Chronic disseminated candidiasis in a patient with acute leukemia - an illustrative case and brief review for clinicians.

Chronic disseminated candidiasis (CDC) is a severe but rarely seen fungal infection presenting in patients with hematologic malignancies after a prolonged duration of neutropenia. A high index of suspicion is required to diagnose CDC as standard culture workup is often negative. While tissue biopsy is the gold standard of diagnosis, it is frequently avoided in patients with profound cytopenias and increased bleeding risks. A presumptive diagnosis can be made in patients with recent neutropenia, persistent fevers unresponsive to antibiotics, imaging findings of hypoechoic, non-rim enhancing target-like lesions in the spleen and liver, and mycologic evidence. Here, we describe the case of an 18-year-old woman with relapsed B-cell acute lymphoblastic leukemia treated with re-induction chemotherapy who subsequently developed CDC with multi-organ involvement. The diagnosis was made based on clinical and radiologic features with positive tissue culture from a skin nodule and hepatic lesion. The patient was treated for a total course of 11 months with anti-fungal therapy, most notably amphotericin B and micafungin, and splenectomy. After initial diagnosis, the patient was monitored with monthly CT abdomen imaging that showed disease control after 5 months of anti-fungal therapy and splenectomy. The diagnosis, treatment, and common challenges of CDC are outlined here to assist with better understanding, diagnosis, and treatment of this rare condition.

Rationale for Hepatitis C Virus Treatment During Hematopoietic Stem Cell Transplant in the Era of Novel Direct-Acting Antivirals.

BACKGROUND AND AIMS: Untreated hepatitis C (HCV) infection in patients undergoing hematopoietic stem cell transplantation (HSCT) can lead to worse outcomes. Traditionally, HSCT patients infected with HCV would wait until after immune reconstitution to receive HCV therapy, as the oncologic urgency of transplant would not allow time for a full preceding treatment course of HCV therapy. However, in the era of newer direct-acting antivirals (DAAs), we propose that concomitant treatment of HCV while undergoing HSCT is safe and feasible, while keeping in mind potential drug-drug interactions. METHODS: A literature review was performed to summarize the available data on the impact of HCV on patients undergoing HSCT. Drug-drug interactions for DAA's and pertinent HSCT drugs were evaluated using Lexicomp online® and http://hep-druginteractions.org . RESULTS: During HSCT, HCV appears to be a conditional risk factor for sinusoidal obstruction syndrome and a potential risk factor for graft versus host disease, both of which are associated with increased mortality. HCV reactivation and exacerbation may impact the use of chemotherapeutics, but available studies haven't shown impact specifically on HSCT. Limited case reports exist but demonstrate safe and effective use DAAs during HSCT. These, along with a drug-drug interaction review demonstrate agents such as sofosbuvir/velpatasvir and glecaprevir/pibrentasvir are promising DAAs for use in HSCT. CONCLUSION: HCV infection may worsen outcomes for patients undergoing HSCT. Concomitant treatment of HCV during HSCT using newer DAAs appears feasible and may improve patient morbidity and mortality, however large-scale studies are needed to further support this practice.

Safety and Outcomes With Combination Therapy With Sarilumab and Baricitinib for Severe COVID-19 Respiratory Infection in Cancer Patients.

OBJECTIVES: This study aims to describe the clinical outcomes of combination therapy with sarilumab and baricitinib for severe novel Coronavirus-19 (COVID-19) infection in cancer patients. With this study, we aim to evaluate the role of expanded immunotherapy for severely ill patients with COVID-19 respiratory infections with limited options. The secondary objective is to assess the safety of combination therapy with sarilumab and baricitinib for severe COVID-19 infection. METHODS: This was a retrospective cohort study of patients admitted to Moffitt Cancer Center with COVID-19 infection between January 2020 and April 2022. Our research received a waiver to sign consent by the patients according to our institutional IRB because it was free of any risk for the patients and respected the patient's privacy. Following the Institutional IRB approval and relevant Equator guidelines, we collected information on patients with severe COVID-19 infection and received sarilumab and baricitinib. We evaluated the survival rate and safety of combination therapy. All the patient's information was de-identified to protect their information according to Health Insurance Portability and Accountability Act (HIPAA). RESULTS: Four patients were included in the data analysis. Two survived, and two of them died (Table 1). All the patients that survived were previously vaccinated. Among the two patients who died, one was vaccinated, and the other was unvaccinated. All the patients tolerated the combination therapy well, and none of the patients who survived developed secondary infections or COVID-19-associated complications beyond 12 months of discharge. CONCLUSION: Our study explores the potential safe combination use of different immune modulators targeting multiple pathways of the inflammatory cascade for severe and refractory COVID-19 respiratory infections in high-risk oncology patients. The small number of patients in our observational study was a limitation. A larger sample of patients will be needed to conclude more precisely the efficacy of the combination therapy of sarilumab and baricitinib for refractory cases of severe COVID-19 respiratory infection. Moreover, exploring other cytokine release signaling pathway targets may be the key to significantly reducing inflammation and further pulmonary fibrosis with chronic unbearable respiratory sequela.

Adverse Effects of Immunosuppression: Infections.

Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a "net state" of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.

A Randomized, Placebo-controlled Trial of Roflumilast. Effect on Proline-Glycine-Proline and Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease.

RATIONALE: Roflumilast is a therapeutic agent in the treatment of chronic obstructive pulmonary disease (COPD). It has antiinflammatory effects; however, it is not known whether it can affect a biologic pathway implicated in COPD pathogenesis and progression. The self-propagating acetyl-proline-glycine-proline (AcPGP) pathway is a novel means of neutrophilic inflammation that is pathologic in the development of COPD. AcPGP is produced by extracellular matrix collagen breakdown with prolyl endopeptidase and leukotriene A4 hydrolase serving as the enzymes responsible for its production and degradation, respectively. OBJECTIVES: We hypothesized that roflumilast would decrease AcPGP, halting the feed-forward cycle of inflammation. METHODS: We conducted a single-center, placebo-controlled, randomized study investigating 12 weeks of roflumilast treatment added to current therapy in moderate-to-severe COPD with chronic bronchitis. Subjects underwent sputum and blood analyses, pulmonary function testing, exercise tolerance, and quality-of-life assessment at 0, 4, and 12 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients were enrolled in the intention-to-treat analysis. Roflumilast treatment decreased sputum AcPGP by more than 50% (P < 0.01) and prolyl endopeptidase by 46% (P = 0.02), without significant improvement in leukotriene A4 hydrolase activity compared with placebo. Roflumilast also reduces other inflammatory markers. There were no significant changes in lung function, quality of life, or exercise tolerance between roflumilast- and placebo-treated groups. CONCLUSIONS: Roflumilast reduces pulmonary inflammation through decreasing prolyl endopeptidase activity and AcPGP. As expected for lower AcPGP levels, markers of neutrophilic inflammation are blunted. Inhibiting this self-propagating pathway lessens the overall inflammatory burden, which may alter the natural history of COPD, including the risk of exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT 01572948).

An aberrant leukotriene A4 hydrolase-proline-glycine-proline pathway in the pathogenesis of chronic obstructive pulmonary disease.

RATIONALE: Chronic neutrophilic inflammation is a hallmark in the pathogenesis of chronic obstructive pulmonary disease (COPD) and persists after cigarette smoking has stopped. Mechanisms involved in this ongoing inflammatory response have not been delineated. OBJECTIVES: We investigated changes to the leukotriene A4 hydrolase (LTA4H)-proline-glycine-proline (PGP) pathway and chronic inflammation in the development of COPD. METHODS: A/J mice were exposed to air or cigarette smoke for 22 weeks followed by bronchoalveolar lavage and lung and cardiac tissue analysis. Two human cohorts were used to analyze changes to the LTA4H-PGP pathway in never smokers, control smokers, COPD smokers, and COPD former smokers. PGP/AcPGP and LTA4H aminopeptidase activity were detected by mass spectroscopy, LTA4H amounts were detected by ELISA, and acrolein was detected by Western blot. MEASUREMENTS AND MAIN RESULTS: Mice exposed to cigarette smoke developed emphysema with increased PGP, neutrophilic inflammation, and selective inhibition of LTA4H aminopeptidase, which ordinarily degrades PGP. We recapitulated these findings in smokers with and without COPD. PGP and AcPGP are closely associated with cigarette smoke use. Once chronic inflammation is established, changes to LTA4H aminopeptidase remain, even in the absence of ongoing cigarette use. Acrolein modifies LTA4H and inhibits aminopeptidase activity to the same extent as cigarette smoke. CONCLUSIONS: These results demonstrate a novel pathway of aberrant regulation of PGP/AcPGP, suggesting this inflammatory pathway may be intimately involved in disease progression in the absence of ongoing cigarette smoke exposure. We highlight a mechanism by which acrolein potentiates neutrophilic inflammation through selective inhibition of LTA4H aminopeptidase activity. Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).

Human Herpes Virus-6 (HHV-6) Reactivation after Hematopoietic Cell Transplant and Chimeric Antigen Receptor (CAR)- T Cell Therapy: A Shifting Landscape.

HHV-6B reactivation affects approximately half of all allogeneic hematopoietic cell transplant (HCT) recipients. HHV-6B is the most frequent infectious cause of encephalitis following HCT and is associated with pleiotropic manifestations in this setting, including graft-versus-host disease, myelosuppression, pneumonitis, and CMV reactivation, although the causal link is not always clear. When the virus inserts its genome in chromosomes of germ cells, the chromosomally integrated form (ciHHV6) is inherited by offspring. The condition of ciHHV6 is characterized by the persistent detection of HHV-6 DNA, often confounding diagnosis of reactivation and disease-this has also been associated with adverse outcomes. Recent changes in clinical practice in the field of cellular therapies, including a wider use of post-HCT cyclophosphamide, the advent of letermovir for CMV prophylaxis, and the rapid expansion of novel cellular therapies require contemporary epidemiological studies to determine the pathogenic role and spectrum of disease of HHV-6B in the current era. Research into the epidemiology and clinical significance of HHV-6B in chimeric antigen receptor T cell (CAR-T cell) therapy recipients is in its infancy. No controlled trials have determined the optimal treatment for HHV-6B. Treatment is reserved for end-organ disease, and the choice of antiviral agent is influenced by expected toxicities. Virus-specific T cells may provide a novel, less toxic therapeutic modality but is more logistically challenging. Preventive strategies are hindered by the high toxicity of current antivirals. Ongoing study is needed to keep up with the evolving epidemiology and impact of HHV-6 in diverse and expanding immunocompromised patient populations.

Real-world Experience of Posaconazole Therapeutic Drug Monitoring in Oncology Patients: Clinical Implications of Hypoalbuminemia as a Predictor of Subtherapeutic Posaconazole Levels.

Background: Posaconazole maintains broad antifungal activity and is employed for prevention and treatment of invasive fungal infections in oncology patients. Older formulations required therapeutic drug monitoring, and specific plasma drug levels have been recommended. This study evaluated factors associated with subtherapeutic concentrations with the newer delayed-release tablet formulation. Methods: In this retrospective, single-center cohort study at a national comprehensive cancer center, all oncology patients receiving delayed-release posaconazole at standard dosing of 300 mg orally per day from 06/2021 to 07/2023 with plasma drug concentration evaluation were identified. Demographic, clinical, and laboratory data were evaluated to identify risk factors associated with subtherapeutic drug levels at targets of ≥1.25 µg/mL and ≥1.8 µg/mL. Results: Of 110 patients identified, 98 met criteria for inclusion in the study. The median time from initiation of posaconazole to drug level assessment was 13 days, and the median concentration was 1.29 µg/mL. Of the 22 patients receiving posaconazole for prophylaxis, 5 (22.7%) failed to achieve concentrations ≥0.7 µg/mL, and of 76 patients receiving posaconazole for treatment, 38 (50%) failed to achieve concentrations of ≥1.25 µg/mL. In multivariable analysis, albumin of ≤3 g/dL and ideal body weight ≥60 kg were found to be associated with subtherapeutic levels. For a higher target of ≥1.8 µg/mL, only albumin ≤3 g/dL was associated with subtherapeutic levels for the variables evaluated. Conclusions: A higher initial dosing strategy and therapeutic drug monitoring for oncology patients with albumin ≤3 g/dL receiving posaconazole, particularly for the treatment of invasive fungal infection, could be considered.

Current Role of Prospective Monitoring and Preemptive and Prophylactic Therapy for Human Herpesvirus 6 After Allogeneic Stem Cell Transplantation.

Human herpesvirus 6 (HHV-6) frequently reactivates after allogeneic stem cell transplantation (SCT). Most patients are asymptomatic and viremia often resolves without therapy; however, transplant-related complications may be associated with reactivation. Multiple presentations have been attributed to HHV-6 reactivation after SCT including encephalitis. Several strategies have been trialed to reduce such risks or complications. Challenges exist with prospective monitoring strategies, and established thresholds of high-level reactivation may be limited. Three published guidelines and extensive trials focusing on preemptive and prophylactic strategies are reviewed. Future areas of investigation and high-risk populations are described. Existing trials and testing platforms have significant limitations, and to date no clear benefit for a preemptive or prophylactic intervention has been demonstrated.

Disseminated Toxoplasmosis in an Allogeneic Hematopoietic Stem Cell Transplant Recipient: A Case Report and Review of the Current Literature.

Reactivation infections in hematopoietic stem cell transplants are mitigated by prophylactic regimens. Despite high rates of exposure, morbidity and mortality secondary to toxoplasmosis are limited to subsets of patients such as immunocompromised persons. We describe the first case of disseminated toxoplasmosis in a double umbilical cord blood transplant recipient.

Nocardia niwae Disseminated Nocardiosis: A Novel Species Presenting Concurrently With Lung Adenocarcinoma.

Nocardia includes over 90 species of filamentous gram-positive bacilli that may cause disease in immunocompromised or immunocompetent hosts. Presentations may include pulmonary, 4, cutaneous, or disseminated infections. Tissue diagnosis may be required as it may mimic alternative etiologies. There is a paucity of data regarding rarer species of Nocardia. Intraspecies variability in antimicrobial susceptibility limits many treatment regimens to in-vitro activity data and treatment regimens often must be tailored to individual patients based on microbiologic cultures. We describe the case of a 63-year-old female who presented with disseminated Nocardia niwae, a species that was previously first identified in Florida for which little clinical data is known, along with concurrent lung adenocarcinoma with pulmonary and central nervous system lesions. Typical susceptibility patterns are discussed along with potential side effects of antimicrobial therapy.

Human herpesvirus 6 and central nervous system disease in oncology patients: A retrospective case series and literature review.

BACKGROUND: Human herpesvirus 6 (HHV-6) can reactivate with immunosuppression and cause central nervous system (CNS) dysfunction. Much of the literature describes cases after hematopoietic stem cell transplantation (HSCT), ranging from encephalitis to a post-transplant acute limbic encephalitis syndrome (PALE). Outside of HSCT, studies of HHV-6 encephalitis are limited to case reports. OBJECTIVES: This study was designed to review HHV-6 CNS infection, and evaluate all patients admitted to MD Anderson Cancer Center between March 2016 and December 2018 with detectable HHV-6 DNA in the cerebrospinal fluid (CSF). STUDY DESIGN: Patients with HHV-6 DNA detected in the CSF using the Viracor or Biofire® Meningitis Encephalitis Panel platforms and no other identified etiology were identified and demographic features, known risk factors, imaging findings, CSF analysis, treatments and patient outcomes were extracted from medical records. RESULTS: 725 patients underwent HHV-6 testing during the study timeframe, with 19 cases (2.6 %) of HHV-6 mediated CNS disease identified. Most patients, 13/19 (68 %), had undergone HSCT with median time to presentation of 31 days after transplant. Survival at 240 days after transplant was 62 %. CSF had lymphocyte predominance and nearly all patients had peripheral lymphopenia. Other at risk populations identified included patients who received chimeric antigen receptor (CAR) T-cell therapy and biologic immunotherapy. Notable discordance among testing platforms was found in 5/9 (55 %) instances. CONCLUSIONS: In addition to HSCT patients, HHV-6 reactivation leading to CNS disease also occurs in settings such as following adoptive T cell therapy or biologic immunotherapy. Significant diagnostic discordance exists between testing platforms.

Distinguishing cytomegalovirus meningoencephalitis from other viral central nervous system infections.

BACKGROUND: Hallmarks of cytomegalovirus (CMV) meningoencephalitis include fever, altered mental status, or meningismus with pleocytosis, elevated protein and hypoglycorrhachia on cerebrospinal fluid (CSF) analysis. Magnetic resonance imaging may show ventriculitis, ependymitis or periventricular enhancement. Studies are limited comparing clinical and laboratory characteristics to other viral etiologies. OBJECTIVES: This multi-center, retrospective cohort analysis reviewed patients with CMV meningitis or encephalitis and compared clinical features, laboratory findings and outcomes to the most common viral causes of meningoencephalitis. STUDY DESIGN: Patients with encephalitis or aseptic meningitis and detectable genetic material by polymerase chain reaction were identified. Clinical characteristics, laboratory findings and neuroimaging were collected from the electronic medical record. Data analysis was performed comparing CMV to other viral etiologies. RESULTS: 485 patients were evaluated and included cases of CMV (n = 36) which were compared with herpes simplex virus (n = 114), enterovirus (n = 207), varicella zoster virus (n = 41) and West Nile virus (n = 81). Human immunodeficiency virus (HIV) infection was seen more frequently in CMV infection compared with all other viral etiologies. Clinical presentations and CSF findings of other viral etiologies differ compared with CMV. Hypoglycorrhacia occurred more often with CMV compared with other viral pathogens. Outcomes were significantly worse compared with enterovirus, herpes simplex virus and varicella zoster virus but not West Nile virus. CONCLUSIONS: CMV meningoencephalitis occurs most often in patients with HIV and encephalitis occurs more frequently than meningitis. Clinical and laboratory findings differ compared with other viral etiologies and can support consideration of CMV in the differential diagnosis of patients with meningoencephalitis.

Human herpesvirus 6 myelitis after chimeric antigen receptor T-cell therapy.

This article reports a fatal case of human herpesvirus 6 (HHV-6) myelitis following CD19-targeted chimeric antigen receptor T-cell therapy. Infection from HHV-6 reactivation after haematopoietic stem cell transplant is established, and outside of this population is limited to case reports. The patient developed cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome that responded to corticosteroids both clinically and on imaging. Subsequently, ascending flaccid paralysis developed, leading to neuromuscular respiratory failure and, ultimately, death. Disease progression was refractory to foscarnet and multiple immunomodulating agents. HHV-6 should be considered in patients with encephalitis and myelitis after adoptive T-cell therapy.