Legionnaires’ disease was first detected in 1976 when an outbreak occurred in Philadelphia, USA. The number of cases reported to the Centre for Disease Control (CDC) has been on the rise since 2000, ...likely due to expanded diagnostic testing and public awareness of symptoms. There was a notable decline of confirmed cases during the first years of the COVID-19 pandemic. Surveillance is important to understand the transmission, pathogenesis, and complications, and to quickly identify the outbreaks, new cases and epidemiologic links between cases. The EPIWATCH system scans vast amounts of open-source data to supplement surveillance when there is a lack of available case data. EPIWATCH reported approximately 28 cases during September to December 2020, 349 cases in 2021 and 114 cases during January to October 2022, which is a decrease in case numbers, possibly due to underreporting during the ongoing COVID-19 pandemic. Annual case numbers may be 1.8 to 2.7 times higher than reported, due to potential underdiagnosis and the requirement for confirmation of infection source before a diagnosis can be made. Key words: Legionella; Legionnaires' disease; outbreak, USA
Background
Shortening tuberculosis (TB) treatment duration is a research priority. We tested the efficacy and safety of 3‐ and 4‐month regimens containing moxifloxacin in a randomised clinical trial ...in pulmonary TB (PTB) patients in South India.
Methods
New, sputum‐positive, adult, HIV‐negative, non‐diabetic PTB patients were randomised to 3‐ or 4‐month moxifloxacin regimens moxifloxacin (M), isoniazid (H), rifampicin (R), pyrazinamide (Z) and ethambutol (E) or to a control regimen (2H3R3Z3E3/4R3H3) C. The 4 test regimens were 3R7H7Z7E7M7 M3, 2R7H7Z7E7M7/2R7H7M7 M4, 2R7H7Z7E7M7/2R3H3M3 M4‐I or 2R7H7Z7E7M7/2R3H3E3M3 M4‐IE. Treatment was directly observed. Clinical and bacteriological assessments were done monthly during treatment and for 24 months post‐treatment. The primary end point was TB recurrence post‐treatment.
Results
Of 1371 patients, randomised, modified intention‐to‐treat (ITT) analysis was done in 1329 and per‐protocol (PP) analysis in 1223 patients. Regimen M3 was terminated due to high TB recurrence rates. ‘Favourable’ response at end of treatment was 96–100% in the moxifloxacin regimens and 93% in the control regimen. Among these, the TB recurrence occurred in 4.1% in the M4 regimen and in 4.5% in the control regimen and demonstrated equivalence within a 5% margin (95% CI −3.68, 4.55). Similar findings were observed in modified ITT analysis. The TB recurrence rates in the M4‐I and M4‐IE regimens did not show equivalence with the control regimen. Sixteen (1.4%) of 1087 patients in the moxifloxacin regimens required treatment modification.
Conclusion
The 4‐month daily moxifloxacin regimen M4 was found to be equivalent and as safe as the 6‐month thrice‐weekly control regimen.
Contexte
La réduction de la durée du traitement de la tuberculose (TB) est une priorité de recherche. Nous avons testé l'efficacité et la sécurité de schémas thérapeutiques contenant de la moxifloxacine pendant 3 et 4 mois dans un essai clinique randomisé chez des patients atteints de TB pulmonaire (PTB) dans le sud de l’Inde.
Méthodes
De nouveaux patients PTB, adultes, non diabétiques, positifs pour les expectorations, VIH négatifs ont été randomisés pour des schémas thérapeutiques contenant de la moxifloxacine pendant 3 mois ou 4 mois moxifloxacine (M), isoniazide (H), rifampicine (R), pyrazinamide (Z), l'éthambutol (E) ou pour un régime témoin (2H3R3Z3E3/4R3H3) C. Les 4 régimes de l’essai étaient 3R7H7Z7E7M7 M3, 2R7H7Z7E7M7/2R7H7M7 M4, 2R7H7Z7E7M7/2R3H3M3 M4‐I ou 2R7H7Z7E7M7/2R3H3E3M3 M4‐IE. Le traitement a été directement observé. Les évaluations cliniques et bactériologiques ont été effectuées mensuellement au cours du traitement et durant 24 mois après le traitement. Le critère d'évaluation principal était la récidive de la TB après le traitement.
Résultats
Des 1.371 patients randomisés, une analyse en intention de traiter (ITT) modifiée a été effectuée sur 1.329 et une analyse par protocole (PP) sur 1.223 patients. Le régime M3 a été interrompu en raison de taux élevés de récidive de la TB. La réponse «favorable» à la fin du traitement était de 96 à 100% dans les bras moxifloxacine et 93% dans le bras témoin. Parmi ceux‐ci, la récidive de la TB est survenue chez 4,1% dans le schéma M4 et chez 4,5% dans le schéma témoin et a démontré une équivalence dans une marge de 5% (IC95%: −3,68, 4,55). Des résultats similaires ont été observés dans l'analyse ITT modifiée. Les taux de récidive de la TB dans les schémas M4‐I et M4‐IE n'ont pas montré d'équivalence avec le schéma témoin. 16 (1,4%) des 1.087 patients dans les régimes à moxifloxacine ont nécessité une modification du traitement.
Conclusion
Le régime quotidien de moxifloxacine pendant 4 mois M4 s'est avéré équivalent et aussi sûr que le régime témoin de trois fois par semaine pendant 6 mois.
We evaluated the relationship between the pharmacokinetic parameters of linezolid (LZD) and development of adverse drug reactions (ADRs) in patients with pulmonary drug-resistant tuberculosis. A ...prospective cohort of adults with pulmonary multidrug-resistant tuberculosis with additional resistance to fluoroquinolone (MDR-TB
) received treatment with bedaquiline, delamanid, clofazimine, and LZD. Blood samples were collected during weeks 8 and 16 at eight time points over 24 h. The pharmacokinetic parameters of LZD were measured using high-performance liquid chromatography and associated with ADRs. Of the 165 MDR-TB
patients on treatment, 78 patients developed LZD-associated anemia and 69 developed peripheral neuropathy. Twenty-three patients underwent intense pharmacokinetic testing. Plasma median trough concentration was 2.08 µg/mL and 3.41 µg/mL, (normal <2 µg/mL) and AUC
was 184.5 µg/h/mL and 240.5 µg/h/mL at weeks 8 and 16, respectively, showing a linear relationship between duration of intake and plasma levels. Nineteen patients showed LZD-associated ADRs-nine at week 8, twelve at week 16, and two at both weeks 8 and 16. Thirteen of the nineteen had high plasma trough and peak concentrations of LZD. A strong association between LZD-associated ADRs and plasma LZD levels was noted. Trough concentration alone or combinations of trough with peak levels are potential targets for therapeutic drug monitoring.
Tuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated ...the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients. New, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment. Of the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1-97.8) and 94.5% (95% CI: 90.8-98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction. The 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
India is replacing culture and drug sensitivity testing (CDST) with rapid molecular tests for diagnosing MDR-TB. We assessed the impact of rapid tests on time to initiation of treatment ...and outcomes in patients with MDR-TB compared with CDST.
Methods
A retrospective cohort study involving MDR-TB patients from six districts in Tamil Nadu state, who underwent CDST (2010–2011) and rapid tests (2012–2013).
Results
There were 135 patients in the CDST group and 389 in the rapid diagnostic test group. Median time from sputum receipt at the laboratory to initiation of MDR-TB treatment was 130 days (IQR 75–213) in the CDST group and 22 days (IQR 14–38) in the rapid diagnostic test group (p<0.001). Overall treatment success was 30% with CDST and 41% with rapid tests (p<0.05), but there was high loss to follow-up >30% in both groups and missing data were higher in CDST (13%) compared with rapid tests (3%). There were significantly higher risks of unfavourable treatment outcomes in males (aRR 1.3, 95% CI 1.1–1.5) and those with treatment initiation delays >30 days (aRR 1.3, 95% CI 1.0–1.6).
Conclusion
Rapid molecular diagnostic tests shortened the time to initiate treatment which was associated with reduced unfavourable outcomes in MDR-TB patients. This supports the policy to scale up these tests in India.
Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an inflammatory phenomenon complicating HIV management in coincidental tuberculosis (TB) infection, upon ...immune reconstitution driven by antiretroviral therapy (ART). Leukotriene A4 hydroxylase (LTA4H), an enzyme which converts LTA4 to LTB4, regulates the balance between the anti-inflammatory lipoxins and pro-inflammatory LTB4, with direct implications in TB-driven inflammation. In humans, a single nucleotide polymorphism (SNP) in the LTA4H promoter which regulates its transcriptional activity (rs17525495) has been identified and described to impact clinical severity of TB presentation and response to corticosteroid therapy. Notably, the role of LTA4H on TB-IRIS has not been previously evaluated. Here, we performed an exploratory investigation testing the association of LTA4H polymorphism with respect to frequency of TB-IRIS occurrence and severity of TB-IRIS presentation in HIV-TB co-infected individuals.
Genotypic evaluation of the LTA4H enzyme from available samples was retrospectively correlated with clinical data captured in case sheets including IRIS details. The cohort included patients recruited from a prospective cohort study nested within a randomized clinical trial (NCT0933790) of ART-naïve HIV+ patients with newly diagnosed rifampicin sensitive pulmonary TB in South India. Frequency of the wild type genotype (CC), as well as of the mutant genotypes (CT or TT) in the IRIS and non-IRIS patients was estimated. Comparative analyses were performed between wild genotype (CC) and the mutant genotypes (CT or TT) and tested for association between the LTA4H polymorphisms and IRIS incidence and clinical severity.
A total of 142 eligible ART-naïve patients were included in the analyses. Eighty-six individuals exhibited the wild genotype (CC) while 56 had mutant genotypes (43-CT and only 13-TT). Variant allele frequency was 0.23 and 0.26 in non-IRIS group and in IRIS group, respectively. Upon ART initiation, 51 patients developed IRIS while 91 did not. IRIS incidence was 34% and 37% in the wild (CC) and mutant type (CT/TT), respectively (p = 0.858) with a higher frequency of severe IRIS presentation in the mutant genotype group compared to the wild type genotype (p = 0.0006). A logistic regression model confirmed the association between the presence of CT/TT genotypes and occurrence of severe IRIS. Corticosteroid therapy successfully resolved IRIS in all cases irrespective of the LTA4H genotype.
A higher incidence of severe IRIS among patients with mutant LTA4H genotypes (CT and TT) was observed compared to the wild type, despite similar IRIS incidence and immune restoration in both groups. Steroids were effective in alleviating IRIS in all the genotypes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metformin (MET), by boosting immunity, has been suggested as a host-adjunctive therapy to anti-tuberculosis treatment (ATT).
We evaluated whether adding MET to the standard ATT can alter the host ...chemokine response. We investigated the influence of metformin on the plasma levels of a wide panel of chemokines in a group of active tuberculosis patients before treatment, at 2nd month of ATT and at 6-months of ATT as part of our clinical study to examine the effect of metformin on ATT.
Our results demonstrated that addition of metformin resulted in diminished CC (CCL1 and CCL3) and CXC (CXCL-2 and CXCL-10) chemokines in MET arm as compared to non-MET arm at the 2nd month and 6th month of ATT. In addition to this, MET arm showed significantly diminished chemokines in individuals with high bacterial burden and cavitary disease.
Our current data suggest that metformin alters chemokines responses that could potentially curb excessive inflammation during ATT.
•Metformin changes chemokine responses in TB treatment, possibly reducing overly inflammatory reactions.•Metformin effectively modulates and balances inflammation during active TB disease.•Metformin effectively balances inflammation and host responses to M.tb.
Children exposed to antiretroviral therapy (ART) are at risk of developing metabolic complications. The association between gene polymorphisms and the development of dyslipidemia in children post ART ...initiation was studied. Children initiating first-line ART were followed for 2 years at the National Institute for Research in Tuberculosis (Chennai, India), and St. John's Medical College Hospital (Bangalore, India). Clinical examination and fasting serum lipid profiles were measured every 6 months. Participants were genotyped for the polymorphisms in the APOC3 gene (rs2854116; rs2854117, and rs5128). Changes in lipid levels from baseline to months 6, 12, and 24, and the difference between the various genotype variants were analyzed using a modified analysis of variance test. Study enrolled 393 ART-naive HIV-infected children (mean age: 7.6 ± 3 years, mean weight: 18 ± 6) of whom 289 (75%) were started on nevirapine (NVP)-based ART and the remaining 96 (25%) were started on efavirenz-based ART. Only children carrying the GG allele of rs5128 genotype showed a decrease in CD4% and serum triglycerides pre-ART. An increasing trend of total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol were seen at 6 months in both EFZ and NVP groups, which subsequently stabilized by 12 months irrespective of genotype variants. Genotype variants of APOC3 (rs2854116 and rs2854117 polymorphism) did not show significant changes in serum lipid levels after 24 months of ART, whereas rs5128 polymorphism with "G" allele showed an association with HDL-c levels when on NVP-based ART. Our results suggest that ART plays a major role in normalizing lipid levels in HIV-infected children and APOC3 polymorphisms may not play a significant role in ART-induced dyslipidemia.
HIV-1
gene sequences were analyzed from 77 HIV-1 positive children infected perinatally and exhibiting virological failure (VF). Viral subtyping, phylogenetic analysis, and genotypic drug resistance ...analysis were carried out on samples collected before start of anti retroviral treatment (ART) (baseline, BL), and at 12 months post-ART initiation (M12). Subtype C was found to be most predominant, seen in 75 of the 77 (97.4%) children. The level of pretreatment drug resistance (PDR) was 14% among these children. At BL, K103N (5), E138A/G (4), and M184V (3) were the most common mutations. At M12 the prevalence of any resistance-associated mutation (RAM) (acquired drug resistance/ADR) was 81.8% (63/77). Dual class resistance mutations were seen in 64% (49/77) of children. M184V/I, K103N/S, and Y181C were the most commonly occurring mutations, seen in 76%, 51%, and 36% children. RAMs to the second-generation non-nucleoside reverse transcriptase inhibitors (NNRTI), etravirine (ETR) and rilpivirine (RPV), were seen in 40.2% (31/77) and 48.05% (37/77) of the children, respectively. Our findings reveal similar prevalence rates of PDR and ADR in children with VF as reported in other studies. Occurrence of ETR and RPV resistance associated mutations (RAMs) is of concern and highlights the need for timely switch of regimens guided by genotypic resistance testing in perinatally infected children from India.
IMPORTANCE: The benefit of daily over thrice-weekly antituberculosis therapy among HIV-positive patients with pulmonary tuberculosis (TB) who are receiving antiretroviral therapy remains unproven. ...OBJECTIVE: To compare the efficacy and safety of daily, part-daily, and intermittent antituberculosis therapy regimens in the treatment of HIV-associated pulmonary TB. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized clinical trial was conducted by the National Institute for Research in Tuberculosis, south India. Adults infected with HIV with newly diagnosed, culture-positive, pulmonary TB were enrolled between September 14, 2009, and January 18, 2016. INTERVENTIONS: Patients were randomized to daily, part-daily, and intermittent antituberculosis therapy regimens, stratified by baseline CD4 lymphocyte count and sputum smear grade. Antiretroviral therapy was initiated as per national guidelines. Clinical and sputum microbiological examinations of patients were performed monthly until 18 months after randomization. Adverse events were recorded using standard criteria. MAIN OUTCOMES AND MEASURES: The primary outcome was favorable response, defined as treatment completion with all available sputum cultures negative for Mycobacterium tuberculosis during the last 2 months of treatment. Unfavorable responses included treatment failures, dropouts, deaths, and toxic effects among regimens. RESULTS: Of 331 patients (251 76% male; mean SD age, 39 9 years; mean SD HIV viral load, 4.9 1.2 log10 copies/mL; and median interquartile range CD4 lymphocyte count, 138 69-248 cells/μL), favorable responses were experienced by 91% (89 of 98), 80% (77 of 96), and 77% (75 of 98) in the daily, part-daily, and intermittent regimens, respectively. With the difference in outcome between daily and intermittent regimens crossing the O’Brien-Fleming group sequential boundaries and acquired rifampicin resistance emergence (n = 4) confined to the intermittent group, the data safety monitoring committee halted the study. A total of 18 patients died and 18 patients dropped out during the treatment period in the 3 regimens. Six, 4, and 6 patients in the daily, part-daily, and intermittent regimens, respectively, had TB recurrence. CONCLUSIONS AND RELEVANCE: Among HIV-positive patients with pulmonary TB receiving antiretroviral therapy, a daily anti-TB regimen proved superior to a thrice-weekly regimen in terms of efficacy and emergence of rifampicin resistance. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00933790
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