Citations

Abstract Introduction: Hemolytic uremic syndrome (HUS) is especially uncommon in adults and can manifest as devasting complications including severe acute kidney injury (AKI) and microangiopathic hemolytic anemia (MAHA). Transfusion-related acute lung injury (TRALI) is a rare complication of blood product transfusion that is characterized by the rapid development of noncardiogenic pulmonary edema. We present a rare case of HUS complicated by TRALI requiring mechanical ventilation. Case Description: A 41-year-old female farmer, who occasionally drank raw cow's milk, was admitted with abdominal pain and distension, bloody diarrhea, poor appetite, decreased urine output and fatigue. She was found to have MAHA and stage 3 AKI. Imaging demonstrated pancolitis and workup revealed Shiga toxin-producing E. coli, O157:H7 serotype which was consistent with a diagnosis of HUS. Tests for DIC, TTP and atypical HUS were negative. She was not a candidate for dialysis, plasma exchange or eculizumab. With supportive measures including 3 units of packed red blood cell (pRBC), her symptoms, renal function, and bicytopenia improved and she was discharged. Two days post-discharge, she presented to the ED for unilateral vision changes, left hemiparesis, and lower extremity tremor. After negative neurological evaluation, this was attributed to encephalopathy secondary to HUS. She received 1 unit of pRBCs for a hemoglobin of 6.8. Within 3 hours of transfusion, she developed acute respiratory distress requiring intubation and ICU transfer. CT chest angiogram was negative for pulmonary embolism but demonstrated diffuse bilateral lower lobe dependent consolidations concerning for TRALI (Figure 1). After diuresis, she was able to be extubated within 48 hours with return to her respiratory and neurologic baselines soon after. Discussion: The pathophysiology of TRALI involves neutrophil sequestration and priming in the pulmonary vasculature with subsequent neutrophil activation by donor blood product factors where active infection is a known risk factor. Active HUS likely contributed to neutrophil priming through endothelial damage and systemic inflammation, predisposing this patient to TRALI. There are few reports of similar cases in the literature. TRALI can be subdivided into type I and type II; type I has no risk factors for acute respiratory distress syndrome (ARDS) while type II does. TRALI must also be distinguished from ARDS and transfusion-associated circulatory overload; these distinctions are predominantly made based on timing of respiratory symptom onset. This case highlights the importance of keeping TRALI in the differential for all patients with active or recent infection, including HUS, who develop acute-onset respiratory decompensation after transfusion.

Abstract Immune checkpoint inhibitor (ICI) therapy has significantly advanced cancer treatment, particularly for metastatic melanoma, but it is associated with severe, life-threatening adverse effects. A rare but critical complication is the overlap syndrome of Myositis, Myocarditis, and Myasthenia Gravis (MMM), affecting approximately 0.21% of ICI-treated solid tumor patients with an in-hospital mortality rate of up to 60%. Early recognition and management are crucial for improving outcomes. Case Presentation: A 76-year-old male with metastatic melanoma, coronary artery disease, ischemic cardiomyopathy (EF 35%), chronic kidney disease, diabetes, and chronic respiratory failure (baseline oxygen requirement of 2L) presented two weeks after starting Nivolumab and Relatlimab. He developed worsening exertional dyspnea, orthopnea, diplopia, dysarthria, and progressive proximal muscle weakness. On presentation, he was hemodynamically stable, with elevated troponin T (1241 ng/L) and NT-proBNP (2698 pg/mL). Initial investigations, including EKG and chest X-ray, were unremarkable with no thymoma. Left heart catheterization revealed severe multivessel coronary artery disease but no treatable lesions. He was noted to have fatigable ptosis and he subsequently developed bulbar symptoms, including hypophonia and dysphagia. A diagnosis of Myasthenia Gravis was suspected. Further evaluation showed respiratory muscle weakness (NIF -12 cm H2O, vital capacity 2L, mild hypercarbia on ABG) and progressive weakness, leading to intubation. Elevated creatine kinase (1527 U/L), persistent troponin elevation, and global hypokinesis on repeat echocardiography pointed to a likely diagnosis of myocarditis/myositis. Electromyography revealed neuropathy without acute findings, and serological testing for acetylcholine receptor antibodies, HMG-CoA reductase antibodies, and myositis was negative. ICI-induced MMM was diagnosed, and the patient was treated with methylprednisolone, IVIG, pyridostigmine, and ICI discontinuation. Despite plasmapheresis, his condition deteriorated. He developed septic shock from multiple infections (E-Coli bacteremia, Stenotrophomonas pneumonia) and progressed to cardiogenic shock, requiring vasopressors. Subsequent imaging revealed pneumoperitoneum concerning bowel perforation, but further diagnostic workup was declined by the family. Comfort care was initiated, and the patient passed away. Discussion: ICI use has grown rapidly, with agents like Nivolumab expanding treatment options for metastatic melanoma. However, MMM, a rare but severe complication, demands prompt recognition. Presentation often occurs within 21 days of ICI initiation, and patients may display elevated CPK and stable or rising troponin levels. Myasthenia gravis within MMM can cause rapid respiratory failure, with significant morbidity. Management includes corticosteroids, IVIG and immediate ICI discontinuation. Treatment should begin without waiting for confirmatory tests, given the syndrome's high mortality. Early, multidisciplinary intervention is essential in managing this fatal condition effectively.

Abstract Immune checkpoint inhibitors (ICIs) work by blocking inhibitory signals that normally restrain the immune system, allowing it to attack cancer cells. However, ICIs can sometimes lead to cross-reactivity, causing the immune system to mistakenly target the body's tissues, including muscle, resulting in myositis. Overactive T cells can attack muscle tissue, while ICIs may also promote autoantibody production, potentially leading to conditions like myasthenia gravis. In rare cases, mitochondrial function is affected, causing further muscle damage. Here, we present a unique case of ICI toxicity resulting in multiple organ damage, known as Triple M syndrome, encompassing myositis, myocarditis, and myasthenia gravis A 67-year-old female with a history of stage IIIA BRAF V600+ melanoma presented with myocarditis, myositis, and myasthenia, all associated with pembrolizumab treatment. Initial management included high-dose steroids, IVIG for suspected myasthenia gravis, and abatacept. Laboratory evaluation showed a creatine kinase (CK) of 14,925 and troponin of 8,427. Cardiac MRI confirmed myocarditis. She developed ventricular arrhythmias requiring Impella support and progressive conduction abnormalities necessitating a leadless pacemaker. Her respiratory status further declined with marked respiratory muscle weakness, consistent with both myasthenia gravis and myositis eventually requiring intubation. EMG studies showed defects in neuromuscular transmission. She underwent plasmapheresis and was started on pyridostigmine. Due to refractory symptoms, she was started on rituximab and eventually initiated sirolimus, mycophenolate, and basiliximab to address worsening immune-mediated toxicities. This case highlights a rare and severe presentation of immune checkpoint inhibitor (ICI)-induced toxicity resulting in Triple M syndrome, characterized by concurrent myocarditis, myositis, and myasthenia gravis. While ICIs are pivotal in activating the immune system to target malignancies, they can also lead to serious immune-related adverse events (irAEs) due to cross-reactivity with healthy tissue. Triple M syndrome is an uncommon but life-threatening complication involving multiple organ systems, which requires rapid recognition and intensive management. Myocarditis is a well-recognized yet infrequent irAE associated with ICIs, with a high mortality rate, especially when presenting alongside myositis and myasthenia gravis. Myasthenia gravis and myositis are believed to occur due to ICI-induced cross-reactivity of T cells and autoantibody formation. Management of severe irAEs, especially in cases involving multiple systems, remains challenging. This case underscores the necessity of a multidisciplinary approach to address overlapping toxicities and prevent further complications. The use of advanced immunosuppression, including sirolimus, mycophenolate, and basiliximab, reflects the need for targeted inhibition of the immune system when corticosteroids alone are insufficient.

AbstractThe sliding filament theory explains skeletal muscle fibre force change as a function of length based on the overlap of actin and myosin filaments. Although this length‐tension (LT) relationship has been well investigated in animal models, it is not known whether this microscopic sarcomere LT property can be scaled up five orders of magnitude to explain the LT behaviour of a long human muscle such as the gracilis. The goal of this study is to validate the sarcomere LT curve in humans based on human filament length combined with in vivo experimental data. Intraoperative measurements of maximal tetanic force and muscle‐tendon unit length at four different joint configurations (JC) were obtained from 19 patients undergoing free functioning muscle transfer surgery. With physiologically measured fibre length and estimated sarcomere shortening resulting from tendon compliance, we show that 79.7% variance in isometric force data is explained by a simple human sarcomere LT model. This study demonstrates that the human whole muscle LT relationship can be modelled by the sliding filament theory given patient‐specific fibre length, filament length, tendon compliance and sarcomere shortening. imageKey points Whole human gracilis muscle isometric length‐tension relationships were measured in the operating room. Grouped whole muscle raw length‐tension curves showed no obvious form. The width of each experimental length‐tension curve was highly variable across subjects and used to predict fibre length (serial sarcomere number). After whole muscle length‐tension curves were normalized to each patient's serial sarcomere number, the whole human muscle length‐tension curve was well predicted by the sliding filament theory.

Abstract Introduction Mediastinal masses may exhibit various clinical and pathological features. Posterior mediastinal lesions are often neurogenic, followed by lymphadenopathy, extramedullary hematopoiesis, paraspinal abscess, and rarely, foregut duplication cysts (prevalence: 0.122%). Given the rarity and diagnostic challenges, these masses are often biopsied, though may not be ideal. We present a case of esophageal duplication cyst (EDC). Case presentation A 33-year-old woman with mild intermittent asthma, had initially presented to an outside facility for chronic productive cough, episodic chest tightness and dyspnea both at rest and with exertion, inspiratory and expiratory wheezes. Despite multiple courses of prednisone for presumed asthma exacerbation, her symptoms persisted. An initial Computer Tomography (CT) Chest demonstrated a 5 x 4 x 3 cm mass within the visceral mediastinum. Bronchoscopy with endobronchial ultrasound and transbronchial needle aspiration of the mediastinal lymph nodes was nondiagnostic, showing scant lymphocytes and abundant mucin. Broad autoimmune, connective tissue disease, and infectious disease workups were negative, prompting referral to our facility. Physical exam and labs were unremarkable and pulmonary function testing showed no evidence of small airway obstruction. A High-Resolution CT Chest revealed a 3.1 x 3.7 x 4.5 cm noncalcified, well-circumscribed mass soft tissue density, adjacent to the esophagus with elevated Hounsfield units close to esophagus. Ultimately duplication cyst was suspected and Magnetic Resonance Imaging (MRI) with contrast showed high T1 and T2 signal within the lesion and no enhancement after contrast, deemed compatible with proteinaceous/hemorrhagic cyst (Figure 1 A-D). Biopsy was deferred given diagnostic MRI characteristics, and risk of secondary infection. The diagnosis of EDC was confirmed via multidisciplinary thoracic tumor board revision. Ultimately, she was referred for surgical resection. Discussion The incidence of EDC is 1 in 8,200, with a two-fold male prevalence over women. These patients may present with dysphagia, cough, stridor, pain, or arrhythmia since childhood, or may be entirely asymptomatic. EDCs can develop along the esophagus, with 90% lacking communication with the esophageal lumen. Although posterior mediastinal mass typically require biopsy to exclude malignancy, tissue biopsy should be avoided in cases with suspected duplication cyst given risk of infection, abscess formation and mediastinitis. Transesophageal endoscopic ultrasonography could further characterize the cyst, however MRI is considered the gold standard diagnostic modality. Conclusion MRI is the gold standard diagnostic modality of EDC. Biopsy should be avoided given the risk of infection. Clinicians should consider a broad differential for posterior mediastinal mass and avoid unnecessary invasive testing.

Abstract Background: Diffuse pulmonary meningotheliomatosis (DPM) is a rare, benign proliferation of minute meningothelial-like nodules ranging from 100mm – 11mm.1 The condition presents primarily in women (9:1) in middle age.2 Discovered incidentally or with mild symptoms such as dyspnea and dry cough, the imaging findings can be concerning for miliary metastatic, atypical infectious, and immune mediated diffuse parenchymal lung disease thereby complicating the diagnostic process. Case Description: A 70-year-old female never smoker presented to our pulmonary clinic for evaluation of dyspnea and dry cough. She described evaluation roughly 20 years prior that had revealed innumerable small ground glass pulmonary nodules on CT imaging. Pulmonary function testing at that time was unremarkable, and laboratory studies had only revealed a weakly (+) SSA antibody. She was referred for a right mini-thoracotomy wedge resection, with pathology demonstrating small nodules partially involving the pleura, suspected to represent hypersensitivity pneumonitis (HP), as well as, several incidentally noted pulmonary “chemodectomas”. She was trialed on inhaled therapies, antibiotics, and even a two-year course of steroids for suspected HP without notable clinical or radiologic improvement. Interestingly, she was subsequently found to have an intracranial meningioma which was treated with external beam radiation. Upon presentation at our institution, a repeat high resolution chest CT showed mosaic attenuation with innumerable groundglass nodules and micronodules in a centrilobular and peri-lymphatic distribution. There was no significant change in appearance or distribution from prior imaging (Figure 1, A-B). Rigid bronchoscopy with transbronchial lung cryobiopsy was performed with pathology showing multiple meningothelial-like nodules (Figure 1, C). This pathologic finding, in conjunction with her clinical history, including past surgical biopsy, led to a diagnosis of DPM. Discussion: This case adds to about 50 cases of DPM and the clinical significance of diffuse perivenular and interstitial meningothelial-like cell proliferations in the lung without clear malignant potential. Additionally, it provides another case to a notable collection of cases with metachronous intracranial meningioma, suggesting possible shared pathogenesis or genetic predisposition.2 While the clinical course of DPM is generally indolent, it poses diagnostic challenges due to overlapping imaging characteristics with more aggressive pulmonary pathologies. The differential may include sarcoidosis, miliary infectious and malignant etiologies, DIPNECH, and follicular bronchiolitis. Conclusions: A systematic approach to this patient's ground-glass nodules with clinical re-evaluation given ineffective empiric treatment ultimately led to the correct diagnosis. It highlights the importance of biopsy for the diagnosis of pulmonary nodules of unclear etiology even with benign clinical progression.

Abstract Introduction: We present a case of constrictive bronchiolitis with paraneoplastic autoimmune multi-organ syndrome (PAMS) treated with lung transplantation. To our knowledge, this is the first reported case of PAMS with constrictive bronchiolitis managed with this approach. Presentation: A 45-year-old woman presented with 3 months of dyspnea. PFTs showed severe airflow obstruction with air trapping and no immediate bronchodilator response. [FEV1 0.94L (z: -3.9), FVC 2.98L (z: -0.515), TLC 4.89L (z: 1.0), RV 1.70L (z: 2.4) and DLCO 22 ml/min/mmhg (z: 0.58)] CT chest with expiratory views showed air trapping in the left upper lobe and ground glass opacities, consistent with constrictive bronchiolitis. 6 months prior, she was diagnosed with abdominal grade 1 follicular lymphoma, treated with Bendamustine and Rituximab. One month into treatment, she developed a lichenoid rash involving the oro-gential mucosa and erythematous papular skin eruptions. Her eruptions and constrictive bronchiolitis were consistent with PAMS with pulmonary involvement. The rash improved with oral steroids and topical therapies, but her pulmonary symptoms did not. The likelihood of progression was low, so lymphoma was not a contraindication for lung transplantation. To ensure complete metabolic remission, she was further treated with R-CHOP and maintained on Rituximab. During transplant evaluation, FEV1 was 30% with NYHA class II, Karnofsky score 60 and she required 4L oxygen. She grew mycobacterium abscessus subspecies abscessus on 3 different sets of induced sputum. Secondary to radiographic findings consistent with NTM-PD (bronchial wall thickening and mucoid impaction) and pending lung transplant, she was treated with omadacycline, tedizolid, amikacin and clofazimine until sputum culture negativity (3-months). She underwent lung transplantation and received pre-operative Mycophenolate and Methylprednisolone without induction immunosuppression. Post-operatively she was started on Tacrolimus, Mycophenolate Mofetil and Prednisone. M. Abscessus therapy continued for 2 months post-transplant. At 6 months post-transplant, she is well, and PFTs are improving without evidence of organ rejection, lymphoma recurrence, or M. abscessus infection. Discussion: Pulmonary involvement in PAMS is associated with high mortality and is not reversed by treatment of the neoplasm, due to non-reversible destruction of small airways. The only disease modifying therapy is lung transplant. Her lymphoma recurrence risk was very low after 2 years of remission following initial treatment, and as her lymphoma was not associated with immunosuppression, post-transplant immunosuppression likely does not increase risk of recurrence. Additionally, while mycobacterium abscessus poses significant risks, intensive treatment in the peri-transplant period can help allow for safe transplantation.

Abstract RATIONALE: Chronic lower respiratory diseases (CLRD) confer higher risks from respiratory viral infections, hence CLRD patients are prioritized for influenza, pneumococcal, and COVID-19 vaccination. Nonetheless, vaccine deferral and declination remain common. Given that COVID-19 vaccination is particularly polarizing, and attitudes toward it may differ from other vaccines, we assessed COVID-19 vaccination behaviors and attitudes in adults with versus without CLRD and/or smoking history, which is strongly associated with CLRD risk. METHODS: We pooled data from 10 cohorts participating in the Collaborative Cohort of Cohorts for COVID-19 Research (C4R) that collected pre-pandemic data on self-reported physician diagnosis of asthma or COPD. C4R assessed COVID-19 vaccination status through three waves of standardized questionnaires (2020-2022, 2021-2023, 2023-2024). Prompt COVID-19 vaccination was defined as self-report of receiving at least one COVID-19 vaccine by May 1, 2021. Cumulative COVID-19 vaccine count was self-reported on the Wave 3 Questionnaire. Vaccine attitudes and receipt of influenza and/or pneumococcal vaccines were self-reported on the Wave 1 or 2 Questionnaire. Age-adjusted Poisson regression was used to test associations of vaccination behaviors with CLRD and smoking status at the most recent pre-pandemic exam. RESULTS: Of 20,034 participants (pre-pandemic COPD, 9.3%; asthma, 11.7%; current smoking, 13.4%; former smoking, 36.3%), 64.2% reported prompt COVID-19 vaccination. Among the subset of 10,626 participants completing the Wave 3 Questionnaire in 2023-24, the median COVID-19 vaccine count was 3 (Q1:2, Q3:4). Compared to participants without CLRD, prompt vaccination was more likely in those with asthma (RR=1.04, 95%CI:1.01-1.07, p=0.008) and less likely with COPD (RR=0.94, 95%CI:0.91-0.98, p=0.001), but there were no differences in doses for asthma and COPD. Compared to never smokers, former smoking participants were more likely to receive prompt vaccination (RR=1.11, 95%CI:1.08-1.13, p<0.0001) and more vaccine doses (RR=1.03, 95%CI:1.01-1.05, p=0.015); conversely, current smoking was inversely associated with prompt vaccination (RR=0.94, 95%CI:0.91-0.97, p=0.001) and was associated with fewer doses (RR=0.93, 95%CI:0.89-0.96, p<0.0001). Participants with CLRD versus without CLRD were more likely to report receiving influenza and pneumococcal vaccines, but they were more likely to believe that vaccines are unsafe or ineffective (figure). CONCLUSIONS: COPD was associated with lower likelihood of prompt COVID-19 vaccination. Current smoking was associated with both lower likelihood of prompt COVID-19 vaccination and a lower number of COVID-19 vaccine doses by 2023-24. These associations may be partly attributed to negative vaccine attitudes and beliefs. How the COVID-19 pandemic may have influenced vaccine behaviors and attitudes merits additional study.

Abstract Rationale Non-cystic fibrosis bronchiectasis (hereafter bronchiectasis) is a chronic and progressive respiratory disease. Neutrophilic inflammation plays a key role in the pathophysiology of bronchiectasis. Neutrophil serine proteases (NSPs), especially neutrophil elastase, have been associated with disease progression and poorer clinical outcomes. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; brensocatib 25-mg also significantly reduced lung function decline and improved patient-reported symptoms. Here, we further evaluate the impact of brensocatib on lung function in patients with bronchiectasis. Methods ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], ≥2; adolescents [12-<18 years], ≥1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Post-hoc analyses were conducted to evaluate the extent of lung function response to treatment, as measured by change from baseline in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) over the 52-week treatment period in patients who did vs did not have ≥1 on-study pulmonary exacerbation, and the level of change in post-BD FEV1 and forced vital capacity (FVC) at week 52. Results A total of 583 patients received brensocatib 10-mg, 575 received brensocatib 25-mg, and 563 received placebo. Overall, a greater decline in FEV1 was observed among patients with ≥1 on-study pulmonary exacerbation vs those without. Treatment with brensocatib 10-mg or 25-mg led to less FEV1 decline at week 52 vs placebo for patients regardless of on-study exacerbation (no exacerbation: -42mL, -8mL, vs -48mL; ≥1 exacerbation: -59mL, -41mL, vs -70mL, for 10-mg, 25-mg brensocatib and placebo, respectively [Figure]). In the overall population, no change or an improvement (≥0 mL difference vs baseline) in post-BD FEV1 at week 52 was observed in 38.7%, 45.4%, and 31.2% of patients in the brensocatib 10-mg, 25-mg, and placebo groups, respectively. Similar impacts of brensocatib were observed in FVC (no change or improvement, 10-mg: 41.3%; 25-mg: 48.9%; placebo: 31.8%). Conclusions Overall, greater lung function decline was observed in patients who had on-study pulmonary exacerbations vs those who did not. Brensocatib 25-mg reduced lung function decline vs placebo regardless of whether patients had on-study exacerbations, consistent with overall ASPEN results.

Abstract RATIONALE: Alveoli form late in development and, for first breath, alveolar type 1 (AT1) as well as AT2 epithelial cell types must be functional. While prior studies have mapped the cellular and transcriptional programs underlying this process and identified AT fate inductive cues, questions remain as to the timing and regulation of their emergence. Thus, we sought to identify when, where, and how AT2 cells first arise and motivated by recent work in embryonic stem cells, we investigated whether the biophysical parameter cell membrane tension (CMT) plays a role. METHODS: Single-cell RNA-sequencing (scRNAseq) datasets sampling mouse lung development were processed using cluster correlation, velocity, and gene ontology analysis. Marker expression and AT2 morphology was assessed by immunostaining, and their migration confirmed by time-lapse confocal microscopy on embryonic precision-cut lung slices (PCLS). CMT was measured via optical tweezers (OT) on isolated cells as well as fluorescence lifetime (FLIM) on organoids and PCLS. Progenitors (E15.5) and AT2s (E16.5- >PN50) were isolated from distal region of the mouse lung, as well as human AT2s recently isolated, expanded, and banked in Mayo Clinic's recently established patient lung cell biorepository. CMT was raised using methyl-β-cyclodextran (MBCD) or polyethylene glycol (PEG). Small molecules CHIR and ICG-001 were used in culture to raise and lower β-catenin levels, respectively. Fluorescently labeled mesenchymal cells were isolated, expanded, and added to organoids in suspension for co-association experiments. RESULTS: No evidence of distal progenitors selecting either AT fate was found until E16.5, at which time we identified a distinct nascent AT2 (nAT2) state that ontology analysis detects upregulation of single-cell migration genes. Resistin-like molecule alpha (RELM-α), a type 2 inflammation regulator, labels nAT2s – which first individually emerged around E16.5 (although instances exist at E15.5) at intermediate zones between the branch tips and stalks of the distal epithelium. Following molecular emergence, we observed nAT2s extruded basally and can subsequently interact with nearby but anatomically distinct lumens, a behavior we provisionally name interlumenal junctioning and whose dynamics we validated by timelapse microscopy. Regarding CMT, we found its reduction in distal progenitors occurs prior to, and is required for, differentiation. We observed CMT reduction is sensitive to the manner of organoid culture, with on top culture resulting in more reduction and differentiation. Finally, we observed CMT is regulated cell-intrinsically via the adaptor protein β-catenin, as well as -extrinsically through osmotic (via PEG) or mesenchymal cell interactions, both of which reduce membrane fluidity.