Variables associated with antibiotic treatment tolerance in patients with Mycobacterium avium complex pulmonary disease.

BACKGROUND: Treatment of Mycobacterium avium complex pulmonary disease (MAC-PD) involves prolonged courses of multiple antibiotics that are variably tolerated and commonly cause adverse drug reactions (ADR). The purpose of this retrospective, single-center study was to identify demographic and disease-related variables associated with significant ADRs among patients treated with antibiotics against MAC-PD. METHODS: We reviewed all patients treated with antibiotic therapy for MAC-PD at a single center from 2000 to 2021. Patients were included if they met diagnostic criteria for MAC-PD, were prescribed targeted antibiotic therapy for any length of time and had their treatment course documented in their health record. We compared patients who completed antibiotics as originally prescribed (tolerant) with those whose antibiotic treatment course was modified or terminated secondary to an ADR (intolerant). RESULTS: Over the study period, 235 patients were prescribed antibiotic treatment with their clinical course documented in our center's electronic health record, and 246 treatment courses were analyzed. One hundred forty-three (57%) tolerated therapy versus 108 (43%) experienced ADRs. Among the 108 intolerant courses, 67 (63%) required treatment modification and 49 (46%) required premature treatment termination. Treatment intolerance was associated more frequently with smear positive sputum cultures (34% vs. 20%, p = 0.009), a higher Charlson Comorbidity Index (CCI) (4 vs. 6, p = 0.007), and existing liver disease (7% vs. 1%, p = 0.03). There was no between-group difference in BMI (21 vs. 22), fibrocavitary disease (24 vs. 19%), or macrolide sensitivity (94 vs. 80%). The use of daily therapy was not associated with intolerance (77 vs. 79%). Intolerant patients were more likely to be culture positive after 6 months of treatment (44 vs. 25%). CONCLUSIONS: Patients prescribed antibiotic therapy for MAC-PD are more likely to experience ADRs if they have smear positive sputum cultures at diagnosis, a higher CCI, or existing liver disease. Our study's rate of early treatment cessation due to ADR's was similar to that of other studies (20%) but is the first of its kind to evaluate patient and disease factors associated with ADR's. A systematic approach to classifying and addressing ADRs for patients undergoing treatment for MAC-PD is an area for further investigation.

Impact of C-reactive Protein on Anticoagulation Monitoring in Extracorporeal Membrane Oxygenation.

OBJECTIVE: To evaluate the impact of inflammation on anticoagulation monitoring for patients supported with extracorporeal membrane oxygenation (ECMO). DESIGN: Prospective single-center cohort study. SETTING: University-affiliated tertiary care academic medical center. PARTICIPANTS: Adult venovenous and venoarterial ECMO patients anticoagulated with heparin/ MEASUREMENTS AND MAIN RESULTS: C-Reactive protein (CRP) was used as a surrogate for overall inflammation. The relationship between CRP and the partial thromboplastin time (PTT, seconds) was evaluated using a CRP-insensitive PTT assay (PTT-CRP) in addition to measurement using a routine PTT assay. Data from 30 patients anticoagulated with heparin over 371 ECMO days was included. CRP levels (mg/dL) were significantly elevated (median, 17.2; interquartile range [IQR], 9.2-26.1) and 93% of patients had a CRP of ≥5. The median PTT (median 58.9; IQR, 46.9-73.3) was prolonged by 11.3 seconds compared with simultaneously measured PTT-CRP (median, 47.6; IQR, 40.1-55.5; p < 0.001). The difference between PTT and PTT-CRP generally increased with CRP elevation from 2.7 for a CRP of <5.0 to 13.0 for a CRP between 5 and 10, 17.7 for a CRP between 10 and 15, and 15.1 for a CRP of >15 (p < 0.001). In a subgroup of patients, heparin was transitioned to argatroban, and a similar effect was observed (median PTT, 62.1 seconds [IQR, 53.0-78.5 seconds] vs median PTT-CRP, 47.6 seconds [IQR, 41.3-57.7 seconds]; p < 0.001). CONCLUSIONS: Elevations in CRP are common during ECMO and can falsely prolong PTT measured by commonly used assays. The discrepancy due to CRP-interference is important clinically given narrow PTT targets and may contribute to hematological complications.

Active surveillance of serious adverse events following transfusion of COVID-19 convalescent plasma.

BACKGROUND: The reported incidence of adverse reactions following Coronavirus disease 2019 (COVID-19) convalescent plasma (CCP) transfusion has generally been lower than expected based on the incidence of transfusion reactions that have been observed in studies of conventional plasma transfusion. This raises the concern for under-reporting of adverse events in studies of CCP that rely on passive surveillance strategies. MATERIALS AND METHODS: Our institution implemented a protocol to actively identify possible adverse reactions to CCP transfusion. In addition, we retrospectively reviewed the charts of inpatients who received CCP at Stanford Hospital between May 13, 2020 and January 31, 2021. We determined the incidence of adverse events following CCP transfusion. RESULTS: A total of 49 patients received CCP. Seven patients (14%) had an increased supplemental oxygen requirement within 4 h of transfusion completion, including one patient who was intubated during the transfusion. An additional 11 patients (total of 18, 37%) had increased oxygen requirements within 24 h of transfusion, including 3 patients who were intubated. Six patients (12%) fulfilled criteria for transfusion-associated circulatory overload (TACO). CONCLUSION: Using an active surveillance strategy, we commonly observed adverse events following the transfusion of CCP to hospitalized patients. It was not possible to definitively determine whether or not these adverse events are related to CCP transfusion. TACO was likely over-diagnosed given overlap with the manifestations of COVID-19. Nevertheless, these results suggest that the potential adverse effects of CCP transfusion may be underestimated by reports from passive surveillance studies.

Low-level mosaicism in tuberous sclerosis complex: prevalence, clinical features, and risk of disease transmission.

PURPOSE: To examine the prevalence and spectrum of mosaic variant allele frequency (MVAF) in tuberous sclerosis complex (TSC) patients with low-level mosaicism and correlate genetic findings with clinical features and transmission risk. METHODS: Massively parallel sequencing was performed on 39 mosaic TSC patients with 170 different tissue samples. RESULTS: TSC mosaic patients (MVAF: 0-10%, median 1.7% in blood DNA) had a milder and distinct clinical phenotype in comparison with other TSC series, with similar facial angiofibromas (92%) and kidney angiomyolipomas (83%), and fewer seizures, cortical tubers, and multiple other manifestations (p < 0.0001 for six features). MVAF of TSC1/TSC2 pathogenic variants was highly variable in different tissue samples. Remarkably, skin lesions were the most reliable tissue for variant identification, and 6 of 39 (15%) patients showed no evidence of the variant in blood. Semen analysis showed absence of the variant in 3 of 5 mosaic men. The expected distribution of MVAF in comparison with that observed here suggests that there is a considerable number of individuals with low-level mosaicism for a TSC2 pathogenic variant who are not recognized clinically. CONCLUSION: Our findings provide information on variability in MVAF and risk of transmission that has broad implications for other mosaic genetic disorders.

Amikacin Liposome Inhalation Suspension for Treatment-Refractory Lung Disease Caused by Mycobacterium avium Complex (CONVERT). A Prospective, Open-Label, Randomized Study.

Rationale: Improved therapeutic options are needed for patients with treatment-refractory nontuberculous mycobacterial lung disease caused by Mycobacterium avium complex (MAC). Objectives: To evaluate the efficacy and safety of daily amikacin liposome inhalation suspension (ALIS) added to standard guideline-based therapy (GBT) in patients with refractory MAC lung disease. Methods: Adults with amikacin-susceptible MAC lung disease and MAC-positive sputum cultures despite at least 6 months of stable GBT were randomly assigned (2:1) to receive ALIS with GBT (ALIS + GBT) or GBT alone. Once-daily ALIS was supplied in single-use vials delivering 590 mg amikacin to the nebulizer. The primary endpoint was culture conversion, defined as three consecutive monthly MAC-negative sputum cultures by Month 6. Measurements and Main Results: Enrolled patients (ALIS + GBT, n = 224; GBT-alone, n = 112) were a mean 64.7 years old and 69.3% female. Most had underlying bronchiectasis (62.5%), chronic obstructive pulmonary disease (14.3%), or both (11.9%). Culture conversion was achieved by 65 of 224 patients (29.0%) with ALIS + GBT and 10 of 112 (8.9%) with GBT alone (odds ratio, 4.22; 95% confidence interval, 2.08-8.57; P < 0.001). Patients in the ALIS + GBT arm versus GBT alone were more likely to achieve conversion (hazard ratio, 3.90; 95% confidence interval, 2.00-7.60). Respiratory adverse events (primarily dysphonia, cough, and dyspnea) were reported in 87.4% of patients receiving ALIS + GBT and 50.0% receiving GBT alone; serious treatment-emergent adverse events occurred in 20.2% and 17.9% of patients, respectively. Conclusions: Addition of ALIS to GBT for treatment-refractory MAC lung disease achieved significantly greater culture conversion by Month 6 than GBT alone, with comparable rates of serious adverse events. Clinical trial registered with www.clinicaltrials.gov (NCT02344004).

Randomized Trial of Liposomal Amikacin for Inhalation in Nontuberculous Mycobacterial Lung Disease.

RATIONALE: Lengthy, multidrug, toxic, and low-efficacy regimens limit management of pulmonary nontuberculous mycobacterial disease. OBJECTIVES: In this phase II study, we investigated the efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory pulmonary nontuberculous mycobacterial (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. METHODS: During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multidrug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. The primary endpoint was change from baseline to Day 84 on a semiquantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute-walk distance, and adverse events. MEASUREMENTS AND MAIN RESULTS: The modified intention-to-treat population included 89 (LAI = 44; placebo = 45) patients. The average age of the sample was 59 years; 88% were female; 92% were white; and 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. The primary endpoint was not achieved (P = 0.072); however, a greater proportion of the LAI group demonstrated at least one negative sputum culture (14 [32%] of 44 vs. 4 [9%] of 45; P = 0.006) and improvement in 6-minute-walk test (+20.6 m vs. -25.0 m; P = 0.017) at Day 84. A treatment effect was seen predominantly in patients without cystic fibrosis with MAC and was sustained 1 year after LAI. Most adverse events were respiratory, and in some patients it led to drug discontinuation. CONCLUSIONS: Although the primary endpoint was not reached, LAI added to a multidrug regimen produced improvements in sputum conversion and 6-minute-walk distance versus placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research in this area is needed. Clinical trial registered with www.clinicaltrials.gov (NCT01315236).

Management of nontuberculous mycobacteria in lung transplant cases: an international Delphi study.

Rationale: Nontuberculous mycobacterial (NTM) diseases are difficult-to-treat infections, especially in lung transplant (LTx) candidates. Currently, there is a paucity of recommendations on the management of NTM infections in LTx, focusing on Mycobacterium avium complex (MAC), M. abscessus and M. kansasii. Methods: Pulmonologists, infectious disease specialists, LTx surgeons and Delphi experts with expertise in NTM were recruited. A patient representative was also invited. Three questionnaires comprising questions with multiple response statements were distributed to panellists. Delphi methodology with a Likert scale of 11 points (5 to -5) was applied to define the agreement between experts. Responses from the first two questionnaires were collated to develop a final questionnaire. The consensus was described as a median rating >4 or <-4 indicating for or against the given statement. After the last round of questionnaires, a cumulative report was generated. Results: Panellists recommend performing sputum cultures and a chest computed tomography scan for NTM screening in LTx candidates. Panellists recommend against absolute contraindication to LTx even with multiple positive sputum cultures for MAC, M. abscessus or M. kansasii. Panellists recommend MAC patients on antimicrobial treatment and culture negative can be listed for LTx without further delay. Panellists recommend 6 months of culture-negative for M. kansasii, but 12 months of further treatment from the time of culture-negative for M. abscessus before listing for LTx. Conclusion: This NTM LTx study consensus statement provides essential recommendations for NTM management in LTx and can be utilised as an expert opinion while awaiting evidence-based contributions.

Severe COVID-19 disease in a 2nd trimester pregnancy: Successful ECMO and mechanical ventilation management.

Extracorporeal membrane oxygenation (ECMO) is an invasive support strategy for cardiac, respiratory, or combined cardiorespiratory failure. ECMO has become increasing utilized in patients with severe respiratory failure due to COVID-19 infection. To our knowledge there is no report of successful ECMO utilization in second trimester of pregnancy leading to a successful outcome. We present a case of severe COVID-19 infection in a patient causing respiratory failure in the second trimester pregnancy. With diligent utilization of ECMO and mechanical ventilation we were able to support the patient's respiratory needs to allow her pregnancy to continue. Ultimately, the patient underwent successful caesarean section in the third trimester. This case highlights excellent lung injury protection and lung recovery can be achieved through optimal utilization of ECMO support together with a careful and closely monitored lung protective ventilation strategy, even while also supporting the patient through the increasing metabolic circumstances of a progressing pregnancy.

Diagnosing invasive fungal disease in critically ill patients.

Fungal infections are increasing, with a changing landscape of pathogens and emergence of new groups at risk for invasive disease. We review current diagnostic techniques, focusing on studies in critically ill patients. Microbiological cultures, the current "gold standard", demonstrate poor sensitivity, thus diagnosis of invasive disease in the critically ill is difficult. This diagnostic dilemma results in under- or over-treatment of patients, potentially contributing to poor outcomes and antifungal resistance. While other current diagnostic tests perform moderately well, many lack timeliness, efficacy, and are negatively affected by treatments common to critically ill patients. New nucleic acid-based research is promising.

The Pathophysiology and Dangers of Silent Hypoxemia in COVID-19 Lung Injury.

The ongoing coronavirus disease (COVID-19) pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormality and change in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia," has led to the speculation of underlying pathophysiological differences between COVID-19 lung injury and acute respiratory distress syndrome (ARDS) from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes, although our ability to confirm these phenotypes by more invasive and longitudinal studies is limited. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiological reasons at present to support a therapeutic approach for these patients that is different from the proven standards of care in ARDS.

Unexpected Interruptions in the Inhaled Epoprostenol Delivery System: Incidence of Adverse Sequelae and Therapeutic Consequences in Critically Ill Patients.

OBJECTIVES: Inhaled epoprostenol is a continuously delivered selective pulmonary vasodilator that is used in patients with refractory hypoxemia, right heart failure, and postcardiac surgery pulmonary hypertension. Published data suggest that inhaled epoprostenol administration via vibrating mesh nebulizer systems may lead to unexpected interruptions in drug delivery. The frequency of these events is unknown. The objective of this study was to describe the incidence and clinical consequences of unexpected interruption in critically ill patients. DESIGN: Retrospective review and analysis. SETTING: Stanford University Hospital, a 605-bed tertiary care center. PATIENTS: Patients receiving inhaled epoprostenol in 2019. INTERVENTIONS: No interventions. MEASUREMENTS AND MAIN RESULTS: Clinical indication, duration of inhaled epoprostenol delivery, mode of respiratory support, and documented unexpected interruption. In 2019, there were 493 administrations of inhaled epoprostenol in 433 unique patients. Primary indications for inhaled epoprostenol were right heart dysfunction (n = 394; 79.9%) and hypoxemia (n = 92; 18.7%). Unexpected delivery interruptions occurred in 31 administrations (6.3%). Median duration of therapy prior to unexpected interruption was 2 days (interquartile range, 2-5 d). Respiratory support at the time of unexpected interruption was mechanical ventilation (61.3%), high-flow nasal cannula (35.5%), and noninvasive positive pressure ventilation (3.2%). Adverse sequelae of unexpected interruption included elevated pulmonary artery pressures (n = 12), systemic hypotension (n = 8), hypoxemia (n = 8), elevated central venous pressure (n = 4), and cardiac arrest (n = 1). Therapeutic interventions following unexpected interruption included initiation of inhaled nitric oxide (n = 21), increase in vasoactive medication (n = 2), and increase in respiratory support (n = 2). Most of the adverse events were Common Terminology Criteria for Adverse Events grade 3 and 4 (93.5%). CONCLUSIONS: A retrospective review of patients receiving inhaled epoprostenol via vibrating mesh nebulizer in 2019 revealed interruptions in 6.3% of administrations with most of these interruptions requiring therapeutic intervention. The true incidence of unexpected interruption and subsequent rate of unexpected interruption's requiring intervention is unknown due to the reliance on unexpected interruption identification and subsequent documentation in the electronic medical record. Sudden interruption in inhaled epoprostenol delivery can result in severe cardiopulmonary compromise, and on rare occasion, death.

Amikacin Liposome Inhalation Suspension for Mycobacterium avium Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial.

Rationale: Patients with refractory Mycobacterium avium complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population.Objectives: Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT.Methods: Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed.Results: In the ALIS-naive cohort, 83.3% of patients (n = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% (n = 32) had serious TEAEs; 26.7% (n = 24) achieved culture conversion by Month 6 and 33.3% (n = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients (n = 34/73) experienced respiratory TEAEs, and 27.4% (n = 20) had serious TEAEs; 9.6% (n = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% (n = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts.Conclusions: In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).

Reamed Intramedullary Nailing of a Femur Fracture in a Polytraumatized Patient on Extracorporeal Membrane Oxygenation: A Case Report.

CASE: We present the case of a young adult with blunt lung trauma and acute respiratory distress syndrome requiring extracorporeal membrane oxygenation (ECMO) after a motor vehicle crash with a concomitant diaphyseal femur fracture who underwent reamed intramedullary nailing (IMN) while on ECMO support. CONCLUSION: This case is important because it demonstrates that reamed IMN of the femur has been performed safely in a critically ill patient on ECMO.

Clevidipine-Induced Extreme Hypoxemia in a Neurosurgical Patient: A Case Report.

Clevidipine-induced pulmonary shunting is a little-reported adverse effect, manifesting as refractory hypoxemia, which may cause significant patient harm. We present the case of a mechanically ventilated patient admitted to the intensive care unit following a neurosurgical procedure. He was treated postoperatively with clevidipine for blood pressure management, and within 16 hours, he developed profound refractory hypoxemia, requiring increased ventilatory support. A workup for other causes was negative. The hypoxemia recovered within 1 hour of clevidipine discontinuation. Though other calcium channel blockers have been reported to cause pulmonary shunting from vasodilation, this is a novel case report for clevidipine-induced hypoxemia.

Tuberculosis in liver transplant recipients: a systematic review and meta-analysis of individual patient data.

Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid-related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short-term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18-fold increase in the prevalence of active MTB infection and a 4-fold increase in the case-fatality rate. For high-risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894-906, 2009. (c) 2009 AASLD.

The NHLBI LAM Registry: Prognostic Physiologic and Radiologic Biomarkers Emerge From a 15-Year Prospective Longitudinal Analysis.

BACKGROUND: The natural history of lymphangioleiomyomatosis (LAM) is mainly derived from retrospective cohort analyses, and it remains incompletely understood. A National Institutes of Health LAM Registry was established to define the natural history and identify prognostic biomarkers that can help guide management and decision-making in patients with LAM. METHODS: A linear mixed effects model was used to compute the rate of decline of FEV1 and to identify variables affecting FEV1 decline among 217 registry patients who enrolled from 1998 to 2001. Prognostic variables associated with progression to death/lung transplantation were identified by using a Cox proportional hazards model. RESULTS: Mean annual decline of FEV1 was 89 ± 53 mL/year and remained remarkably constant regardless of baseline lung function. FEV1 decline was more rapid in those with greater cyst profusion on CT scanning (P = .02) and in premenopausal subjects (118 mL/year) compared with postmenopausal subjects (74 mL/year) (P = .003). There were 26 deaths and 43 lung transplantations during the evaluation period. The estimated 5-, 10-, 15-, and 20-year transplant-free survival rates were 94%, 85%, 75%, and 64%, respectively. Postmenopausal status (hazard ratio, 0.30; P = .0002) and higher baseline FEV1 (hazard ratio, 0.97; P = .008) or diffusion capacity of lung for carbon monoxide (hazard ratio, 0.97; P = .001) were independently associated with a lower risk of progression to death or lung transplantation. CONCLUSIONS: The median transplant-free survival in patients with LAM is > 20 years. Menopausal status, as well as structural and physiologic markers of disease severity, significantly affect the rate of decline of FEV1 and progression to death or lung transplantation in LAM.