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Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available. The purpose of this joint European Respiratory Society (ERS) and European Society for Blood and Marrow Transplantation task force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine and methodology, as well as patient advocates, formulated eight PICO (patient, intervention, comparison, outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the Grading of Recommendations Assessment, Development and Evaluation approach to develop recommendations. The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.
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Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Pulmão , Adulto , Humanos , Doença Enxerto-Hospedeiro/terapia , Doença Enxerto-Hospedeiro/etiologia , Pulmão , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Pulmão/efeitos adversos , Doença CrônicaRESUMO
Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS.
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Antineoplásicos , Fosfatidilinositol 3-Quinases , Humanos , Administração por Inalação , Inibidores de Proteínas Quinases , Fosfatidilinositol 3-QuinaseRESUMO
BackgroundEvidence of an oseltamivir treatment effect on influenza A(H3N2) virus infections in hospitalised patients is incomplete.AimsThis cohort study aimed to evaluate risk factors for death among PCR-confirmed hospitalised cases of seasonal influenza A(H3N2) of all ages and the impact of oseltamivir.MethodsParticipants included all 332 PCR-confirmed influenza A(H3N2) cases diagnosed between 30 August 2016 and 17 March 2017 in an English university teaching Hospital. Oseltamivir treatment effect on odds of inpatient death was assessed by backward stepwise multivariable logistic regression analysis.ResultsThe odds of death were reduced by two thirds (odds ratio (OR): 0.32; 95% confidence interval (CI): 0.11-0.93), in inpatients treated with a standard course of oseltamivir 75â¯mg two times daily for 5â¯days - compared with those untreated with oseltamivir, after adjustment for age, sex, current excess alcohol intake, receipt of 2016/17 seasonal influenza vaccine, serum haemoglobin and hospital vs community attribution of acquisition of influenza.ConclusionsOseltamivir treatment given according to National Institutes of Clinical Excellence (NICE); United States Centres for Disease Control and Prevention (CDC); Infectious Diseases Society of America (IDSA) and World Health Organization (WHO) guidelines was shown to be effective in reducing the odds of mortality in inpatients with PCR-confirmed seasonal influenza A(H3N2) after adjustment in a busy routine English hospital setting. Our results highlight the importance of hospitals complying with relevant guidelines for prompt seasonal influenza PCR testing and ensuring standard oseltamivir treatment to all PCR-confirmed cases of seasonal influenza.
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Antivirais/uso terapêutico , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/tratamento farmacológico , Oseltamivir/uso terapêutico , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Fidelidade a Diretrizes , Mortalidade Hospitalar , Hospitais de Ensino , Humanos , Lactente , Recém-Nascido , Vírus da Influenza A Subtipo H3N2/genética , Influenza Humana/diagnóstico , Influenza Humana/mortalidade , Pacientes Internados , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: There is an urgent need for improved vaccines to protect against tuberculosis. The currently available vaccine Bacille Calmette-Guerin (BCG) has varying immunogenicity and efficacy across different populations for reasons not clearly understood. MVA85A is a modified vaccinia virus expressing antigen 85A from Mycobacterium tuberculosis which has been in clinical development since 2002 as a candidate vaccine to boost BCG-induced protection. A recent efficacy trial in South African infants failed to demonstrate enhancement of protection over BCG alone. The immunogenicity was lower than that seen in UK trials. The enzyme Indoleamine 2,3-dioxygenase (IDO) catalyses the first and rate-limiting step in the breakdown of the essential amino acid tryptophan. T cells are dependent on tryptophan and IDO activity suppresses T-cell proliferation and function. METHODS: Using samples collected during phase I trials with MVA85A across the UK and South Africa we have investigated the relationship between vaccine immunogenicity and IDO using IFN-γ ELISPOT, qPCR and liquid chromatography mass spectrometry. RESULTS: We demonstrate an IFN-γ dependent increase in IDO mRNA expression in peripheral blood mononuclear cells (PBMC) following MVA85A vaccination in UK subjects. IDO mRNA correlates positively with the IFN-γ ELISPOT response indicating that vaccine specific induction of IDO in PBMC is unlikely to limit the development of vaccine specific immunity. IDO activity in the serum of volunteers from the UK and South Africa was also assessed. There was no change in serum IDO activity following MVA85A vaccination. However, we observed higher baseline IDO activity in South African volunteers when compared to UK volunteers. In both UK and South African serum samples, baseline IDO activity negatively correlated with vaccine-specific IFN-γ responses, suggesting that IDO activity may impair the generation of a CD4+ T cell memory response. CONCLUSIONS: Baseline IDO activity was higher in South African volunteers when compared to UK volunteers, which may represent a potential mechanism for the observed variation in vaccine immunogenicity in South African and UK populations and may have important implications for future vaccination strategies. TRIAL REGISTRATION: Trials are registered at ClinicalTrials.gov; UK cohort NCT00427830, UK LTBI cohort NCT00456183, South African cohort NCT00460590, South African LTBI cohort NCT00480558.
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Indolamina-Pirrol 2,3,-Dioxigenase/efeitos dos fármacos , Interferon gama/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , RNA Mensageiro/metabolismo , Vacinas contra a Tuberculose/farmacologia , Tuberculose/prevenção & controle , Adulto , Vacina BCG , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , ELISPOT , Feminino , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , África do Sul , Reino Unido , Vacinação , Vacinas de DNA , Adulto JovemRESUMO
Background: Antibody deficiencies result from reduced immunoglobulin levels and function, increasing susceptibility to, primarily, bacterial infection. Primary antibody deficiencies comprise intrinsic defects in B-cell physiology, often due to inherited errors. Hematological malignancies or B-cell suppressive therapy are major causes of secondary antibody deficiency. Although immunoglobulin replacement therapy (IGRT) reduces infectious burden in antibody deficiency patients, respiratory tract infections remain a significant health burden. We hypothesize that lung pathology and gastroesophageal reflux disease (GORD) increase the risk of pneumonia in antibody deficiency patients, as in the general population. Objective: For our cohort of patients with primary antibody deficiency and secondary antibody deficiency, we reviewed their respiratory infectious burden and the impact of lung pathologies and GORD. Methods: The medical records of 231 patients on IGRT at a tertiary referral center, from October 26, 2014, to February 19, 2021, were reviewed to determine microbial isolates from sputum samples and prevalence of common lung pathologies and GORD. Results: Haemophilus and Pseudomonas species represent a large infectious burden, being identified in 30.2% and 21.4% of sputum samples demonstrating growth, respectively; filamentous fungal and mycobacterial infections were rare. Diagnosed lung pathology increased the proportion of patients with Pseudomonas, Klebsiella, Stenotrophomonas, and Candida species isolated in their sputum, and diagnosed GORD increased the proportion with Enterobacter and Candida species isolated. Conclusions: Bacterial respiratory infectious burden remains in primary antibody deficiency and secondary antibody deficiency despite IGRT. Lung pathologies encourage growth of species less susceptible to IGRT, so specialist respiratory medicine input and additional treatments such as inhaled antibiotics are indicated to optimize respiratory outcomes.
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Standard course oseltamivir 75mg two times daily for five days was associated with an 82% reduction of odds of in-patient death (OR 0.18 (0.07,0.51)) compared to no oseltamivir treatment (OR 1.0 Reference) in a final multivariable logistic regression model of a retrospective cohort of PCR confirmed influenza B and influenza A (H3N2) infected patients admitted to a large UK teaching hospital in influenza seasons 2016-17 and 2017-18. No difference of protective odds for standard course oseltamivir was observed between influenza B and influenza A (H3N2) nor between influenza seasons. These observations strongly support clinical guidelines for molecular testing for respiratory viruses on admission to hospital and prompt treatment of confirmed seasonal influenza B and A with oseltamivir 75mg twice daily for five days.
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Influenza Humana , Oseltamivir , Humanos , Oseltamivir/uso terapêutico , Influenza Humana/diagnóstico , Influenza Humana/tratamento farmacológico , Influenza Humana/epidemiologia , Vírus da Influenza A Subtipo H3N2/genética , Antivirais/uso terapêutico , Estudos Retrospectivos , Mortalidade Hospitalar , Estações do Ano , Reação em Cadeia da PolimeraseRESUMO
Hypothesis/Gap Statement. The impacts of increased biomarker testing on antifungal prescribing have not yet been fully examined in a real-life setting.Objectives. Biomarkers for invasive fungal disease (IFD) have been shown to reduce antifungal prescriptions in neutropaenic haemato-oncology patients. Our study aimed to assess the real-life impacts of introducing a novel biomarker-based pathway, incorporating serum galactomannan and Aspergillus PCR, for pyrexial haemato-oncology admissions.Methods. Patients with neutropaenic fever were identified prospectively after introduction of the new pathway from 2013-2015. A historical group of neutropaenic patients who had blood cultures taken from 2009-2012 was generated for comparison. Clinical details, including demographics, underlying diagnosis, investigations, radiology and antimicrobial treatment were obtained.Results. Prospective data from 308 patients were compared to retrospective data from 302 patients. The proportion of patients prescribed an antifungal medication was unchanged by the pathway (P=0.79), but the pattern was different, with more patients receiving targeted antifungals (P=0.04). A negative serum galactomannan test was not sufficient evidence to withhold therapy, with 17.2% of these episodes felt to have possible or probable IFD using the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) criteria. There was no difference in 30-day mortality (P=0.21) or 1-year mortality (P=0.57) following introduction of the pathway.Conclusions. Biomarkers can be used safely as part of a multidisciplinary approach to the diagnosis of IFD in neutropaenic haemato-oncology patients. Whilst they do not necessarily result in antifungal therapy being withheld, they can allow more confident diagnosis of IFD and more specific antifungal therapy in selected cases.
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Infecções Fúngicas Invasivas , Micoses , Neoplasias , Antifúngicos/uso terapêutico , Biomarcadores/análise , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/tratamento farmacológico , Micoses/diagnóstico , Neoplasias/complicações , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) from antigen-specific T cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4(+) and CD8(+) T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas.
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Aciltransferases/imunologia , Antígenos de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vaccinia virus/imunologia , Adulto , Ensaio de Imunoadsorção Enzimática/métodos , Mapeamento de Epitopos , Humanos , Imunidade Celular/imunologia , Interferon gama/imunologia , Pessoa de Meia-Idade , Linfócitos T Auxiliares-Indutores/imunologia , Tuberculose/imunologia , Vacinas Sintéticas/imunologia , Vaccinia virus/metabolismoRESUMO
Boosting bacillus Calmette-Guérin (BCG)-primed mice with a recombinant adenovirus expressing Mycobacterium tuberculosis Ag 85A by different administration routes has very different effects on protection against aerosol challenge with M. tuberculosis. Mice boosted intradermally make very strong splenic CD4 and CD8 Th1 cytokine responses to Ag 85A, but show no change in lung mycobacterial burden over BCG primed animals. In contrast, intranasally boosted mice show greatly reduced mycobacterial burden and make a much weaker splenic response but a very strong lung CD4 and CD8 response to Ag 85A and an increased response to purified protein derivative. This effect is associated with the presence in the lung of multifunctional T cells, with high median fluorescence intensity and integrated median fluorescence intensity for IFN-gamma, IL-2, and TNF. In contrast, mice immunized with BCG alone have few Ag-specific cells in the lung and a low proportion of multifunctional cells, although individual cells have high median fluorescence intensity. Successful immunization regimes appear to induce Ag-specific cells with abundant intracellular cytokine staining.
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Citocinas/biossíntese , Pulmão/imunologia , Mycobacterium tuberculosis/imunologia , Baço/imunologia , Células Th1/imunologia , Células Th1/microbiologia , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/prevenção & controle , Aciltransferases/administração & dosagem , Aciltransferases/imunologia , Adenovírus Humanos/genética , Adenovírus Humanos/imunologia , Administração Intranasal , Aerossóis , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/administração & dosagem , Antígenos de Bactérias/imunologia , Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Citocinas/fisiologia , Feminino , Humanos , Imunização Secundária/métodos , Injeções Intradérmicas , Pulmão/citologia , Pulmão/metabolismo , Pulmão/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/imunologia , Baço/citologia , Baço/metabolismo , Baço/microbiologia , Células Th1/metabolismo , Tuberculose Pulmonar/microbiologiaRESUMO
RATIONALE: An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. OBJECTIVES: To evaluate the safety and immunogenicity of a leading new TB vaccine, recombinant Modified Vaccinia Ankara expressing Antigen 85A (MVA85A) in individuals with LTBI. METHODS: An open-label, phase I trial of MVA85A was performed in 12 subjects with LTBI recruited from TB contact clinics in Oxford and London or by poster advertisements in Oxford hospitals. Patients were assessed clinically and had blood samples drawn for immunological analysis over a 52-week period after vaccination with MVA85A. Thoracic computed tomography scans were performed at baseline and at 10 weeks after vaccination. Safety of MVA85A was assessed by clinical, radiological, and inflammatory markers. The immunogenicity of MVA85A was assessed by IFNgamma and IL-2 ELISpot assays and FACS. MEASUREMENTS AND MAIN RESULTS: MVA85A was safe in subjects with LTBI, with comparable adverse events to previous trials of MVA85A. There were no clinically significant changes in inflammatory markers or thoracic computed tomography scans after vaccination. MVA85A induced a strong antigen-specific IFN-gamma and IL-2 response that was durable for 52 weeks. The magnitude of IFN-gamma response was comparable to previous trials of MVA85A in bacillus Calmette-Guérin-vaccinated individuals. Antigen 85A-specific polyfunctional CD4(+) T cells were detectable prior to vaccination with statistically significant increases in cell numbers after vaccination. CONCLUSIONS: MVA85A is safe and highly immunogenic in individuals with LTBI. These results will facilitate further trials in TB-endemic areas. Clinical trial registered with www.clinicaltrials.gov (NCT00456183).
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Mycobacterium tuberculosis/imunologia , Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Tuberculose/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Teste Tuberculínico , Tuberculose/diagnóstico , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/imunologia , Adulto JovemRESUMO
Plastic bronchitis is a rare condition characterised by endobronchial cast formation. We report the case of a 53-year-old women who deteriorated following an elective bronchoscopy procedure. She developed refractory ventilatory failure and required repeated bronchoscopy, which identified thick tenacious casts as the cause of her airway compromise. She did not respond to conventional therapies including endoscopic clearance, mucolytic therapy and nebulised tissue plasminogen activator (TPA). Total parenteral nutrition and a fat-free enteral diet were instituted while the patient was on extracorporeal membrane oxygenation (ECMO), which led to substantial improvement in her condition and demonstrated the importance of dietary strategies in this case. LEARNING POINTS: Plastic bronchitis can rarely present in adults with acute ventilatory failure and life-threatening airway obstruction.Although there are no established guidelines on management, dietary intervention (e.g., a fat-free diet) should be strongly considered as a therapeutic option.Extracorporeal membrane oxygenation (ECMO) is feasible and should be considered in plastic bronchitis with airway compromise.
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In the light of the recent emergence of multidrug-resistant and extensively drug-resistant strains of Mycobacterium tuberculosis, the epidemic of tuberculosis (TB) in populations coinfected with human immunodeficiency virus, and the failure of Mycobacterium bovis bacillus Calmette-Guerin (BCG) to protect against disease, new vaccines against TB are urgently needed. Two promising new vaccine candidates are the recombinant DeltaureC hly(+) BCG (recBCG), which has been developed to replace the current BCG vaccine strain, and modified vaccinia virus Ankara (MVA) expressing M. tuberculosis antigen 85A (MVA85A), which is a leading candidate vaccine designed to boost the protective efficacy of BCG. In the present study, we examined the effect of MVA85A boosting on the protection afforded at 12 weeks postchallenge by BCG and recBCG by using bacterial CFU as an efficacy readout. recBCG-immunized mice were significantly better protected against aerosol challenge with M. tuberculosis than mice immunized with the parental strain of BCG. Intradermal boosting with MVA85A did not reduce the bacterial burden any further. In order to identify a marker for the development of a protective immune response against M. tuberculosis challenge, we analyzed splenocytes after priming or prime-boosting by using intracytoplasmic cytokine staining and assays for cytokine secretion. Boosting with MVA85A, but not priming with BCG or recBCG, greatly increased the antigen 85A-specific T-cell response, suggesting that the mechanism of protection may differ from that against BCG or recBCG. We show that the numbers of systemic multifunctional cytokine-producing cells did not correlate with protection against aerosol challenge in BALB/c mice. This emphasizes the need for new biomarkers for the evaluation of TB vaccine efficacy.
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Aciltransferases/metabolismo , Antígenos de Bactérias/metabolismo , Vacina BCG/imunologia , Mycobacterium bovis/genética , Tuberculose Pulmonar/imunologia , Vaccinia virus/genética , Aciltransferases/genética , Animais , Antígenos de Bactérias/genética , Linfócitos T CD8-Positivos/imunologia , Feminino , Regulação Bacteriana da Expressão Gênica , Engenharia Genética , Imunização Secundária , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/metabolismo , Proteínas Recombinantes , Teste TuberculínicoRESUMO
RATIONALE: In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain. OBJECTIVES: To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT. METHODS: The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data. MEASUREMENTS AND MAIN RESULTS: Increasingly extensive disease on HRCT was a powerful predictor of mortality (P < 0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVC >or= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC < 70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P < 0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P < 0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly < 20% or clearly > 20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60). CONCLUSIONS: An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.
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Algoritmos , Doenças Pulmonares Intersticiais/diagnóstico , Escleroderma Sistêmico/complicações , Índice de Gravidade de Doença , Adulto , Estudos de Coortes , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Escleroderma Sistêmico/diagnóstico por imagem , Escleroderma Sistêmico/fisiopatologia , Análise de Sobrevida , Tomografia Computadorizada por Raios X , Capacidade Vital/fisiologiaRESUMO
Introduction. Evidence for the clinical utility of bronchoalveolar lavage (BAL) galactomannan in the management of fungal disease outside of haemato-oncology patients is limited.Aim. To determine how the introduction of BAL galactomannan testing impacted on the diagnosis and management of invasive aspergillosis and other fungal diseases in non-haemato-oncology patients.Methodology. Retrospective review of all adult patients (age ≥16 years) without a diagnosis of haematological malignancy who had a positive BAL galactomannan from 1 November 2014 to 30 April 2018. Using electronic patient records we obtained demographic data, clinical details, laboratory investigations, relevant radiology and antimicrobial history for each case.Results. In total, 121 episodes with a galactomannan OD index of ≥0.500 were included in the study; 29 cases (24â%) were felt to reflect fungal disease. Antifungal therapy was commenced as a direct consequence of a positive BAL galactomannan result in 13 patients where the ultimate diagnosis was subsequently considered to be non-mycological: associated medication-related side-effects in this group included deranged liver function tests (n=3), rash (n=1) and fever (n=1), related to amphotericin B (n=1) and voriconazole (n=4).Conclusion. We show that vigilance is required when interpreting galactomannan results in non-haematology patients to avoid potentially harmful overtreatment.
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Antifúngicos/uso terapêutico , Líquido da Lavagem Broncoalveolar/química , Mananas/análise , Uso Excessivo dos Serviços de Saúde , Micoses/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Feminino , Galactose/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/tratamento farmacológico , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE OF REVIEW: The aim of this article is to examine significant advances in our understanding of the late respiratory effects of cancer treatment, including surgery, radiotherapy, chemotherapy, biological therapies and haematopoietic stem cell transplant, and to provide a framework for assessing such patients. RECENT FINDINGS: Oncology therapies have advanced considerably over recent years but pulmonary toxicity remains a concern. Advances have been made in our understanding of the risk factors, including genetic ones that lead to toxicity from radiotherapy and chemotherapy and risk stratification models are being developed to aid treatment planning. Targeted biological treatments are continuously being developed and consequently the Pneumotox database of pulmonary toxicity continues to be an essential resource. Early detection of bronchiolitis obliterans in haematopoietic stem cell transplant patients has been found to be critical, with some positive results from intervention trials. SUMMARY: Pulmonary toxicity is a common unwanted consequence of life enhancing or saving cancer treatments which remain difficult to treat. Developments in these fields are mainly in the areas of prevention, early detection and monitoring of unwanted side effects. We discuss some of these developments within this review.
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Antineoplásicos/efeitos adversos , Neoplasias/terapia , Complicações Pós-Operatórias/fisiopatologia , Radioterapia/efeitos adversos , Doenças Respiratórias/etiologia , Produtos Biológicos/efeitos adversos , Humanos , Sistema de Registros , Transplante de Células-Tronco/efeitos adversosRESUMO
A proportion of people living with common variable immunodeficiency disorders develop granulomatous-lymphocytic interstitial lung disease (GLILD). We aimed to develop a consensus statement on the definition, diagnosis, and management of GLILD. All UK specialist centers were contacted and relevant physicians were invited to take part in a 3-round online Delphi process. Responses were graded as Strongly Agree, Tend to Agree, Neither Agree nor Disagree, Tend to Disagree, and Strongly Disagree, scored +1, +0.5, 0, -0.5, and -1, respectively. Agreement was defined as greater than or equal to 80% consensus. Scores are reported as mean ± SD. There was 100% agreement (score, 0.92 ± 0.19) for the following definition: "GLILD is a distinct clinico-radio-pathological ILD occurring in patients with [common variable immunodeficiency disorders], associated with a lymphocytic infiltrate and/or granuloma in the lung, and in whom other conditions have been considered and where possible excluded." There was consensus that the workup of suspected GLILD requires chest computed tomography (CT) (0.98 ± 0.01), lung function tests (eg, gas transfer, 0.94 ± 0.17), bronchoscopy to exclude infection (0.63 ± 0.50), and lung biopsy (0.58 ± 0.40). There was no consensus on whether expectant management following optimization of immunoglobulin therapy was acceptable: 67% agreed, 25% disagreed, score 0.38 ± 0.59; 90% agreed that when treatment was required, first-line treatment should be with corticosteroids alone (score, 0.55 ± 0.51).
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Imunodeficiência de Variável Comum , Granuloma , Doenças Pulmonares Intersticiais , Instituições de Caridade , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/diagnóstico por imagem , Imunodeficiência de Variável Comum/tratamento farmacológico , Imunodeficiência de Variável Comum/patologia , Consenso , Granuloma/diagnóstico , Granuloma/diagnóstico por imagem , Granuloma/tratamento farmacológico , Granuloma/patologia , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/patologia , Sociedades Médicas , Reino UnidoRESUMO
There is an urgent need for an improved vaccine against tuberculosis. Heterologous prime-boost immunization regimes induce higher levels of cellular immunity than homologous boosting with the same vaccine. Using BCG as the priming immunization in such a regime allows for the retention of the beneficial protective effects of BCG against disseminated disease in childhood. Recombinant poxviruses are powerful boosting agents, for both CD4+ and CD8+ T cells. Here we review the preclinical data from a BCG prime-recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A) boost strategy. MVA85A is now in clinical trials in the UK and Africa and the design of these trials, including the ethical and regulatory issues are discussed.
Assuntos
Vacina BCG/imunologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/imunologia , Vaccinia virus/imunologia , Vacina BCG/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Imunidade Celular , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Tuberculose/prevenção & controle , Vacinas contra a Tuberculose/uso terapêutico , Vacinas de Subunidades Antigênicas/imunologia , Vacinas de Subunidades Antigênicas/uso terapêuticoRESUMO
PURPOSE: A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG. METHODS: Healthy BCG-vaccinated volunteers were vaccinated with either 1×10(7) or 1×10(8)PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5×10(7)PFU MVA85A had been administered. RESULTS: There were no serious adverse events recorded following administration of either 1×10(7) or 1×10(8)PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1×10(8)PFU of MVA85A when compared to either 5×10(7) or 1×10(7)PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1×10(8)PFU compared to the 5×10(7) and 1×10(7) doses. Additionally, a broader range of Ag85A epitopes are detected following 1×10(8)PFU of MVA85A. CONCLUSION: A higher dose of 1×10(8)PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.
Assuntos
Vacinas contra a Tuberculose/efeitos adversos , Vacinas contra a Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinas Virais/efeitos adversos , Vacinas Virais/imunologia , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , ELISPOT , Feminino , Experimentação Humana , Humanos , Interferon gama/metabolismo , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Reino Unido , Vacinas de DNA , Vacinas Virais/administração & dosagem , Adulto JovemRESUMO
Vaccination with Bacille Calmette-Guérin (BCG) has traditionally been used for protection against disease caused by the bacterium Mycobacterium tuberculosis (M.tb). The efficacy of BCG, especially against pulmonary tuberculosis (TB) is variable. The best protection is conferred in temperate climates and there is close to zero protection in many tropical areas with a high prevalence of both tuberculous and non-tuberculous mycobacterial species. Although interferon (IFN)-γ is known to be important in protection against TB disease, data is emerging on a possible role for interleukin (IL)-17 as a key cytokine in both murine and bovine TB vaccine studies, as well as in humans. Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) is a novel TB vaccine designed to enhance responses induced by BCG. Antigen-specific IFN-γ production has already been shown to peak one week post-MVA85A vaccination, and an inverse relationship between IL-17-producing cells and regulatory T cells expressing the ectonucleosidease CD39, which metabolises pro-inflammatory extracellular ATP has previously been described. This paper explores this relationship and finds that consumption of extracellular ATP by peripheral blood mononuclear cells from MVA85A-vaccinated subjects drops two weeks post-vaccination, corresponding to a drop in the percentage of a regulatory T cell subset expressing the ectonucleosidase CD39. Also at this time point, we report a peak in co-production of IL-17 and IFN-γ by CD4(+) T cells. These results suggest a relationship between extracellular ATP and effector responses and unveil a possible pathway that could be targeted during vaccine design.
Assuntos
Trifosfato de Adenosina/metabolismo , Mycobacterium tuberculosis/imunologia , Células Th1/imunologia , Células Th17/imunologia , Vacinas contra a Tuberculose/imunologia , Vacinação , Vacinas Virais/imunologia , Adolescente , Adulto , Animais , Antígenos CD/metabolismo , Apirase/antagonistas & inibidores , Apirase/metabolismo , Bovinos , Contagem de Células , Inibidores Enzimáticos/farmacologia , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Pessoa de Meia-Idade , Mycobacterium tuberculosis/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Vacinas de DNA , Adulto JovemRESUMO
Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.