Predictors and outcomes of acute pulmonary embolism in COVID-19; insights from US National COVID cohort collaborative.

OBJECTIVES: To investigate whether COVID-19 patients with pulmonary embolism had higher mortality and assess the utility of D-dimer in predicting acute pulmonary embolism. PATIENTS AND METHODS: Using the National Collaborative COVID-19 retrospective cohort, a cohort of hospitalized COVID-19 patients was studied to compare 90-day mortality and intubation outcomes in patients with and without pulmonary embolism in a multivariable cox regression analysis. The secondary measured outcomes in 1:4 propensity score-matched analysis included length of stay, chest pain incidence, heart rate, history of pulmonary embolism or DVT, and admission laboratory parameters. RESULTS: Among 31,500 hospitalized COVID-19 patients, 1117 (3.5%) patients were diagnosed with acute pulmonary embolism. Patients with acute pulmonary embolism were noted to have higher mortality (23.6% vs.12.8%; adjusted Hazard Ratio (aHR) = 1.36, 95% CI [1.20-1.55]), and intubation rates (17.6% vs. 9.3%, aHR = 1.38[1.18-1.61]). Pulmonary embolism patients had higher admission D-dimer FEU (Odds Ratio(OR) = 1.13; 95%CI [1.1-1.15]). As the D-dimer value increased, the specificity, positive predictive value, and accuracy of the test increased; however, sensitivity decreased (AUC 0.70). At cut-off D-dimer FEU 1.8 mcg/ml, the test had clinical utility (accuracy 70%) in predicting pulmonary embolism. Patients with acute pulmonary embolism had a higher incidence of chest pain and history of pulmonary embolism or deep vein thrombosis. CONCLUSIONS: Acute pulmonary embolism is associated with worse mortality and morbidity outcomes in COVID-19. We present D-dimer as a predictive risk tool in the form of a clinical calculator for the diagnosis of acute pulmonary embolism in COVID-19.

Anionic fluoroquinolones as antibacterials against biofilm-producing Pseudomonas aeruginosa.

Pseudomonas aeruginosa is a common biofilm-forming bacterial pathogen implicated in diseases of the lungs. The extracellular polymeric substances (EPS) of respiratory Pseudomonas biofilms are largely comprised of anionic molecules such as rhamnolipids and alginate that promote a mucoid phenotype. In this Letter, we examine the ability of negatively-charged fluoroquinolones to transverse the EPS and inhibit the growth of mucoid P. aeruginosa. Anionic fluoroquinolones were further compared with standard antibiotics via a novel microdiffusion assay to evaluate drug penetration through pseudomonal alginate and respiratory mucus from a patient with cystic fibrosis.

Bilateral Lung Transplantation in Kartagener's Syndrome and Situs Inversus.

Kartagener's syndrome (KS) is a genetic disorder and a subgroup of primary ciliary dyskinesia characterized by situs inversus, chronic sinusitis and bronchiectasis. Patients with KS can develop severe bronchiectasis with end-stage lung disease due to recurrent pulmonary infections. Lung transplantation is a treatment option with good outcomes reported in the literature. Lung transplantation in such patients can be technically challenging given the dextrocardia, bronchial asymmetry and anatomical variation of major vascular structures due to situs inversus. We present a case of a 45-year-old male with KS complicated by recurrent infections and chronic respiratory failure, who successfully underwent a bilateral sequential lung transplant (BSLTx). Because of repeated infections and severe bronchiectasis, the patient's quality of life was impaired, and he was oxygen dependent. As a definitive treatment, successful lung transplantation led to a reversal of hypoxic respiratory failure and the patient's symptoms markedly improved, reinforcing data in the literature to consider lung transplantation in this patient population.

Severe Bicuspid Aortic Valve Disease in an Adult Cystic Fibrosis Patient.

Bicuspid aortic valve is the most common congenital heart disease. Bicuspid aortic valves are prone to accelerated degenerative changes and aortopathies. These changes often manifest in adulthood as severe aortic stenosis or mixed aortic valve disease. Cystic fibrosis patients are at high risk of adverse surgical outcomes. As survival in cystic fibrosis continues to increase, managing comorbidities including severe aortic stenosis requires consideration. The relatively non-invasive transcatheter aortic valve replacement has been posed as an intervention for high-risk patients with severe symptomatic aortic stenosis. However, traditional randomized trials have excluded patients with bicuspid aortic valves. Herein we present an extremely rare association of severe bicuspid aortic valve stenosis in an adult cystic fibrosis patient. Furthermore, we discuss the clinical course and a multi-disciplinary approach for the management of this rare scenario.

Position paper: Models of post-transplant care for individuals with cystic fibrosis.

There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication.

Double Lung Transplantation Bridged With Direct Central Ambulatory Veno-Arterial Extracorporeal Membrane Oxygenation in a Pulmonary Hypertension Patient With Extreme Mediastinal Shift.

Lung transplantation is increasingly being performed for end-stage lung disease in patients with bronchiectasis and pulmonary hypertension. Outcomes of bilateral lung transplantation (BLT) are better in patients with pulmonary hypertension, whereas single lung transplant remains a controversy in bronchiectasis with fear of infections from the residual diseased lung. However, in patients with adhesions and extreme structural changes due to severe disease, BLT may be considered technically challenging. We describe a case of successful management of a patient with bronchiectasis-induced lung disease causing extreme mediastinal shift with a BLT. The patient was successfully bridged to transplant with central veno-arterial extracorporeal membrane oxygenation (VA-ECMO) for acute decompensated pulmonary hypertension while awaiting transplantation.

Lung Transplantation in a Patient With COVID-19-Associated Acute Respiratory Failure.

Coronavirus disease 2019 (COVID-19) is currently a significant cause of acute respiratory failure worldwide, leading to irreversible fibrotic lung disease. In patients with persistent respiratory failure after acute COVID-19 infection, lung transplant is an emerging option. Here, we have presented a case where the patient required venovenous extracorporeal membrane oxygenation (VV-ECMO) support for 33 days until a bilateral lung transplant was performed on day 71 after the initial COVID-19 infection. The early outcomes have been favorable. Currently, no guidelines exist for an acceptable time period after initial COVID-19 infection, duration of negative COVID polymerase chain reaction (PCR) testing, or negative Vero cell culture in the setting of persistent positive COVID PCR testing before listing for a lung transplant. Due to a lack of standardized guidelines, this patient was not listed for a lung transplant until the COVID-19 PCRs came negative on days 47 and 49 after the infection.

Cerebral paradoxical embolisation in a patient with cystic fibrosis with patent foramen ovale: a comparative review of literature.

A 52-year-old woman with cystic fibrosis presented to the emergency department with expressive aphasia and right-sided hemiparesis. CT scan of the brain revealed a left middle cerebral artery territory infarct. A diagnosis of cerebral paradoxical embolisation associated with patent foramen ovale and a history of deep venous thrombosis was made. The patient underwent endovascular thrombectomy and percutaneous closure of patent foramen ovale. Current literature, including five published case reports, pertaining to the subject is discussed. The unique aspects of the case are highlighted, including the particular risk of cerebral paradoxical embolisation in patients with cystic fibrosis. The result of this case report, in context to previously reported literature, suggests that clinicians should be aware of paradoxical embolisation in patients with cystic fibrosis via an intracardiac shunt, particularly with implanted vascular access devices and a history of deep venous thrombosis.

Immunomodulatory Effects of Azithromycin Revisited: Potential Applications to COVID-19.

The rapid advancement of the COVID-19 pandemic has prompted an accelerated pursuit to identify effective therapeutics. Stages of the disease course have been defined by viral burden, lung pathology, and progression through phases of the immune response. Immunological factors including inflammatory cell infiltration and cytokine storm have been associated with severe disease and death. Many immunomodulatory therapies for COVID-19 are currently being investigated, and preliminary results support the premise of targeting the immune response. However, because suppressing immune mechanisms could also impact the clearance of the virus in the early stages of infection, therapeutic success is likely to depend on timing with respect to the disease course. Azithromycin is an immunomodulatory drug that has been shown to have antiviral effects and potential benefit in patients with COVID-19. Multiple immunomodulatory effects have been defined for azithromycin which could provide efficacy during the late stages of the disease, including inhibition of pro-inflammatory cytokine production, inhibition of neutrophil influx, induction of regulatory functions of macrophages, and alterations in autophagy. Here we review the published evidence of these mechanisms along with the current clinical use of azithromycin as an immunomodulatory therapeutic. We then discuss the potential impact of azithromycin on the immune response to COVID-19, as well as caution against immunosuppressive and off-target effects including cardiotoxicity in these patients. While azithromycin has the potential to contribute efficacy, its impact on the COVID-19 immune response requires additional characterization so as to better define its role in individualized therapy.

Effect of azithromycin on pulmonary function in patients with cystic fibrosis uninfected with Pseudomonas aeruginosa: a randomized controlled trial.

CONTEXT: Azithromycin is recommended as therapy for cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, but there has not been sufficient evidence to support the benefit of azithromycin in other patients with CF. OBJECTIVE: To determine if azithromycin treatment improves lung function and reduces pulmonary exacerbations in pediatric CF patients uninfected with P. aeruginosa. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, double-blind placebo-controlled trial was conducted from February 2007 to July 2009 at 40 CF care centers in the United States and Canada. Of the 324 participants screened, 260 were randomized and received study drug. Eligibility criteria included age of 6 to 18 years, a forced expiratory volume in the first second of expiration (FEV(1)) of at least 50% predicted, and negative respiratory tract cultures for P. aeruginosa for at least 1 year. Randomization was stratified by age of 6 to 12 years vs 13 to 18 years and by CF center. INTERVENTION: The active group (n = 131) received 250 mg (weight 18-35.9 kg) or 500 mg (weight > or = 36 kg) of azithromycin 3 days per week (Monday, Wednesday, and Friday) for 168 days. The placebo group (n = 129) received identically packaged placebo tablets on the same schedule. MAIN OUTCOME MEASURES: The primary outcome was change in FEV(1). Exploratory outcomes included additional pulmonary function end points, pulmonary exacerbations, changes in weight and height, new use of antibiotics, and hospitalizations. Changes in microbiology and adverse events were monitored. RESULTS: The mean (SD) age of participants was 10.7 (3.17) years. The mean (SD) FEV(1) at baseline and 168 days were 2.13 (0.85) L and 2.22 (0.86) L for the azithromycin group and 2.12 (0.85) L and 2.20 (0.88) L for the placebo group. The difference in the change in FEV(1) between the azithromycin and placebo groups was 0.02 L (95% confidence interval [CI], -0.05 to 0.08; P = .61). None of the exploratory pulmonary function end points were statistically significant. Pulmonary exacerbations occurred in 21% of the azithromycin group and 39% of the placebo group. Participants in the azithromycin group had a 50% reduction in exacerbations (95% CI, 31%-79%) and an increase in body weight of 0.58 kg (95% CI, 0.14-1.02) compared with placebo participants. There were no significant differences between groups in height, use of intravenous or inhaled antibiotics, or hospitalizations. Participants in the azithromycin group had no increased risk of adverse events, but had less cough (-23% treatment difference; 95% CI, -33% to -11%) and less productive cough (-11% treatment difference; 95% CI, -19% to -3%) compared with placebo participants. CONCLUSION: In children and adolescents with CF uninfected with P. aeruginosa, treatment with azithromycin for 24 weeks did not result in improved pulmonary function. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00431964.

Pregabalin-Induced Myopathy in a Double Lung Transplant Recipient.

Pregabalin is a gamma-aminobutyric acid (GABA) derivative that was commercially approved by the Food and Drug Administration (FDA) in 2004. It is commonly used in the treatment of diabetic neuropathy, peripheral neuropathy, and spinal cord injury. We present the case of a 36-year-old Caucasian male double lung transplant recipient who presented with an 18-month history of fatigue and muscle weakness. He had elevated creatinine kinase level and his muscle biopsy showed evidence of drug-induced myopathy that improved after the cessation of pregabalin. We present a case of drug-induced myopathy as a rare complication of pregabalin therapy in a double lung transplant recipient.

Insomnia and chronic heart failure.

Insomnia is highly prevalent in patients with chronic disease including chronic heart failure (CHF) and is a significant contributing factor to fatigue and poor quality of life. The pathophysiology of CHF often leads to fatigue, due to nocturnal symptoms causing sleep disruption, including cough, orthopnea, paroxysmal nocturnal dyspnea, and nocturia. Inadequate cardiac function may lead to hypoxemia or poor perfusion of the cerebrum, skeletal muscle, or visceral body organs, which result in organ dysfunction or failure and may contribute to fatigue. Sleep disturbances negatively affect all dimensions of quality of life and is related to increased risk of comorbidities, including depression. This article reviews insomnia in CHF, cardiac medication side-effects related to sleep disturbances, and treatment options.

Voriconazole-induced Myositis in a Double Lung Transplant Recipient.

Voriconazole is a triazole antifungal agent commercially approved in 2002. It is commonly used in immunocompromised patients as a therapeutic and prophylactic agent. We present the case of a 26-year-old Caucasian female who is a double lung transplant recipient who presented with complaints of generalized left lower extremity swelling and extreme tenderness of her left thigh. Although her muscle enzymes were not significantly elevated, inflammatory changes were noticed on T2-weighted fat-suppressed short-TI inversion recovery (STIR) sequence magnetic resonance imaging (MRI). These findings were later confirmed with tissue biopsy. We hereby present the case of drug-induced myositis as a rare complication of voriconazole used as chemoprophylaxis in a double lung transplant recipient patient.

Disseminated Mucormycosis with Extensive Cardiac Involvement.

Mucormycosis is an opportunistic fungal infection. Cardiac involvement is a rare, yet fatal, complication that can occur in disseminated disease. A strong index of suspicion is necessary for prompt treatment, especially in high-risk patients. We present a 62-year-old male patient with a history of diabetes and acute myeloid leukemia; he had pulmonary mucormycosis that was complicated by cardiac involvement as part of disseminated mucormycosis syndrome.

Patients and families experience with pharmacist care at cystic fibrosis foundation accredited clinics.

Cystic fibrosis (CF) is a complex genetic, multiorgan disease. The CF Foundation (CFF) recommends a multidisciplinary team (physician, nurse, respiratory therapist, dietitian, physical therapist, social worker, mental health coordinator, clinic coordinator, and pharmacist) to work with patients and families. The objective of our study was to describe the impact of a pharmacist involved in the care of patients and families from their perspective. The CF Patient and Family Experience of Care (PFEC) is a voluntary, 50-question telephonic or internet-based survey designed to continuously collect information from patients and their families regarding their care experience. From August of 2017 through February of 2018, five questions were added to the internet survey to assess the impact of the pharmacist on the care experience. From the 666 respondents, 54% reported that a pharmacist was involved in their CF care. At two CF clinics designated as "full access" to a pharmacist, respondents reported a higher percentage of the CF-team discussed medications compared to those from three clinics designated as "limited access" to the pharmacist (95% vs 67%). Respondents in clinics with "full access" to a pharmacist were significantly more likely to get their medications refilled on time (78% vs 63%) and reported using fewer pharmacies to fill their medications. Pharmacist involvement in CF care may improve patient's access to medication and the ability to sustain use.

Outcomes of Lung Transplantation for Cystic Fibrosis in the Setting of Extensively Drug-Resistant Organisms.

INTRODUCTION: Since the largest study on extensively drug-resistant organisms and lung transplantation in patients with cystic fibrosis, there have been innovations and advancements in the treatment of Pseudomonas aeruginosa. RESEARCH QUESTION: What differences exist for patients with cystic fibrosis with a history of extensively drug-resistant infections who undergo lung transplantation despite treatment advances with antimicrobial therapy? STUDY DESIGN: Two-center, retrospective, cohort study conducted in 44 patients with cystic fibrosis chronically infected with extensively drug-resistant organisms who received a lung transplant from January 2008 through August 2016. Patients in the resistant cohort were chronically infected with pan-resistant P aeruginosa, polymyxin-sensitive only, or sensitive to 2 antibiotic classes (polymyxin plus one other); remaining patients with more susceptible P aeruginosa or no P aeruginosa remained in the control cohort. The primary outcome is a composite of patient survival, retransplantation, chronic lung allograft dysfunction, and acute rejection 12 months posttransplant. Categorical variables were analyzed using χ2 testing. The independent samples t test was utilized for continuous variables. RESULTS: There was no difference in the primary outcome (40% vs 37%, P = .831). Differences between patient survival (84% vs 95%, P = .487), the incidence of acute rejection (20% vs 33%, P = .323), and the incidence of chronic lung allograft rejection (12% vs 5%, P = .441) were not different between groups. DISCUSSION: Recipients chronically infected with an extensively resistant P aeruginosa had similar outcomes compared to those infected with more sensitive organisms.

Azithromycin alters macrophage phenotype.

OBJECTIVES: To investigate the in vitro effects of azithromycin on macrophage phenotype. Utilizing a mouse macrophage cell line (J774), we examined the effect of azithromycin on the properties that define classical macrophage activation (M1) and alternative macrophage activation (M2). METHODS: J774 cells were cultured in the presence of azithromycin and stimulated with classical activation [interferon-gamma (IFNgamma)] and alternative activation [interleukin (IL)-4 and IL-13] cytokines along with lipopolysaccharide (LPS). Macrophages were analysed for inflammatory cytokine production, surface receptor expression, inducible nitric oxide synthase (iNOS) protein expression and arginase activity. RESULTS: Azithromycin altered the overall macrophage phenotype. Azithromycin-treated J774 macrophages demonstrated a significantly reduced production of the pro-inflammatory cytokines IL-12 and IL-6, increased production of the anti-inflammatory cytokine IL-10 and decreased the ratio of IL-12 to IL-10 by 60%. Receptor expression indicative of the M2 phenotype (mannose receptor and CD23) was increased, and receptor expression typically up-regulated in M1 cells (CCR7) was inhibited. The presence of azithromycin increased arginase (M2 effector molecule) activity 10-fold in cells stimulated with IFNgamma and LPS, and iNOS protein (M1 effector molecule) concentrations were attenuated by the drug. CONCLUSIONS: These data provide evidence that azithromycin affects the inflammatory process at the level of the macrophage and shifts macrophage polarization towards the alternatively activated phenotype. This recently defined M2 phenotype has been described in conditions in which pulmonary inflammation and fibrosis are major determinants of clinical outcome, but the concept of antibiotics altering macrophage phenotype has not yet been critically evaluated.

Azithromycin in the extremely low birth weight infant for the prevention of bronchopulmonary dysplasia: a pilot study.

BACKGROUND: Azithromycin reduces the severity of illness in patients with inflammatory lung disease such as cystic fibrosis and diffuse panbronchiolitis. Bronchopulmonary dysplasia (BPD) is a pulmonary disorder which causes significant morbidity and mortality in premature infants. BPD is pathologically characterized by inflammation, fibrosis and impaired alveolar development. The purpose of this study was to obtain pilot data on the effectiveness and safety of prophylactic azithromycin in reducing the incidence and severity of BPD in an extremely low birth weight (< or = 1000 grams) population. METHODS: Infants < or = 1000 g birth weight admitted to the University of Kentucky Neonatal Intensive Care Unit (level III, regional referral center) from 9/1/02-6/30/03 were eligible for this pilot study. The pilot study was double-blinded, randomized, and placebo-controlled. Infants were randomized to treatment or placebo within 12 hours of beginning mechanical ventilation (IMV) and within 72 hours of birth. The treatment group received azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for the duration of the study. Azithromycin or placebo was continued until the infant no longer required IMV or supplemental oxygen, to a maximum of 6 weeks. Primary endpoints were incidence of BPD as defined by oxygen requirement at 36 weeks gestation, post-natal steroid use, days of IMV, and mortality. Data was analyzed by intention to treat using Chi-square and ANOVA. RESULTS: A total of 43 extremely premature infants were enrolled in this pilot study. Mean gestational age and birth weight were similar between groups. Mortality, incidence of BPD, days of IMV, and other morbidities were not significantly different between groups. Post-natal steroid use was significantly less in the treatment group [31% (6/19)] vs. placebo group [62% (10/16)] (p = 0.05). Duration of mechanical ventilation was significantly less in treatment survivors, with a median of 13 days (1-47 days) vs. 35 days (1-112 days)(p = 0.02). CONCLUSION: Our study suggests that azithromycin prophylaxis in extremely low birth weight infants may effectively reduce post-natal steroid use for infants. Further studies are needed to assess the effects of azithromycin on the incidence of BPD and possible less common side effects, before any recommendations regarding routine clinical use can be made.

Pharmacokinetic and Pharmacodynamic Analyses of Ceftaroline in Adults with Cystic Fibrosis.

STUDY OBJECTIVE: To evaluate the pharmacokinetics and pharmacodynamics of ceftaroline in adults with cystic fibrosis (CF). DESIGN: Open-label, single-center, prospective study. SETTING: University-affiliated teaching institution. PATIENTS: Eight patients with a diagnosis of CF and a history of methicillin-resistant Staphylococcus aureus who were treated with ceftaroline between November 2013 and September 2014. INTERVENTION: All patients received at least three doses of intravenous ceftaroline 600 mg every 12 hours, administered as a 60-minute infusion, to achieve steady-state concentrations before blood sample collection. After an interim analysis of the first four patients' pharmacokinetic data, the remaining four patients received a change in dosage of ceftaroline to 600 mg every 8 hours. MEASUREMENTS AND MAIN RESULTS: Patients' blood samples were collected at two time points, 2 and 6 hours after infusion initiation, after administration of at least three doses of ceftaroline. Serum ceftaroline concentrations were determined by using a validated mass spectrometry, with a lower limit of detection of 20 ng/ml. These ceftaroline concentrations were used to estimate patient-specific pharmacokinetic parameters, and 10,000-patient Monte Carlo simulations were performed to determine the pharmacodynamic probability of target attainment (PTA) for ceftaroline in adults with CF. A PTA of 90% or higher for the desired pharmacodynamic target was considered adequate. The PTA for 60% or higher of the dosing interval during which free (unbound) drug concentrations exceed the minimum inhibitory concentration (%fT > MIC) was simulated for various MICs. Compared with values previously reported in other populations, the volume of distribution was increased in the study patients, and the estimated half-life was shorter. Monte Carlo simulations revealed that a dose of ceftaroline 600 mg every 8 hours, infused over 60 minutes, maintained a higher than 90% PTA for %fT > MIC of 60% or higher for an MIC at the susceptibility breakpoint of 1 mg/L. CONCLUSION: The pharmacokinetics of ceftaroline is altered in adults with CF, which suggests the need for modified dosing in this patient population to achieve adequate %fT > MIC. A dosage of intravenous ceftaroline 600 mg every 8 hours administered as a 60-minute infusion should be considered to achieve 60% fT > MIC.