Autophagy Gene Variant IRGM −261T Contributes to Protection from Tuberculosis Caused by Mycobacterium tuberculosis but Not by M. africanum Strains

The human immunity-related GTPase M (IRGM) has been shown to be critically involved in regulating autophagy as a means of disposing cytosolic cellular structures and of reducing the growth of intracellular pathogens in vitro. This includes Mycobacterium tuberculosis, which is in agreement with findings indicating that M. tuberculosis translocates from the phagolysosome into the cytosol of infected cells, where it becomes exposed to autophagy. To test whether IRGM plays a role in human infection, we studied IRGM gene variants in 2010 patients with pulmonary tuberculosis (TB) and 2346 unaffected controls. Mycobacterial clades were classified by spoligotyping, IS6110 fingerprinting and genotyping of the pks1/15 deletion. The IRGM genotype −261TT was negatively associated with TB caused by M. tuberculosis (OR 0.66, CI 0.52–0.84, Pnominal 0.0009, Pcorrected 0.0045) and not with TB caused by M. africanum or M. bovis (OR 0.95, CI 0.70–1.30. P 0.8). Further stratification for mycobacterial clades revealed that the protective effect applied only to M. tuberculosis strains with a damaged pks1/15 gene which is characteristic for the Euro-American (EUAM) subgroup of M. tuberculosis (OR 0.63, CI 0.49–0.81, Pnominal 0.0004, Pcorrected 0.0019). Our results, including those of luciferase reporter gene assays with the IRGM variants −261C and −261T, suggest a role for IRGM and autophagy in protection of humans against natural infection with M. tuberculosis EUAM clades. Moreover, they support in vitro findings indicating that TB lineages capable of producing a distinct mycobacterial phenolic glycolipid that occurs exclusively in strains with an intact pks1/15 gene inhibit innate immune responses in which IRGM contributes to the control of autophagy. Finally, they raise the possibility that the increased frequency of the IRGM −261TT genotype may have contributed to the establishment of M. africanum as a pathogen in the West African population

Variant G57E of Mannose Binding Lectin Associated with Protection against Tuberculosis Caused by Mycobacterium africanum but not by M. tuberculosis

Structural variants of the Mannose Binding Lectin (MBL) cause quantitative and qualitative functional deficiencies, which are associated with various patterns of susceptibility to infectious diseases and other disorders. We determined genetic MBL variants in 2010 Ghanaian patients with pulmonary tuberculosis (TB) and 2346 controls and characterized the mycobacterial isolates of the patients. Assuming a recessive mode of inheritance, we found a protective association between TB and the MBL2 G57E variant (odds ratio 0.60, confidence interval 0.4–0.9, P 0.008) and the corresponding LYQC haplotype (Pcorrected 0.007) which applied, however, only to TB caused by M. africanum but not to TB caused by M. tuberculosis. In vitro, M. africanum isolates bound recombinant human MBL more efficiently than did isolates of M. tuberculosis. We conclude that MBL binding may facilitate the uptake of M. africanum by macrophages, thereby promoting infection and that selection by TB may have favoured the spread of functional MBL deficiencies in regions endemic for M. africanum

Xpert MTB/RIF Ultra and mycobacterial culture in routine clinical practice at a Tertiary Paediatric Hospital

Introduction World Health Organization approved the use of Xpert MTB/RIF Ultra (Ultra) in children due to quick turn-around time, improved yield over smear microscopy, and ability to detect rifampicin resistance despite culture being the “gold standard”. This study reviewed published literature on current childhood tuberculosis diagnostic modalities. It also retrospectively compared demographic, clinical, and radiological features of children with confirmed and unconfirmed PTB, reviewed criteria for microbiologically unconfirmed PTB, and assessed incremental microbiological yield on second and third Ultra and/or mycobacterial culture results in routine clinical care at a tertiary paediatric hospital. Method For the review on childhood TB diagnostic modalities, PubMed was searched using Boolean terms OR/AND between childhood tuberculosis and words such as diagnosis, polymerase chain reaction, molecular, histology, imaging, and cultures. All abstracts were read after which selected articles that met the objectives of the thesis were fully reviewed and referenced appropriately. The retrospective study was conducted in children (0 to 13 years) treated for Pulmonary TB (PTB) between 1 February 2018 and 31 January 2019 and who had at least one respiratory specimen investigated by Ultra and/or mycobacterial culture before TB treatment was commenced. Relevant demographic, clinical information, tuberculin skin test results and laboratory results were abstracted from paper-based medical records and electronic database. Baseline chest radiographic findings were obtained from the radiology digital imaging database. All data was entered anonymously into a Microsoft Excel spreadsheet and exported to R-statistical software for statistical analysis. Descriptive and inferential statistics were used in the analysis. Incremental yield of Ultra and/or mycobacterial cultures on sequential respiratory specimens was determined. Results Ultra is an important diagnostic method for confirming TB in children even though mycobacterial culture, molecular, and histology tests are also available. Other modalities such as imaging and immunologic tests support the diagnosis of microbiologically unconfirmed TB. 174 children with PTB ± EPTB were included in the retrospective study. The median age was 2.5 years. Tuberculosis was microbiologically confirmed in 93 (53.4%). Yield on Ultra in first respiratory specimens was 39.1%. When the results of Ultra and mycobacterial culture on first respiratory specimens were combined, 47.1% (82/174) had microbiologically confirmed TB. Microcytic anaemia and pulmonary pathology were more common in confirmed TB. Of 81 children with microbiologically unconfirmed TB, 31 (38.3%) met a consensus definition of unconfirmed intrathoracic TB formulated by an international expert committee. In the subset of children (n=70) who were screened by Ultra on two sequential respiratory specimens, the incremental yield was 30.3%. When the results of Ultra and mycobacterial culture were combined the incremental yield in children who had 2 sequential respiratory specimens tested was 24.4% and 3.1% on Ultra and mycobacterial culture, respectively. Conclusion Ultra and/or mycobacterial culture on single respiratory specimens resulted in high microbiological yield. Ultra on second sequential respiratory specimens increased microbiological confirmation. The value of additional Ultra and/or mycobacterial culture testing in routine clinical practice requires further study

Evaluating the Contribution of Nocardia spp. and Mycobacterium tuberculosis to Pulmonary Infections among HIV and Non-HIV Patients at the Komfo Anokye Teaching Hospital, Ghana

Tuberculosis (TB) is a major cause of human mortality particularly in association with the human immunodeficiency virus (HIV). Nocardia spp. has emerged as an opportunistic infection especially in HIV patients. The high prevalence of TB and HIV coupled with the lack of a definitive laboratory diagnosis for Nocardia spp. could lead to misdiagnosed pulmonary TB. This study determined the prevalence of pulmonary infections due to Nocardia spp. and Mycobacterium tuberculosis in sputum of HIV and non-HIV patients with suspected pulmonary tuberculosis at KATH. A total of sixty sputum samples were obtained from HIV and non-HIV patients with suspected pulmonary tuberculosis. Samples were examined by fluorescence based Ziehl–Neelsen staining, culture, and PCR methods. The prevalence of Nocardia spp. and Mycobacterium tuberculosis was 18.3% and 20%, respectively, with the latter having the highest rate among patients aged 21–40 years (P=0.075). The prevalence of Nocardia spp. among HIV patients was 90.9% whilst 16.7% of the patients had HIV/Nocardia spp. coinfection. Detection of Mycobacterium tuberculosis by fluorescence-based Ziehl–Neelsen staining, culture, and PCR yielded 9 (15%), 11 (18.3%), and 12 (20%), respectively. There is a high prevalence of nocardiosis especially in HIV patients. PCR is a better diagnostic method that detects both Nocardia spp. and Mycobacterium tuberculosis and should be incorporated into routine diagnosis for pulmonary infections

Pattern of Antimicrobial Susceptibility and Antimicrobial Treatment of Neonates Admitted with Suspected Sepsis in a Teaching Hospital in Ghana, 2021

Neonatal sepsis is a life-threatening emergency, and empirical antimicrobial prescription is common. In this cross-sectional study of neonates admitted with suspected sepsis in a teaching hospital in Ghana from January–December 2021, we described antimicrobial prescription patterns, compliance with national standard treatment guidelines (STG), blood culture testing, antimicrobial resistance patterns and treatment outcomes. Of the 549 neonates admitted with suspected sepsis, 283 (52%) were males. Overall, 529 (96%) received empirical antimicrobials. Most neonates (n = 407, 76.9%) were treated empirically with cefuroxime + gentamicin, while cefotaxime was started as a modified treatment in the majority of neonates (46/68, 67.6%). Only one prescription complied with national STGs. Samples of 257 (47%) neonates underwent blood culture testing, of which 70 (27%) were positive. Isolates were predominantly Gram-positive bacteria, with coagulase-negative Staphylococcus and Staphylococcus aureus accounting for 79% of the isolates. Isolates showed high resistance to most penicillins, while resistance to aminoglycosides and quinolones was relatively low. The majority of neonates (n = 497, 90.5%) were discharged after successfully completing treatment, while 50 (9%) neonates died during treatment. Strengthening of antimicrobial stewardship programmes, periodic review of STGs and increased uptake of culture and sensitivity testing are needed to improve management of sepsis

Effect of Rifampin-Isoniazid-Containing Antituberculosis Therapy on Efavirenz Pharmacokinetics in HIV-Infected Children 3 to 14 Years Old

We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration ( ), concentration at 12 h ( ), , and total area under the curve from time 0 to 24 h (AUC ) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz , , and AUC values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.)

Frailty syndrome and associated factors among patients with hypertension: A cross‐sectional study in Kumasi, Ghana

Abstract Background and Aim Frailty is a condition marked by accumulation of biological deficits and dysfunctions that come with aging and it is correlated with high morbidity and mortality in patients with cardiovascular diseases, particularly hypertension. Hypertension continues to be a leading cause of cardiovascular diseases and premature death globally. However, there is dearth of literature in sub‐Saharan Africa on frailty syndrome among hypertensives on medication. This study evaluated frailty syndrome and its associated factors among Ghanaian hypertensives. Methods This cross‐sectional study recruited 303 patients with hypertension from the University Hospital, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana. Data on sociodemographic, lifestyle and clinical factors were collected using a well‐structured questionnaire. Medication adherence was measured using Adherence in Chronic Disease Scale, and frailty was assessed by Tilburg Frailty Indicator. Statistical analyses were performed using SPSS Version 26.0 and GraphPad prism 8.0. p‐value of < 0.05 and 95% confidence interval (CI) were considered statistically significant. Results The prevalence of frailty was 59.7%. The proportion of high, medium and low medication adherence was 23.4%, 64.4% and 12.2%, respectively. Being ≥ 70years (adjusted odds ratio [aOR]: 8.33, 95% CI [3.72–18.67], p < 0.0001), unmarried (aOR: 2.59, 95% CI [1.37–4.89], p = 0.0030), having confirmed hypertension complications (aOR: 3.21, 95% CI [1.36–7.53], p = 0.0080), medium (aOR: 1.99, 95% CI [1.05–3.82], p = 0.0360) and low antihypertensive drug adherence (aOR: 27.69, 95% CI [7.05–108.69], p < 0.0001) were independent predictors of increased odds of developing frailty syndrome. Conclusion Approximately 6 out of 10 Ghanaian adult patients with hypertension experience frailty syndrome. Hypertension complications, older age, being unmarried, and low antihypertensive drug adherence increased the chances of developing frailty syndrome. These should be considered in intervention programmes to prevent frailty among patients with hypertension