be low; a larger study is required to confirm these findings.

Factors Influencing Sputum Conversion among Smear-Positive Pulmonary Tuberculosis Patients in Morocco

Background: Sputum smear positive pulmonary tuberculosis patients expel infectious viable bacilli for a period following commencement of treatment. Objective: To determine the time to sputum smear conversion and study the factors influenceng it. Design: A prospective study was undertaken at our hospital in Rabat over a six months period on a cohort of 119 sputum smear positive patients. Patients were followed up fortnightly. At each follow up, specimens were collected and processed for microscopy using standard protocol. Results: 96.6% of our patients completed the study (4 deaths). Sputum conversion rate was 42% after two weeks, 73% after one month, and 95% after two months. Univariate and stepwise regression analysis showed that patients who had high smear grading, military, bilateral radiologic lesions were more likely to undergo delayed or non-conversion [P Conclusion: Since viable bacilli continue to be expelled for up to two months, infection control measures should be maintained for such time. Patients with high smear grading, miliary, bilateral radiologic lesions need to be monitored more closely.

First line anti-tuberculosis induced hepatotoxicity: incidence and risk factors

In our days, tuberculosis, whet ever its localization, became a curable disease. The cornerstone is a 6 month course of isoniazid, rifampicine and pyrazinamide. All of the three first line antituberculosis drugs may induce hepatic damage which may have negative consequences for treatment outcome. Several risk factors were associated with the development of antituberculosis- drug-induced hepatotoxicity (ATDH). A retrospective study was conducted from July 2014 to March 2015 regarding all therapeutic drug-monitoring requests sent to the Laboratory of Poison Control and Pharmacovigilance Centre of Morocco. 142 patients diagnosed with active tuberculosis were included in study. Plasma peak levels of isoniazid, rifampicin and pyrazinamide were analyzed in plasma samples after 2 to 3 hours of administration of anti-tuberculosis treatment. Logistic regression was used to identify the ATDH risk factors. The incidence of ATDH was found 24.6% (35 patients out of 142). Intergroup differences in the plasma levels were statistically significant for isoniazid (p=0.036). ATDH was found to be associated with combined form of anti-TB drugs (p=0.002, COR=13.1, AOR= 13.5) and plasma concentration of INH superior to 2mg/l (p=0.045, COR=1.3, AOR= 1.4).age, gender, alcohol intake and smoking status were not significantly associated with ATDH. The finding of 24.6% incidence of hepatotoxicity is extremely high. Many factors can be associated with the development of ATDH such as genetic factors, combined forms of treatment and plasma peak levels.

Postmenopausal breast tuberculosis - report of 4 cases.

Background: Breast tuberculosis is an uncommon disease even in countries where the incidence of tuberculosis is high. Case Report: This is a case series concerning 4 postmenopausal breast tuberculosis cases encountered in Moulay Youssef Hospital between January 2007 and December 2010. Breast tuberculosis represents 0.25% of all hospitalized tuberculosis patients in our department. The mean age of our patients was 62.5 ± 5.8 years. Clinical findings were heterogeneous; 1 case was multifocal tuberculosis, and another case was coexistent tuberculosis and malignancy of the breast. Mammography and ultrasonography findings were suspicious for malignancy in all 4 cases. Fine needle aspiration was negative in 3 cases. The diagnosis was made in all patients by histological examination of biopsy specimens, which revealed typical tuberculous lesions. Antituberculosis therapy formed the mainstay of treatment. Conclusion: The clinical and radiological features of mammary tuberculosis can be very confusing and easily mistaken for breast cancer. Symptoms suggestive of tuberculosis warrant a biopsy to exclude possible cancer.

Fistule oeso-bronchique congénitale chez l'adulte. A propos d'un cas.

Congenital esophagobronchial fistulae are uncommon anomalies generally discovered during the neonatal period due to overt symptoms. Rarely symptoms are discrete, leading to discovery in adulthood; exceptionally the patients are totally symptom free or present minimal signs such as coughing at ingestion of fluids. Less than 200 adult cases have been reported in the literature. We report a new case of this type II congenital esophagobronchial fistula. A 59-year-old woman was hospitalized for exploration of cough at ingestion of fluids. The radiographic work-up reveal dilatation of the left bronchial tree and suspected esophagobronchial fistula. An esophago-gastro-duodenal barium study demonstrated a fistula between the mid esophagus and the left posterobasal bronchus. Fistulectomy and left lower lobectomy were performed. Outcome was favorable. The diagnosis of adult esophagobronchial fistula should be entertained in patients with an uneventful history who present localized bronchial dilatation associated with cough induced by fluid ingestion.

Performance of GenoType® MTBDRplus assay in the diagnosis of drug-resistant tuberculosis in Tangier, Morocco.

OBJECTIVES In Morocco, tuberculosis (TB) is a major public health problem with high morbidity and mortality. The main problem faced by the national TB programme is the high rate of drug-resistant (DR), particularly multi-drug resistant (MDR) strains. Diagnosis of DR-TB is mainly performed by conventional techniques that are time consuming with limited efficacy. In 2014, the GenoType® MTBDRplus assay was introduced in Morocco for drug susceptibility testing (DST). In this regard, the present study was planned to assess the diagnostic accuracy of the GenoType® MTBDRplus assay. METHODS A total of 70 samples from suspected TB cases in Tangier (Morocco) were analysed by conventional DST and GenoType® MTBDRplus assay. RESULTS Among the 70 samples, 37.1% were MDR, whereas monoresistance to isoniazid (INH) and rifampicin (RIF) was detected in 186% and 17.1% of strains, respectively, by DST. Using the GenoType® MTBDRplus approach, 12 isolates (17.1%) were identified as INH monoresistant, 9 (12.9%) as RIF monoresistant and 26 (37.1%) as MDR. rpoB531 and katG315 mutations were the most common mutations associated with resistance to RIF and INH, respectively. Significantly, all phenotypically MDR strains were also MDR by GenoType® MTBDRplus. The sensitivity of GenoType® MTBDRplus was 92.1% for RIF resistance and 97.4% for INH resistance, whereas the specificity was 100% for the two tested drugs. CONCLUSIONS GenoType® MTBDRplus assay is a rapid, reliable and accurate tool for the detection of DR-TB in clinical specimens. Its routine use will be of a great interest to prevent the dissemination of DR-TB in the community.

Contribution of Imaging in Diagnosis of Primitive Cyst Hydatid in Unusual Localization: Pleura—A Report of Two Cases

Hydatic disease has always been the most common in countries where large amount of sheep and cattle is raised, but increased travel and immigration have made this condition a serious worldwide public problem. Cyst hydatid may affect all parts of the human body like the heart, the bone marrow, the eye, the brain, the kidney, and the spermatic cord. Humans can become infested by accidentally ingesting the eggs that are passed in the feces from definitive hosts (usually a canid, such as a wolf, fox, or dog). Even in endemic countries, the primitive pleural hydatid cyst is exceptional, and it is very difficult to distinguish from other pleural and parietal cystic masses especially that in majority of cases the immunologic tests are negative. We report two cases of pleural hydatid cyst discovered in two young patients, with a nonspecific clinical presentation. The interest of this paper is to raise the primordial role of imaging in the positive diagnosis of primary pleural hydatid cyst.

Primary Pleuropulmonary Synovial Sarcoma: A Case

Primary pleuropulmonary synovial sarcoma is extremely rare. The diagnosis can only be made after having eliminated an extrapleuropulmonary localization in the past and at the time of diagnosis. Our presentation is about a 40-year-old woman having a cough and dyspnea since three weeks ago; imaging had showed a left pleurisy with pleuropulmonary process. Histological study of the biopsy confirmed the diagnosis of pleuropulmonary synovial sarcoma. PET-SCAN had not identified any extrathoracic localization. This tumor is known for its aggressive nature and high risk of metastasis. Its primitive character is retained following a diagnostic procedure of exclusion. Surgical treatment remains the best therapeutic tool when it is technically feasible; otherwise the prognosis is often unfortunate. In this paper, we report a case of primary pleuropulmonary synovial sarcoma. Through this case, we present a rare disease that is often difficult to diagnose.

Molecular characterization of mutations associated with resistance to second-line tuberculosis drug among multidrug-resistant tuberculosis patients from high prevalence tuberculosis city in Morocco

BackgroundThe emergence of extensively drug-resistant tuberculosis (XDR-TB) has raised public health concern for global TB control. Although multi drug-resistant tuberculosis (MDR- TB) prevalence and associated genetic mutations in Morocco are well documented, scarce information on XDR TB is available. Hence, the evaluation of pre-XDR and XDR prevalence, as well as the mutation status of gyrA, gyrB, rrs, tlyA genes and eis promoter region, associated with resistance to second line drugs, is of great value for better management of M/XDR TB in Morocco.MethodsDrug susceptibility testing (DST) was performed by the proportional method for first line drugs, and then the selected MDR isolates were tested for second line drugs (Ofloxacin, Kanamycin, Amikacin and Capreomycin). Along with DST, all samples were subjected to rpoB, katG and p-inhA mutation analysis by PCR and DNA sequencing. MDR isolates as well as 30 pan-susceptible strains were subjected to PCR and DNA sequencing of gyrA, gyrB, rrs, tlyA genes and eis promoter, associated with resistance to fluoroquinolones and injectable drugs.ResultsAmong the 703 analysed strains, 12.8% were MDR; Ser531Leu and Ser315Thr being the most common recorded mutations within rpoB and katG genes associated with RIF and INH resistance respectively. Drug susceptibility testing for second line drugs showed that among the 90 MDR strains, 22.2% (20/90) were resistant to OFX, 2.22% (2/90) to KAN, 3.33% (3/90) to AMK and 1.11% (1/90) to CAP. Genotypic analysis revealed that 19 MDR strains harbored mutations in the gyrA gene; the most recorded mutation being Asp91Ala accounting for 47.6% (10/21), and 2 isolates harbored mutations in the promoter region of eis gene. No mutation was found in gyrB, rrs and tlyA genes. Moreover, none of the pan-susceptible isolates displayed mutations in targeted genes.ConclusionMost of mutations associated with SLD resistance occurred in gyrA gene (codons 90-94) and eis promoter region. These findings highlight the impact of mutations in gyrA on the development of fluroquinolones resistance and provide the first estimates of the proportion of pre-XDR-TB among MDR-TB cases in Morocco.