Aminoglycoside resistance of Pseudomonas aeruginosa in cystic fibrosis results from convergent evolution in the mexZ gene.

RATIONALE: Aminoglycoside (AG) resistance of Pseudomonas aeruginosa in cystic fibrosis (CF) is associated with poorer clinical outcomes and is usually due to overexpression of the efflux pump MexXY. MexXY is regulated by mexZ, one of the most commonly mutated genes in CF P. aeruginosa isolates. Little is known about the evolutionary relationship between AG resistance, MexXY expression and mexZ mutations. OBJECTIVES: To test the hypothesis that AG resistance in P. aeruginosa develops in parallel with higher MexXY expression and mexZ mutations. METHODS: CF P. aeruginosa isolates were compared for chronically infected (CI) adults, CI children and children with new infection. MEASUREMENTS: One P. aeruginosa isolate from each patient was analysed for mexZ mutations, mexY mRNA expression and amikacin resistance. MAIN RESULTS: 56 patients with CF were enrolled: 21 children with new P. aeruginosa infection, 18 CI children and 17 CI adults. Amikacin resistance and mexY mRNA expression were higher in cohorts with longer P. aeruginosa infection. The prevalence of non-conservative mexZ mutations was 0%, 33% and 65% in children with new infection, CI children and CI adults, respectively. The same trend was seen in the ratio of non-conservative to non-synonymous mexZ mutations. Of isolates with non-conservative mexZ mutations, 59% were amikacin-resistant compared with 18% of isolates with non-synonymous mutations. The doubling rate of amikacin resistance and non-conservative mexZ mutations was approximately 5 years. CONCLUSIONS: P. aeruginosa mexZ mutations undergo positive selection resulting in increased mexY mRNA expression and amikacin resistance and likely play a role in bacterial adaption in the CF lung.

Antibiotic duration and changes in FEV1 are not associated with time until next exacerbation in adult cystic fibrosis: a single center study.

BACKGROUND: Pulmonary exacerbations (PEx) are a major driver of morbidity and mortality in cystic fibrosis and reducing their frequency by extending the time between them is an important therapeutic goal. Although treatment decisions for exacerbations are often made based on dynamic changes in lung function, it is not clear if these changes truly impact future exacerbation risk. We analyzed adults with chronic Pseudomonas aeruginosa infection to determine whether changes in FEV1 or duration of intravenous antibiotic therapy were associated with time to the next pulmonary exacerbation. METHODS: Medical records and Cystic Fibrosis Foundation Patient Registry data were examined retrospectively to assess whether various patient-specific demographic factors and exacerbation-specific characteristics were associated with time until next exacerbation using the Andersen-Gill model in order to control for previous exacerbation frequency history. RESULTS: We examined 59 patients with 221 CF pulmonary exacerbations over a 3-year study period. Mean age was 28.2 years and mean baseline FEV1 was 62% predicted. In our univariable model, fall in FEV1 at onset of exacerbation (median absolute -3% predicted change), recovery of FEV1 with treatment (median absolute +3% predicted change) and duration of IV antibiotics (median 16 days) were not associated with time to next exacerbation (median 93.5 days). Paradoxically each one-year increase in age was associated with a reduction in hazard of PEx by 3% (HR 0.97, P = 0.03, 95% CI 0.95-1.00). CONCLUSIONS: FEV1 drop and recovery associated with onset and treatment of a CF pulmonary exacerbation or duration of intravenous antibiotics were not predictive of time until next exacerbation. Our finding that older age may be associated with decreased hazard of exacerbation is likely due to a healthy survivor effect and should be controlled for in clinical trials of pulmonary exacerbations.

Telehealth and CFTR modulators: Accelerating innovative models of cystic fibrosis care.

Better health and longer survival for many people with cystic fibrosis (PwCF) compels the continued evolution of the CF care model. Designed to deliver specialized care for a complex chronic condition, the model is organized around interdisciplinary healthcare teams at dedicated care centers. Introduction of CFTR modulators and the COVID-19 pandemic have catalyzed the model's evolution. Many PwCF on modulator therapies are experiencing better health and considering changes in their daily care routines. Some of the growing number of adults with CF are experiencing age-associated co-morbidities, requiring coordination with new specialists. The pandemic accelerated the use of telehealth, revealing tradeoffs from new configurations of care delivery. Herein we review the implications of these recent shifts and offer recommendations to improve the quality of care coordinated across the interdisciplinary teams and an expanding field of subspecialists, while supporting the ability of the patient to take on greater responsibility in disease management.

Adult-Onset Still's Disease Presenting as Macrophage-Activation Syndrome With Critical Illness in the Third Trimester of Pregnancy: A Case Report.

We report a case of a young woman with adult-onset Still's disease presenting as macrophage-activation syndrome complicated by shock and respiratory failure during the third trimester of pregnancy. CASE SUMMARY: A previously healthy 26-year-old woman at 35 weeks of gestation presented with 1 week of constitutional symptoms and was found to be febrile, tachycardic, and hypotensive. She delivered a healthy neonate by cesarean section. Following delivery, she had worsening hypotension and fevers despite fluid resuscitation and antibiotics, and developed progressive hypoxemia requiring up to 60% Fio2, with bilateral upper-lobe predominant opacities on chest CT. She also had laboratory derangements including anemia, thrombocytopenia, low fibrinogen, elevated ferritin, and abnormal liver chemistries. After extensive testing to exclude infections, hemolysis, and other pertinent disorders, the development of polyarthralgias and a characteristic rash fulfilled criteria for adult-onset Still's disease complicated by macrophage-activation syndrome. Her condition improved with immunosuppressive therapy. CONCLUSION: To our knowledge, this is the first report of new-onset adult-onset Still's disease during the third trimester of pregnancy, which presented as macrophage-activation syndrome. In the context of late pregnancy, macrophage-activation syndrome can mimic or raise concern for hemolysis, elevated liver enzymes, and low platelet syndrome and other peripartum disorders. Furthermore, the characteristic articular symptoms of adult-onset Still's disease may be mild and/or delayed, and pulmonary involvement with severe hypoxemia can occur. Clinicians should consider this diagnosis when evaluating a pregnant patient with unexplained fever and multiorgan dysfunction.

Bronchoscopy on Intubated COVID-19 Patients is Associated with Low Infectious Risk to Operators at a High-Volume Center Using an Aerosol-minimizing Protocol.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic raised concern for exposure to healthcare providers through aerosol generating procedures, such as bronchoalveolar lavage (BAL). Current society guidelines recommended limiting use of BAL to reduce operators' risk for infection, yet data on the infection rate for providers after BAL is sparse. Since March 2020, our institution used a modified protocol to perform over 450 BALs on intubated COVID-19 patients. We therefore sought to describe the subsequent infectious risks to providers associated with BAL. METHODS: Fifty-two pulmonary and critical care providers (faculty and fellows) at our tertiary-care, urban medical center were surveyed. Survey participants were asked to provide the number of BALs on COVID-19 patients they performed, the number of weeks they cared for intensive care unit (ICU) patients with COVID-19, and the results of any SARS-CoV-2 testing that they received. Participants were asked to assess the difficulty of BAL on intubated COVID-19 patients as compared to routine ICU BAL using a numeric perceived difficulty score ranging from 1 (easier) to 10 (harder). RESULTS: We received forty-seven responses from fifty-two surveyed (90% response rate), with 2 declining to participate. Many respondents (19/45, 42%) spent >5 weeks on an ICU service with COVID-19 patients. The number of BALs performed by providers ranged from 0 to >60. Sixteen of the 35 providers (46%) who performed BALs underwent at least one nasopharyngeal (NP) swab to test for SARS-CoV-2, but none were positive. Twenty-seven of the 35 providers (77%) who performed BALs underwent SARS-CoV-2 serology testing, and only one (3.7%) was positive. Respondents indicated occasionally not being able to follow aerosol-minimizing steps but overall felt BALs in COVID-19 patients was only slightly more difficult than routine ICU BAL. DISCUSSION: At a high-volume center having performed >450 BALs on intubated COVID-19 patients with aerosol-limiting precautions, our survey of bronchoscopists found no positive NP SARS-CoV-2 tests and only one positive antibody test result. While the optimal role for COVID-19 BAL remains to be determined, these data suggest that BAL can be safely performed in intubated COVID-19 patients if experienced providers take precautions to limit aerosol generation and wear personal protective equipment.