RESUMO
To better understand primary and recall T cell responses during coronavirus disease 2019 (COVID-19), it is important to examine unmanipulated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells. By using peptide-human leukocyte antigen (HLA) tetramers for direct ex vivo analysis, we characterized CD8+ T cells specific for SARS-CoV-2 epitopes in COVID-19 patients and unexposed individuals. Unlike CD8+ T cells directed toward subdominant epitopes (B7/N257, A2/S269, and A24/S1,208) CD8+ T cells specific for the immunodominant B7/N105 epitope were detected at high frequencies in pre-pandemic samples and at increased frequencies during acute COVID-19 and convalescence. SARS-CoV-2-specific CD8+ T cells in pre-pandemic samples from children, adults, and elderly individuals predominantly displayed a naive phenotype, indicating a lack of previous cross-reactive exposures. T cell receptor (TCR) analyses revealed diverse TCRαß repertoires and promiscuous αß-TCR pairing within B7/N105+CD8+ T cells. Our study demonstrates high naive precursor frequency and TCRαß diversity within immunodominant B7/N105-specific CD8+ T cells and provides insight into SARS-CoV-2-specific T cell origins and subsequent responses.
Assuntos
Linfócitos T CD8-Positivos/imunologia , COVID-19/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Epitopos Imunodominantes/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , SARS-CoV-2/imunologia , Adulto , Idoso , Motivos de Aminoácidos , Linfócitos T CD4-Positivos , Criança , Convalescença , Proteínas do Nucleocapsídeo de Coronavírus/química , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Feminino , Humanos , Epitopos Imunodominantes/química , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosfoproteínas/química , Fosfoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologiaAssuntos
COVID-19 , Células T Matadoras Naturais , Citocinas , Citometria de Fluxo , Humanos , SARS-CoV-2RESUMO
Solid organ transplant recipients (SOTRs) frequently receive adjunctive glucocorticoid therapy (AGT) for Pneumocystis jirovecii pneumonia (PJP). This multicenter cohort of SOTRs with PJP admitted to 20 transplant centers in Canada, the United States, Europe, and Australia, was examined for whether AGT was associated with a lower rate of all-cause intensive care unit (ICU) admission, 90-day death, or a composite outcome (ICU admission or death). Of 172 SOTRs with PJP (median [IQR] age: 60 (51.5-67.0) years; 58 female [33.7%]), the ICU admission and death rates were 43.4%, and 20.8%, respectively. AGT was not associated with a reduced risk of ICU admission (adjusted odds ratio [aOR] [95% CI]: 0.49 [0.21-1.12]), death (aOR [95% CI]: 0.80 [0.30-2.17]), or the composite outcome (aOR [95% CI]: 0.97 [0.71-1.31]) in the propensity score-adjusted analysis. AGT was not significantly associated with at least 1 unit of the respiratory portion of the Sequential Organ Failure Assessment score improvement by day 5 (12/37 [32.4%] vs 39/111 [35.1%]; P = .78). We did not observe significant associations between AGT and ICU admission or death in SOTRs with PJP. Our findings should prompt a reevaluation of routine AGT administration in posttransplant PJP treatment and highlight the need for interventional studies.
Assuntos
Transplante de Órgãos , Pneumocystis carinii , Pneumonia por Pneumocystis , Feminino , Humanos , Pessoa de Meia-Idade , Europa (Continente) , Glucocorticoides/uso terapêutico , Transplante de Órgãos/efeitos adversos , Pneumonia por Pneumocystis/tratamento farmacológico , Pneumonia por Pneumocystis/etiologia , Estudos Retrospectivos , Transplantados , Masculino , IdosoRESUMO
BACKGROUND: Despite the burden of pyelonephritis after kidney transplantation, there is no consensus on initial empirical antibiotic management. METHODS: We surveyed clinicians throughout the world on their practice and opinions about the initial empirical therapy of post-transplant pyelonephritis, using clinical vignettes. A panel of experts from 19 countries on six continents designed this survey, and invited 2145 clinicians to participate. RESULTS: A total of 721 clinicians completed the survey (response rate: 34%). In the hypothetical case of a kidney transplant recipient admitted with pyelonephritis but not requiring intensive care, most respondents reported initiating either a 3rd-generation cephalosporin (37%) or piperacillin-tazobactam (21%) monotherapy. Several patient-level factors dictated the selection of broader-spectrum antibiotics, including having a recent urine culture showing growth of a resistant organism (85% for extended-spectrum ß-lactamase-producing organisms, 90% for carbapenemase-producing organisms, and 94% for Pseudomonas aeruginosa). Respondents attributed high importance to the appropriateness of empirical therapy, which 87% judged important to prevent mortality. Significant practice and opinion variations were observed between and within countries. CONCLUSION: High-quality studies are needed to guide the empirical management of post-transplant pyelonephritis. In particular, whether prior urine culture results should systematically be reviewed and considered remains to be determined. Studies are also needed to clarify the relationship between the appropriateness of initial empirical therapy and outcomes of post-transplant pyelonephritis.
RESUMO
BACKGROUND: Patients without human immunodeficiency virus (HIV) are increasingly recognized as being at risk for cryptococcosis. Knowledge of characteristics of cryptococcosis in these patients remains incomplete. METHODS: We conducted a retrospective study of cryptococcosis in 46 Australian and New Zealand hospitals to compare its frequency in patients with and without HIV and describe its characteristics in patients without HIV. Patients with cryptococcosis between January 2015 and December 2019 were included. RESULTS: Of 475 patients with cryptococcosis, 90% were without HIV (426 of 475) with marked predominance in both Cryptococcus neoformans (88.7%) and Cryptococcus gattii cases (94.3%). Most patients without HIV (60.8%) had a known immunocompromising condition: cancer (n = 91), organ transplantation (n = 81), or other immunocompromising condition (n = 97). Cryptococcosis presented as incidental imaging findings in 16.4% of patients (70 of 426). The serum cryptococcal antigen test was positive in 85.1% of tested patients (319 of 375); high titers independently predicted risk of central nervous system involvement. Lumbar puncture was performed in 167 patients to screen for asymptomatic meningitis, with a positivity rate of 13.2% where meningitis could have been predicted by a high serum cryptococcal antigen titer and/or fungemia in 95% of evaluable cases. One-year all-cause mortality was 20.9% in patients without HIV and 21.7% in patients with HIV (P = .89). CONCLUSIONS: Ninety percent of cryptococcosis cases occurred in patients without HIV (89% and 94% for C. neoformans and C. gattii, respectively). Emerging patient risk groups were evident. A high level of awareness is warranted to diagnose cryptococcosis in patients without HIV.
Assuntos
Criptococose , Cryptococcus gattii , Cryptococcus neoformans , Infecções por HIV , Meningite , Humanos , HIV , Estudos Retrospectivos , Nova Zelândia/epidemiologia , Austrália/epidemiologia , Criptococose/diagnóstico , Criptococose/epidemiologia , Hospitais , Antígenos de Fungos , Infecções por HIV/complicações , Infecções por HIV/epidemiologiaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe coronavirus disease 2019 (COVID-19) in a small proportion of infected individuals. The immune system plays an important role in the defense against SARS-CoV-2, but our understanding of the cellular immune parameters that contribute to severe COVID-19 disease is incomplete. Here, we show that populations of effector γδ T cells are associated with COVID-19 in unvaccinated patients with acute disease. We found that circulating CD27neg CD45RA+ CX3CR1+ Vδ1effector cells expressing Granzymes (Gzms) were enriched in COVID-19 patients with acute disease. Moreover, higher frequencies of GzmB+ Vδ2+ T cells were observed in acute COVID-19 patients. SARS-CoV-2 infection did not alter the γδ T cell receptor repertoire of either Vδ1+ or Vδ2+ subsets. Our work demonstrates an association between effector populations of γδ T cells and acute COVID-19 in unvaccinated individuals.
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COVID-19 , Subpopulações de Linfócitos T , Humanos , Doença Aguda , Receptores de Antígenos de Linfócitos T gama-delta , SARS-CoV-2RESUMO
Malakoplakia is a chronic granulomatous disease associated with incomplete clearance of bacterial pathogens. A multimodal approach to therapy includes antimicrobials with intracellular activity, reduction in immunosuppression, and debulking of lesions. Azithromycin has an intracellular mechanism of action and enhanced Gram-negative activity compared to other macrolides. Despite some in vitro data to support its use, there are no clinical breakpoints or epidemiological cut-off values for most Enterobacterales from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) or the Clinical and Laboratory Standards Institute (CLSI). We present two cases, previously unreported, of Escherichia coli associated renal allograft malakoplakia successfully treated with azithromycin.
Assuntos
Aloenxertos/microbiologia , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Infecções por Escherichia coli/tratamento farmacológico , Transplante de Rim/efeitos adversos , Malacoplasia/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Escherichia coli/efeitos dos fármacos , Escherichia coli/genética , Escherichia coli/fisiologia , Infecções por Escherichia coli/microbiologia , Feminino , Humanos , Malacoplasia/etiologia , Malacoplasia/microbiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/microbiologiaRESUMO
Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in the immunocompromised host. Atypical presentations which include pseudotumors or "cancer mimics" have been described. The etiology of these lesions remains unclear. The authors describe two previously unpublished cases that have arisen in the context of newer immunomodulating therapy and review the existing non-HIV-associated CMV pseudotumors described in the literature.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Humanos , Hospedeiro ImunocomprometidoRESUMO
Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.
Assuntos
Aspergilose , COVID-19 , Adulto , Antifúngicos/uso terapêutico , Aspergilose/diagnóstico , Aspergilose/tratamento farmacológico , Aspergillus fumigatus , Criança , Farmacorresistência Fúngica , Humanos , SARS-CoV-2 , Voriconazol/uso terapêuticoRESUMO
BACKGROUND: Countries with a high prevalence of COVID-19 have identified a reduction in crude hospital admission rates for non-COVID-19 conditions during the pandemic. There remains a paucity of such data from lower prevalence countries, including Australia. AIMS: To describe the patterns of unplanned hospital daily admission rates during the COVID-19 pandemic in a major Australian metropolitan hospital, with a focus on acute medical presentations including acute coronary syndrome (ACS), stroke and falls. METHODS: This single-centre retrospective analysis analysed hospital admission episodes between 1 March and 30 April 2020 (COVID-19-era) and compared this to a historical cohort during the same period between 2017 and 2019 (pre-COVID-19). Information collected included total admission rates and patient characteristics for ACS, stroke and falls patients. RESULTS: A total of 12 278 unplanned admissions was identified across the study period. The daily admission rate was lower in the COVID-19-era compared with pre-COVID-19 (46.59 vs 51.56 days, P < 0.001). There was also a reduced average daily admission rate for falls (7.79 vs 9.95 days, P < 0.001); however, similar admission rates for ACS (1.52 vs 1.49 days, P = 0.83) and stroke (1.56 vs 1.76 days, P = 0.33). CONCLUSIONS: Public health interventions have been effective in reducing domestic cases of COVID-19 in Australia. At our tertiary metropolitan hospital, we have observed a significant reduction in unplanned hospital admission rates during the COVID-19-era, particularly for falls. Public health messaging needs to focus on educating the public how to seek medical care safely and promptly in the context of the ongoing COVID-19 crisis.
Assuntos
COVID-19 , Pandemias , Austrália/epidemiologia , Humanos , Estudos Retrospectivos , SARS-CoV-2 , Centros de Atenção TerciáriaRESUMO
PURPOSE OF REVIEW: The gut microbiome presents a novel source of diagnostic and therapeutic potential to modify post allogeneic stem cell transplant complications. There is an explosion of interest in microbiome research, mostly in the form of single-centre prospective time-series cohorts utilizing a variety of sampling frequencies and metagenomic technologies to sequence the microbiome. The purpose of this review is to summarize important recent publications and contextualize them within what has already been described in this rapidly growing field. RECENT FINDING: Results from observational human cohort and animal transplant models add to the growing body of evidence that the microbiome modulates the immunopathogenesis of posttransplant complications. This is particularly the case for recipients of grafts replete with T cells where the evidence that acute graft-versus-host disease is mediated by anaerobic commensal-associated short-chain fatty acids, which interact with mucosa-associated (CD4FOXP3) T-regulatory cells. SUMMARY: Future human research into the role of the microbiome in allogeneic stem transplant should incorporate rigorous and considered experimental design in addition to next-generation sequencing technology to better portray microbiome functional potential and active gene expression. In combination with host immune phenotyping, which would facilitate a robust understanding of the host--microbiome interaction that is required before meaningful translation into clinical diagnostics and therapeutics can be expected.
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Doenças Transmissíveis/microbiologia , Microbiota , Transplante de Células-Tronco/efeitos adversos , Animais , Antibacterianos/efeitos adversos , Doenças Transmissíveis/epidemiologia , Microbioma Gastrointestinal , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/microbiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Metagenômica , Estudos Observacionais como Assunto , Estudos Prospectivos , Linfócitos T Reguladores/metabolismoAssuntos
Abatacepte/efeitos adversos , Infecções por Citomegalovirus/diagnóstico , Imunossupressores/efeitos adversos , Transplante de Rim , Púrpura Trombocitopênica Idiopática/diagnóstico , Transplantados , Abatacepte/uso terapêutico , Adulto , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/tratamento farmacológico , Diagnóstico Diferencial , Diarreia/etiologia , Feminino , Hemorragia Gastrointestinal/etiologia , Humanos , Imunossupressores/uso terapêutico , Rim/diagnóstico por imagem , Púrpura Trombocitopênica Idiopática/etiologia , Trombocitopenia/etiologia , Tomografia Computadorizada por Raios XAssuntos
Dor Abdominal/etiologia , Criptococose/diagnóstico , Cryptococcus neoformans/isolamento & purificação , Hospedeiro Imunocomprometido , Linfoma Difuso de Grandes Células B/complicações , Antineoplásicos Imunológicos/efeitos adversos , Criptococose/complicações , Diagnóstico Diferencial , Evolução Fatal , Glucocorticoides/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
Cryptococcosis is a common invasive fungal infection (IFI) in solid organ transplant (SOT) recipients. Little is known about cryptococcosis in lung transplant (LTx) recipients despite having one of the highest risks of infection. The aim of this study was to describe demographic and clinical features of cryptococcal infection in LTx recipients. We performed a retrospective, observational study of cryptococcal infection in LTx recipients at The Alfred Hospital in Melbourne, Australia, from 2012 to 2017. A total of 11 cases were identified. Seven patients (64%) were male and the median age was 54.7 years (range 34-69 years). Diagnosis occurred at a median of 233 days (range 1-3650 days) post-transplant. Nine patients (82%) had isolated pulmonary infection of whom 7 (78%) were asymptomatic. All were treated with oral antifungal therapy and 1 required surgical resection of infected lung. Two patients (18%) had disseminated infection; 1 with pulmonary and central nervous system (CNS) infection and 1 with isolated CNS infection. Both patients presented with headache and brain imaging demonstrated cerebral edema, myelinosis, and leptomeningeal enhancement. One of these patients died. This study highlights the fact that cryptococcal infection should remain a consideration in asymptomatic LTx recipients, especially in the presence of non-specific nodules on chest imaging, and that the presence of headache in these patients requires urgent investigation for CNS infection.
Assuntos
Infecções Fúngicas do Sistema Nervoso Central/epidemiologia , Criptococose/epidemiologia , Cryptococcus/isolamento & purificação , Pneumopatias Fúngicas/epidemiologia , Transplante de Pulmão/efeitos adversos , Adulto , Idoso , Austrália/epidemiologia , Infecções Fúngicas do Sistema Nervoso Central/microbiologia , Criptococose/microbiologia , Feminino , Humanos , Pneumopatias Fúngicas/microbiologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Mycobacterium abscessus infection following lung transplantation has historically been associated with poor outcomes. We report a case of bilateral lung retransplantation complicated by obstruction of the right pulmonary artery secondary to M. abscessus mycotic aneurysm. Aggressive surgical management, including reconstruction of the right pulmonary artery, was undertaken with prolonged antimicrobial therapy. Thirty-six months later, antibiotics have been discontinued and the patient has stable soft tissue chest wall disease with good graft function. Mortality and morbidity associated with M. abscessus infection is considerable but this case illustrates that with aggressive early management, outcomes may be favorable.
Assuntos
Antibacterianos/uso terapêutico , Transplante de Pulmão/efeitos adversos , Infecções por Mycobacterium não Tuberculosas/etiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Mycobacterium abscessus , Artéria Pulmonar/patologia , Adulto , Antibacterianos/administração & dosagem , Humanos , Masculino , Complicações Pós-Operatórias/terapia , Artéria Pulmonar/microbiologia , Artéria Pulmonar/cirurgiaRESUMO
Given the long term sequelae of untreated neurosyphilis and insensitive tests to detect treponemes in the cerebrospinal fluid, questions regarding the utility of a lumbar puncture and cerebrospinal fluid analysis either to confirm or exclude neurosyphilis are raised.
Assuntos
Gerenciamento Clínico , Neurossífilis/diagnóstico , Neurossífilis/terapia , Treponema pallidum/isolamento & purificação , Australásia/epidemiologia , Testes Diagnósticos de Rotina/métodos , Humanos , Neurossífilis/epidemiologia , Sorodiagnóstico da Sífilis/métodos , Fatores de TempoRESUMO
BACKGROUND: Invasive and disseminated Mycoplasma hominis infections are well recognized but uncommon complications in solid organ transplant recipients. In a single center, a cluster of M. hominis infections were identified in lung transplant recipients from the same thoracic intensive care unit (ICU). We sought to determine the source(s) of these infections. METHODS: Medical records of the donor and infected transplant recipients were reviewed for clinical characteristics. Clinical specimens underwent routine processing with subculture on Mycoplasma-specific Hayflick agar. Mycoplasma hominis identification was confirmed using sequencing of the 16S ribosomal RNA gene. Mycoplasma hominis isolates were subjected to whole-genome sequencing on the Illumina NextSeq platform. RESULTS: Three lung transplant recipients presented with invasive M. hominis infections at multiple sites characterized by purulent infections without organisms detected by Gram staining. Each patient had a separate donor; however, pretransplant bronchoalveolar lavage fluid was only available from the donor for patient 1, which subsequently grew M. hominis. Phylo- and pangenomic analyses indicated that the isolates from the donor and the corresponding recipient (patient 1) were closely related and formed a distinct single clade. In contrast, isolates from patients 2 and 3 were unrelated and divergent from one another. CONCLUSIONS: Mycoplasma hominis should be considered a cause of donor-derived infection. Genomic data suggest donor-to-recipient transmission of M. hominis. Additional patients co-located in the ICU were found to have genetically unrelated M. hominis isolates, excluding patient-to-patient transmission.
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Transplante de Pulmão/efeitos adversos , Infecções por Mycoplasma/etiologia , Infecções por Mycoplasma/microbiologia , Mycoplasma hominis/genética , Transplantados , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Filogenia , Doadores de TecidosAssuntos
Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Humanos , SARS-CoV-2RESUMO
We used a next-generation sequencing platform to characterize microbial cell-free DNA (mcfDNA) in plasma samples from patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). In this observational study, we sought to characterize plasma mcfDNA in order to explore its potential association with the immunologic complications of transplantation. We compared serially collected patient samples with plasma collected from healthy control subjects. We observed changes in total mcfDNA burden in the plasma after transplantation, which was most striking during the early posttransplant neutropenic phase. This elevation could be attributed to a number of specific bacterial taxa, including Veillonella, Bacteroides, and Prevotella (genus level). For an additional cohort of patients, we compared the data of mcfDNA from plasma with 16s-ribosomal RNA sequencing data from stool samples collected at matched time points. In a number of patients, we confirmed that mcfDNA derived from specific microbial taxa (eg, Enterococcus) could also be observed in the matched stool sample. Quantification of mcfDNA may generate novel insights into mechanisms by which the intestinal microbiome influences systemic cell populations and, thus, has been associated with outcomes for patients with cancer.