RESUMO
Over the last decade, the therapeutic landscape for hematological malignancies (HMs) has witnessed a remarkable surge in the development of novel biological and small-molecule-targeted immunomodulatory agents. These therapies have drastically improved survival, but some come at the cost of increased risk of bacterial, viral, and/or fungal infections and on-target off-tumor immunological side effects. To mitigate such risks, physicians must be well informed about infectious complications and necessary preventive measures, such as screening, vaccinations, and antimicrobial prophylaxis. Furthermore, physicians should be vigilant about the noninfectious side effects of these agents that can mimic infections and understand their potential drug-drug interactions with antimicrobials. Strengthening and harmonizing the current surveillance and reporting system for drug-associated infections in real-world settings is essential to better ascertain the potential infections associated with these agents. In this review, we aimed to summarize the infection risks associated with novel agents used for specific HMs and outline recommended strategies for monitoring and prophylaxis.
Assuntos
Neoplasias Hematológicas , Terapia de Alvo Molecular , Humanos , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Adulto , Micoses/prevenção & controle , Micoses/tratamento farmacológicoRESUMO
Aspergillus species and Mucorales agents are the primary etiologies of invasive fungal disease (IFD). Biomarkers that predict outcomes are needed to improve care. Patients diagnosed with invasive aspergillosis and mucormycosis using plasma cell-free DNA (cfDNA) PCR were retested weekly for 4 weeks. The primary outcome included all-cause mortality at 6 weeks and 6 months based on baseline cycle threshold (CT) values and results of follow-up cfDNA PCR testing. Forty-five patients with Aspergillus and 30 with invasive Mucorales infection were retested weekly for a total of 197 tests. Using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSG) criteria, 30.7% (23/75), 25.3% (19/75), and 38.7% (29/75) had proven, probable, and possible IFD, respectively. In addition, 97.3% (73/75) were immunocompromised. Baseline CT increased significantly starting at week 1 for Mucorales and week 2 for Aspergillus. Aspergillosis and mucormycosis patients with higher baseline CT (CT >40 and >35, respectively) had a nonsignificantly higher survival rate at 6 weeks, compared with patients with lower baseline CT. Mucormycosis patients with higher baseline CT had a significantly higher survival rate at 6 months. Mucormycosis, but not aspergillosis patients, with repeat positive cfDNA PCR results had a nonsignificantly lower survival rate at 6 weeks and 6 months compared with patients who reverted to negative. Aspergillosis patients with baseline serum Aspergillus galactomannan index <0.5 and <1.0 had significantly higher survival rates at 6 weeks when compared with those with index ≥0.5 and ≥1.0, respectively. Baseline plasma cfDNA PCR CT can potentially be used to prognosticate survival in patients with invasive Aspergillus and Mucorales infections. IMPORTANCE: We show that Aspergillus and Mucorales plasma cell-free DNA PCR can be used not only to noninvasively diagnose patients with invasive fungal disease but also to correlate the baseline cycle threshold with survival outcomes, thus potentially allowing the identification of patients at risk for poor outcomes, who may benefit from more targeted therapies.
Assuntos
Ácidos Nucleicos Livres , DNA Fúngico , Infecções Fúngicas Invasivas , Mucormicose , Reação em Cadeia da Polimerase , Humanos , Mucormicose/diagnóstico , Mucormicose/mortalidade , Mucormicose/sangue , Mucormicose/microbiologia , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Ácidos Nucleicos Livres/sangue , Reação em Cadeia da Polimerase/métodos , Adulto , DNA Fúngico/genética , DNA Fúngico/sangue , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/mortalidade , Infecções Fúngicas Invasivas/microbiologia , Aspergillus/genética , Aspergillus/isolamento & purificação , Aspergilose/diagnóstico , Aspergilose/mortalidade , Aspergilose/microbiologia , Mucorales/genética , Mucorales/isolamento & purificação , Biomarcadores/sangue , Idoso de 80 Anos ou mais , Estudos ProspectivosRESUMO
BACKGROUND: Neuroinvasive infection with Francisella tularensis, the causative agent of tularemia, is rare. Establishing clinical suspicion is challenging if risk factors or clinical features classically associated with tularemia are absent. Tularemia is treatable with antibiotics; however, there are limited data to inform management of potentially fatal neuroinvasive infection. METHODS: We collected epidemiologic and clinical data on 2 recent US cases of neuroinvasive F. tularensis infection, and performed a literature review of cases of neuroinvasive F. tularensis infection published after 1950. RESULTS: One patient presented with focal neurologic deficits and brain lesions; broad-range molecular testing on resected brain tissue detected F. tularensis. The other patient presented with meningeal signs; tularemia was suspected based on animal exposure, and F. tularensis grew in cerebrospinal fluid (CSF) culture. Both patients received combination antibiotic therapy and recovered from infection. Among 16 published cases, tularemia was clinically suspected in 4 cases. CSF often displayed lymphocytic pleocytosis. Among cases with available data, CSF culture was positive in 13 of 16 cases, and F. tularensis antibodies were detected in 11 of 11 cases. Treatment typically included an aminoglycoside combined with either a tetracycline or a fluoroquinolone. Outcomes were generally favorable. CONCLUSIONS: Clinicians should consider neuroinvasive F. tularensis infection in patients with meningitis and signs suggestive of tularemia or compatible exposures, lymphocyte-predominant CSF, unrevealing standard microbiologic workup, or lack of response to empiric bacterial meningitis treatment. Molecular testing, culture, and serologic testing can reveal the diagnosis. Favorable outcomes can be achieved with directed antibiotic treatment.
Assuntos
Francisella tularensis , Meningite , Tularemia , Animais , Humanos , Tularemia/diagnóstico , Tularemia/tratamento farmacológico , Tularemia/microbiologia , Antibacterianos/uso terapêutico , Aminoglicosídeos/uso terapêuticoRESUMO
Leptospirosis is typically a self-limited febrile illness; when it occurs, meningitis usually develops early in the course. Here, we describe a patient who had engaged in freshwater activities in Kauai that was immunocompromised due to a history of mantle cell lymphoma, autologous hematopoietic cell transplant, and hypogammaglobulinemia. He developed leptospiral meningoencephalitis 11 weeks after illness onset and persistently detectable Leptospira DNA in blood and cerebrospinal fluid along with ongoing clinical illness, despite appropriate treatment.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leptospira , Leptospirose , Masculino , Humanos , Adulto , Recidiva Local de Neoplasia , Leptospirose/diagnóstico , Leptospirose/tratamento farmacológico , Leptospira/genética , Hospedeiro ImunocomprometidoRESUMO
Invasive fungal diseases (IFDs) are common in patients with acute myeloid leukemia (AML), but no recent data on incidence without antifungal prophylaxis are available. We evaluated the incidence of IFDs in patients with AML undergoing induction chemotherapy at Stanford University Hospital from 2012 to 2017, for up to 12 weeks after induction. We also analyzed factors associated with IFD development. Thirty-six of 240 patients (13%) developed at least one proven or probable IFD. Seventy-eight percent of the proven or probable IFDs were due to Candida or Aspergillus species. Infection due to Fusarium and Mucorales was uncommon. Absolute neutrophil count (ANC) of <500 µL/L at the start of induction was associated with an increased risk of IFD. One hundred and eighty-seven patients (78%) were started on systemic antifungal drugs, even without microbiologic evidence of an IFD. IFDs remain frequent in AML patients undergoing induction chemotherapy without antifungal prophylaxis.
Assuntos
Infecções Fúngicas Invasivas , Leucemia Mieloide Aguda , Adulto , Antifúngicos/uso terapêutico , Humanos , Incidência , Quimioterapia de Indução , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/epidemiologia , Infecções Fúngicas Invasivas/etiologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/epidemiologia , Estudos RetrospectivosAssuntos
Hematúria , Bexiga Urinária , Adulto , Feminino , Hematúria/diagnóstico , Hematúria/etiologia , Humanos , MasculinoRESUMO
BACKGROUND: Skull base osteomyelitis (SBO) is an infection of the central cranial bones, most commonly resulting from contiguous spread of infection from adjacent head and neck structures. SBO is a well-recognized complication of treatment of head and neck cancer (HNC) that results in significant morbidity. METHODS: We conducted a retrospective chart review of HNC patients diagnosed with SBO. RESULTS: SBO was commonly diagnosed with nasal endoscopy showing mucosal breakdown between the naso/oropharynx and skull base and with characteristic changes on CT/MRI. Culture data were often polymicrobial, inclusive of naso/oropharyngeal flora, but half of the patients additionally had antibiotic-resistant or atypical pathogens. The mean duration of antimicrobial therapy was 117 +/- 94 days. Recurrent SBO was found in half of the patients, associated with Pseudomonas aeruginosa and with persistent defects in the mucosa abutting the skull base. CONCLUSIONS: Diagnosis and management of SBO in HNC patients are challenging. Recommendations to aid in clinical care are proposed. LEVEL OF EVIDENCE: 4, case series.
RESUMO
Histoplasmosis-associated hemophagocytic lymphohistiocytosis is a rate but lethal disease in immunocompromised hosts. Unusual clinical presentations make diagnosing invasive fungal infection even more challenging. Here we present a case of hemophagocytic lymphohistiocytosis secondary to progressive disseminated histoplasmosis presenting as cellulitis in a patient with systemic lupus erythematous. A high index of suspicion combined with histopathology and molecular diagnostic techniques are important to establish an accurate and timely diagnosis of opportunistic infections in immunocompromised patients.
RESUMO
BACKGROUND: Invasive fungal infection (IFI) is a growing cause of morbidity and mortality in oncology and transplant patients. Diagnosis of IFI is often delayed due to need for invasive biopsy and low sensitivity of conventional diagnostic methods. Fungal cell-free DNA (cfDNA) detection in plasma is a novel testing modality for the noninvasive diagnosis of IFI. METHODS: A novel bioinformatic pipeline was created to interrogate fungal genomes and identify multicopy sequences for cfDNA polymerase chain reaction (PCR) targeting. A real-time PCR panel was developed for 12 genera and species most commonly causing IFI. Sensitivity and specificity of the fungal PCR panel were determined using plasma samples from patients with IFI and non-IFI controls. Clinical impact of the fungal PCR panel was evaluated prospectively based on the treating team's interpretation of the results. RESULTS: Overall, the sensitivity and specificity were 56.5% (65/115; 95% confidence interval [CI], 47.4-65.2) and 99.5% (2064/2075; 95% CI, 99.0-99.7), respectively. In the subset of patients with an optimized plasma volume (2 mL), sensitivity was 69.6% (48/69; 95% CI, 57.9-79.2). Sensitivity was 91.7% (11/12; 95% CI, 62.5-100) for detection of Mucorales agents, 56.3% (9/16; 95% CI, 33.2-76.9) for Aspergillus species, and 84.6% (11/13; 95% CI, 56.5-96.9) for Candida albicans. In a prospective evaluation of 226 patients with suspected IFI, cfDNA testing was positive in 47 (20.8%) patients and resulted in a positive impact on clinical management in 20 of 47 (42.6%). CONCLUSIONS: The fungal cfDNA PCR panel offers a noninvasive approach to early diagnosis of IFI, providing actionable results for personalized care.
Assuntos
Ácidos Nucleicos Livres , Infecções Fúngicas Invasivas , Micoses , Candida albicans , DNA Fúngico/genética , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Micoses/diagnóstico , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Cytomegalovirus (CMV) reactivation is common in organ transplant recipients and can lead to significant morbidity and mortality. Cutaneous CMV findings are rarely reported in the literature and diagnosis can be delayed if not clinically recognized. We describe a case of a female patient 20 years post renal transplant who presented with extensive ulcerative skin lesions and diarrhea. She rapidly deteriorated and died on day 5 of hospitalization. Autopsy noted extensive CMV involvement of skin and gastrointestinal (GI) tract by CMV-specific immunohistochemistry. These findings, along with high-grade CMV viremia, led to the final postmortem diagnosis of disseminated CMV infection. This case focuses on the cutaneous findings of disseminated CMV as recognition of CMV skin lesions can lead to earlier initiation of appropriate therapy in transplant recipients.
Assuntos
Infecções por Citomegalovirus , Transplante de Rim , Citomegalovirus , Infecções por Citomegalovirus/diagnóstico , Feminino , Humanos , Transplante de Rim/efeitos adversos , Transplantados , ViremiaRESUMO
Solid organ transplant recipients are at risk for infectious complications due to chronic immunosuppression. The outbreak of coronavirus disease 2019 (COVID-19) in the United States has raised growing concerns for the transplant patient population. We seek to add to the current limited literature on COVID-19 in transplant recipients by describing the clinical course of two kidney transplant recipients with SARS-CoV-2 infection monitored by both RT-PCR and serology. Through careful adjustment of their immunosuppression regimen, both patients had excellent recovery with intact graft function and development of anti-SARS-CoV-2 antibodies.
Assuntos
Imunossupressores/administração & dosagem , Imunossupressores/uso terapêutico , Transplante de Rim , SARS-CoV-2 , Transplantados , Idoso , Feminino , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , SoroconversãoRESUMO
BACKGROUND: Many studies have shown that invasive pulmonary aspergillosis, cryptococcosis, and mucormycosis can mimic radiographic and clinical features of primary lung cancer. However, more research surveying the incidence and outcomes of these fungal infections among patients with a history of lung cancer is needed. The aim of this study was to describe the occurrence and clinical outcomes of opportunistic invasive fungal infections that can mimic tumors in non-small-cell lung cancer patients. PATIENTS AND METHODS: Patients seen at Stanford University Medical Center from January 1, 2007, to May 1, 2020, with pulmonary aspergillosis, cryptococcosis, or mucormycosis after non-small-cell lung cancer (NSCLC) diagnosis were reviewed. The European Organization for Research and Treatment of Cancer National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria was used to classify patients with evidence of proven or probable invasive fungal infection within our cohort. RESULTS: A total of 12 patients with proven or probable invasive mold infection (including 8 cases of aspergillosis) and 1 patient with proven cryptococcosis were identified, without any cases of mucormycosis. Of this cohort, 6 patients (46%) showed radiographic findings that were found to be most consistent with lung cancer by radiologists. Eight cases (62%) were suspected of cancer recurrence or progression by the treatment team on the basis of additional considerations of medical history and clinical symptoms. Most patients had active NSCLC or had a history of recurrence without active NSCLC at the time of fungal discovery (11 patients; 85%). Most patients died without full recovery (7 patients; 54%). CONCLUSIONS: Invasive pulmonary aspergillosis and cryptococcosis can often be mistaken as cancer recurrence or progression in patients with a history of NSCLC because of mimicking radiographic and clinical characteristics.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/complicações , Infecções Fúngicas Invasivas/complicações , Neoplasias Pulmonares/complicações , Infecções Oportunistas/complicações , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/uso terapêutico , Antineoplásicos/uso terapêutico , Aspergilose/complicações , Aspergilose/diagnóstico , Aspergilose/patologia , Aspergilose/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Criptococose/complicações , Criptococose/diagnóstico , Criptococose/patologia , Criptococose/terapia , Diagnóstico Diferencial , Feminino , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/patologia , Infecções Fúngicas Invasivas/terapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/patologia , Infecções Oportunistas/terapia , Resultado do TratamentoRESUMO
Advances in solid organ transplantation have improved the survival of end-stage organ disease at the expense of an increased risk for opportunistic infections. Unusual clinical presentations and the possibility of concurrent infections make diagnosing invasive fungal infection (IFI) more difficult. Here, we present a case of simultaneous vertebral infection caused by Coccidioides immitis-posadasii and subcutaneous phaeohyphomycosis due to Nigrograna mackinnonii in a kidney transplant recipient. The diagnosis of both infections required invasive procedures to obtain tissue and a high index of suspicion that more than one IFI could be present. A multidisciplinary team approach for the management of immunocompromised patients with suspected or diagnosed IFI is warranted.
Assuntos
Coccidioidomicose/diagnóstico , Coinfecção/diagnóstico , Coinfecção/microbiologia , Transplante de Rim/efeitos adversos , Feoifomicose/diagnóstico , Antifúngicos/uso terapêutico , Ascomicetos/isolamento & purificação , Biópsia/métodos , Coccidioides/isolamento & purificação , Coccidioidomicose/tratamento farmacológico , Coccidioidomicose/microbiologia , Coinfecção/tratamento farmacológico , Humanos , Hospedeiro Imunocomprometido , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/microbiologia , Feoifomicose/tratamento farmacológico , Feoifomicose/microbiologia , Reação em Cadeia da Polimerase/métodos , Resultado do TratamentoAssuntos
Blastomicose/diagnóstico por imagem , Linfonodos/diagnóstico por imagem , Linfadenopatia/diagnóstico por imagem , Sarcoidose/diagnóstico , Infecções dos Tecidos Moles/diagnóstico , Nódulo Pulmonar Solitário/diagnóstico por imagem , Doença Aguda , Adulto , Antifúngicos/uso terapêutico , Blastomyces/genética , Blastomyces/isolamento & purificação , Blastomicose/tratamento farmacológico , Blastomicose/patologia , Broncoscopia , California , DNA Fúngico/genética , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Febre , Humanos , Índia/etnologia , Itraconazol/uso terapêutico , Linfonodos/patologia , Linfadenopatia/patologia , Ohio , Análise de Sequência de DNA , Infecções dos Tecidos Moles/tratamento farmacológico , Nódulo Pulmonar Solitário/tratamento farmacológico , TexasRESUMO
Herpesviruses such as herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), and cytomegalovirus (CMV) maintain lifelong latency in the host after primary infection and can reactivate periodically either as asymptomatic viral shedding or as clinical disease. Immunosuppression, including biologic therapy, may increase frequency and severity of herpesvirus reactivation and infection. Licensed biologics are reviewed regarding their risks of potentiating HSV, VZV, and CMV reactivation and infection. Approaches to prophylaxis against HSV, VZV, and CMV infection or reactivation are discussed.
Assuntos
Alphaherpesvirinae/fisiologia , Produtos Biológicos/efeitos adversos , Infecções por Herpesviridae/induzido quimicamente , Alphaherpesvirinae/efeitos dos fármacos , Produtos Biológicos/farmacologia , Infecções por Herpesviridae/virologia , Herpesvirus Humano 1/fisiologia , Herpesvirus Humano 2/fisiologia , Herpesvirus Humano 3/fisiologia , Humanos , Imunossupressores/efeitos adversos , Ativação Viral , Latência Viral/efeitos dos fármacosRESUMO
The risk of JC polyomavirus encephalopathy varies among biologic classes and among agents within the same class. Of currently used biologics, the highest risk is seen with natalizumab followed by rituximab. Multiple other agents have also been implicated. Drug-specific causality is difficult to establish because many patients receive multiple immunomodulatory medications concomitantly or sequentially, and have other immunocompromising factors related to their underlying disease. As use of biologic therapies continues to expand, further research is needed into pathogenesis, treatment, and prevention of JC polyomavirus encephalopathy such that risk for its development is better understood and mitigated, if not eliminated altogether.
Assuntos
Produtos Biológicos/efeitos adversos , Vírus JC/fisiologia , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Infecções por Polyomavirus/induzido quimicamente , Produtos Biológicos/farmacologia , Comorbidade , Humanos , Imunidade Humoral/efeitos dos fármacos , Vírus JC/efeitos dos fármacos , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/virologia , Infecções por Polyomavirus/imunologia , Infecções por Polyomavirus/virologia , Prognóstico , Fatores de Risco , Ativação Viral , Latência Viral/efeitos dos fármacosRESUMO
Hematopoietic cell transplantation (HCT) is potentially curative for patients with hematologic disorders, but carries significant risks of infection-related morbidity and mortality. Infectious diseases are the second most common cause of death in HCT recipients, surpassed only by progression of underlying disease. Many infectious diseases are difficult to diagnose and treat, and may only be first identified by autopsy. However, autopsy rates are decreasing despite their value. The clinical and autopsy records of adult HCT recipients at our center who underwent autopsy between 1 January 2000 and 31 December 2017 were reviewed. Discrepancies between premortem clinical diagnoses and postmortem autopsy diagnoses were evaluated. Of 185 patients who underwent autopsy, 35 patients (18.8%) had a total of 41 missed infections. Five patients (2.7%) had >1 missed infection. Of the 41 missed infections, 18 (43.9%) were viral, 16 (39.0%) were fungal, 5 (12.2%) were bacterial, and 2 (4.9%) were parasitic. According to the Goldman criteria, 31 discrepancies (75.6%) were class I, 5 (12.2%) were class II, 1 (2.4%) was class III, and 4 (9.8%) were class IV. Autopsies of HCT recipients frequently identify clinically significant infectious diseases that were not suspected premortem. Had these infections been suspected, a change in management might have improved patient survival in many of these cases. Autopsy is underutilized and should be performed regularly to help improve infection-related morbidity and mortality. Illustrative cases are presented and the lessons learned from them are also discussed.