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1.
Blood Adv ; 5(23): 5312-5322, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34619768

RESUMO

Infections are a known complication of chimeric antigen receptor (CAR) T-cell therapy with data largely emerging from CD19 CAR T-cell targeting. As CAR T-cell therapy continues to evolve, infection risks and management thereof will become increasingly important to optimize outcomes across the spectrum of antigens and disease targeted. We retrospectively characterized infectious complications occurring in 162 children and adults treated among 5 phase 1 CAR T-cell clinical trials. Trials included targeting of CD19, CD22, disialoganglioside (GD2) or B-cell maturation antigen (BCMA). Fifty-three patients (32.7%) had 76 infections between lymphocyte depleting (LD) chemotherapy and day 30 (D30); with the majority of infections (61, 80.3%) occurring between day 0 (D0) and D30. By trial, the highest proportion of infections was seen with CD22 CAR T cells (n = 23/53; 43.4%), followed by BCMA CAR T cells (n = 9/24; 37.5%). By disease, patients with multiple myeloma had the highest proportion of infections (9/24; 37.5%) followed by acute lymphoblastic leukemia (36/102; 35.3%). Grade 4 infections were rare (n = 4; 2.5%). Between D0 and D30, bacteremia and bacterial site infections were the most common infection type. In univariate analysis, increasing prior lines of therapy, recent infection within 100 days of LD chemotherapy, corticosteroid or tocilizumab use, and fever and neutropenia were associated with a higher risk of infection. In a multivariable analysis, only prior lines of therapy and recent infection were associated with higher risk of infection. In conclusion, we provide a broad overview of infection risk within the first 30 days post infusion across a host of multiple targets and diseases, elucidating both unique characteristics and commonalities highlighting aspects important to improving patient outcomes.

2.
Transpl Infect Dis ; 23(5): e13714, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34435415

RESUMO

BACKGROUND: Invasive fungal infection (IFI) in heart transplant recipients is associated with poor outcomes. Estimated risk of 1-year IFI in heart transplant recipients is 3.4-8.6% with risk factors inconsistently identified in previous studies. The role of antifungal prophylaxis is unclear. The transplant program at Mayo Clinic provides 6 months of universal azole prophylaxis for those heart transplant recipients in Arizona. We sought to define risk factors for 1-year IFI and determine the effect of antifungal prophylaxis. METHODS: We conducted a retrospective cohort study of patients undergoing heart transplantation at Mayo Clinic from January 2000 to March 2019. We analyzed demographics, details of transplant hospitalization, antifungal prophylaxis, and fungal infection. Multivariable Cox analyses were performed to identify risk factors of 1-year IFI and impact of IFI on posttransplant mortality. RESULTS: A total of 966 heart transplant recipients were identified with a median age of 56 years (IQR 47, 62). A total of 444 patients received antifungal prophylaxis. Over 1-year follow-up, 62 patients developed IFI with a cumulative incidence of 6.4%. In multivariable analysis, factors associated with IFI were renal replacement therapy (RRT) (HR 3.24, 95% CI 1.65-6.39), allograft rejection (HR 2.33, 95% CI 1.25-4.34), and antifungal prophylaxis (HR 0.32, 95% CI 0.11-0.96). RRT was also associated with invasive mold infection (HR 3.00, 95% CI 1.29-6.97). CONCLUSIONS: RRT and allograft rejection after transplantation are associated with 1-year IFI, and RRT is also associated with invasive mold infection. Antifungal prophylaxis appears to be protective and further study is needed in the heart transplant population.


Assuntos
Transplante de Coração , Infecções Fúngicas Invasivas , Antifúngicos/uso terapêutico , Transplante de Coração/efeitos adversos , Humanos , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/prevenção & controle , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Transplantados
3.
Medicine (Baltimore) ; 100(24): e26371, 2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34128896

RESUMO

ABSTRACT: Most patients with coronavirus disease 2019 (COVID-19) have mild to moderate illness not requiring hospitalization. However, no study has detailed the evolution of symptoms in the first month of illness.At our institution, we conducted remote (telephone and video) visits for all adult outpatients diagnosed with COVID-19 within 24 h of a positive nasopharyngeal polymerase chain test for SARS-CoV-2. We repeated regular video visits at 7, 14, and 28 days after the positive test, retrospectively reviewed the prospective data collected in the remote visits, and constructed a week by week profile of clinical illness, through week 4 of illness.We reviewed the courses of 458 symptomatic patients diagnosed between March 12, 2020, and June 22, 2020, and characterized their weekly courses. Common initial symptoms included fever, headache, cough, and chest pain, which frequently persisted through week 3 or longer. Upper respiratory or gastrointestinal symptoms were much shorter lived, present primarily in week 1. Anosmia/ageusia peaked in weeks 2 to 3. Emergency department visits were frequent, with 128 visits in the 423 patients who were not hospitalized and 48 visits among the 35 outpatients (7.6%) who were eventually hospitalized (2 subsequently died). By the fourth week, 28.9% said their illness had completely resolved. After the 4-week follow up, 20 (4.7%) of the 423 nonhospitalized patients had further medical evaluation and management for subacute or chronic COVID-19 symptoms.Mild to moderate outpatient COVID-19 is a prolonged illness, with evolving symptoms commonly lasting into the fourth week of illness.


Assuntos
Assistência Ambulatorial , COVID-19/complicações , COVID-19/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anosmia/etiologia , COVID-19/diagnóstico , Dor no Peito/etiologia , Tosse/etiologia , Dispneia/etiologia , Serviço Hospitalar de Emergência , Fadiga/etiologia , Feminino , Febre/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mialgia/etiologia , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
4.
J Fungi (Basel) ; 7(5)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925759

RESUMO

Coccidioides is an endemic fungus of the Southwest United States that causes the disease coccidioidomycosis. Immunocompromised persons are at increased risk for severe infection and dissemination. One such population is allogeneic bone marrow transplant (allo-HCT) recipients, but accounts of coccidioidal infection in these patients have rarely been documented. We present two cases of Coccidioides in allo-HCT recipients with good outcomes: one patient who developed pulmonary coccidioidomycosis in the late post-engraftment phase and another with known controlled disseminated infection at the time of transplant. A review of the literature identified 19 allo-HCT recipients with coccidioidomycosis. Due to the limited published literature, no guidelines have yet been established regarding optimal prophylaxis and treatment of Coccidioides infection in allo-HCT recipients. Candidates for transplantation should undergo a rigorous pre-transplant assessment to identify evidence of prior or active coccidioidomycosis. In our experience, patients who visit or live in Coccidioides-endemic areas should receive primary prophylaxis for at least the first 100 days post-transplant, and duration should be extended as long as the patient remains on immunosuppression. Those with prior infection should receive secondary prophylaxis while immunosuppressed. Patients with active infection should have treatment and stabilization of infection and continue anti-fungal treatment through immunosuppression.

5.
Case Rep Crit Care ; 2021: 6612710, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33552603

RESUMO

Background: Hemophagocytic lymphohistiocytosis (HLH) was originally described in pediatric patients presenting with fever, hepatosplenomegaly, and blood cell abnormalities. Later, HLH was recognized to occur in adults, often associated with hematologic malignancies or serious infections. Conclusion: Patients presenting with HLH are critically ill, and rapid diagnosis is key. In adults, the search for the trigger must begin promptly as time to diagnosis effects survival. The underlying trigger in our patients was Histoplasma capsulatum infection, which is rare in the southwestern United States. Prompt diagnosis led to recovery in one patient, while the other did not survive.

6.
J Clin Immunol ; 40(7): 1045-1047, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32696284

RESUMO

This is a report of a successful bone marrow transplant in an IFN-γR1 patient with progressive mycobacterial infection. PURPOSE: Hematopoietic cell transplant in patients with interferon gamma receptor deficiencies has been fraught with challenges, not the least of which is failure of engraftment and infectious complications. METHODS: This is a report of a successful hematopoietic cell transplant in an actively infected patient of advanced age. RESULTS: This case report shows successful engraftment and resolution of infection posttransplant using a matched related donor in a single institution. CONCLUSION: A successful curative HCT despite persistent, disseminated, nontuberculous mycobacterial infection in a patient with AD-IFNγR1 suggests that this approach, while difficult, may be useful in other patients with otherwise refractory disease.


Assuntos
Transplante de Medula Óssea , Genes Dominantes , Estudos de Associação Genética , Predisposição Genética para Doença , Receptores de Interferon/deficiência , Transplante de Células-Tronco Hematopoéticas , Humanos , Infecções por Mycobacterium/diagnóstico , Infecções por Mycobacterium/etiologia , Infecções por Mycobacterium/terapia , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/etiologia , Infecções por Mycobacterium não Tuberculosas/terapia , Índice de Gravidade de Doença , Transplante Homólogo , Resultado do Tratamento
7.
JAMA Oncol ; 6(5): 696-705, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105293

RESUMO

Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/imunologia , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Feminino , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
Biol Blood Marrow Transplant ; 26(1): 94-106, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31493539

RESUMO

Allogeneic blood or marrow transplantation (BMT) is a potentially curative therapy for patients with primary immunodeficiency (PID). Safe and effective reduced-intensity conditioning (RIC) approaches that are associated with low toxicity, use alternative donors, and afford good immune reconstitution are needed to advance the field. Twenty PID patients, ranging in age from 4 to 58 years, were treated on a prospective clinical trial of a novel, radiation-free and serotherapy-free RIC, T-cell-replete BMT approach using pentostatin, low-dose cyclophosphamide, and busulfan for conditioning with post-transplantation cyclophosphamide-based graft-versus-host-disease (GVHD) prophylaxis. This was a high-risk cohort with a median hematopoietic cell transplantation comorbidity index of 3. With median follow-up of survivors of 1.9 years, 1-year overall survival was 90% and grade III to IV acute GVHD-free, graft-failure-free survival was 80% at day +180. Graft failure incidence was 10%. Split chimerism was frequently observed at early post-BMT timepoints, with a lower percentage of donor T cells, which gradually increased by day +60. The cumulative incidences of grade II to IV and grade III to IV acute GVHD (aGVHD) were 15% and 5%, respectively. All aGVHD was steroid responsive. No patients developed chronic GVHD. Few significant organ toxicities were observed. Evidence of phenotype reversal was observed for all engrafted patients, even those with significantly mixed chimerism (n = 2) or with unknown underlying genetic defect (n = 3). All 6 patients with pre-BMT malignancies or lymphoproliferative disorders remain in remission. Most patients have discontinued immunoglobulin replacement. All survivors are off immunosuppression for GVHD prophylaxis or treatment. This novel RIC BMT approach for patients with PID has yielded promising results, even for high-risk patients.


Assuntos
Transplante de Medula Óssea , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Pentostatina/administração & dosagem , Condicionamento Pré-Transplante , Adolescente , Adulto , Bussulfano/efeitos adversos , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Transfusão de Linfócitos , Masculino , Pessoa de Meia-Idade , Pentostatina/efeitos adversos , Doenças da Imunodeficiência Primária/mortalidade , Doenças da Imunodeficiência Primária/terapia , Estudos Prospectivos , Taxa de Sobrevida
9.
Clin Infect Dis ; 70(4): 676-679, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-31190050

RESUMO

Patients with primary immunodeficiencies undergoing allogeneic hematopoietic cell transplantation (HCT) for difficult-to-control infections can experience immune reconstitution inflammatory syndrome (IRIS) following engraftment. In 3 patients with post-HCT IRIS related to mycobacterial infection, in vitro data demonstrate the emergence of pathogen-specific immune responses and a concomitant rise in plasma inflammatory markers.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndrome Inflamatória da Reconstituição Imune , Infecções por Mycobacterium , Doenças da Imunodeficiência Primária , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Mycobacterium avium
10.
mBio ; 10(5)2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530672

RESUMO

Strains of Pseudomonas aeruginosa with deficiencies in DNA mismatch repair have been studied in the context of chronic infection, where elevated mutational rates ("hypermutation") may facilitate the acquisition of antimicrobial resistance. Whether P. aeruginosa hypermutation can also play an adaptive role in the more dynamic context of acute infection remains unclear. In this work, we demonstrate that evolved mismatch repair deficiencies may be exploited by P. aeruginosa to facilitate rapid acquisition of antimicrobial resistance in acute infection, and we directly document rapid clonal succession by such a hypermutating lineage in a patient. Whole-genome sequencing (WGS) was performed on nine serially cultured blood and respiratory isolates from a patient in whom ceftazidime-avibactam (CZA) resistance emerged in vivo over the course of days. The CZA-resistant clone was differentiated by 14 mutations, including a gain-of-function G183D substitution in the PDC-5 chromosomal AmpC cephalosporinase conferring CZA resistance. This lineage also contained a substitution (R656H) at a conserved position in the ATPase domain of the MutS mismatch repair (MMR) protein, and elevated mutational rates were confirmed by mutational accumulation experiments with WGS of evolved lineages in conjunction with rifampin resistance assays. To test whether MMR-deficient hypermutation could facilitate rapid acquisition of CZA resistance, in vitro adaptive evolution experiments were performed with a mutS-deficient strain. These experiments demonstrated rapid hypermutation-facilitated acquisition of CZA resistance compared with the isogenic wild-type strain. Our results suggest a possibly underappreciated role for evolved MMR deficiency in facilitating rapid adaptive evolution of P. aeruginosa in the context of acute infection.IMPORTANCE Antimicrobial resistance in bacteria represents one of the most consequential problems in modern medicine, and its emergence and spread threaten to compromise central advances in the treatment of infectious diseases. Ceftazidime-avibactam (CZA) belongs to a new class of broad-spectrum beta-lactam/beta-lactamase inhibitor combinations designed to treat infections caused by multidrug-resistant bacteria. Understanding the emergence of resistance to this important new drug class is of critical importance. In this work, we demonstrate that evolved mismatch repair deficiency in P. aeruginosa, an important pathogen responsible for significant morbidity and mortality among hospitalized patients, may facilitate rapid acquisition of resistance to CZA in the context of acute infection. These findings are relevant for both diagnosis and treatment of antimicrobial resistance emerging in acute infection in the hypermutator background and additionally have implications for the emergence of more virulent phenotypes.


Assuntos
Compostos Azabicíclicos/farmacologia , Ceftazidima/farmacologia , Reparo de Erro de Pareamento de DNA , Farmacorresistência Bacteriana Múltipla/genética , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Doença Aguda , Antibacterianos/farmacologia , Evolução Molecular Direcionada , Combinação de Medicamentos , Evolução Fatal , Humanos , Testes de Sensibilidade Microbiana , Mutação , Infecções por Pseudomonas/sangue , Infecções por Pseudomonas/microbiologia , Sistema Respiratório/microbiologia , Sequenciamento Completo do Genoma
12.
Biol Blood Marrow Transplant ; 25(2): 362-368, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30287390

RESUMO

We analyzed late fatal infections (LFIs) in allogeneic stem cell transplantation (HCT) recipients reported to the Center for International Blood and Marrow Transplant Research. We analyzed the incidence, infection types, and risk factors contributing to LFI in 10,336 adult and 5088 pediatric subjects surviving for ≥2 years after first HCT without relapse. Among 2245 adult and 377 pediatric patients who died, infections were a primary or contributory cause of death in 687 (31%) and 110 (29%), respectively. At 12 years post-HCT, the cumulative incidence of LFIs was 6.4% (95% confidence interval [CI], 5.8% to 7.0%) in adults, compared with 1.8% (95% CI, 1.4% to 2.3%) in pediatric subjects; P < .001). In adults, the 2 most significant risks for developing LFI were increasing age (20 to 39, 40 to 54, and ≥55 years versus 18 to 19 years) with hazard ratios (HRs) of 3.12 (95% CI, 1.33 to 7.32), 3.86 (95% CI, 1.66 to 8.95), and 5.49 (95% CI, 2.32 to 12.99) and a history of chronic graft-versus-host disease GVHD (cGVHD) with ongoing immunosuppression at 2 years post-HCT compared with no history of GVHD with (HR, 3.87; 95% CI, 2.59 to 5.78). In pediatric subjects, the 3 most significant risks for developing LFI were a history of cGVHD with ongoing immunosuppression (HR, 9.49; 95% CI, 4.39 to 20.51) or without ongoing immunosuppression (HR, 2.7; 95% CI, 1.05 to 7.43) at 2 years post-HCT compared with no history of GVHD, diagnosis of inherited abnormalities of erythrocyte function compared with diagnosis of acute myelogenous leukemia (HR, 2.30; 95% CI, 1.19 to 4.42), and age >10 years (HR, 1.92; 95% CI, 1.15 to 3.2). This study emphasizes the importance of continued vigilance for late infections after HCT and institution of support strategies aimed at decreasing the risk of cGVHD.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Infecções/mortalidade , Leucemia Mieloide Aguda , Adolescente , Adulto , Fatores Etários , Idoso , Aloenxertos , Criança , Pré-Escolar , Doença Crônica , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
13.
Biol Blood Marrow Transplant ; 25(3): 577-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30342913

RESUMO

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.


Assuntos
Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Antivirais/uso terapêutico , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Estudos Retrospectivos , Fatores de Risco , Esteroides/efeitos adversos , Doadores de Tecidos , Estados Unidos
14.
Curr Opin Organ Transplant ; 23(4): 375-380, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29889152

RESUMO

PURPOSE OF REVIEW: The current review highlights the most relevant articles on lung infections following hematopoietic stem cell transplantation (HCT) published over the last year. Between 30 and 50% of HCT recipients will develop pulmonary infiltrates. These pulmonary complications may be infectious (caused by virus, bacteria, fungi, or protozoa) or noninfectious (e.g., fluid overload, heart failure, transfusion reactions like transfusion associated lung injury and transfusion-associated circulatory overload, drug reactions, engraftment syndrome, idiopathic pneumonia syndrome, diffuse alveolar hemorrhage, cryptogenic organizing pneumonia, and bronchiolitis obliterans syndrome). RECENT FINDINGS: New data on the yield of bronchoscopy and bronchoalveolar lavage (BAL), the prevalence and clinical manifestations of respiratory viruses and the usefulness of molecular techniques for diagnosis have been published. In addition, guidelines or meta-analyses on the management of neutropenic fever, serological diagnosis of fungal infections and diagnosis and management of Pneumocystis and aspergillosis have been published. SUMMARY: Respiratory viruses are important pathogens after HCT. PCR in the BAL is becoming the diagnostic modality of choice for a variety of infections. The best approach for the empirical management of pulmonary infiltrates following HCT remains to be defined.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pneumopatias/diagnóstico , Pneumopatias/etiologia , Humanos , Pneumopatias/microbiologia , Pneumopatias/patologia , Guias de Prática Clínica como Assunto
15.
Blood Rev ; 32(5): 387-399, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29571669

RESUMO

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies.


Assuntos
Infecções/etiologia , Leucemia Linfocítica Crônica de Células B/complicações , Terapia de Alvo Molecular/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Imunoterapia/efeitos adversos , Imunoterapia/métodos , Controle de Infecções , Infecções/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Leucemia Linfocítica Crônica de Células B/metabolismo
16.
Lancet Haematol ; 5(1): e44-e52, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29248669

RESUMO

BACKGROUND: Haemopoietic stem-cell transplantation (HSCT) eradicates host haemopoiesis before venous infusion of haemopoietic stem cells (HSCs). The pathway to cellular recovery has been difficult to study in human beings because of risks associated with interventions during aplasia. We investigated whether 18F-fluorothymidine (18F-FLT) imaging was safe during allogenic HSCT and allowed visualisation of early cellular proliferation and detection of patterns of cellular engraftment after HSCT. METHODS: Eligible patients were aged 18-55 years, had high-risk haematological malignancies. All patients underwent myeloablation followed by HSCT. The imaging primary endpoint was detection of early subclinical engraftment after HSCT with 18F-FLT PET or CT. Imaging was done 1 day before and 5 or 9, and 28 days, and 1 year after HSCT. This study is registered with ClinicalTrials.gov, number NCT01338987. FINDINGS: Between April 1, 2014, and Dec 31, 2015, 23 patients were enrolled and assessable for toxic effects after completing accrual. 18F-FLT was not associated with any adverse events or delayed engraftment. 18F-FLT imaging objectively identified subclinical bone-marrow recovery within 5 days of HSC infusion, which was up to 20 days before engraftment became clinically evident. Quantitatively, 18F-FLT intensity differed significantly between myeloablative infusion before HSCT and subclinical HSC recovery (p=0·00031). 18F-FLT biodistribution over time revealed a previously unknown path of cellular recovery of haemopoiesis in vivo that mirrored fetal ontogeny. INTERPRETATION: 18F-FLT allowed quantification and tracking of subclinical bone-marrow repopulation in human beings and revealed new insights into the biology of HSC recovery after HSCT. FUNDING: National Institutes of Health, Ben's Run/Ben's Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund, and Oklahoma Center for Adult Stem Cell Research.


Assuntos
Neoplasias Hematológicas/diagnóstico por imagem , Neoplasias Hematológicas/cirurgia , Transplante de Células-Tronco Hematopoéticas , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Adulto , Didesoxinucleosídeos/farmacocinética , Feminino , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos , Distribuição Tecidual
17.
Cytotherapy ; 19(11): 1256-1269, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28916227

RESUMO

Granulocyte transfusions (GTXs) have been used to treat and prevent infections in neutropenic patients for more than 40 years, despite persistent controversy regarding their efficacy. This narrative review attempts to complement recent systematic reviews by the Cochrane Collaboration and provide both historical context and critical assessment of the most significant clinical studies published over the years. The data suggest that properly collected and promptly infused granulocytes are active against infections, both bacterial and fungal. The most important question that remains unanswered is in which patients the administration of granulocytes will be beneficial. The preponderance of evidence suggests that granulocyte transfusions may be efficacious in few select cases as a temporizing measure to control an infection that is expected (or proven) to be refractory to optimal antimicrobial treatment, and that could otherwise be controlled by marrow recovery, which is expected to happen. In this regard, they are best considered a "bridge" that grants enough time for the recipient to develop their own response to the infection. The challenges to use GTXs successfully are both clinical, in terms of timely identifying the patients who may benefit, and logistical, in terms of optimal selection of donors and collection technique.


Assuntos
Granulócitos/transplante , Infecções/terapia , Transfusão de Leucócitos/métodos , Anemia Aplástica/tratamento farmacológico , Anemia Aplástica/microbiologia , Anemia Aplástica/terapia , Estudos de Casos e Controles , Criança , Ensaios Clínicos Controlados como Assunto , Humanos , Controle de Infecções/métodos , Transfusão de Leucócitos/efeitos adversos , Neutropenia/terapia , Doadores de Tecidos , Resultado do Tratamento
18.
Leuk Res Rep ; 8: 4-6, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28794968

RESUMO

Disseminated Fusarium infection is associated with high mortality in immunocompromised patients. Patients with acute myeloid leukemia (AML) often have an extended duration of neutropenia during intensive induction chemotherapy, consolidation chemotherapy, and hematopoietic stem cell transplantation (SCT). There is no consensus regarding management of invasive disseminated Fusarium infections in the setting of prolonged neutropenia (Tortorano et al., 2014) [1]. We report a case of disseminated Fusarium in a patient with relapsed AML who underwent successful chemotherapy and haplo-identical allogeneic SCT with administration of granulocyte colony stimulating factor (G-CSF) and granulocyte infusions.

19.
Cancer Cell ; 31(6): 833-843.e5, 2017 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-28552327

RESUMO

Primary CNS lymphoma (PCNSL) harbors mutations that reinforce B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, targets BCR signaling and is particularly active in lymphomas with mutations altering the BCR subunit CD79B and MYD88. We performed a proof-of-concept phase Ib study of ibrutinib monotherapy followed by ibrutinib plus chemotherapy (DA-TEDDi-R). In 18 PCNSL patients, 94% showed tumor reductions with ibrutinib alone, including patients having PCNSL with CD79B and/or MYD88 mutations, and 86% of evaluable patients achieved complete remission with DA-TEDDi-R. Increased aspergillosis was observed with ibrutinib monotherapy and DA-TEDDi-R. Aspergillosis was linked to BTK-dependent fungal immunity in a murine model. PCNSL is highly dependent on BCR signaling, and ibrutinib appears to enhance the efficacy of chemotherapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Linfoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Idoso , Idoso de 80 Anos ou mais , Animais , Aspergilose/epidemiologia , Aspergilose/imunologia , Neoplasias Encefálicas/metabolismo , Antígenos CD79/genética , Quimioterapia Combinada , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Técnicas de Inativação de Genes , Humanos , Linfoma/metabolismo , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Piperidinas , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/imunologia , Pirazóis/efeitos adversos , Pirazóis/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Br J Haematol ; 177(3): 357-374, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28295178

RESUMO

Granulocyte transfusions have a long history of being used in patients with neutropenia or neutrophil dysfunction to prevent and treat invasive fungal infections. However, there are limited and conflicting data concerning its clinical effectiveness, considerable variations in current granulocyte transfusion practices, and uncertainties about its benefit as an adjunct to modern antifungal therapy. In this review, we provide an overview on granulocyte transfusions and summarize the evidence on their role in the prevention and treatment of invasive fungal infections.


Assuntos
Granulócitos/transplante , Infecções Fúngicas Invasivas/terapia , Transfusão de Leucócitos/métodos , Seleção do Doador , Medicina Baseada em Evidências/métodos , Humanos , Infecções Fúngicas Invasivas/sangue , Transfusão de Leucócitos/efeitos adversos , Neutrófilos/fisiologia
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