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.

Wild-type S100A3 and S100A13 restore calcium homeostasis and mitigate mitochondrial dysregulation in pulmonary fibrosis patient-derived cells.

Patients with digenic S100A3 and S100A13 mutations exhibited an atypical and progressive interstitial pulmonary fibrosis, with impaired intracellular calcium homeostasis and mitochondrial dysfunction. Here we provide direct evidence of a causative effect of the mutation on receptor mediated calcium signaling and calcium store responses in control cells transfected with mutant S100A3 and mutant S100A13. We demonstrate that the mutations lead to increased mitochondrial mass and hyperpolarization, both of which were reversed by transfecting patient-derived cells with the wild type S100A3 and S100A13, or extracellular treatment with the recombinant proteins. In addition, we demonstrate increased secretion of inflammatory mediators in patient-derived cells and in control cells transfected with the mutant-encoding constructs. These findings indicate that treatment of patients' cells with recombinant S100A3 and S100A13 proteins is sufficient to normalize most of cellular responses, and may therefore suggest the use of these recombinant proteins in the treatment of this devastating disease.

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.

COVID-19: Lung-Centric Immunothrombosis.

The respiratory tract is the major site of infection by SARS-CoV-2, the virus causing COVID-19. The pulmonary infection can lead to acute respiratory distress syndrome (ARDS) and ultimately, death. An excessive innate immune response plays a major role in the development of ARDS in COVID-19 patients. In this scenario, activation of lung epithelia and resident macrophages by the virus results in local cytokine production and recruitment of neutrophils. Activated neutrophils extrude a web of DNA-based cytoplasmic material containing antimicrobials referred to as neutrophil extracellular traps (NETs). While NETs are a defensive strategy against invading microbes, they can also serve as a nidus for accumulation of activated platelets and coagulation factors, forming thrombi. This immunothrombosis can result in occlusion of blood vessels leading to ischemic damage. Herein we address evidence in favor of a lung-centric immunothrombosis and suggest a lung-centric therapeutic approach to the ARDS of COVID-19.

Superior vena cava stenting in IgG4-associated mediastinal fibrosis.

We report a rare case of IgG4-associated mediastinal fibrosis with complete superior vena cava (SVC) obstruction successfully managed by thrombolysis and stenting in a 33-year-old male. The patient presented with a mediastinal mass lesion with clinical findings of SVC obstruction. Surgical biopsy of the mediastinal mass lesion with histology and immunohistochemistry staining established the diagnosis of IgG4 associated mediastinal fibrosis. The patient was treated with a systemic steroid and rituximab, but despite treatment, SVC obstruction and thromboses persisted, surgical intervention was declined by the thoracic surgeon due to extensive mediastinal fibrosis and an expected poor outcome. Percutaneous SVC angioplasty, intravascular thrombolysis with tissue plasminogen activator and afterward stent placement was done by the interventional radiology service. This intervention is rare and possibly was lifesaving as it restored complete patency of the SVC. Our case is probably the first with IgG4 mediastinitis and SVC complete obstruction relieved by intravascular thrombolysis and SVC stent placement. It demonstrates that SVC stenting can relieve SVC obstruction in patients with a high risk of surgery either due to medical comorbidities or an expected high surgical risk like bleeding in the mediastinal fibrosis, which in our case of SVC obstruction was due to a nonoperable mediastinal tumor. SIMILAR CASES PUBLISHED: None to our knowledge.

Iacta Alea Est: The Inexorable Advance of Tofacitinib in the Treatment of Dermatomyositis-Associated Rapidly Progressive Interstitial Lung Disease. A Case Report.

Rapidly progressive interstitial lung disease is typically associated with clinically amyopathic dermatomyositis and the anti-melanoma differentiation associated gene 5 antibody, a condition with high mortality and resistance to classic immunosuppression. Recent reports have described the efficacy of the Janus kinase inhibitor tofacitinib in the treatment of rapidly progressive interstitial lung disease in anti-melanoma differentiation associated gene 5 antibody-positive clinically amyopathic dermatomyositis. It is uncertain, however, whether tofacitinib alters the course of rapidly progressive interstitial lung disease in other variants of dermatomyositis that are unrelated to the anti-melanoma differentiation associated gene 5 antibody and whether the early addition of the anti-fibrotic tyrosine kinase inhibitor nintedanib interferes with the development of fibrosis. To answer these questions, we present and discuss the case of an elderly woman who presented with a flare of dermatomyositis sine myositis. Based upon the detection of anti-Jo-1 antibodies and the absence of anti-melanoma differentiation associated gene 5 antibodies, anti-synthetase syndrome was diagnosed. While the cutaneous manifestations quickly resolved with prednisone, azathioprine and tacrolimus, the respiratory function paradoxically and rapidly deteriorated, and invoked the use of tofacitinib. Markedly raised ferritin levels and a severe numerical deficiency of circulating natural killer cells paralleled the acute lung inflammation, which was reflected by 18F-fluorodeoxyglucose hypermetabolism on positron emission tomography/CT. Tofacitinib lead to a prompt clinical recovery, with a reduction in oxygen requirement, correction of hyperferritinemia, reversal of the natural killer cell deficiency, and a decrease in 18F-fluorodeoxyglucose uptake in the affected lung segments. Subsequently, nintedanib was added at a point in time when inflammation subsided. Apart from cytomegalovirus reactivation no adverse events occurred. In conclusion, tofacitinib reversed the pronounced inflammatory component of anti-Jo-1 antibody-positive, anti-melanoma differentiation associated gene 5 antibody-negative rapidly progressive interstitial lung disease, confirming that Janus kinase signaling pathways are critically involved in the pathogenesis of rapidly progressive interstitial lung disease, apparently independently of the targeted autoantigen. Although some improvement in pulmonary function was observed, it seems premature to conclusively judge on reversibility or prevention of pulmonary fibrosis by pairing both kinase inhibitors for which an extended follow-up and ideally, prospective and controlled studies are needed.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13.

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.

Ribavirin and interferon-α2b as primary and preventive treatment for Middle East respiratory syndrome coronavirus: a preliminary report of two cases.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly recognized transmissible viral infection with high virulence and case fatality rates for which there is no currently defined primary treatment or prophylaxis. Saudi Arabia has the largest reported number of cases so far. Like severe acute respiratory syndrome (SARS), MERS is caused by a coronavirus. Combination therapy with interferon-α2b and ribavirin has been used successfully as primary treatment and prophylaxis in SARS. Because of similarities between the two coronaviruses, treatment with ribavarin and interferon-α2b has been suggested as a potential therapy for MERS-CoV. Studies in animal models of MERS-CoV have shown the combination of ribavirin and interferon-α2b to be effective both as primary treatment and prophylaxis. In this report, we describe for the first time use of this combination as a primary treatment for a patient with MERS-CoV infection and as prophylaxis for his spouse and discuss its possible role.

Middle Eastern Respiratory Syndrome Corona Virus (MERS CoV): case reports from a tertiary care hospital in Saudi Arabia.

BACKGROUND AND OBJECTIVES: Middle Eastern respiratory syndrome caused by novel coronavirus (MERS CoV) has been a major public health challenge since it was first described in 2012 in Saudi Arabia. So far, there is no effective treatment for this serious illness, which features a high mortality rate. We report an initial experience of the use of ribavirin and interferon (IFN)-a2b in the management of MERS CoV at a tertiary care hospital. DESIGN AND SETTINGS: A case series of 6 patients admitted with a confirmed diagnosis of MERS CoV were treated with ribavirin and IFN-a2b in addition to supportive management. The patients' demographics, clinical parameters, and outcomes were recorded. Fifty-four close contacts of these patients were screened for MERS CoV. METHODS: Six patients with MERS CoV infection were included in this study. Four cases featured symptomatic disease, including pneumonia and respiratory failure, while 2 were asymptomatic close contacts of the MERS CoV patients. The MERS CoV infection was confirmed by reverse transcription-polymerase chain reaction detection of the consensus viral RNA targets upstream of the E gene (UPE) and open reading frame (ORF1b) on a sputum sample. The patients' demographics, comorbid conditions, time to diagnosis and initiation of treatment, and clinical outcomes were recorded. RESULTS: Three out of 6 patients who had comorbid conditions died during the study period, while 3 had suc.cessful outcomes. The diagnosis and treatment was delayed by an average of 15 days in those patients who died. Only 2 close contacts out of the 54 screened (3.7%) were positive for MERS CoV. CONCLUSION: Treatment with ribavirin and IFN-a2b may be effective in patients infected with MERS CoV. There appears to be a low infectivity rate among close contacts of MERS CoV patients.