Prediction Models for Adverse Drug Reactions During Tuberculosis Treatment in Brazil.

BACKGROUND: Tuberculosis (TB) treatment-related adverse drug reactions (TB-ADRs) can negatively affect adherence and treatment success rates. METHODS: We developed prediction models for TB-ADRs, considering participants with drug-susceptible pulmonary TB who initiated standard TB therapy. TB-ADRs were determined by the physician attending the participant, assessing causality to TB drugs, the affected organ system, and grade. Potential baseline predictors of TB-ADR included concomitant medication (CM) use, human immunodeficiency virus (HIV) status, glycated hemoglobin (HbA1c), age, body mass index (BMI), sex, substance use, and TB drug metabolism variables (NAT2 acetylator profiles). The models were developed through bootstrapped backward selection. Cox regression was used to evaluate TB-ADR risk. RESULTS: There were 156 TB-ADRs among 102 of the 945 (11%) participants included. Most TB-ADRs were hepatic (n = 82 [53%]), of moderate severity (grade 2; n = 121 [78%]), and occurred in NAT2 slow acetylators (n = 62 [61%]). The main prediction model included CM use, HbA1c, alcohol use, HIV seropositivity, BMI, and age, with robust performance (c-statistic = 0.79 [95% confidence interval {CI}, .74-.83) and fit (optimism-corrected slope and intercept of -0.09 and 0.94, respectively). An alternative model replacing BMI with NAT2 had similar performance. HIV seropositivity (hazard ratio [HR], 2.68 [95% CI, 1.75-4.09]) and CM use (HR, 5.26 [95% CI, 2.63-10.52]) increased TB-ADR risk. CONCLUSIONS: The models, with clinical variables and with NAT2, were highly predictive of TB-ADRs.

Tuberculosis Treatment Outcomes in Brazil: Different Predictors for Each Type of Unsuccessful Outcome.

BACKGROUND: Successful tuberculosis (TB) treatment is necessary for disease control. The World Health Organization (WHO) has a target TB treatment success rate of ≥90%. We assessed whether the different types of unfavorable TB treatment outcome had different predictors. METHODS: Using data from Regional Prospective Observational Research for Tuberculosis-Brazil, we evaluated biological and behavioral factors associated with each component of unsuccessful TB outcomes, recently updated by WHO (death, loss to follow-up [LTFU], and treatment failure). We included culture-confirmed, drug-susceptible, pulmonary TB participants receiving standard treatment in 2015-2019. Multinomial logistic regression models with inverse probability weighting were used to evaluate the distinct determinants of each unsuccessful outcome. RESULTS: Of 915 participants included, 727 (79%) were successfully treated, 118 (13%) were LTFU, 44 (5%) had treatment failure, and 26 (3%) died. LTFU was associated with current drug-use (adjusted odds ratio [aOR] = 5.3; 95% confidence interval [CI], 3.0-9.4), current tobacco use (aOR = 2.9; 95% CI, 1.7-4.9), and being a person with HIV (PWH) (aOR = 2.0; 95% CI, 1.1-3.5). Treatment failure was associated with PWH (aOR = 2.7; 95% CI, 1.2-6.2) and having diabetes (aOR = 2.2; 95% CI, 1.1-4.4). Death was associated with anemia (aOR = 5.3; 95% CI, 1.4-19.7), diabetes (aOR = 3.1; 95% CI, 1.4-6.7), and PWH (aOR = 3.9; 95% CI, 1.3-11.4). Direct observed therapy was protective for treatment failure (aOR = 0.5; 95% CI, .3-.9) and death (aOR = 0.5; 95% CI, .2-1.0). CONCLUSIONS: The treatment success rate was below the WHO target. Behavioral factors were most associated with LTFU, whereas clinical comorbidities were correlated with treatment failure and death. Because determinants of unsuccessful outcomes are distinct, different intervention strategies may be needed to improve TB outcomes.

A Clinical Prediction Model for Unsuccessful Pulmonary Tuberculosis Treatment Outcomes.

BACKGROUND: Despite widespread availability of curative therapy, tuberculosis (TB) treatment outcomes remain suboptimal. Clinical prediction models can inform treatment strategies to improve outcomes. Using baseline clinical data, we developed a prediction model for unsuccessful TB treatment outcome and evaluated the incremental value of human immunodeficiency virus (HIV)-related severity and isoniazid acetylator status. METHODS: Data originated from the Regional Prospective Observational Research for Tuberculosis Brazil cohort, which enrolled newly diagnosed TB patients in Brazil from 2015 through 2019. This analysis included participants with culture-confirmed, drug-susceptible pulmonary TB who started first-line anti-TB therapy and had ≥12 months of follow-up. The end point was unsuccessful TB treatment: composite of death, treatment failure, regimen switch, incomplete treatment, or not evaluated. Missing predictors were imputed. Predictors were chosen via bootstrapped backward selection. Discrimination and calibration were evaluated with c-statistics and calibration plots, respectively. Bootstrap internal validation estimated overfitting, and a shrinkage factor was applied to improve out-of-sample prediction. Incremental value was evaluated with likelihood ratio-based measures. RESULTS: Of 944 participants, 191 (20%) had unsuccessful treatment outcomes. The final model included 7 baseline predictors: hemoglobin, HIV infection, drug use, diabetes, age, education, and tobacco use. The model demonstrated good discrimination (c-statistic = 0.77; 95% confidence interval, .73-.80) and was well calibrated (optimism-corrected intercept and slope, -0.12 and 0.89, respectively). HIV-related factors and isoniazid acetylation status did not improve prediction of the final model. CONCLUSIONS: Using information readily available at treatment initiation, the prediction model performed well in this population. The findings may guide future work to allocate resources or inform targeted interventions for high-risk patients.

The effect of previous SARS-CoV-2 infection on systemic immune responses in individuals with tuberculosis.

Background: The impact of previous SARS-CoV-2 infection on the systemic immune response during tuberculosis (TB) disease has not been explored. Methods: An observational, cross-sectional cohort was established to evaluate the systemic immune response in persons with pulmonary tuberculosis with or without previous SARS-CoV-2 infection. Those participants were recruited in an outpatient referral clinic in Rio de Janeiro, Brazil. TB was defined as a positive Xpert-MTB/RIF Ultra and/or a positive culture of Mycobacterium tuberculosis from sputum. Stored plasma was used to perform specific serology to identify previous SARS-CoV-2 infection (TB/Prex-SCoV-2 group) and confirm the non- infection of the tuberculosis group (TB group). Plasmatic cytokine/chemokine/growth factor profiling was performed using Luminex technology. Tuberculosis severity was assessed by clinical and laboratory parameters. Participants from TB group (4.55%) and TB/Prex-SCoV-2 (0.00%) received the complete COVID-19 vaccination. Results: Among 35 participants with pulmonary TB, 22 were classified as TB/Prex-SCoV-2. The parameters associated with TB severity, together with hematologic and biochemical data were similar between the TB and TB/Prex-SCoV-2 groups. Among the signs and symptoms, fever and dyspnea were significantly more frequent in the TB group than the TB/Prex-SCoV-2 group (p < 0,05). A signature based on lower amount of plasma EGF, G-CSF, GM-CSF, IFN-α2, IL-12(p70), IL-13, IL-15, IL-17, IL-1ß, IL-5, IL-7, and TNF-ß was observed in the TB/Prex-SCoV-2 group. In contrast, MIP-1ß was significantly higher in the TB/Prex-SCoV-2 group than the TB group. Conclusion: TB patients previously infected with SARS-CoV-2 had an immunomodulation that was associated with lower plasma concentrations of soluble factors associated with systemic inflammation. This signature was associated with a lower frequency of symptoms such as fever and dyspnea but did not reflect significant differences in TB severity parameters observed at baseline.

Systematic review of prediction models for pulmonary tuberculosis treatment outcomes in adults.

OBJECTIVE: To systematically review and critically evaluate prediction models developed to predict tuberculosis (TB) treatment outcomes among adults with pulmonary TB. DESIGN: Systematic review. DATA SOURCES: PubMed, Embase, Web of Science and Google Scholar were searched for studies published from 1 January 1995 to 9 January 2020. STUDY SELECTION AND DATA EXTRACTION: Studies that developed a model to predict pulmonary TB treatment outcomes were included. Study screening, data extraction and quality assessment were conducted independently by two reviewers. Study quality was evaluated using the Prediction model Risk Of Bias Assessment Tool. Data were synthesised with narrative review and in tables and figures. RESULTS: 14 739 articles were identified, 536 underwent full-text review and 33 studies presenting 37 prediction models were included. Model outcomes included death (n=16, 43%), treatment failure (n=6, 16%), default (n=6, 16%) or a composite outcome (n=9, 25%). Most models (n=30, 81%) measured discrimination (median c-statistic=0.75; IQR: 0.68-0.84), and 17 (46%) reported calibration, often the Hosmer-Lemeshow test (n=13). Nineteen (51%) models were internally validated, and six (16%) were externally validated. Eighteen (54%) studies mentioned missing data, and of those, half (n=9) used complete case analysis. The most common predictors included age, sex, extrapulmonary TB, body mass index, chest X-ray results, previous TB and HIV. Risk of bias varied across studies, but all studies had high risk of bias in their analysis. CONCLUSIONS: TB outcome prediction models are heterogeneous with disparate outcome definitions, predictors and methodology. We do not recommend applying any in clinical settings without external validation, and encourage future researchers adhere to guidelines for developing and reporting of prediction models. TRIAL REGISTRATION: The study was registered on the international prospective register of systematic reviews PROSPERO (CRD42020155782).

Cutaneous mucormycosis in advanced HIV disease.

Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease.

Dengue infection as a potential trigger of an imported Plasmodium ovale malaria relapse or a long incubation period in a non-endemic malaria region.

OBJECTIVES: To report that dengue fever (DF) could have triggered Plasmodium ovale wallikeri malaria. METHODS: A retrospective case report of P. ovale malaria and DF in a single patient in Rio de Janeiro, Brazil, who had lived in Angola, is presented. RESULTS: On the second week of illness, the patient was referred to our research service. As symptoms had persisted up to day 14, malaria was also considered, based on the patient's long-standing epidemiological history. On day 16 of illness, a thick blood smear was positive for P. ovale (3480 parasites/mm(3)), PCR for malaria was positive for P. ovale wallikeri, and the kinetics of dengue virus (DENV) antibodies suggested a recent primary dengue infection. CONCLUSIONS: Concurrent infections of DENV and malaria have rarely been reported; the actual impact of these sequential or simultaneous infections remains unknown. Therefore, DF must be considered as a potential co-morbidity for malaria, because of its influence on fluid electrolyte management. The case presented showed consistent temporal, clinical, and laboratory evidence that the relapse or the long incubation period of P. ovale malaria may have been triggered by a recent DF episode. To the authors' knowledge, this is the first report of DENV and P. ovale co-infection.

Cutaneous mucormycosis in advanced HIV disease

ABSTRACT Angionvasive mucormycosis is an emerging fungal disease known to affect mainly diabetics or subjects with profound neutropenia. Infection usually occurs through the inhalation route, but cutaneous inoculation may occur after trauma or burns. However, mucormycosis remains unusual in HIV infection. We report a fatal case of cutaneous mucormycosis due to Rhizopus arrhizus involving the scalp following herpes zoster infection. The patient was a 42-year-old man with advanced AIDS failing on salvage antiretroviral therapy. The fungus was diagnosed on the basis of histopathology and culture. Our case emphasizes the need to consider mucormycosis in the differential diagnosis of necrotic cutaneous lesions in patients with late-stage HIV disease.

Efetividade dos esquemas anti-tuberculose que substituem a rifampicina ou isoniazida por aminoglicosídeo ou quinolona

Um regime de primeira linha ou regime padrão (RP) em uma combinação de dose fixa com quatro drogas (isoniazida, rifampicina, pirazinamida e etambutol) é recomendado para o tratamento da tuberculose. A toxicidade, a resistência e as interações medicamentosas podem levar a modificações desse regime padrão. Alternativas medicamentosas comuns nessas situações são aminoglicosídeos (A) e/ou quinolonas (Q). Avaliamos a eficácia de regimes não-padrão (RnP) em comparação com o RP no tratamento da tuberculose. Este estudo de coorte incluiu participantes com idade \2265 18 anos, com TB confirmada, incluídos previamente em uma coorte prospectiva entre janeiro de 2004 e dezembro de 2016. Casos de TB multirresistentes foram excluídos. Comparamos as características basais, a duração do tratamento e as proporções de cura entre os participantes que receberam RP ou RnP \2013 este último subdividido em regimes contendo A e/ou Q que substituíram os medicamentos padrão permanentemente (por A, Q, A+Q) e regimes que usavam A e/ou Q, mas retornaram aos medicamentos padrão (definidos como subgrupo \201Coutros RnP"). Foram incluídos 258 participantes que receberam RP e 92 que receberam RnP. A TB pulmonar foi a forma clínica mais comum em todos os grupos, exceto em A+Q. O HIV e a TB prévia foram associados à substituição do RP (p <0,001 em ambos). A duração do tratamento foi maior nos RnP do que no RP - mediana dos dias 365,5 (IQR: 200-400) e 192 (174-267), respectivamente Entre os RnP, 20% usaram A, 40% Q, 24% A+Q e 16% usaram outros RnP. O RP foi substituído principalmente por toxicidade. As proporções de cura foram semelhantes entre RP e RnP: 80% e 77%, respectivamente (p=0,53). Entre os RnP, o subgrupo \201Coutros RnP\201D apresentou a maior proporção de cura, enquanto o subgrupo A+Q teve a menor proporção de cura. Potenciais confundidores não foram avaliados. Os regimes não padrão tiveram proporções de cura semelhantes ao regime padrão, exceto o subgrupo que usou o RnP A + Q, que teve proporções de cura mais baixas. Os resultados reforçam ainda a necessidade de tratamentos de TB mais bem tolerados.

Contribuição da imuno-histoquímica no diagnóstico do câncer de próstata / Immunohistochemistry contribution to the diagnosis of prostate cancer

INTRODUCTION: Efforts for the identification of prostate cancer in the initial clinical and pathological stages led to an increase in the number of biopsies, sometimes making the histological diagnosis of adenocarcinoma difficult. This is due to the presence of minimal carcinoma or atypical glands suspicious for carcinoma, also known as atypical small acinar proliferation (ASAP). In these cases, the use of immunohistochemistry (IHC) has become a common practice in laboratories of pathology. OBJECTIVES: The aims of this study were to assess the incidence of diagnoses of ASAP and minimal adenocarcinoma in two laboratories of pathology and to evaluate the contribution of IHC and repeat biopsy to the diagnosis of prostate cancer. METHODS: We reviewed 641 sets of modified sextant needle biopsies of the prostate performed in two laboratories of pathology between January 2005 and December 2010. IHC using 34âE12 and p63 antibodies was performed on 35 of 73 (11.38%) cases diagnosed as ASAP and on 7 (1.1%) cases diagnosed as minimal adenocarcinoma. RESULTS: The incidence of ASAP diagnosis was 11.38% (n = 73). IHC was performed in 35 of the 73 ASAP cases and provided conclusive results in 31 cases (88.57%), resulting in a final diagnosis of adenocarcinoma in 19 patients (54.28%), benign lesions in 12 patients (34 28%); only 4 (11.42%) were inconclusive. CONCLUSION: The results suggest that IHC should be routinely used in evaluation of borderline biopsies and in ASAP cases. IHC strongly contributes to the diagnosis of prostate cancer.

INTRODUÇÃO: Os esforços de detecção precoce do câncer de próstata, identificados em fases clínicas e patológicas iniciais, levou ao aumento no número de biópsias e, por vezes, indefinição do diagnóstico histológico de adenocarcinoma devido à presença de carcinomas mínimos ou alterações pseudoneoplásicas, como proliferação atípica de pequenos ácinos (PAPA). Nesses casos, o uso da imuno-histoquímica (IMH) para evidenciar a presença de células basais tornou-se uma prática comum em laboratórios de patologia. OBJETIVOS: O presente estudo visa a avaliar a incidência de PAPA e de adenocarcinoma mínimo em dois laboratórios de patologia do interior, bem como avaliar a contribuição da IMH e da rebiópsia no diagnóstico do câncer de próstata. MÉTODOS: Foram revistas 641 biópsias de próstata por agulha realizadas entre janeiro de 2005 e dezembro de 2010. Dos 73 casos diagnosticados como PAPA (11,38%), 35 foram submetidos ao exame imuno-histoquímico, usando anticorpos anti-34ßE12 e p63, assim como sete casos diagnosticados como adenocarcinoma mínimo (1,1%). Resultados: Os resultados mostraram que a técnica foi conclusiva em 31 casos (88,57%), com diagnóstico final de adenocarcinoma em 19 pacientes (54,28%); 12 (34,28%) com lesões benignas; e apenas quatro (11,42%) inconclusivos (PAPA). CONCLUSÃO: Os resultados sugerem que IMH deve ser rotineiramente usada em biópsias limítrofes e casos de PAPA, pois contribui significativamente para o diagnóstico de câncer de próstata.