Confronting the multidimensional challenges of research in the context of emerging infectious diseases in Brazil: The example of yellow fever

In the most recent Brazilian yellow fever (YF) outbreak, a group of clinicians and researchers initiated in mid-January 2018 a considerable effort to develop a multicenter randomized controlled clinical trial to evaluate the effect of sofosbuvir on YF viremia and clinical outcomes (Brazilian Clinical Trials Registry: RBR-93dp9n). The approval of this protocol had urgency given the seasonal/short-lived pattern of YF transmission, large number of human cases, and epidemic transmission at the outskirts of a large urban center. However, many intricacies in the research regulatory and ethical submission systems in Brazil were indomitable even under such pressing conditions. By April 2018, we had enrolled 29 patients for a target sample size of 90 participants. Had enrollment been initiated 3 weeks earlier, an additional 31 patients could have been enrolled, reaching the prespecified sample size for the interim analysis. This recent experience highlights the urgent need to improve local preparedness for research in the setting of explosive outbreaks, as has been seen in the last few years in different countries

Should we perform the serum cryptococcal antigen test in people living with HIV hospitalized due to a community-acquired pneumonia episode?

Community-acquired pneumonia (CAP) is a common cause of hospitalization among people living with human immunodeficiency virus (PLWH), particularly those with severe immunosuppression. Pulmonary disease due to cryptococcosis is uncommonly reported and likely under-diagnosed. There is scarce information about cryptococcal antigen (CrAg) prevalence in PLWH with CAP. The objectives of this study were to identify among PLWH who were hospitalized with CAP: (i) the prevalence of serum CrAg positivity, (ii) the proportion with asymptomatic vs. symptomatic cryptococcosis; and (iii) the prevalence of serum CrAg positivity in CD4þ T-cell count <100 cells/mm3.We performed a sub-analysis of a prospective cohort of hospitalized adults enrolled into a randomized clinical trial testing therapy for CAP. We included 202 participants who had serum CrAg testing performed. We found a 3.5% prevalence of serum CrAg-positivity overall, being higher (5.7%) in CD4þ T-cell count <100 cells/mm3. Overall, asymptomatic and symptomatic cryptococcosis were present in 2.0% and 1.5%, respectively. This study identifies a target population for CrAg testing: PLWH hospitalized with diagnosis of CAP, particularly those with CD4þ T-cell count <100 cells/mm3 where the number needed to test was 18 to detect 1 CrAg-positive person. This approach may facilitate the detection of asymptomatic cryptococcal infection and allow a timely diagnosis of symptomatic cryptococcal disease

Efficacy of sofosbuvir as treatment for yellow fever: protocol for a randomised controlled trial in Brazil (SOFFA study)

INTRODUCTION: An ongoing outbreak of yellow fever (YF) has been reported in Brazil with 1261 confirmed cases and 409 deaths since July 2017. To date, there is no specific treatment available for YF. Recently published papers describing in vitro and animal models suggest a potential effect of antiviral drugs (approved for the treatment of hepatitis virus) against flaviviruses, including YF. The primary aim of this study is to analyse the effect of sofosbuvir on viral kinetics and clinical outcomes among patients presenting with YF. This is a multicentre open-label randomised controlled trial with 1:1 individual allocation, stratified by severity and by recruiting centre. METHODS AND ANALYSIS: Adults with suspected or confirmed YF infection and symptoms lasting up to 15 days are screened. Eligible and consenting patients are randomised to receive oral sofosbuvir 400 mg daily for 10 days or to receive standard clinical care. Viral kinetics are measured daily and the reduction in YF plasma viral load from the sample at inclusion to 72 hours after randomisation will be compared between active and control groups. Clinical outcomes include severity meeting criteria for intensive care support, liver transplantation, in-hospital mortality and mortality within 60 days. ETHICS AND DISSEMINATION: Ethics approval was obtained at the participating sites and at the national research ethics committee (CAAE 82673018.6.1001.0068). The trial has been submitted for ethical approval at additional potential recruiting centres. Results of the study will be published in journals and presented at scientific meetings. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (RBR-93dp9n)

Ceftriaxone versus ceftriaxone plus a macrolide for community-acquired pneumonia in hospitalized patients with HIV/AIDS: a randomized controlled trial

OBJECTIVES: To evaluate if treatment with ceftriaxone and a macrolide, improved patient outcome when compared with monotherapy with ceftriaxone, in hospitalized patients with human immunodeficiency virus/acquired immunodeficient syndrome (HIV/AIDS) with community-acquired pneumonia (CAP). METHODS: Adult patients with HIV hospitalized due to suspected CAP were randomized to receive one of two regimens, ceftriaxone plus macrolide or ceftriaxone plus placebo, at a 1:1 proportion (Brazilian Clinical Trials Registry: RBR-8wtq2b). The primary outcome was in-hospital mortality and the secondary outcomes were mortality within 14 days, need for vasoactive drugs, need for mechanical ventilation, time to clinical stability and length of hospitalization. RESULTS: A total of 227 patients were randomized, two were excluded after randomization; 225 patients were analysed (112 receiving ceftriaxone plus placebo and 113 receiving ceftriaxone plus macrolide). The frequency of the primary outcome, in-hospital mortality, was not statistically different between the regimens: 12/112 (11%) patients who received ceftriaxone plus placebo and 17/113 (15%) who received ceftriaxone plus macrolide died during hospitalization (hazard ratio 1.22, 95% CI 0.57-2.59). We did not find differences between the regimens for any of the secondary outcomes, including mortality within 14 days, which occurred in 5/112 (4%) patients with ceftriaxone plus placebo and in 12/113 (11%) patients with ceftriaxone plus macrolide (relative risk 2.38, 95% CI 0.87-6.53) CONCLUSIONS: Among hospitalized patients with HIV/AIDS with CAP, treatment with ceftriaxone and a macrolide did not improve patient outcomes, when compared with ceftriaxone monotherapy

Prospective etiological investigation of community-acquired pulmonary infections in hospitalized people living with HIV

The study of the etiological agents of community-acquired pulmonary infections is important to guide empirical therapy, requires constant updating, and has a substantial impact on the prognosis of patients. The objective of this study is to determine prospectively the etiology of community-acquired pulmonary infections in hospitalized adults living with HIV. Patients were submitted to an extended microbiological investigation that included molecular methods. The microbiological findings were evaluated according to severity of the disease and pneumococcal vaccine status. Two hundred twenty-four patients underwent the extended microbiological investigation of whom 143 (64%) had an etiology determined. Among the 143 patients with a determined etiology, Pneumocystis jirovecii was the main agent, detected in 52 (36%) cases and followed by Mycobacterium tuberculosis accounting for 28 (20%) cases. Streptococcus pneumoniae and Rhinovirus were diagnosed in 22 (15%) cases each and influenza in 15 (10%) cases. Among atypical bacteria, Mycoplasma pneumoniae was responsible for 12 (8%) and Chlamydophila pneumoniae for 7 (5%) cases. Mixed infections occurred in 48 cases (34%). S pneumoniae was associated with higher severity scores and not associated with vaccine status. By using extended diagnostics, a microbiological agent could be determined in the majority of patients living with HIV affected by community-acquired pulmonary infections. Our findings can guide clinicians in the choice of empirical therapy for hospitalized pulmonary disease

Asymptomatic cryptococcal antigen prevalence detected by lateral flow assay in hospitalised HIV-infected patients in São Paulo, Brazil

OBJECTIVE: To determine the prevalence of asymptomatic cryptococcal antigen (CRAG) using lateral flow assay (LFA) in hospitalised HIV-infected patients with CD4 counts <200 cells/ll. METHODS: Hospitalised HIV-infected patients were prospectively recruited at Instituto de Infectologia Emilio Ribas, a tertiary referral hospital to HIV-infected patients serving the S~ao Paulo State, Brazil. All patients were >18 years old without prior cryptococcal meningitis, without clinical suspicion of cryptococcal meningitis, regardless of antiretroviral (ART) status, and with CD4 counts <200 cells/ll. Serum CRAG was tested by LFA in all patients, and whole blood CRAG was tested by LFA in positive cases. RESULTS: We enrolled 163 participants of whom 61% were men. The duration of HIV diagnosis was a median of 8 (range, 1­29) years. 26% were antiretroviral (ART)-na€ive, and 74% were ARTexperienced. The median CD4 cell count was 25 (range, 1­192) cells/ll. Five patients (3.1%; 95%CI, 1.0­7.0%) were asymptomatic CRAG-positive. Positive results cases were cross-verified by performing LFA in whole blood. CONCLUSIONS: 3.1% of HIV-infected inpatients with CD4 <200 cells/ll without symptomatic meningitis had cryptococcal antigenemia in São Paulo, suggesting that routine CRAG screening may be beneficial in similar settings in South America. Our study reveals another targeted population for CRAG screening: hospitalised HIV-infected patients with CD4 <200 cells/ll, regardless of ART status. Whole blood CRAG LFA screening seems to be a simple strategy to prevention of symptomatic meningitis

Vacinação contra papilomavírus humano / Vaccination against human papillomavirus

A infecção pelo papilomavírus humano é comum e produz manifestações diversas. Essa infecção adquire importância para saúde pública, pois tem sido associada a malignidades do trato genital em homens e mulheres. Atualmente, temos disponíveis duas vacinas para prevenção da infecção pelo papilomavírus humano e, consequentemente, de doenças a ele associadas.

Human papillomavirus infection is common and causes different manifestations. This infection is a public health concern because it has been associated with genital tract malignant diseases among men and women. Currently two vaccines are available to prevent the human papillomavirus infection and its associated diseases.

Toxoplasmose gástrica em paciente infectado pelo vírus da imunodeficiência humana. Relato de caso / Gastric toxoplasmosis in patient infected with human immunodeficiency virus. Case report

A toxoplasmose é uma zoonose altamente disseminada. A maio­ria das infecções em imunocompetentes é assintomática. Porém, em pacientes imunodeprimidos, a infecção adquire um curso variável. Em pacientes com contagem de CD4 abaixo de 100 e que foram previamente expostos ao Toxoplasma gondii, pode haver reativação da doença em diversos tecidos. Envolvimento do trato gastrintestinal por Toxoplasma gondii é raramente relatado. Embora os sintomas gastrintestinais sejam comuns entre os pacientes com síndrome da imunodeficiência adquirida, a maioria é causada por infecções entéricas que não o Toxoplasma gondii. O objetivo deste estudo foi relatar um caso raro de toxoplasmose gástrica. Paciente do gênero feminino, 38 anos, com diagnóstico recente de vírus da imunodeficiência humana, iniciou sintomas gástricos inespecíficos como: epigastralgia, náuseas, vômitos e perda ponderal. O diagnóstico definitivo foi fechado com o estudo anatomopatológico da lesão na mucosa gástrica. Foi instituído tratamento para a toxoplasmose com clindamicina, pirimetamina e ácido folínico (devido à mielotoxicidade), com melhora parcial dos sintomas. Embora raro, a toxoplasmose gástrica deve entrar no diagnóstico diferencial de dor epigástrica em pacientes portadores da síndrome da imunodeficiência adquirida com contagem de CD4 baixa. Seu diagnóstico pre­suntivo pode ser dado pelo quadro clínico, mas o diagnóstico definitivo é obtido pela biópsia da lesão...

Toxoplasmosis is a highly disseminated zoonosis. Most infections are asymptomatic in immunocompetent patients. However, in immunocompromised patients, infection acquires a variable course. In patients with CD4 counts lower than 100 and who have been previously exposed to Toxoplasma gondii, there may be reactivation of the disease in various tissues. Involvement of the gastrointestinal tract by Toxoplasma gondii is rarely reported. Although gastrointestinal symptoms are common among patients with acquired immunodeficiency syndrome, most are caused by enteric infections other than Toxoplasma gondii. The aim of this study was to report a rare case of gastric toxoplasmosis. A 38-year-­old female patient, recently diagnosed with immunodeficiency human virus, presented with nonspecific gastric symptoms such as epigastric pain, nausea, vomiting and weight loss. The definitive diagnosis was reached with anatomopathological examination of gastric mucosa damage. She was treated for toxoplasmosis with clindamycin, pyrimethamine and folinic acid (due to myelotoxicity), with partial improvement of symptoms. Although rare, gastric toxoplasmosis should enter the differential diagnosis of epigastric pain in patients with acquired immunodeficiency syndrome with low CD4 count. Its presumptive diagnosis can be made on a clinical basis, but the definitive diagnosis is reached with biopsy...

Vaccination against human papillomavirus.

Human papillomavirus infection is common and causes different manifestations. This infection is a public health concern because it has been associated with genital tract malignant diseases among men and women. Currently two vaccines are available to prevent the human papillomavirus infection and its associated diseases.

Impact of macrolide therapy on mortality of HIV-infected patients with community-acquired pneumonia in a tertiary teaching hospital.

BACKGROUND: Bacterial pneumonia is one of the main causes of morbidity and mortality in patients infected by the human immunodeficiency virus (HIV). The main objective of this study was to evaluate the effect of macrolide therapy in combination with a beta-lactam based empiric regimen for inpatients with community-acquired pneumonia and HIV. METHODS: This is a retrospective cohort study of hospitalized patients. Adult patients who had received treatment with ceftriaxone or ceftriaxone plus clarithromycin were included. RESULTS: 76 patients met the inclusion criteria. Among baseline characteristics analyzed, only respiratory rate showed significant difference: patients who had received clarithromycin were more likely to have a respiratory rate > 30/min than patients who received only ceftriaxone (64% versus 36%, p = 0.03). ICU admission was the only outcome that showed a significant difference, more frequent in the ceftriaxone plus clarithromycin group (45% versus 20%, p = 0.03). CONCLUSIONS: This study does not support the addition of a macrolide to a beta-lactam based regimen in HIV-infected patients. This is probably related to the patients' immunodeficiency status, which impairs the immunomodulatory properties of the macrolides.

Impact of macrolide therapy on mortality of HIV-infected patients with community-acquired pneumonia in a tertiary teaching hospital

BACKGROUND: Bacterial pneumonia is one of the main causes of morbidity and mortality in patients infected by the human immunodeficiency virus (HIV). The main objective of this study was to evaluate the effect of macrolide therapy in combination with a beta-lactam based empiric regimen for inpatients with community-acquired pneumonia and HIV. METHODS: This is a retrospective cohort study of hospitalized patients. Adult patients who had received treatment with ceftriaxone or ceftriaxone plus clarithromycin were included. RESULTS: 76 patients met the inclusion criteria. Among baseline characteristics analyzed, only respiratory rate showed significant difference: patients who had received clarithromycin were more likely to have a respiratory rate > 30/min than patients who received only ceftriaxone (64 percent versus 36 percent, p = 0.03). ICU admission was the only outcome that showed a significant difference, more frequent in the ceftriaxone plus clarithromycin group (45 percent versus 20 percent, p = 0.03). CONCLUSIONS: This study does not support the addition of a macrolide to a beta-lactam based regimen in HIV-infected patients. This is probably related to the patients' immunodeficiency status, which impairs the immunomodulatory properties of the macrolides.

Impacto dos macrolídeos na mortalidade de pacientes com HIV e pneumonia em um hospital terciário de ensino / Impact of macrolide therapy on mortality of patients infected by HIV with comunity-acquired pneumonia in a tertiary teaching hospital

A pneumonia bacteriana é uma das principais causas de morbidade e mortalidade nos pacientes com vírus da imunodeficência humana (HIV). A escolha do tratamento empírico de pneumonia nestes pacientes é um grande desafio, já que a maioria dos estudos e consensos é voltada para imunocompetentes. O objetivo deste estudo é avaliar o efeito da adição do macrolídeo à terapia empírica inicial com betalactâmico em pacientes internados com pneumonia e HIV. Trata-se de um estudo de coorte, retrospectivo, de pacientes hospitalizados com HIV e pneumonia adquirida na comunidade em um hospital terciário de ensino. Foram incluídos pacientes adultos, com diagnóstico de pneumonia adquirida na comunidade e infecção pelo vírus da imunodeficiência humana, que fizeram uso de ceftriaxone ou ceftriaxone e claritromicina nas primeiras 24 horas da admissão. 76 pacientes preencheram os critérios de inclusão. Dentre as características de base investigadas, a única que apresentou diferença estatisticamente significante foi a freqüência respiratória: os pacientes que receberam claritromicina tinham mais chance de ter uma freqüência acima de 30 incursões por minuto do que os pacientes que receberam somente ceftriaxone (64% versus 36%, p=0,03). O desfecho primário pesquisado foi mortalidade durante a internação e os desfechos secundários necessidade de internação em unidade de terapia intensiva (UTI), tempo de total de internação e tempo de internação em UTI. O único que apresentou diferença estatística foi a internação em UTI, mais comum no grupo que recebeu ceftriaxone e claritromicina (45% versus 20%, p=0,03). Este estudo não mostra superioridade do regime de betalactâmico com adição de macrolídeo em relação a monoterapia com betalactâmico para tratamento de pneumonia em pacientes infectados pelo HIV.Este resultado difere do que é demonstrado em estudos que analisam a população em geral. Provavelmente este achado se relaciona com a imunodepressão apresentada por estes pacientes, que impossibilita a ação imunomodulatória dos macrolídeos

Antagonista de opioides para o tratamento do prurido associado à colestase. Relato de caso / Opiate antagonist therapy for the cholestasis pruritus. Case report

JUSTIFICATIVA E OBJETIVOS: Pacientes com lep­tospirose podem desenvolver colestase, levando à queixa de prurido. Existem vários tratamentos propostos para o prurido, porém nenhum deles é satisfatoriamente efetivo. O objetivo deste artigo foi relatar o emprego de um antagonista opioide para o tratamento de prurido associado à 3 colestase em paciente com leptospirose.RELATO DO CASO: Paciente do sexo masculino, 51 anos, apresentou quadro de leptospirose, referindo dentre 11 as principais queixas prurido intenso. A queixa manteve-se até o quarto dia de internação, quando se optou pelaprescrição de um antagonista opioide, levando à remissão completa do quadro. CONCLUSÃO: O sucesso da terapia no caso apresentado soma-se a outros relatos da literatura que demonstram evidências de que os antagonistas opioides são bem tolerados e rêduzem significativamente o prurido associado à colestase.