Salim Allana

Transmission of Extensively Drug-Resistant Tuberculosis in South Africa.

BACKGROUND Drug‐resistant tuberculosis threatens recent gains in the treatment of tuberculosis and human immunodeficiency virus (HIV) infection worldwide. A widespread epidemic of extensively drug‐resistant (XDR) tuberculosis is occurring in South Africa, where cases have increased substantially since 2002. The factors driving this rapid increase have not been fully elucidated, but such knowledge is needed to guide public health interventions. METHODS We conducted a prospective study involving 404 participants in KwaZulu‐Natal Province, South Africa, with a diagnosis of XDR tuberculosis between 2011 and 2014. Interviews and medical‐record reviews were used to elicit information on the participants’ history of tuberculosis and HIV infection, hospitalizations, and social networks. Mycobacterium tuberculosis isolates underwent insertion sequence (IS)6110 restriction‐fragment–length polymorphism analysis, targeted gene sequencing, and whole‐genome sequencing. We used clinical and genotypic case definitions to calculate the proportion of cases of XDR tuberculosis that were due to inadequate treatment of multidrug‐resistant (MDR) tuberculosis (i.e., acquired resistance) versus those that were due to transmission (i.e., transmitted resistance). We used social‐network analysis to identify community and hospital locations of transmission. RESULTS Of the 404 participants, 311 (77%) had HIV infection; the median CD4+ count was 340 cells per cubic millimeter (interquartile range, 117 to 431). A total of 280 participants (69%) had never received treatment for MDR tuberculosis. Genotypic analysis in 386 participants revealed that 323 (84%) belonged to 1 of 31 clusters. Clusters ranged from 2 to 14 participants, except for 1 large cluster of 212 participants (55%) with a LAM4/KZN strain. Person‐to‐person or hospital‐based epidemiologic links were identified in 123 of 404 participants (30%). CONCLUSIONS The majority of cases of XDR tuberculosis in KwaZulu‐Natal, South Africa, an area with a high tuberculosis burden, were probably due to transmission rather than to inadequate treatment of MDR tuberculosis. These data suggest that control of the epidemic of drug‐resistant tuberculosis requires an increased focus on interrupting transmission. (Funded by the National Institute of Allergy and Infectious Diseases and others.)

A High Throughput Whole Blood Assay for Analysis of Multiple Antigen-Specific T Cell Responses in Human Mycobacterium tuberculosis Infection

Antigen-specific CD4 and CD8 T cells are important components of the immune response to Mycobacterium tuberculosis, yet little information is currently known regarding how the breadth, specificity, phenotype, and function of M. tuberculosis–specific T cells correlate with M. tuberculosis infection outcome in humans. To facilitate evaluation of human M. tuberculosis–specific T cell responses targeting multiple different Ags, we sought to develop a high throughput and reproducible T cell response spectrum assay requiring low blood sample volumes. We describe here the optimization and standardization of a microtiter plate-based, diluted whole blood stimulation assay utilizing overlapping peptide pools corresponding to a functionally diverse panel of 60 M. tuberculosis Ags. Using IFN-γ production as a readout of Ag specificity, the assay can be conducted using 50 μl of blood per test condition and can be expanded to accommodate additional Ags. We evaluated the intra- and interassay variability, and implemented testing of the assay in diverse cohorts of M. tuberculosis–unexposed healthy adults, foreign-born adults with latent M. tuberculosis infection residing in the United States, and tuberculosis household contacts with latent M. tuberculosis infection in a tuberculosis-endemic setting in Kenya. The M. tuberculosis–specific T cell response spectrum assay further enhances the immunological toolkit available for evaluating M. tuberculosis–specific T cell responses across different states of M. tuberculosis infection, and can be readily implemented in resource-limited settings. Moreover, application of the assay to longitudinal cohorts will facilitate evaluation of treatment- or vaccine-induced changes in the breadth and specificity of Ag-specific T cell responses, as well as identification of M. tuberculosis–specific T cell responses associated with M. tuberculosis infection outcomes.

Polymorphisms in the Vitamin D receptor gene are associated with reduced rate of sputum culture conversion in multidrug-resistant tuberculosis patients in South Africa

Background Vitamin D modulates the inflammatory and immune response to tuberculosis (TB) and also mediates the induction of the antimicrobial peptide cathelicidin. Deficiency of 25-hydroxyvitamin D and single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene may increase the risk of TB disease and decrease culture conversion rates in drug susceptible TB. Whether these VDR SNPs are found in African populations or impact multidrug-resistant (MDR) TB treatment has not been established. We aimed to determine if SNPs in the VDR gene were associated with sputum culture conversion among a cohort of MDR TB patients in South Africa. Methods We conducted a prospective cohort study of adult MDR TB patients receiving second-line TB treatment in KwaZulu-Natal province. Subjects had monthly sputum cultures performed. In a subset of participants, whole blood samples were obtained for genomic analyses. Genomic DNA was extracted and genotyped with Affymetrix Axiom Pan-African Array. Cox proportional models were used to determine the association between VDR SNPs and rate of culture conversion. Results Genomic analyses were performed on 91 MDR TB subjects enrolled in the sub-study; 60% were female and median age was 35 years (interquartile range [IQR] 29–42). Smoking was reported by 21% of subjects and most subjects had HIV (80%), were smear negative (57%), and had cavitary disease (55%). Overall, 87 (96%) subjects initially converted cultures to negative, with median time to culture conversion of 57 days (IQR 17–114). Of 121 VDR SNPs examined, 10 were significantly associated (p<0.01) with rate of sputum conversion in multivariable analyses. Each additional risk allele on SNP rs74085240 delayed culture conversion significantly (adjusted hazard ratio 0.30, 95% confidence interval 0.14–0.67). Conclusions Polymorphisms in the VDR gene were associated with rate of sputum culture conversion in MDR TB patients in this high HIV prevalence setting in South Africa.

Spatial distribution of extensively drug-resistant tuberculosis (XDR TB) patients in KwaZulu-Natal, South Africa.

Background KwaZulu-Natal province, South Africa, has among the highest burden of XDR TB worldwide with the majority of cases occurring due to transmission. Poor access to health facilities can be a barrier to timely diagnosis and treatment of TB, which can contribute to ongoing transmission. We sought to determine the geographic distribution of XDR TB patients and proximity to health facilities in KwaZulu-Natal. Methods We recruited adults and children with XDR TB diagnosed in KwaZulu-Natal. We calculated distance and time from participants’ home to the closest hospital or clinic, as well as to the actual facility that diagnosed XDR TB, using tools within ArcGIS Network analyst. Speed of travel was assigned to road classes based on Department of Transport regulations. Results were compared to guidelines for the provision of social facilities in South Africa: 5km to a clinic and 30km to a hospital. Results During 2011–2014, 1027 new XDR TB cases were diagnosed throughout all 11 districts of KwaZulu-Natal, of whom 404 (39%) were enrolled and had geospatial data collected. Participants would have had to travel a mean distance of 2.9 km (CI 95%: 1.8–4.1) to the nearest clinic and 17.6 km (CI 95%: 11.4–23.8) to the nearest hospital. Actual distances that participants travelled to the health facility that diagnosed XDR TB ranged from <10 km (n = 143, 36%) to >50 km (n = 109, 27%), with a mean of 69 km. The majority (77%) of participants travelled farther than the recommended distance to a clinic (5 km) and 39% travelled farther than the recommended distance to a hospital (30 km). Nearly half (46%) of participants were diagnosed at a health facility in eThekwini district, of whom, 36% resided outside the Durban metropolitan area. Conclusions XDR TB cases are widely distributed throughout KwaZulu-Natal province with a denser focus in eThekwini district. Patients travelled long distances to the health facility where they were diagnosed with XDR TB, suggesting a potential role for migration or transportation in the XDR TB epidemic.

pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia

Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.

Establishing a hospital based fracture liaison service to prevent secondary insufficiency fractures

In the aging population worldwide, osteoporosis is a relatively common condition and a major cause of long-term morbidity. Initial fragility fractures can lead to subsequent fractures. After a vertebral fracture, the risk of any another fracture increases 200% and that of a subsequent hip fracture increases 300%. For starting a hospital based Fracture Liaison Service (FLS) program, the nucleus is based on a physician champion, a FLS coordinator, and a nurse manager. A Fracture Liaison Service (FLS) is a multidisciplinary system approach to reducing subsequent fracture risk in patients with a recent fragility fracture due to compromised bone health by identifying them at or close to the time when they are treated at the hospital for fracture and providing them with easy access to osteoporosis care. It has been shown that when compared to other models such as referral letters to primary care physicians or endocrinologists, the FLS model results in a higher rate of diagnosis and treatment with less attrition in the posffracture phase. Insufficiency fracture care requires more than surgery to stabilize a fractured bone. The FLS program provides an opportunity to treat osteoporosis from a public health perspective rather than leaving this to the whims of individual physicians. This is achieved by providing a seamless integration of care by health care providers, nursing staff and administration. The FLS can be adapted to any model of care including academic health systems. FLS provides a holistic approach to identify patients as well as to provide evidence-based interventions to prevent subsequent fractures. The long term goal is that internationally FLS will result in in decreased fracture-related morbidity, mortality and overall health care expenditure.

Osteoid osteoma: Contemporary management

Osteoid osteoma is a benign bone-forming tumor with hallmark of tumor cells directly forming mature bone. Osteoid osteoma accounts for around 5% of all bone tumors and 11% of benign bone tumors with a male predilection. It occurs predominantly in long bones of the appendicular skeleton. According to Musculoskeletal Tumor Society staging system for benign tumors, osteoid osteoma is a stage-2 lesion. It is classified based on location as cortical, cancellous, or subperiosteal. Nocturnal pain is the most common symptom that usually responds to salicyclates and non-steroidal anti-inflammatory medications. CT is the modality of choice not only for diagnosis but also for specifying location of the lesion, i.e. cortical vs sub periosteal or medullary. Non-operative treatment can be considered as an option since the natural history of osteoid osteoma is that of spontaneous healing. Surgical treatment is an option for patients with severe pain and those not responding to NSAIDs. Available surgical procedures include radiofrequency (RF) ablation, CT-guided percutaneous excision and en bloc resection.

Extensively drug-resistant tuberculosis in South Africa: genomic evidence supporting transmission in communities

Despite evidence that transmission is driving an extensively drug-resistant TB (XDR-TB) epidemic, our understanding of where and between whom transmission occurs is limited. We sought to determine whether there was genomic evidence of transmission between individuals without an epidemiologic connection. We conducted a prospective study of XDR-TB patients in KwaZulu-Natal, South Africa, during the 2011–2014 period. We collected sociodemographic and clinical data, and identified epidemiologic links based on person-to-person or hospital-based connections. We performed whole-genome sequencing (WGS) on the Mycobacterium tuberculosis isolates and determined pairwise single nucleotide polymorphism (SNP) differences. Among 404 participants, 123 (30%) had person-to-person or hospital-based links, leaving 281 (70%) epidemiologically unlinked. The median SNP difference between participants with person-to-person and hospital-based links was 10 (interquartile range (IQR) 8–24) and 16 (IQR 10–23), respectively. The median SNP difference between unlinked participants and their closest genomic link was 5 (IQR 3–9) and half of unlinked participants were within 7 SNPs of at least five participants. The majority of epidemiologically-unlinked XDR-TB patients had low pairwise SNP differences with at least one other participant, consistent with transmission. These data suggest that much of transmission may result from casual contact in community settings between individuals not known to one another. Much of XDR-TB transmission may arise from casual contact between individuals not known to one another http://ow.ly/4Wqt30lnHtp

Improved Survival and Cure Rates With Concurrent Treatment for Multidrug-Resistant Tuberculosis–Human Immunodeficiency Virus Coinfection in South Africa

Background Mortality in multidrug-resistant (MDR) tuberculosis-human immunodeficiency virus (HIV) coinfection has historically been high, but most studies predated the availability of antiretroviral therapy (ART). We prospectively compared survival and treatment outcomes in MDR tuberculosis-HIV-coinfected patients on ART to those in patients with MDR tuberculosis alone. Methods This observational study enrolled culture-confirmed MDR tuberculosis patients with and without HIV in South Africa between 2011 and 2013. Participants received standardized MDR tuberculosis and HIV regimens and were followed monthly for treatment response, adverse events, and adherence. The primary outcome was survival. Results Among 206 participants, 150 were HIV infected, 131 (64%) were female, and the median age was 33 years (interquartile range [IQR], 26-41). Of the 191 participants with a final MDR tuberculosis outcome, 130 (73%) were cured or completed treatment, which did not differ by HIV status (P = .50). After 2 years, CD4 count increased a median of 140 cells/mm3 (P = .005), and 64% had an undetectable HIV viral load. HIV-infected and HIV-uninfected participants had high rates of survival (86% and 94%, respectively; P = .34). The strongest risk factor for mortality was having a CD4 count ≤100 cells/mm3 (adjusted hazards ratio, 15.6; 95% confidence interval, 4.4-55.6). Conclusions Survival and treatment outcomes among MDR tuberculosis-HIV individuals receiving concurrent ART approached those of HIV-uninfected patients. The greatest risk of death was among HIV-infected individuals with CD4 counts ≤100 cells/mm3. These findings provide critical evidence to support concurrent treatment of MDR tuberculosis and HIV.

Unicameral bone cysts: Current concepts

Unicameral bone cysts (UBC) or simple/solitary bone cysts are benign fluid filled cavities that enlarge over time, resulting in thinning of the bone. Usually these cysts are reported in the metaphyseal areas of long bones with open physes. 85% of UBCs occur almost exclusively in children and adolescents. UBCs are more aggressive in the first decade of life and correspondingly the recurrence rate for these patients is four times that for adolescents. The proximal humerus and femur account for almost 90% of these cases. UBCs are classified as active when they are within 1 cm of the physis and latent as they progress to a diaphyseal location. Differential diagnoses for UBC include aneurysmal bone cyst, fibrous dysplasia, enchondroma, and intraosseous ganglia. By the time of skeletal maturity most UBCs tend to resolve. Nonoperative treatment may be a viable option for many patients with small or symptomatic lesions. Interventions include steroid injection, open curettage and bone grafting, decompression and percutaneous injection of marrow or graft substitutes.