Occult Lung Cancer-Associated Autoimmune Encephalitis Presenting as Acute Psychosis.

During deployment, a 52-year-old male developed acute behavioral changes. Though initially considered to have PTSD and related agitation and confusional state, his evaluation was consistent with acute encephalopathy. Magnetic resonance imaging of the brain showed T2 hyperintensities, and CSF analysis was positive for anti-N-methyl-D-aspartate receptor antibody. A nuclear protein in testis carcinoma midline carcinoma was discovered in the lung. Immunotherapy and surgical resection led to steady improvement prior to adjuvant chemotherapy. Autoimmune encephalitis due to anti-N-methyl-D-aspartate receptor antibodies is increasingly being recognized as causal of acute behavioral change.

Patients with telomere biology disorders show context specific somatic mosaic states with high frequency of U2AF1 variants.

Somatic mosaic states in telomere biology disorders are characterized by somatic variants in the spliceosome and DNA damage response and repair pathways. A likely maladaptive response to short telomeres that may lead to increased hematological cancer.

Suicide attempts in adolescents with cystic fibrosis on Elexacaftor/Tezacaftor/Ivacaftor therapy.

Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a recently approved cystic fibrosis (CF) transmembrane conductance regulator modulator therapy that has shown promising clinical and laboratory improvements on multiple organ systems in people with CF (pwCF). While original clinical trials found little to no effect on depression and anxiety, many post-marketing reports have suggested that ETI may be associated with adverse mental health effects. Here we report on two pwCF with adverse mental health effects shortly after starting ETI. Although many factors such as the burden of living with a chronic disease or widespread effects of the Covid-19 pandemic may have contributed to these events, similar reports have led to mounting concern that ETI may be the cause of such events. Regular mental health screening before the initiation of ETI and monitoring for signs and symptoms of mental diseases afterward should be a routine part of care, given the gravity of possible outcomes.

Aminoglycoside induced ototoxicity risk in the cystic fibrosis population: The utility of large-scale screening.

BACKGROUND: MT-RNR1 variants are a well-known cause of aminoglycoside-induced hearing loss (AIHL). Individuals with cystic fibrosis (CF) routinely receive aminoglycosides and are at high risk of AIHL. However, genetic testing before treatment is not routinely performed due to perceived rarity of risk, and cost ineffectiveness with traditional technologies. AIM: Assess the utility of large-scale screening for AIHL risk in the CF population, using digital droplet polymerase chain reaction (ddPCR), a novel and scalable low-cost molecular technique. METHODS: Using a clinically validated ddPCR assay, we performed retrospective testing on 122 and prospective testing on 32 individuals with CF for the two most common pathogenic variants associated with AIHL, MT-RNR1 m.1555 A > G and m.1494 C > T. Our study screened the largest known cohort of pediatric cases of CF (94/154) for these specific alterations. RESULTS: We identified two individuals positive for MT-RNR1 m.1555 A > G and no positives for m.1494 C > T. Of 32 prospective cases, 17 had aminoglycoside exposure. The positive case in our prospective group recently began inhaled tobramycin and denied hearing issues. The clinician adjusted to care for both the patient and sibling with CF (not included in cohort) who is presumed positive for m.1555 A > G due to the nature of mitochondrial inheritance. CONCLUSION: Our findings demonstrate the utility of pretreatment screening in the cystic fibrosis population for AIHL risk using ddPCR, a scalable and robust testing methodology at a fraction of the cost as compared to other sequencing-based methods. Therefore, the use of large-scale screening for AIHL risk in the cystic fibrosis community should be re-visited.

Routine Donor and Recipient Screening for Mycoplasma hominis and Ureaplasma Species in Lung Transplant Recipients.

Background: Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum may cause post-transplant infections in lung transplant recipients. We evaluated routine pretransplant screening for these Mollicutes. Methods: We retrospectively reviewed records of lung transplant recipients at our tri-site institution from 01/01/2015 to 11/15/2019. M. hominis and/or Ureaplasma polymerase chain reaction (PCR) was performed on pretransplant recipient urine specimens and donor bronchial swabs at the time of transplantation. Development of Mollicute infection and hyperammonemia syndrome (HS) was recorded. Results: A total of 268 patients underwent lung transplantation during the study period, of whom 105 were screened with at least 1 Mollicute PCR. Twelve (11%) screened positive; 10 donors, 1 recipient, and 1 both. Among positive donors, 3 were positive for M. hominis, 5 for U. urealyticum, and 4 for U. parvum. Preemptive therapy included doxycycline, levofloxacin, and/or azithromycin administered for 1-12 weeks. Despite therapy, 1 case of M. hominis mediastinitis and 1 case of HS associated with Ureaplasma infection occurred, both donor-derived. Of those screened before transplant, cases with positive screening were more likely (P < 0.05) to develop Mollicute infection despite treatment (2/12, 17%) than those who screened negative (1/93, 1%). Conclusions: Pretransplant recipient urine screening had a low yield and was not correlated with post-transplant Mollicute infection, likely because most M. hominis and U. parvum/urealyticum infections in lung transplant recipients are donor-derived. Routine donor bronchus swab PCR for M. hominis, U. urealyticum, and U. parvum followed by preemptive therapy did not obviously impact the overall incidence of Mollicute infection or HS in this cohort.

Workflow to develop 3D designed personalized neonatal CPAP masks using iPhone structured light facial scanning.

BACKGROUND: Continuous positive airway pressure (CPAP) is a common mode of respiratory support used in neonatal intensive care units. In preterm infants, nasal CPAP (nCPAP) therapy is often delivered via soft, biocompatible nasal mask suitable for long-term direct skin contact and held firmly against the face. Limited sizes of nCPAP mask contribute to mal-fitting related complications and adverse outcomes in this fragile population. We hypothesized that custom-fit nCPAP masks will improve the fit with less skin pressure and strap tension improving efficacy and reducing complications associated with nCPAP therapy in neonates. METHODS: After IRB approval and informed consent, we evaluated several methods to develop 3D facial models to test custom 3D nCPAP masks. These methods included camera-based photogrammetry, laser scanning and structured light scanning using a Bellus3D Face Camera Pro and iPhone X running either Bellus3D FaceApp for iPhone, or Heges application. This data was used to provide accurate 3D neonatal facial models. Using CAD software nCPAP inserts were designed to be placed between proprietary nCPAP mask and the model infant's face. The resulted 3D designed nCPAP mask was form fitted to the model face. Subsequently, nCPAP masks were connected to a ventilator to provide CPAP and calibrated pressure sensors and co-linear tension sensors were placed to measures skin pressure and nCPAP mask strap tension. RESULTS: Photogrammetry and laser scanning were not suited to the neonatal face. However, structured light scanning techniques produced accurate 3D neonatal facial models. Individualized nCPAP mask inserts manufactured using 3D printed molds and silicon injection were effective at decreasing surface pressure and mask strap pressure in some cases by more than 50% compared to CPAP masks without inserts. CONCLUSIONS: We found that readily available structured light scanning devices such as the iPhone X are a low cost, safe, rapid, and accurate tool to develop accurate models of preterm infant facial topography. Structured light scanning developed 3D nCPAP inserts applied to commercially available CPAP masks significantly reduced skin pressure and strap tension at clinically relevant CPAP pressures when utilized on model neonatal faces. This workflow maybe useful at producing individualized nCPAP masks for neonates reducing complications due to misfit.

Identification of cbiO Gene Critical for Biofilm Formation by MRSA CFSa36 Strain Isolated from Pediatric Patient with Cystic Fibrosis.

The colonization of Staphylococcus aureus, especially methicillin-resistant S. aureus (MRSA), has a detrimental effect on the respiratory care of pediatric patients with cystic fibrosis (CF). In addition to being resistant to multiple antibiotics, S. aureus also has the ability to form biofilms, which makes the infection more difficult to treat and eradicate. In this study, we examined the ability of S. aureus strains isolated from pediatric patients with CF to form biofilms. We screened a transposon mutant library of MRSA and identified a putative cobalt transporter ATP binding domain (cbiO) that is required for biofilm formation. We discovered that deleting cbiO creating a cbiO null mutant in CFSa36 (an MRSA strain isolated from a patient with cystic fibrosis) significantly hinders the ability of CFSa36 to form biofilm. The complementation of cbiO restored the ability of the cbiO deletion mutant to generate biofilm. Interestingly, we revealed that incorporating extra copper ions to the chemically defined medium (CDM) complemented the function of cbiO for biofilm formation in a dose-dependent manner, while the addition of extra iron ions in CDM enhanced the effect of cbiO null mutation on biofilm formation. In addition, neither the addition of certain extra amounts of copper ions nor iron ions in CDM had an impact on bacterial growth. Taken together, our findings suggest that cbiO mediates biofilm formation by affecting the transportation of copper ions in the MRSA CFSa36 strain. This study provides new insights into the molecular basis of biofilm formation by S. aureus.

Sulfa-induced acute eosinophilic pneumonia.

Acute eosinophilic pneumonia (AEP) is an infrequently seen interstitial lung disease secondary to medications. We report a series of 3 case of severe AEP which developed as a result of sulfa medication. 2 patients had received treatment with sulfamethoxazole for acne and 1 was treated with sulfasalazine for colitis. Patients were on sulfa medication for 1-3 weeks prior to presentation. All patients presented with fever, acute onset bilateral pulmonary infiltrates as well as marked peripheral eosinophilia. Mean eosinophil count was 2.21 × 109/L. There was a lack of response to steroids. One patient required extracorporeal membrane oxygenation and prolonged mechanical ventilation via tracheostomy. 2 patients underwent successful lung transplantation (1 bilateral living-related lobar lung transplant and 1 orthotropic cardiopulmonary allotransplantation). In all cases lung biopsy and explants showed acute and organizing diffuse alveolar damage with increased interstitial and airspace eosinophils. To our knowledge, our series is the first to show the clinical features of sulfa induced AEP in an adolescent population.

Pathology, Radiology, and Genetics of Interstitial Lung Disease in Patients With Shortened Telomeres.

Interstitial lung diseases (ILDs) in patients with shortened telomeres have not been well characterized. We describe demographic, radiologic, histopathologic, and molecular features, and p16 expression in patients with telomeres ≤10th percentile (shortened telomeres) and compare them to patients with telomere length >10th percentile. Lung explants, wedge biopsies, and autopsy specimens of patients with telomere testing were reviewed independently by 3 pathologists using defined parameters. High-resolution computed tomography scans were reviewed by 3 radiologists. p16-positive fibroblast foci were quantified. A multidisciplinary diagnosis was recorded. Patients with shortened telomeres (N=26) were morphologically diagnosed as usual interstitial pneumonia (UIP) (N=11, 42.3%), chronic hypersensitivity pneumonitis (N=6, 23.1%), pleuroparenchymal fibroelastosis, fibrotic nonspecific interstitial pneumonia, desquamative interstitial pneumonia (N=1, 3.8%, each), and fibrotic interstitial lung disease (fILD), not otherwise specified (N=6, 23.1%). Patients with telomeres >10th percentile (N=18) showed morphologic features of UIP (N=9, 50%), chronic hypersensitivity pneumonitis (N=3, 16.7%), fibrotic nonspecific interstitial pneumonia (N=2, 11.1%), or fILD, not otherwise specified (N=4, 22.2%). Patients with shortened telomeres had more p16-positive foci (P=0.04). The number of p16-positive foci correlated with outcome (P=0.0067). Thirty-nine percent of patients with shortened telomeres harbored telomere-related gene variants. Among 17 patients with shortened telomeres and high-resolution computed tomography features consistent with or probable UIP, 8 (47.1%) patients showed morphologic features compatible with UIP; multidisciplinary diagnosis most commonly was idiopathic pulmonary fibrosis (N=7, 41.2%) and familial pulmonary fibrosis (N=5, 29%) in these patients. In conclusion, patients with shortened telomeres have a spectrum of fILDs. They often demonstrate atypical and discordant features on pathology and radiology leading to diagnostic challenges.

A 48-Year-Old Woman With Chronic Cough, Dyspnea, and Bronchiectasis.

CASE PRESENTATION: A 48-year-old woman sought a second opinion for dyspnea and chronic productive cough; she was a never smoker. Mild respiratory symptoms persisted since childhood and had progressively worsened over the previous decade. In addition, an unintentional 30-pound weight loss had occurred over several years. Six years previously, a diagnosis of hypersensitivity pneumonitis was made following right upper lobe wedge resection that revealed chronic bronchiolitis with interstitial pneumonia and non-necrotizing granulomatous inflammation. Subsequent use of prednisone elicited mild intermittent improvement. She had used feather pillows in the past without any other significant exposures. There were no reports of sinus or GI symptoms.

Mate-pair sequencing identifies a cryptic BMPR2 mutation in hereditary pulmonary arterial hypertension.

Current guidelines suggest screening all patients with idiopathic pulmonary arterial hypertension for genetic aberrations, particularly mutations in Bone Morphogenic Protein Receptor Type II (BMPR2), the gene most commonly implicated in the pathogenesis of PAH. Herein, we present a novel technique used to identify a pathogenic germline BMPR2 alteration in a 36-year-old female and family members with hereditary pulmonary arterial hypertension who each screened negative by standard cytogenetics and molecular genetics testing.

Methicillin-Resistant Staphylococcus aureus Infection and Treatment Options.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of infection worldwide, including a wide array of both hospital- and community-acquired infections-most commonly bacteremia, upper and lower respiratory tract infection, skin and soft-tissue infection, osteomyelitis, and septic arthritis. This chapter describes the epidemiology of MRSA infection, its ability to confer antibiotic resistance and produce a wide array of virulence factors, and its pivotal role in human infection, especially cystic fibrosis. It also provides an introduction to the strategies for treatment of both chronic and acute MRSA infections.

Whole-lung Lavage and Pulmonary Alveolar Proteinosis: Review of Clinical and Patient-centered Outcomes.

OBJECTIVE: The objective of this retrospective review was to evaluate the perioperative and procedural management of patients with pulmonary alveolar proteinosis (PAP) who presented for whole-lung lavage (WLL). DESIGN: The records of all adult patients with PAP who underwent WLL between January 1, 1988 and August 20, 2017 were reviewed and pertinent demographic, preoperative, anesthetic, procedural, and postoperative data were recorded. SETTING: Large academic tertiary referral center. PARTICIPANTS: Forty patients with PAP underwent 79 WLL procedures. INTERVENTIONS: Patients with PAP undergoing WLL. MEASUREMENTS: Successful WLL, defined by visual clearing of lavage fluid, was completed in 91% of cases. Whole-lung lavage was terminated prematurely in 9% of cases (refractory hypoxia most common), while 8% of cases were found to have 30-day complications. There were no cases of intraoperative death, hemodynamic collapse, pneumothorax or hydrothorax, or need for emergent reintubation. Postoperative clinical follow-up at the authors' institution within 6 months of WLL showed 68% of patients reported improvement in symptoms and/or functional status. CONCLUSION: The authors here present a retrospective study describing the perioperative and procedural management of PAP patients undergoing WLL to help familiarize providers with the management of this population (Fig 1). The findings of this study outline a successful and consistent approach to WLL using a multidisciplinary team experienced in this procedure. Even in experienced hands, procedural complications and 30-day postoperative complications emphasize the risk in this complex patient population.

Why do lung transplant patients discontinue triazole prophylaxis?

BACKGROUND: Lung transplant recipients are prone to invasive fungal infections prompting many transplant centers to use prolonged triazole antifungal prophylaxis. From a practical standpoint, it is unclear if lung transplant recipients are able to continue prolonged or lifelong prophylaxis without premature discontinuation from side effects, drug interactions, development of fungal disease, or medication cost. We examined the number of patients that are able to reach a prophylactic endpoint and understand the reasons for early termination. METHODS: We conducted a retrospective chart review of all lung and heart-lung transplant patients at Mayo Clinic Rochester from May 1, 2002 to December 31, 2017. Type, duration, and reason for discontinuation of triazole prophylaxis were examined. RESULTS: During the study period, 193 patients underwent lung or heart-lung transplantation. Itraconazole, voriconazole, and posaconazole were given to 180, 73, and 60 post-transplant patients, respectively. Providers switched itraconazole to another prophylactic antifungal medication for reasons other than prophylactic completion in 61.8% (126 out of 204) of exposure episodes; this was similar with voriconazole (68.8%, 53 out of 77, P = 0.41). Posaconazole was actively discontinued significantly less often (18.3%, 11 out of 60, P < 0.05). The most common reasons for discontinuing itraconazole were malabsorption (15.5% of exposure episodes) and concern for breakthrough fungal infection (10.2%). In comparison, the most common reason for voriconazole discontinuation was side effect or intolerance (54.5% of VR exposure episodes vs 9.8% of IT exposure episodes, P < 0.05). CONCLUSIONS: Itraconazole and posaconazole appeared to have fewer side effects prompting discontinuation than voriconazole, but itraconazole was discontinued more often because of malabsorption and clinical suspicion of fungal infections.

Clinical Correlates and Treatment Outcomes for Patients With Short Telomere Syndromes.

Short telomere syndromes (STSs) are accelerated aging syndromes with multisystemic manifestations that present complex management challenges. In this article, we discuss a single-institution experience in diagnosing and managing patients with inherited STSs. In total, we identified 17 patients with short telomeres, defined by flow-fluorescence in-situ hybridization telomere lengths of less than first centile in granulocytes/lymphocytes OR the presence of a characteristic germline pathogenic variant in the context of a highly suggestive clinical phenotype. Genetic variations in the telomere complex were identified in 6 (35%) patients, with 4 being known pathogenic variants involving TERT (n=2), TERC (n=1), and DKC1 (n=1) genes, while 2 were variants of uncertain significance in TERT and RTEL1 genes. Idiopathic interstitial pneumonia (IIP) (n=12 [71%]), unexplained cytopenias (n=5 [29%]), and cirrhosis (n=2 [12%]) were most frequent clinical phenotypes at diagnosis. At median follow-up of 48 (range, 0-316) months, Kaplan-Meier estimate of overall survival, median (95% CI), was 182 (113, not reached) months. Treatment modalities included lung transplantation for IIP (n=5 [29%]), with 3 patients developing signs of acute cellular rejection (2, grade A2; 1, grade A1); danazol therapy for cytopenias (n=4 [24%]), with only 1 out of 4 patients showing a partial hematologic response; and allogeneic hematopoietic stem cell transplant for progressive bone marrow failure (n=2), with 1 patient dying from transplant-related complications. In summary, patients with STSs present with diverse clinical manifestations and require a multidisciplinary approach to management, with organ-specific transplantation capable of providing clinical benefit.

Extracorporeal Photopheresis Improves Survival in Hematopoietic Cell Transplant Patients with Bronchiolitis Obliterans Syndrome without Significantly Impacting Measured Pulmonary Functions.

We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non-ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV1 percentage predicted (FEV1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P = .33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR, .1; 95% CI, .03 to .5; P = .002), ECP (HR, .1; 95% CI, .01 to .3; P = .001), and slower rate of decline in FEV1PP before the ECP/index date (HR, .7; 95% CI, .6 to .8; P = .001) were associated with a better overall survival. At last follow-up, non-ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P = .04) and had a greater decline in their Karnofsky performance score (mean difference, -9.5 versus -1.6; P = .06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort.