Nontuberculous mycobacterial infections in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation.

BACKGROUND: The incidence of mycobacterial infections in patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients is increasing, contributing to significant mortality and morbidity. This review explores the epidemiology, risk factors, clinical presentation, diagnosis, and treatment of nontuberculous mycobacteria (NTM) in this population. METHODS: A literature search was performed using PubMed with keywords and MeSH terms pertaining to the topics of nontuberculous mycobacteria, hematologic malignancies, hematopoietic stem cell transplant, cellular therapies, chimeric antigen therapies, epidemiology, diagnosis, and treatment. Additionally, we examined the reference lists of the included articles to identify other pertinent studies. RESULTS: Diagnosing mycobacterial disease among patients with hematologic disease and treatment-associated immunosuppressive conditions is challenging due to the lack of distinctive clinical, radiographic, and laboratory markers, as well as the atypical manifestations compared to immunocompetent patients. Treatment involves using a combination of antibiotics for extended durations, coupled with strategies to achieve source control and reduce immunosuppression when feasible. This is complicated by the absence of clear data correlating in-vitro drug susceptibility and clinical outcome for many antimicrobials use to treat NTM, adverse drug-drug interactions, and the frequent challenges related to poor medication tolerability and toxicities. CONCLUSION: The rising incidence and corresponding clinical challenges of mycobacterial infections in this unique patient population necessitate a heightened awareness and familiarity of NTM disease by clinicians to achieve timely diagnosis and favorable treatment outcomes.

Clinical manifestations, treatment and outcomes of patients infected with Mycobacterium haemophilum with a focus on immune reconstitution inflammatory syndrome: a retrospective multi-site study.

BACKGROUND: Mycobacterium haemophilum is a nontuberculous mycobacterium with fastidious in vitro growth requirements and an increasingly reported cause of extrapulmonary disease. Timely diagnosis and management of M. haemophilum infections and the immune reconstitution inflammatory syndromes (IRIS) observed in a subset of patients during treatment remain challenging. METHODS: We conducted a retrospective chart review between January 1, 2010, and January 1, 2022 and identified 26 patients diagnosed with M. haemophilum infection at our institution. We describe their clinical presentation, diagnostic results, management, and outcomes. RESULTS: The majority of patients in our cohort had upper and/or lower extremity skin involvement, were immunosuppressed, and had generally favourable treatment outcomes. All tested M. haemophilum isolates were susceptible in vitro to clarithromycin and trimethoprim-sulfamethoxazole. Moreover, high rates of susceptibility were noted for ciprofloxacin (95%), linezolid (90%), and rifampin (85%). IRIS was identified in 31% of cases and should be considered in patients who develop worsening skin lesions or systemic symptoms following the initiation of effective antimicrobial therapy. Visualisation of acid-fast bacilli on initial tissue stains, a positive mycobacterial blood culture, and rapid de-escalation of tumour necrosis factor-α inhibitors and/or corticosteroids were more frequently encountered among patients in our cohort who developed IRIS. CONCLUSION: M. haemophilum infection should be considered among patients receiving immunomodulatory therapy who develop discoloured or nodular skin lesions involving the extremities, worsening focal arthritis, tenosynovitis, or isolated adenopathy. A heightened awareness of this pathogen's clinical and laboratory characteristics can lead to a timely diagnosis and favourable outcome.

Pharmacogenomic panel testing provides insight and enhances medication management in people with HIV.

OBJECTIVE: Our study aimed to assess the impact of pharmacogenomic panel testing in people with HIV (PWH). DESIGN: Prospective, observational intervention assessment. METHODS: One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants' current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes. RESULTS: Ninety-six participants (median age 53 years, 74% white, 84% men, 89% viral load <50 copies/ml) completed panel testing, yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild-moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in one participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants. CONCLUSION: Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.

Feasibility of the A-STEP for the assessment of exercise capacity in people with cystic fibrosis.

OBJECTIVES: To evaluate feasibility of the Alfred Step Test Exercise Protocol (A-STEP) for the assessment of exercise capacity in adults and children with cystic fibrosis (CF); in adults to test whether demographics and/or lung function correlated with exercise capacity. METHODS: Adults and children with stable CF from two centres completed the A-STEP (a recently developed incremental maximal-effort step test). Feasibility was evaluated by: usefulness for exercise capacity assessment (measures of exercise capacity were: level reached, exercise-induced desaturation, and achievement of at least one maximal effort criteria); safety; operational factors; time to complete; floor and/or ceiling effects. We used multiple linear regression to test whether demographics and/or lung function correlated with exercise capacity. RESULTS: A total of 49 participants: 38 adults (18 male), percent predicted (pp) forced expiration in one second (FEV1 ) 29-109, aged 22-48 years and 11 children (6 male), ppFEV1 68-107, aged 10-15 years were included. Levels reached (mean (SD) [range]) were 10.2 (2.4) [6-15] (adults), 10.1 (2.5) [7-14] (children); desaturation (change between baseline and peak-exercise SpO2 ): was 8.4 (3.8 [0-15]% (adults), 2.0 (2.0) [0-7]% (children). A total of 8 (21%) adults and no children desaturated <90% SpO2 . At least one criterion for maximal effort was reached by 33 (84%) adults and 10 (91%) children. There were no adverse events. The A-STEP was straightforward to use and carried out by one operator. A total of 26 (68.4%) adults and 7 (63.6%) children completed the test within the recommended 8-12 min. All participants completed a minimum of 6 levels, and completed the test before the final 16th level. In adults, ppFEV1 and ppFVC correlated with the level reached (r = 0.55; p = <0.001 and r = 0.66, p = <0.0001) and desaturation (r = 0.55, p = <0.001 and r = 0.45, p = <0.005). CONCLUSION: In adults and children with stable CF, the A-STEP was feasible, safe, and operationally easy to use for the assessment of exercise capacity, without floor or ceiling effects. In adults, lung function correlated with exercise capacity.

Cardiovascular device infections due to rapidly growing Mycobacteria: A review of cases at a tertiary care hospital.

Cardiovascular device infection due to rapidly growing mycobacteria (RGM) is rarely encountered in clinical practice. Due to the increasing number of indications and use of cardiovascular devices in an aging population, optimized management of these infections is of great importance. We report seven cases of RGM cardiovascular device infection. Three patients had left-ventricular assist device (LVAD) infections; two patients had cardiovascular implantable device (CIED) infections; and one had an aortic vascular stent infection. Specific cardiac valvular infection was not detected among any of the patients. All patients had a high number of comorbidities which limited some patients from receiving optimal combination antimicrobial therapy. The prognosis of cardiovascular device infections with RGM is guarded with only four patients still alive; however, the treatment approach for each patient varied considerably and often based on concurrent medical conditions, overall adjustments to goals of care, and specific patient preferences. Further analysis of cardiovascular device infections with RGM is warranted to establish a more systematic approach in successful management.

Recurrent nocardiosis in solid organ transplant recipients: An evaluation of secondary prophylaxis.

BACKGROUND: Immunocompromised individuals are at risk for Nocardia infection, with a recurrence rate of approximately 5%. Solid organ transplant (SOT) recipients often receive secondary prophylaxis due to their requirement of lifelong immunosuppression. However, data supporting this practice is sparse. We sought to evaluate Nocardia recurrence in SOT recipients, specifically evaluating secondary prophylaxis. METHODS: We conducted a retrospective cohort study of SOT recipients diagnosed with nocardiosis from 2000 through 2020. We included adult SOT recipients who completed their course of Nocardia therapy and had at least 6 months of posttherapy follow-up. The primary outcome was Nocardia recurrence, which included relapse and reinfection. RESULTS: One hundred two patients met inclusion criteria. Sixty-six (64.7%) were male and mean age was 58.6 ± 11.7 years. Most common SOT types were kidney (46.1%), heart (18.6%), kidney-pancreas (11.8%), and lung (10.8%). Most common sites of infection were lung (85.3%), skin (17.6%), and brain (14.7%). Secondary prophylaxis was utilized in 53 (52.0%) patients. Trimethoprim-sulfamethoxazole (TMP-SMX) single-strength daily was the most common prophylaxis agent and dose. Five patients (4.9%) experienced Nocardia recurrence, three of which were receiving secondary prophylaxis at time of recurrence. Two recurrences were with the same Nocardia species. Factors associated with recurrence were lung transplantation (p = .011), chronic lung disease (p = .032), and treatment ≤120 days (p = .006). Time from treatment completion to recurrence ranged from 107 to 875 days. CONCLUSIONS: Nocardia recurrence in SOT recipients is an uncommon event. TMP-SMX secondary prophylaxis is incompletely protective and recurrence may be dependent upon other factors. Further study of secondary prophylaxis is warranted.

Development of the A-STEP: A new incremental maximal exercise capacity step test in cystic fibrosis.

BACKGROUND: Exercise testing is important in people with cystic fibrosis (pwCF). The aim was to develop an incremental maximal step test to assess exercise capacity across the range of pwCF, without floor or ceiling effects, within restrictions of space, and infection prevention. METHODS: The step test was developed in adults with stable CF. Subjects assisted in selecting: step height, start rate, increments, stage and test duration parameters. Equipment to externally pace and time the test and measure exercise parameters were selected. Reasons for stopping, criteria for achieving a maximal test, and key outcome measures were determined. Documentation to record and standardize the test and instructions to set up the metronome and timer App were developed. Infection control practices were considered. RESULTS: Eight subjects were recruited to develop the Alfred Step Test Exercise Protocol (A-STEP) on a 20 cm portable step. The A-STEP package included a pretest information sheet, clinical assessment and instructions, recording worksheet, and the metronome/timer instructions. The test started at 18 steps/min. Each level increased by two steps/min to a maximum of 48 steps (Level 16). Results were presented as mean (SD) [range] for: age 30.63 (5.89) [21-39] years; FEV1 58.13 (18.33) [32-89]%; levels: 10.31 (3.29) [6-15.5]. The A-STEP required space of 2 m2 and complied with current infection control guidelines. CONCLUSIONS: The A-STEP is a new incremental maximal step test to assess exercise capacity in pwCF, without floor or ceiling effects. It addresses the issues of space restrictions and the need for strict infection prevention in the clinical setting.

The AWESCORE, a patient-reported outcome measure: development, feasibility, reliability, validity and responsiveness for adults with cystic fibrosis.

BACKGROUND: Quality of life has improved dramatically over the past two decades in people with cystic fibrosis (CF). Quantification has been enabled by patient-reported outcome measures (PROMs); however, many are lengthy and can be challenging to use in routine clinical practice. We propose a short-form PROM that correlates well with established quality-of-life measures. METHODS: We evaluated the utility of a 10-item score (AWESCORE) by measuring reliability, validity and responsiveness in adults with CF. The questions were developed by thematic analysis of survey questions to patients in a single adult CF centre. Each question was scored using a numerical rating scale 0 to 10. Total scores ranged from 0 to 100. Test-retest reliability was assessed over 24 h. To determine validity, comparisons were sought between stable subjects and those in pulmonary exacerbation, and between AWESCORE and Cystic Fibrosis Questionnaire - Revised (CFQ-R). Responsiveness to pulmonary exacerbation in individual subjects was evaluated. RESULTS: Five domains, each with two questions, were identified for respiratory, physical, nutritional, psychological and general health. A total of 246 consecutive adults attending the outpatient clinic completed the AWESCORE. Scores were higher during clinical stability compared to pulmonary exacerbation (mean± sd): 73±11 versus 48±11 (p<0.001). Each domain scored worse during an acute exacerbation (p<0.001). No differences in reliability were observed in scores on retesting using Bland-Altman comparison. The CFQ-R scores (mean±sd: 813±125) and AWESCORE (81±13) were moderately correlated (Pearson's r=0.649; p=0.002). CONCLUSIONS: The AWESCORE is valid, reliable and responsive to altered health status in CF.

Updated Experience of Mycobacterium chimaera Infection: Diagnosis and Management in a Tertiary Care Center.

BACKGROUND: Despite safety communications from the Food and Drug Administration (FDA) regarding the outbreak of Mycobacterium chimaera infections (MCIs) from contaminated heater-cooler devices, new cases continue to be identified. METHODS: We retrospectively reviewed confirmed cases of MCI that were managed at Mayo Clinic sites (Arizona, Florida, and Minnesota) from 09/2015 to 01/2021. Clinical histories including prior cardiovascular surgery were recorded. Diagnostic workup including ophthalmologic examination, imaging, and laboratory testing was reviewed. Treatment and survival outcomes on follow-up were obtained. RESULTS: Twelve patients with MCI were included. All patients had aortic valve or graft replacement. Five patients had their surgical procedures following the 10/15/2015 FDA safety communication. The mean time from surgery to symptom onset (range) was 32 (13-73) months. Ten of 11 patients who underwent ophthalmologic examination had chorioretinal abnormalities. Three patients who underwent microbial cell-free deoxyribonucleic acid sequencing tested positive for M. chimaera, which was subsequently confirmed with blood culture growth. Echocardiography and positron emission tomography/computed tomography (PET/CT) revealed evidence of prosthetic valve/graft infection in 7/12 (58.3%) and 6/10 (60.0%) of cases, respectively. Seven patients (58.3%) underwent redo cardiovascular surgery. Of these, 1 patient died 2 days postdischarge, 1 experienced spinal osteomyelitis relapse, and another had interval prosthetic valve fluorodeoxyglucose (FDG) uptake on PET/CT suspicious for recurrent infection. Among 4 patients on medical therapy only, 3 expired or transitioned to hospice during follow-up. CONCLUSIONS: MCI continues to occur despite the FDA communications. Incorporation of ophthalmologic examination and use of advanced tools may improve MCI diagnosis. The mortality in these patients is high even with aggressive surgical/medical management.

Lumacaftor/ivacaftor-associated health stabilisation in adults with severe cystic fibrosis.

INTRODUCTION: Lumacaftor/ivacaftor (LUM/IVA) has been shown to improve clinical outcomes in cystic fibrosis (CF) patients homozygous for Phe508del with forced expiratory volume in 1 s (FEV1) % pred >40%. We assessed the clinical utility of LUM/IVA in all eligible adult CF patients with FEV1 % pred <40% treated for at least 1 year under a single-centre managed access programme. METHODS: Following clinical optimisation, eligible patients (n=40) with FEV1 % pred <40% were commenced on LUM/IVA and monitored for tolerance and clinical outcomes, including health service utilisation, pulmonary function, weight and body composition. 24 patients reached 1 year of treatment by the time of evaluation. Six patients discontinued due to adverse events (five for increased airways reactivity) and three underwent lung transplantation. RESULTS: In comparison with the year prior to LUM/IVA commencement, significant reductions (median per year) were observed in the treatment year in the number of pulmonary exacerbations requiring hospitalisation (from 3 to 1.5; p=0.0002), hospitalisation days (from 27 to 17; p=0.0002) and intravenous antibiotic (IVAB) usage days (from 45 to 27; p=0.0007). Mean±sd change in FEV1 % pred was -2.10±1.18% per year in the year prior, with the decline reversed in the year following (+1.45±1.13% per year; p=0.035), although there was significant heterogeneity in individual responses. Mean±sd weight gain at 1 year was 2.5±4.1 kg (p=0.0007), comprising mainly fat mass (mean 2.2 kg). The proportion of patients severely underweight (body mass index <18.5 kg·m-2) decreased from 33% at baseline to 13% at 1 year (p=0.003). CONCLUSION: This real-world evaluation study demonstrated benefits over several clinical domains (infective exacerbations requiring hospitalisation, IVABs, pulmonary function decline and nutritional parameters) in CF patients with severe lung disease.

Body composition and weight changes after ivacaftor treatment in adults with cystic fibrosis carrying the G551 D cystic fibrosis transmembrane conductance regulator mutation: A double-blind, placebo-controlled, randomized, crossover study with open-label extension.

OBJECTIVES: In patients with cystic fibrosis (CF) who carry the G551D mutation, treatment with ivacaftor improves lung function and weight; however, short- and long-term impacts on body composition have not been well studied. METHODS: Twenty adults with CF carrying the G551D mutation (mean ± standard deviation body mass index [BMI] 23.3 ± 4.3 kg/m2) were recruited for a single-center, double-blind, placebo-controlled, 28-d, crossover study of ivacaftor, followed by an open-label extension (OLE) for 5 mo. Eleven patients underwent measurements 2 y later. The study variables included weight, BMI, and body composition (including fat-free mass [FFM] and fat mass). RESULTS: After 28 d of treatment with ivacaftor, weight increased by 1.1 ± 1.3 kg, BMI by 0.4 ± 0.5 kg/m2, and FFM by 1.1 ± 1.2 kg (all P < .005) with no change in fat mass. Differences between 28-d changes on ivacaftor and placebo were not statistically significant. In the following 5 mo of the OLE, there were significant increases in weight (1.2 ± 1.9 kg; P < .05) and fat mass (1.5 ± 1.9 kg; P < .01), but not in FFM. Between baseline and the end of the OLE, the total weight gain was 2.5 ± 2.4 kg (P < .005), comprised of 0.9 ± 1.5 kg FFM (P < .05) and 1.6 ± 1.8 kg fat mass (P < .005). For the 11 participants who were followed for a further 2 y, no further changes in mean weight, BMI, or body composition parameters between 6 mo and 2 y later were observed. CONCLUSIONS: Small gains were seen in FFM in the first month of ivacaftor treatment. Weight, BMI, and fat-mass gains in the first 6 mo on ivacaftor plateaued by 2.5 y. The metabolic and clinical consequences of weight and fat-mass gains remain to be determined.

Linezolid use for the treatment of multidrug-resistant tuberculosis, TB centers of excellence, United States, 2013-2018.

BACKGROUND: In 2019, the World Health Organization released guidelines reflecting major changes in multidrug-resistant tuberculosis (MDR-TB) management-prioritizing fluoroquinolones, bedaquiline, and linezolid (LZD) while de-emphasizing previously favored injectable agents. In some cases, linezolid use is associated with gastrointestinal intolerance, mitochondrial toxicity, and significant drug interactions. CDC's Division of Tuberculosis Elimination supports a network of regional TB Centers of Excellence, which provide medical consultation to healthcare providers. Consultations are documented in a medical consultation database (MCD) enabling evaluation of management questions and recommendations. We describe the scope of clinical inquiries and responses specific to linezolid use for MDR-TB in the US. RESEARCH QUESTION: What are the major themes of provider and patient challenges regarding the use of linezolid for the treatment of MDR-TB in the US? METHODS: We queried MCD consults categorized as "MDR/XDR-TB" from 1/1/2013 to 12/31/2018. Only linezolid-specific consultations were included; incomplete and duplicate entries were excluded as were those citing linezolid historically or theoretically. Subgroup characteristics were assessed (e.g., Center, year, provider type). A descriptive coding scheme was developed through inductive thematic analysis. RESULTS: In 2013-2018 of the 1889 consults regarding MDR/XDR-TB, 934 MDR-TB consults referenced linezolid; 137 met inclusion criteria, representing between 4 and 10% of MDR-TB consults annually. Four main themes emerged: adverse effects (71.5%); concerns about linezolid use due to co-morbidities or concurrent medication use (15.3%); dosing adjustments (8.8%); and monitoring and maintenance logistics (4.4%). INTERPRETATIONS: Linezolid consults consistently exceeded 4% of all consults annually over the 6-year period, suggesting a need for access to expert opinion for providers using linezolid to manage MDR-TB. While only a snapshot of MDR-TB in the US, this evaluation summarizes major provider concerns regarding particular adverse effects, and highlights a need for evidence-based guidance regarding linezolid dosing and toxicity management.

Mycobacterium septicum: a 6-Year Clinical Experience from a Tertiary Hospital and Reference Laboratory.

Mycobacterium septicum is a rarely identified nontuberculous mycobacterium capable of causing infections in both healthy and immunocompromised individuals. Only a few cases of M. septicum infections have been reported, which makes recognizing corresponding clinical disease more challenging for clinicians. Antimicrobial susceptibility profiles for this organism are not well described, and corresponding optimal therapeutic regimens have not been established. We report a tertiary care center's experience with M. septicum from 2014 to 2020. Twelve adult patients with positive cultures for M. septicum were identified. Most cases were identified from sputum samples of individuals with underlying lung disease. Most cases involving M. septicum isolation in culture were not felt to be clinically significant. Two cases were considered possible infections, while only one case was considered a definite infection that required antimicrobial treatment. All M. septicum isolates were susceptible in vitro to amikacin, ciprofloxacin, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole. Isolates were universally resistant to clarithromycin and doxycycline. The isolation of M. septicum in culture is uncommon and requires clinical correlation to determine its clinical relevance and need for treatment. Susceptibility testing should be performed to guide therapy.

A model for bringing TB expertise to HIV providers: Medical consultations to the CDC-funded Regional Tuberculosis Training and Medical Consultation Centers, 2013-2017.

BACKGROUND: Persons living with human immunodeficiency virus (HIV) are at a greater risk of developing tuberculosis (TB) compared to people without HIV and of developing complications due to the complexity of TB/HIV coinfection management. METHODS: During 2013-2017, the Centers for Disease Control and Prevention (CDC) funded 5 TB Regional Training and Medical Consultation Centers (RTMCCs) (now known as TB Centers of Excellence or COEs) to provide medical consultation to providers for TB disease and latent TB infection (LTBI), with data entered into a Medical Consultation Database (MCD). Descriptive analyses of TB/HIV-related consultations were conducted using SAS® software, version [9.4] to determine the distribution of year of consultation, medical setting and provider type, frequency of consultations regarding a pediatric (<18 years) patient, and to categorize key concepts and themes arising within consultation queries and medical consultant responses. RESULTS: Of 14,586 consultations captured by the MCD in 2013-2017, 544 (4%) were categorized as TB/HIV-related, with 100 (18%) received in 2013, 129 (24%) in 2014, 104 (19%) in 2015, 117 (22%) in 2016, and 94 (17%) in 2017. Most TB/HIV consultations came from nurses (54%) or physicians (43%) and from local (65%) or state health departments (10%). Only 17 (3%) of HIV-related consultations involved pediatric cases. Off the 544 TB/HIV consultations, 347 (64%) concerned the appropriate treatment regimen for TB/HIV or LTBI/HIV for a patient on or not on antiretroviral therapy (ART). CONCLUSIONS: The data support a clear and ongoing gap in areas of specialized HIV knowledge by TB experts that could be supplemented with proactive educational outreach. The specific categories of TB/HIV inquiries captured by this analysis are strategically informing future targeted training and educational activities planned by the CDC TB Centers of Excellence, as well as guiding HIV educational efforts at regional and national TB meetings.