Increased susceptibility to pneumonia due to tumour necrosis factor inhibition and prospective immune system rescue via immunotherapy.

Immunomodulators such as tumour necrosis factor (TNF) inhibitors are used to treat autoimmune conditions by reducing the magnitude of the innate immune response. Dampened innate responses pose an increased risk of new infections by opportunistic pathogens and reactivation of pre-existing latent infections. The alteration in immune response predisposes to increased severity of infections. TNF inhibitors are used to treat autoimmune conditions such as rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, transplant recipients, and inflammatory bowel disease. The efficacies of immunomodulators are shown to be varied, even among those that target the same pathways. Monoclonal antibody-based TNF inhibitors have been shown to induce stronger immunosuppression when compared to their receptor-based counterparts. The variability in activity also translates to differences in risk for infection, moreover, parallel, or sequential use of immunosuppressive drugs and corticosteroids makes it difficult to accurately attribute the risk of infection to a single immunomodulatory drug. Among recipients of TNF inhibitors, Mycobacterium tuberculosis has been shown to be responsible for 12.5-59% of all infections; Pneumocystis jirovecii has been responsible for 20% of all non-viral infections; and Legionella pneumophila infections occur at 13-21 times the rate of the general population. This review will outline the mechanism of immune modulation caused by TNF inhibitors and how they predispose to infection with a focus on Mycobacterium tuberculosis, Legionella pneumophila, and Pneumocystis jirovecii. This review will then explore and evaluate how other immunomodulators and host-directed treatments influence these infections and the severity of the resulting infection to mitigate or treat TNF inhibitor-associated infections alongside antibiotics.

Etiology and the challenge of diagnostic testing of community-acquired pneumonia in children and adolescents.

BACKGROUND: Pneumonia is the leading cause of mortality in pediatric population. The etiology of pneumonia in this population is variable and changes according to age and disease severity and where the study is conducted. Our aim was to determine the etiology of community-acquired pneumonia (CAP) in children aged 1 month to 17 years admitted to 13 Colombian hospitals. METHODS: Prospective cohort study. Hospitalized children with radiologically confirmed CAP and ≤ 15 days of symptoms were included and followed together with a control group. Induced sputum (IS) was submitted for stains and cultures for pyogenic bacteria and Mycobacterium tuberculosis, and multiplex PCR (mPCR) for bacteria and viruses; urinary antigens for pneumococcus and Legionella pneumophila; nasopharyngeal swabs for viruses, and paired serology for atypical bacteria and viruses. Additional cultures were taken at the discretion of primary care pediatricians. RESULTS: Among 525 children with CAP, 71.6% had non-severe pneumonia; 24.8% severe and 3.6% very severe pneumonia, and no fatal cases. At least one microorganism was identified in 84% of children and 61% were of mixed etiology; 72% had at least one respiratory virus, 28% pyogenic bacteria and 21% atypical bacteria. Respiratory syncytial virus, Parainfluenza, Rhinovirus, Influenza, Mycoplasma pneumoniae, Adenovirus and Streptococcus pneumoniae were the most common etiologies of CAP. Respiratory syncytial virus was more frequent in children under 2 years and in severe pneumonia. Tuberculosis was diagnosed in 2.3% of children. IS was the most useful specimen to identify the etiology (33.6%), and blood cultures were positive in 3.6%. The concordance between all available diagnostic tests was low. A high percentage of healthy children were colonized by S. pneumoniae and Haemophilus influenzae, or were infected by Parainfluenza, Rhinovirus, Influenza and Adenovirus. CONCLUSIONS: Respiratory viruses are the most frequent etiology of CAP in children and adolescents, in particular in those under 5 years. This study shows the challenges in making an etiologic diagnosis of CAP in pediatric population because of the poor concordance between tests and the high percentage of multiple microorganisms in healthy children. IS is useful for CAP diagnosis in pediatric population.

Incidence and Risk Factors Associated with Latent Tuberculosis Infection and Pulmonary Tuberculosis among People Deprived of Liberty in Colombian Prisons.

People deprived of liberty (PDL) are at high risk of acquiring Mycobacterium tuberculosis infection (latent tuberculosis infection [LTBI]) and progressing to active tuberculosis (TB). We sought to determine the incidence rates and factors associated with LTBI and active TB in Colombian prisons. Using information of four cohort studies, we included 240 PDL with two-step tuberculin skin test (TST) negative and followed them to evaluate TST conversion, as well as, 2,134 PDL that were investigated to rule out active TB (1,305 among people with lower respiratory symptoms of any duration, and 829 among people without respiratory symptoms and screened for LTBI). Latent tuberculosis infection incidence rate was 2,402.88 cases per 100,000 person-months (95% CI 1,364.62-4,231.10) in PDL with short incarceration at baseline, and 419.66 cases per 100,000 person-months (95% CI 225.80-779.95) in individuals with long incarceration at baseline (who were enrolled for the follow after at least 1 year of incarceration). The TB incidence rate among PDL with lower respiratory symptoms was 146.53 cases/100,000 person-months, and among PDL without respiratory symptoms screened for LTBI the incidence rate was 19.49 cases/100,000 person-months. History of Bacillus Calmette-Guerin vaccination decreased the risk of acquiring LTBI among PDL who were recently incarcerated. Female sex, smoked drugs, and current cigarette smoking were associated with an increased risk of developing active TB. This study shows that PDL have high risk for LTBI and active TB. It is important to perform LTBI testing at admission to prison, as well as regular follow-up to control TB in prisons.

Is It Possible to Differentiate Pneumocystis jirovecii Pneumonia and Colonization in the Immunocompromised Patients with Pneumonia?

Respiratory sample staining is a standard tool used to diagnose Pneumocystis jirovecii pneumonia (PjP). Although molecular tests are more sensitive, their interpretation can be difficult due to the potential of colonization. We aimed to validate a Pneumocystis jirovecii (Pj) real-time PCR (qPCR) assay in bronchoscopic bronchoalveolar lavage (BAL) and oropharyngeal washes (OW). We included 158 immunosuppressed patients with pneumonia, 35 lung cancer patients who underwent BAL, and 20 healthy individuals. We used a SYBR green qPCR assay to look for a 103 bp fragment of the Pj mtLSU rRNA gene in BAL and OW. We calculated the qPCR cut-off as well as the analytical and diagnostic characteristics. The qPCR was positive in 67.8% of BAL samples from the immunocompromised patients. The established cut-off for discriminating between disease and colonization was Ct 24.53 for BAL samples. In the immunosuppressed group, qPCR detected all 25 microscopy-positive PjP cases, plus three additional cases. Pj colonization in the immunocompromised group was 66.2%, while in the cancer group, colonization rates were 48%. qPCR was ineffective at diagnosing PjP in the OW samples. This new qPCR allowed for reliable diagnosis of PjP, and differentiation between PjP disease and colonization in BAL of immunocompromised patients with pneumonia.

Delayed HIV treatment, barriers in access to care and mortality in tuberculosis/HIV co-infected patients in Cali, Colombia / Retraso en el tratamiento para VIH, barreras en el acceso a la atención en salud y mortalidad en personas coinfectadas con tuberculosis y VIH en Cali, Colombia

Abstract Objective: To determine factors associated with mortality in tuberculosis/HIV co-infected patients in Cali, Colombia Methods: This retrospective cohort design included tuberculosis/HIV co-infected persons. Kaplan-Meier and Cox regression were used to estimate survival and risk factors associated with mortality. Results: Of the 279 tuberculosis/HIV co-infected participants, 27.2% died during the study. Participants mainly were adults and males. CD4 count information was available for 41.6% (the median count was 83 cells/mm3), and half were subject to tuberculosis susceptibility testing. The median time between HIV diagnosis and antiretroviral therapy initiation was 372 days. HIV was identified prior to tuberculosis in 53% and concurrent HIV-tuberculosis were diagnosed in 37% of patients. 44.8% had tuberculosis treatment success. Body mass index above 18 kg/m2, initiation of tuberculosis treatment within two weeks, having any health insurance coverage and CD4 count information conferred a survival advantage. Conclusions: Delays in treatment initiation and factors associated with limited health care access or utilization were associated with mortality. As HIV and tuberculosis are both reportable conditions in Colombia, strategies should be focused on optimizing treatment outcomes within both tuberculosis and HIV programs, particularly improving early HIV diagnosis, early antiretroviral therapy treatment initiation, and adherence to tuberculosis treatment.

Resumen Objetivo: Determinar factores asociados con mortalidad en personas con co-infeccion Tuberculosis/VIH en Cali, Colombia. Métodos: Este diseño de cohorte retrospectiva incluyó personas co-infectadas con tuberculosis /VIH. Se utilizó Kaplan Meier y regresion de Cox para estimar supervivencia y factores de riesgo asociados con mortalidad. Resultados: De los 279 participantes coinfectados con tuberculosis/VIH, el 27.2% falleció durante el estudio. Los participantes fueron principalmente adultos y hombres. Se dispuso de información de recuento de CD4 en el 41.6% (la mediana del recuento fue 83 células/mm3), y en la mitad se realizaron pruebas de susceptibilidad para tuberculosis. La mediana de tiempo entre el diagnóstico de VIH e inicio de terapia antirretroviral fue 372 días. Se identificó VIH previo a tuberculosis en un 53%, e infección concurrente tuberculosis-VIH en el 37% de los pacientes. El 44.8% presentó éxito en el tratamiento para tuberculosis. Un índice de masa corporal superior a 18 kg/m2, inicio del tratamiento para TB dentro de las primeras dos semanas, contar con aseguramiento en salud y con recuento de CD4 se asociaron con mayor supervivencia. Conclusiones: Retraso en el inicio de tratamiento y factores relacionados con brechas en el acceso a atención en salud se asociaron con mortalidad. Dado que VIH y tuberculosis son enfermedades de notificación obligatoria en Colombia, las estrategias deben centrarse en optimizar los desenlaces del tratamiento dentro de ambos programas, en particular mejorar el diagnóstico temprano de VIH, el inicio temprano de la terapia antirretroviral y fomentar la adherencia al tratamiento para tuberculosis.

Transmission and Colonization of Pneumocystis jirovecii.

Pneumocystis spp. was discovered in 1909 and was classified as a fungus in 1988. The species that infects humans is called P. jirovecii and important characteristics of its genome have recently been discovered. Important advances have been made to understand P. jirovecii, including aspects of its biology, evolution, lifecycle, and pathogenesis; it is now considered that the main route of transmission is airborne and that the infectious form is the asci (cyst), but it is unclear whether there is transmission by direct contact or droplet spread. On the other hand, P. jirovecii has been detected in respiratory secretions of hosts without causing disease, which has been termed asymptomatic carrier status or colonization (frequency in immunocompetent patients: 0-65%, pregnancy: 15.5%, children: 0-100%, HIV-positive patients: 20-69%, cystic fibrosis: 1-22%, and COPD: 16-55%). This article briefly describes the history of its discovery and the nomenclature of Pneumocystis spp., recently uncovered characteristics of its genome, and what research has been done on the transmission and colonization of P. jirovecii. Based on the literature, the authors of this review propose a hypothetical natural history of P. jirovecii infection in humans.

Inflammatory Cell Differentiation and Chemotaxis and Extracellular Tissue Repair Markers Are Correlated with Pulmonary Dysfunction in HIV Infected Individuals Presenting with Community-Acquired Pneumonia.

Prior studies have shown that HIV patients develop permanent pulmonary dysfunction following an episode of community-acquired pneumonia (CAP). However, the mechanism causing pulmonary dysfunction remains an enigma. HIV patients experience chronic inflammation. We hypothesized that CAP exacerbates inflammation in HIV patients resulting in an accelerated decline in lung function. A prospective cohort pilot study enrolled HIV patients hospitalized in Medellin, Colombia, with a diagnosis of CAP. Sixteen patients were eligible for the study; they were split into 2 groups: HIV and HIV+CAP. Plasma, sputum, and pulmonary function test (PFT) measurements were retrieved within 48 h of hospital admission and at 1 month follow-up. The concentrations of 13 molecules and PFT values were compared between the 2 cohorts. The HIV+CAP group had lower lung function compared to the HIV group; forced vital capacity (FVC)% predicted and forced expiratory volume in 1 s (FEV1)% predicted decreased, while FEV1/FVC remained constant. APRIL, BAFF, CCL3, and TIMP-1 correlated negatively with FVC% predicted and FEV1% predicted; the relationships however were moderate in strength. Furthermore, the concentrations of BAFF, CCL3, and TIMP-1 were statistically significant between the 2 groups (P ≤ 0.05). Our results indicate that HIV patients with CAP have a different inflammatory pattern and lower lung function compared to HIV patients without CAP. BAFF, CCL3, and TIMP-1 were abnormally elevated in HIV patients with CAP. Future studies with larger cohorts are required to verify these results. In addition, further investigation is required to determine if BAFF, CCL3, and TIMP-1 play a role in the process causing pulmonary dysfunction.

Is tuberculosis elimination a feasible goal in Colombia by 2050?

Colombia has an underreporting of 30% of the total cases, according to World Health Organization (WHO) estimations. In 2016, successful tuberculosis (TB) treatment rate was 70%, and the mortality rate ranged between 3.5% and 10%. In 2015, Colombia adopted and adapted the End TB strategy and set a target of 50% reduction in incidence and mortality by 2035 compared with 2015. The aims of this study were: To evaluate whether Colombia will be able to achieve the goals of TB incidence and mortality by 2050, using the current strategies; and whether the implementation of new screening, diagnosis and TB treatment strategies will allow to achieve those WHO targets. An ecological study was conducted using TB case-notification, successful treatment and mortality rates from the last 8 years (2009-17). System dynamics analysis was performed using simulated scenarios: (1) continuation with the same trends following the trajectory of the last 8 years (Status quo) and (2) modification of the targets between 2017 through 2050, assuming the implementation of multimodal strategies to increase the screening, to improve the early diagnosis and to improve the treatment adherence. Following the current strategies, it is projected that Colombia will not achieve the End TB strategy targets. Achieving the goal of TB incidence of 10/100 000 by 2050 will only be possible by implementing combined strategies for increasing screening of people with respiratory symptoms, improving access to rapid diagnostic tests and improving treatment adherence. Therefore, it is necessary to design and implement simultaneous strategies according to the population needs and resources, in order to stride towards the End TB targets.

Inflammatory mediators and lung abnormalities in HIV: A systematic review.

HIV and pneumonia infections have both been shown to negatively impact lung function. However, evidence of the role of inflammation on lung dysfunction in HIV and pneumonia co-infected individuals remains limited. We aimed to systematically review the association of inflammatory markers and lung abnormalities in HIV and pneumonia co-infected individuals. This systematic review was registered with the International Prospective Register of Systematic Reviews on August 15, 2017 (registration number CRD42017069254) and used 4 databases (Cochrane Central Register of Controlled Trials, PubMed Central, Clinical Trials.gov and Google Scholar). All clinical trial, observational, and comparative studies targeting adult (> 18 years old) populations with HIV, pneumonia, or both, that report on immune response (cytokine, chemokine, or biomarker), and lung abnormality as an outcome were eligible. Data selection, risk of bias and extraction were performed independently by 2 blinded reviewers. Due to heterogeneity among the articles, a qualitative synthesis was performed. Our search strategy identified 4454 articles of which, 7 met our inclusion criteria. All of the studies investigated the ability of circulating biomarkers to predict lung damage in HIV. None of the articles included patients with both HIV and pneumonia, nor pneumonia alone. Markers of inflammation (IL-6, TNF-α, CRP), innate defense (cathelicidin), monocyte and macrophage activation (sCD14, sCD163 and, IL-2sRα), endothelial dysfunction (ET-1) and general immune health (CD4/CD8 ratio) were associated with lung abnormalities in HIV. This review highlights the lack of available information regarding the impact of inflammatory mediators on lung function in HIV and pneumonia populations, therefore opportunities to prevent lung damage with available anti-inflammatory treatment or to investigate new ones still remain.

Cervical Extraoral Traction Therapy in Early Treatment of Class II Malocclusion. A systematic review / Terapia de tracción extraoral cervical en el tratamiento temprano de la maloclusión de clase II. Una revisión sistemática / Terapia de Tração Extraoral Cervical no Tratamento Precoce da Maloclusão Classe II. Uma revisão sistemática

Abstract Introduction and objective: Cervical headgear has been used for decades as a treatment of class II malocclusion. Although the effects have been reported previously they are somewhat contradictory. The objective was to determine the available scientific evidence that supports the parameters of clinical use for therapy with cervical extraoral traction in early treatment for class II malocclusion. Materials and methods: A systematic search was conducted using Medline, Google Scholar, Cochrane, and Lilacs data-bases. The search involved articles in English, Spanish, Portuguese, and German using previously selected MeSH terms and free-text terms. The search included articles dealing with cervical extraoral traction treatment, systematic reviews, meta-analysis, clinical trials, and cohort, case-control, and cross-sectional studies. Methodological quality was evaluated using various scales according to the type of study. Results: The search generated 334 articles, 259 were eliminated because they were duplicates, and 34 were eliminated because they did not meet the inclusion criteria. 41 articles were evaluated in full text, 21 were excluded because they did not meet the inclusion criteria, leaving a total of 20 articles. Conclusions: The articles offered varied, yet clear, recommendations. According to the literature and clinical judgment, treatment timing is recommended during the pubertal growth spurt. The most efficient force is 450 to 500g per side for 12 to 14 hours per day. A long outer bow bent 15o degrees upward should be used in patients with normal and hypodivergent patterns. Maxillary growth control depends on age, force, treatment duration, etc. Changes in overjet can be expected due to changes in dental inclination, growth, or the use of additional appliances; an average molar distalization of 1 mm to 2 mm can be achieved.

Resumen Introducción y objetivo: La Tracción cervical se ha utilizado durante décadas como tratamiento para la maloclusión de clase II. Aunque los efectos se han informado previamente, son algo contradictorios. El objetivo fué determinar la evidencia científica disponible que respalde los parámetros de uso clínico para la terapia con tracción extraoral cervical en el tratamiento temprano de la maloclusión de clase II. Materiales y métodos: Se realizó una búsqueda sistemática utilizando las bases de datos Medline, Google Scholar, Cochrane y Lilacs. La búsqueda incluyó artículos en inglés, español, portugués y alemán utilizando términos MeSH previamente seleccionados y términos de texto libre. La búsqueda incluyó artículos relacionados con el tratamiento de tracción extraoral cervical, revisiones sistemáticas, metanálisis, ensayos clínicos y estudios de cohortes, casos y controles y estudios transversales. La calidad metodológica se evaluó utilizando varias escalas según el tipo de estudio. Resultados: La búsqueda generó 334 artículos, 259 fueron eliminados porque eran duplicados y 34 fueron eliminados porque no cumplían con los criterios de inclusión. Se evaluaron 41 artículos en texto completo, se excluyeron 21 porque no cumplían con los criterios de inclusión, dejando un total de 20 artículos. Conclusiones: Los artículos ofrecieron recomendaciones variadas, pero claras. De acuerdo con la literatura y el juicio clínico, se recomienda el momento del tratamiento durante el período de crecimiento puberal. La fuerza más eficiente es de 450 a 500 g por lado durante 12 a 14 horas por día. Se debe usar un arco externo largo doblado 15 grados hacia arriba en pacientes con patrones normales e hipodivergentes. El control del crecimiento maxilar depende de la edad, la fuerza, la duración del tratamiento, etc. Se pueden esperar cambios en la sobrecarga debido a cambios en la inclinación dental, el crecimiento o el uso de aparatos adicionales. Se puede lograr una distalización molar promedio de 1 mm a 2 mm.

Resumo Introdução e objetivo: A tração cervical tem sido utilizada como tratamento da má oclsão de classe II. Embora os efeitos tenham sido relatados anteriormente, eles são contraditórios. O objetivo foi determinar as evidências científicas disponíveis que suportamos parâmetros de uso clínico para terapia com tração extraoral cervical no tratamentoprecoce da má oclusão de classe II. Materiais e métodos: Uma pesquisa sistemática foirealizada usando Medline, Google Scholar, Cochrane e Lilacs. Foram incluidos artigos em inglês, espanhol, português e alemão, usando termos MeSH selecionados anteriormente e termos de texto livre. A pesquisa incluiu artigos que tratavam do tratamento da tração extraoral cervical, revisões sistemáticas, meta-análise, ensaios clínicos e estudos de coorte, caso-controle e transversais. A qualidade metodológica foi avaliada usando várias escalas de acordo com o tipo de estudo. Resultados: a busca gerou 334 artigos, 259 foram eliminados por serem duplicados e 34 foram eliminados por não atenderem aos critérios de inclusão. 41 artigos foram avaliados em texto completo, 21 foram excluídos por não atenderem aos critérios de inclusão, totalizando 20 artigos. Conclusões: Os artigos oferecidos apresentaram recomendações variadas, porém claras. De acordo com a literatura e o julgamento clínico, o momento do tratamento é recomendado durante o surto de crescimento puberal. A força mais eficiente é de 450 a 500g por lado, durante 12 a 14 horas por dia. Um arco externo longo e dobrado de 15 graus deve ser usado em pacientes com padrões normais e hipodivergentes. O controle do crescimento maxilar depende da idade, força, duração do tratamento, etc. Alterações no overjet podem ser esperadas devido a alterações na inclinação dentária, crescimento ou uso de aparelhos adicionais; uma distalização molar média de 1 mm a 2 mm pode ser alcançada.