Intravenous Immunoglobulins Alone for the Desensitization of Lung Transplant Recipients with Preformed Donor Specific Antibodies and Negative Flow Cytometry Crossmatch.

BACKGROUND: The lack of evidence regarding optimal desensitization strategies for lung transplant candidates with preformed donor specific anti-human leukocyte antigen antibodies (DSAs) has led to varying approaches among centers towards this patient group. Our institution's desensitization protocol for recipients with preformed DSAs and negative flow cytometry crossmatch (FCXM) consists of intravenous immunoglobulin (IVIG) as the sole therapy. The study aimed to determine outcomes using this approach. METHODS: This retrospective study included adults who underwent lung-only transplantation for the first time between January 2015 and March 2022 at a single center. We excluded patients with positive or missing FCXM results. Transplant recipients with any DSA ≥ 1000 MFI on latest testing within three months of transplant were considered DSA-positive, while recipients with DSAs <1000 MFI and those without DSAs were assigned to the low-level/negative group. Graft survival (time to death/retransplantation) and chronic lung allograft dysfunction (CLAD)-free times were compared between groups using Cox proportional hazards models. RESULTS: Thirty-six out of 167 eligible patients (22%) were DSA-positive. At least 50% of preformed DSAs had documented clearance (decrease to <1000 MFI) within the first 6 months of transplant. Multivariable Cox regression analyses did not detect a significantly increased risk of graft failure (aHR 1.04 95%CI 0.55-1.97) or chronic lung allograft dysfunction (aHR 0.71 95%CI 0.34-1.52) in DSA-positive patients compared to patients with low-level/negative DSAs. Incidences of antibody-mediated rejection (p = 1.00) and serious thromboembolic events (p = 0.63) did not differ between study groups. CONCLUSION: We describe a single-center experience of administering IVIG alone to lung transplant recipients with preformed DSAs and negative FCXM. Further studies are required to confirm the efficacy of this strategy against other protocols.

Donor respiratory multidrug-resistant bacteria and lung transplantation outcomes.

RATIONALE: Respiratory culture screening is mandatory for all potential lung transplant donors. There is limited evidence on the significance of donor multidrug-resistant (MDR) bacteria on transplant outcomes. Establishing the safety of allografts colonized with MDR bacteria has implications for widening an already limited donor pool. OBJECTIVES: We aimed to describe the prevalence of respiratory MDR bacteria among our donor population and to test for associations with posttransplant outcomes. METHODS: This retrospective observational study included all adult patients who underwent lung-only transplantation for the first time at King Faisal Specialist Hospital & Research Centre in Riyadh from January 2015 through May 2022. The study evaluated donor bronchoalveolar lavage and bronchial swab cultures. MAIN RESULTS: Sixty-seven of 181 donors (37%) had respiratory MDR bacteria, most commonly MDR Acinetobacter baumannii (n = 24), methicillin-resistant Staphylococcus aureus (n = 18), MDR Klebsiella pneumoniae (n = 8), MDR Pseudomonas aeruginosa (n = 7), and Stenotrophomonas maltophilia (n = 6). Donor respiratory MDR bacteria were not significantly associated with allograft survival or chronic lung allograft dysfunction (CLAD) in adjusted hazard models. Sensitivity analyses revealed an increased risk for 90-day mortality among recipients of allografts with MDR Klebsiella pneumoniae (n = 6 with strains resistant to a carbapenem and n = 2 resistant to a third-generation cephalosporin only) compared to those receiving culture-negative allografts (25.0% versus 11.1%, p = 0.04). MDR Klebsiella pneumoniae (aHR 3.31, 95%CI 0.95-11.56) and Stenotrophomonas maltophilia (aHR 5.35, 95%CI 1.26-22.77) were associated with an increased risk for CLAD compared to negative cultures. CONCLUSION: Our data suggest the potential safety of using lung allografts with MDR bacteria in the setting of appropriate prophylaxis; however, caution should be exercised in the case of MDR Klebsiella pneumoniae.

Donor blood cultures and outcomes after lung transplantation: a single-center report.

BACKGROUND: Transplanting lungs from donors with positive blood cultures has not been shown to adversely affect survival. There is limited evidence for potential effects on other outcomes, such as hospital course, graft function, and transmission of infection. METHODS: This retrospective cohort study included adult patients who underwent lung-only transplantation for the first time between March 2010 and December 2022. Outcomes of patients whose donors had positive blood cultures within 72 h of transplant were compared to patients whose donors had negative blood cultures. RESULTS: Twenty-five (10.8%) of 232 donors had positive blood cultures, including a single, unexpected case with candidemia. The most commonly isolated bacteria were Enterobacter cloacae (n = 5), Klebsiella pneumoniae (n = 5), Acinetobacter baumannii (n = 3), Pseudomonas aeruginosa (n = 3), and Staphylococcus aureus (n = 3). Eleven donors had identical bacteria in their respiratory cultures. All patients who were transplanted from donors with positive blood cultures survived beyond 90 days. Positive donor blood cultures were not associated with longer hospital stay, in-hospital complications, acute cellular rejection, or the achievement of 80% predicted forced expiratory volume in the first second. Probable transmission of donor bacteremia occurred in only two cases (both with S. aureus). These two donors had positive respiratory cultures with the same organism. CONCLUSION: The study did not find an increased risk of adverse events when transplanting lungs from donors with positive blood cultures. Allograft cultures may be more predictive of the risk of transmitting infections.

Diagnostic Utility of Bronchoalveolar Lavage in Immunocompromised Patients with Lung Infiltrates.

Introduction: Lung infections are associated with a high mortality rate in immunocompromised patients. Achieving an accurate and rapid diagnosis is vital to help guide management, and thus improve survival. Objective: To establish the diagnostic yield, clinical value, and safety of bronchoscopy with bronchoalveolar lavage (BAL) in immunocompromised adult patients with pulmonary infiltrates. Methods: This retrospective study included all immunocompromised adult patients who underwent bronchoscopy with BAL for investigation of radiologically confirmed pulmonary infiltrates at a tertiary care hospital between January 01, 2014, and June 30, 2021. Clinically significant findings of BAL were defined as a positive microbiological result of a potential pathogen determined using routine culture, acid-fast bacilli smear, mycobacterial culture, tuberculosis PCR, fungal culture, Aspergillus antigen, and multiplex PCR panel and/or positive cytology. Results: A total of 103 unique patients were included (mean ± SD age: 44.5 ± 14.1 years), of which the majority were male (60.2%). The BAL diagnostic yield was 52.4% (95% CI: 42.6-62.2%). In the multiple logistic regression model, positive BAL was predicted by symptom of sputum (aOR 4.01, 95% CI: 1.27-12.70, P = 0.018). Almost half of the procedures (43.7%, 95% CI: 33.9-53.4%) resulted in a change in the management plan, with positive BAL findings more than twice as likely to result in a change (OR 2.39, 95% CI: 1.07-5.33, P = 0.033). Only three (2.9%) procedures resulted in complications and required ventilator support and/or oxygen escalation. Conclusions: BAL is a safe clinical tool that can be useful in impacting clinical management in a significant proportion of immunocompromised patients with pulmonary infiltrates.

Lung transplantation outcomes in underweight recipients: A single center experience.

Background: Current guidelines recommend a body mass index (BMI) of 16 kg/m2 as the minimum threshold for lung transplantation, despite mixed evidence on outcomes in underweight patients. The current study aimed to describe survival outcomes of underweight patients who underwent lung transplantation at a single center. Methods: This retrospective observational study included adult lung transplant recipients who underwent transplantation for the first time between March 2010 and March 2022 at King Faisal Specialist Hospital and Research Center and excluded patients with obesity. We defined an underweight status as a BMI <17 kg/m2. Results: Forty-eight of the 202 lung transplant recipients were underweight at the time of surgery. The underweight patients had similar lengths of hospital (p = 0.53) and intensive care unit (p = 0.81) stays compared to other patients. Thirty-three percent of underweight patients had died within 5-year follow-up, compared to 34% of patients who were not underweight. There was no significant difference in mortality risk between underweight patients and patients with normal BMIs in our multivariable Cox regression model (adjusted HR 1.57, 95%CI: 0.77-3.20, p = 0.21). Exploratory analyses revealed that a pre-transplant BMI <13 kg/m2 was associated with a trend towards increased 5-year mortality (adjusted HR 4.00, 95%CI: 0.87-18.35, p = 0.07). Conclusions: Our findings suggest that patients with BMIs of 13-17 kg/m2 may be candidates for lung transplantation. Large multi-center cohort studies are needed to confirm the lower BMI limit for safely transplanting patients.

Treatment of bronchial anastomotic fistula using autologous platelet-rich plasma post lung transplantation.

BACKGROUND: Bronchial anastomotic dehiscence is considered one of the most catastrophic early airway complications post-transplant. The presence of a partial dehiscence can also cause further complications such as a fistula between the bronchus and the pleural membrane. Platelet-rich plasma (PRP) is known to significantly enhance the healing process and is being used in the treatment of various conditions, however, so far, there are no reports of the use of PRP in the treatment of bronchial anastomotic dehiscence fistula. CASE PRESENTATION: We present a 37-year-old male, with non-cystic fibrosis bronchiectasis underwent bilateral lung transplantation. The patient developed partial dehiscence of the right bronchial anastomosis that was complicated by a small bronchopleural fistula. Two bronchoscopic applications of autologous platelet-rich plasma were carried out. Follow-up a few weeks later showed complete closure and healing of the fistula. CONCLUSIONS: This case report suggests that the treatment of post-lung transplant small bronchial anastomotic partial dehiscence fistula with PRP is safe and effective.

Assessing cough symptom severity in refractory or unexplained chronic cough: findings from patient focus groups and an international expert panel.

Background: Cough symptom severity represents an important subjective end-point to assess the impact of therapies for patients with refractory or unexplained chronic cough (RCC/UCC). As existing instruments assessing the severity of cough are neither widely available nor tested for measurement properties, we aim to develop a new patient-reported outcome measure addressing cough severity. Objective: The aim of this study was to establish items and domains that would inform development of a new cough severity instrument. Methods: Three focus groups involving 16 adult patients with RCC/UCC provided data that we analysed using directed content analysis. Discussions led to consensus among an international panel of 15 experts on candidate items and domains to assess cough severity. Results: The patient focus group provided 48 unique items arranged under broad domains of urge-to-cough sensations and cough symptom. Feedback from expert panel members confirmed the appropriateness of items and domains, and provided an additional subdomain related to cough triggers. The final conceptual framework comprised 51 items in the following domains: urge-to-cough sensations (subdomains: frequency and intensity) and cough symptom (subdomains: triggers, control, frequency, fit/bout duration, intensity, quality and associated features/sequelae). Conclusions: Consensus findings from patients and international experts established domains of urge-to-cough and cough symptom with associated subdomains and relevant items. The results support item generation and content validity for a novel patient-reported outcome measure for use in health research and clinical practice.

An open-label study of the tolerability and potential efficacy of memantine for treating refractory chronic cough.

Blocking NMDA receptors with memantine in refractory chronic cough patients is poorly tolerated and demonstrates no improvement in cough https://bit.ly/3kgx2g1.

A Randomized Controlled Trial to Assess the Effect of Lidocaine Administered via Throat Spray and Nebulization in Patients with Refractory Chronic Cough.

BACKGROUND: Refractory chronic cough (RCC) is a debilitating condition for which there are no licensed treatments. Lidocaine is a nonselective inhibitor of voltage-gated sodium channels with potential antitussive effects, but randomized placebo-controlled studies evaluating its efficacy in RCC are lacking. OBJECTIVE: To investigate the efficacy of nebulized lidocaine and lidocaine throat spray versus matched placebos in RCC. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, 3-way crossover study, comparing the effect of single doses of nebulized lidocaine with lidocaine delivered by a throat spray and matched placebo. The primary end point was cough frequency over the 10 hours following treatment. Secondary end points were visual analog scale scores for urge-to-cough and cough severity; an exploratory analysis evaluated hourly cough rates up to 5 hours after treatment. RESULTS: Twenty-six subjects with RCC were recruited (22 females; mean age, 53.5 ± 12.1 years; FEV1 %predicted, 105.2 ± 16.8 L; forced vital capacity %predicted, 112.4 ± 18 L). Lidocaine throat spray, but not nebulized lidocaine, significantly reduced 10-hour cough frequency as compared with placebo (throat spray, 22.6 coughs/h; nebulization, 26.9 coughs/h; and placebos, 27.6 coughs/h; P = .04,). Lidocaine throat spray showed the greatest effect on cough compared with placebo in the first hour after administration (31.7 coughs/h vs 74.2 coughs/h; P = .004). Both nebulizer and spray treatments significantly alleviated urge-to-cough and cough severity visual analog scale scores compared with placebo (P < .05). There were no serious adverse events associated with lidocaine therapy. CONCLUSIONS: Lidocaine throat spray was effective in reducing cough frequency in patients with RCC. Voltage-gated sodium channel inhibitors applied to pharynx have potential as therapies for RCC.

Clinical, epidemiological, and laboratory characteristics of mild-to-moderate COVID-19 patients in Saudi Arabia: an observational cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged from China in December 2019 and has presented as a substantial and serious threat to global health. We aimed to describe the clinical, epidemiological, and laboratory findings of patients in Saudi Arabia infected with SARS-CoV-2 to direct us in helping prevent and treat coronavirus disease 2019 (COVID-19) across Saudi Arabia and around the world. MATERIALS AND METHODS: Clinical, epidemiological, laboratory, and radiological characteristics, treatment, and outcomes of pediatric and adult patients in five hospitals in Riyadh, Saudi Arabia, were surveyed in this study. RESULTS: 401 patients (mean age 38.16 ± 13.43 years) were identified to be SARS-CoV-2 positive and 80% of cases were male. 160 patients had moderate severity and 241 were mild in severity. The most common signs and symptoms at presentation were cough, fever, fatigue, and shortness of breath. Neutrophil and lymphocyte counts, aspartate aminotransferase, C-reactive protein, and ferritin were higher in the COVID-19 moderate severity patient group. Mild severity patients spent a shorter duration hospitalized and had slightly higher percentages of abnormal CT scans and X-ray imaging. CONCLUSIONS: This study provides an understanding of the features of non-ICU COVID-19 patients in Saudi Arabia. Further national collaborative studies are needed to streamline screening and treatment procedures for COVID-19.

Clinical characteristics of non-intensive care unit COVID-19 patients in Saudi Arabia: A descriptive cross-sectional study.

INTRODUCTION: The ongoing pandemic of the coronavirus disease 2019 (COVID-19) is a global health concern. It has affected more than 5 million patients worldwide and resulted in an alarming number of deaths globally. While clinical characteristics have been reported elsewhere, data from our region is scarce. We investigated the clinical characteristics of mild to moderate cases of COVID-19 in Saudi Arabia. METHODS: This is a descriptive, cross-sectional study. Data of 401 confirmed COVID-19 patients were collected from 22 April 2020 to 21 May 2020 at five tertiary care hospitals in Riyadh, Saudi Arabia. The patients were divided into four groups according to age, Group 1: 0-<18 years, Group 2: 18-<50 years, Group 3: 50-60 years, and Group 4: >60 years; and their clinical symptoms were compared. RESULTS: The median (IQR) age in years was 10.5 (1.5-16) in group I, 34 (29-41) in group II, 53 (51-56) in group III, and 66 (61-76) in group IV. Most patients were male (80%, n = 322) and of Arabian or Asian descent. The median length of stay in the hospital was 10 (8-17) days (range 3-42 days). The most common symptoms were cough (53.6%), fever (36.2%), fatigue (26.4%), dyspnea (21.9%), and sore throat (21.9%). Hypertension was the most common underlying comorbidity (14.7%), followed by obesity (11.5%), and diabetes (10%). Hypertensive patients were less likely to present with shortness of breath, cough, sputum, diarrhea, and fever. CONCLUSION: There was no significant difference in the symptoms among different age groups and comorbidities were mostly seen in the older age group. Interestingly, hypertensive patients were found to have milder symptoms and a shorter length of stay. Further larger collaborative national studies are required to effectively understand clinical characteristics in our part of the world to efficiently manage and control the spread of SARS-CoV-2.

Patients' perceptions and patient-reported outcomes in progressive-fibrosing interstitial lung diseases.

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be used to assess an array of constructs affected by a disease or the interventions implemented to treat it. Here, we review the impact of ILD that may present with a progressive-fibrosing phenotype on patients' lives and examine how PROs have been used to measure that impact and the effectiveness of therapeutic interventions.

P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study.

BACKGROUND: Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough. We aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. METHODS: We did a double-blind, placebo-controlled, two-period, crossover study at one UK centre. With a computer-generated sequence, we randomly assigned patients with refractory chronic cough to AF-219, 600 mg twice a day, or to placebo (1:1), and then, after a 2 week washout, assigned patients to receive the other treatment. Patients, health-care providers, and investigators were masked to sequence assignment. We assessed daytime cough frequency (primary endpoint) at baseline and after 2 weeks of treatment using 24 h ambulatory cough recordings. The primary analysis used a mixed effects model with the intention-to-treat population. This study was registered at ClinicalTrials.gov, number NCT01432730. FINDINGS: Of 34 individuals assessed between Sept 22, 2011, and Nov 29, 2012, we randomly assigned 24 patients (mean age 54·5 years; SD 11·1). In the observed case analysis, cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219. INTERPRETATION: P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives. FUNDING: Afferent Pharmaceuticals.

Gastro-oesophageal reflux and cough.

Gastro-oesophageal reflux, either singly or in association with postnasal drip and/or asthma is considered to be a cause of chronic cough. The amount and nature of gastro-oesophageal reflux however is often normal with acid suppression having very little, if any therapeutic effect in these patients. This review examines the challenges posed when exploring the reflux-cough link, and discusses the merits and limitations of the proposed mechanisms of reflux leading to cough.