Pediatric Lung Transplantation: Overview of Pediatric Lung Transplantation, History of Lung Transplantation ...

Inhaled Amikacin Shows Promise For Untreated MAC Lung Infections

SAN DIEGO -- Adding amikacin liposome inhalation suspension (ALIS; Arikayce) to a macrolide-based regimen appeared to reduce respiratory symptoms and improve culture conversion rates in patients with newly diagnosed or recurrent Mycobacterium avium complex (MAC) lung infections, the randomized ARISE trial showed.

As measured by the nine-item Quality of Life-Bronchiectasis Respiratory Domain (QOL-B RD), 43.8% of patients in the ALIS arm achieved a meaningful improvement in symptoms from baseline to 7 months, as compared with 33.3% of those assigned to the macrolide-based regimen plus placebo, reported Charles Daley, MD, of National Jewish Health and the University of Colorado School of Medicine in Denver.

Culture conversion rates were numerically higher in the ALIS arm both following the 6-month period of daily treatment (80.6% vs 63.9% P=0.071) and at 7 months, a month after stopping treatment (78.8% vs 47.1%, nominal P=0.001), according to findings presented here at the American Thoracic Society annual meeting.

The main goal of the ARISE study was to validate patient-reported-outcome (PRO) tools using modern psychometric methods for key symptoms of MAC lung disease -- with respiratory symptoms and fatigue previously established as the most prevalent and bothersome to patients.

"It turns out there's no currently validated fit-for purpose PRO instrument for people with MAC lung disease," said Daley. "The symptoms that are most important to our patients are covered in two instruments" -- the QOL-B RD and the Patient-Reported Outcomes Measurement Information System (PROMIS)-Fatigue 7a.

Daley's presentation focused on the validation of the QOL-B RD (against the Patient Global Impression of Severity-Respiratory scale); the impact of ALIS on patients' respiratory symptoms using the QOL-B RD; and microbiologic outcomes with ALIS as part of a macrolide-based regimen for this patient population.

The QOL-B RD is a self-administered questionnaire with nine items to assess sputum, coughing, congestion, wheezing, chest pain, and other symptoms -- with eight of the items scored on a Likert Scale (a lot, a moderate amount, a little, not at all) and the sputum question requiring a descriptive answer.

Each score is standardized on a 0-100 scale, with 100 indicating no symptoms. Ultimately a 14.8-point change in an individual patient was deemed to be a meaningful difference on the QOL-B RD, said Daley.

While the study was not powered to show a significant difference between arms, the least-squares mean change from baseline to 7 months on the QOL-B RD favored the ALIS arm (12.24 vs 7.76, P=0.1073).

Results of the ARISE trial are "a significant step toward an area of unmet need in patients with non-cavitary [MAC lung disease]," said Sarah Taimur, MD, of the Icahn School of Medicine at Mount Sinai in New York City, who was not involved in the study.

"It provides much-needed evidence for validation of a self-administered, patient-reported outcome measure that has been previously lacking in this patient population, and could serve as a critical tool that patients and their medical teams can use to gauge response to treatment," Taimur told MedPage Today.

ALIS is currently approved only for patients with MAC lung infections that do not respond to traditional treatments; the validated QOL-B RD instrument will help support the evaluation of the inhaled therapy in an ongoing phase III registrational study (ENCORE) testing a macrolide-based regimen plus either ALIS versus placebo in patients with newly diagnosed or recurrent MAC lung infections who have not received antibiotics for their current infection.

Daley presented findings from ARISE (Validation of Patient-Reported Outcome Measures in Participants With Nontuberculous Mycobacterial Lung Infection Caused by Mycobacterium Avium Complex), which randomized 99 adults with newly diagnosed or recurrent MAC lung infections and non-cavitary disease who had not yet been treated with antibiotics for their current infection. Patients were enrolled at 76 sites across 15 countries, including the U.S.

All patients received azithromycin and ethambutol as their macrolide-based regimen and were randomized 1:1 to ALIS or an empty liposomal control (placebo) once daily for 6 months, followed by a month off of treatment for follow-up. All patients had a mean QOL-B RD score of 85 or less. Patients with mixed infections were allowed in the trial so long as MAC was the dominant species present.

Exclusion criteria included refractory or relapsed MAC infections, more than three previous MAC lung infections, prior ALIS exposure, a smoking history, and certain comorbidities (cystic fibrosis, prior lung transplant, active malignancy).

Participants had a median age of 67-72 years, three-fourths were women, and 81% were white. Most were enrolled from either North America (39%) or Europe (38%). Concurrent respiratory illnesses included bronchiectasis in 49%, asthma in 21%, chronic obstructive pulmonary disease in 16%, cough in 16%, and allergic rhinitis in 11%.

For 73% of the patients, this was their initial MAC infection. Overall, 32% had M. Avium infections, 43% had M. Intracellulare infections, and the rest had other or unspecified MAC infections.

Culture conversion was defined as no growth of MAC in sputum cultures on agar and broth media. Four sputum samples were collected from patients at each monthly visit during the study.

Patients in the ALIS arm achieved culture conversions a median 1 month earlier than those in the comparator arm. Overall, 12.8% of patients who achieved culture conversion in the ALIS arm experienced recurrence at any point in the study compared with 50% of those in the placebo arm. No patients in either group developed MAC isolates with resistance to ALIS.

Treatment-emergent adverse events (TEAEs) were reported in 92% of patients in the ALIS arm and 80% of those in the placebo arm, the most common of which included dysphonia (42% vs 4%, respectively), cough (27% vs 8%), diarrhea (27% vs 25%), and COVID-19 (13% vs 10%). Treatment discontinuation of ALIS specifically occurred in 19%, as compared with 6% with the placebo.

Serious TEAEs were reported in 15% of the ALIS arm and 6% of the comparator arm. No deaths were reported.

Adverse events of special interest included dizziness (4.2% in the ALIS arm vs 9.8% in the placebo arm), tinnitus (4.2% vs 7.8%, respectively), vertigo (4.2% vs 2%), deafness (2.1% vs 2%), dyspnea (10.4% vs 7.8%) or dyspnea on exertion (2.1% vs none), wheezing (6% vs none), hemoptysis (10.4% vs 5.9%), exacerbation of an underlying pulmonary disease (none vs 3.9%), and neuromuscular disorders (2% in each arm).

Elizabeth Short is a staff writer for MedPage Today. She often covers pulmonology and allergy & immunology. Follow

Disclosures

The study was funded by Insmed.

Daley reported relationships with Insmed, AN2 Therapeutics, Bugworks, Paratek Pharmaceuticals, Juvabis, AstraZeneca, Cepheid, Hyfe, MannKind, Matinas Biopharma, Nob Hill Therapeutics, Spero Therapeutics, Zambon, Genentech, Pfizer, Otsuka Pharmaceutical, Eli Lilly, and the Bill and Melinda Gates Foundation.

Taimur reported no disclosures.

Primary Source

American Thoracic Society

Source Reference: Daley CL "Change in patient reported respiratory symptoms in a randomized, double-blind, trial of amikacin liposome inhalation suspension in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease: the ARISE study" ATS 2024; Abstract A1032.

Secondary Source

American Thoracic Society

Source Reference: Daley CL "Microbiologic outcomes from a randomized, double-blind trial of amikacin liposome inhalation suspension in adults with newly diagnosed or recurrent Mycobacterium avium complex lung disease: the ARISE study" ATS 2024; Abstract A1033.

Please enable JavaScript to view the comments

Severe RSV Infections Can Damage The Lungs

A study in mice, researchers at the University of Michigan have found infection with RSV can alter lung function in young children.

Children who are younger than 2 years of age who get respiratory syncytial virus (RSV) are likely to have long-term changes to their lungs, according to a recent study published in the American Journal of Physiology-Lung Cellular and Molecular Physiology.

RSV is a common virus that can lead to potentially serious respiratory illness. The virus can affect the lungs and breathing passages of an infected person and can potentially cause severe illness in young infants, older adults, and those with certain chronic medical conditions. Among children younger than 5 years of age in the United States, RSV infections account for about 2.1 million outpatient visits and 58,000 hospitalizations each year.

New research from the University of Michigan in Ann Arbor has found that a severe infection with RSV can compromise children's lung function and could affect respiratory health later in life.

To study severe RSV, the researchers measured lung function and the development of alveoli in infant mice. Alveoli are the sacs in the lungs responsible for exchanging oxygen and carbon dioxide. The development of alveoli continues into adulthood but has maximum production between 2 and 3 years of age. Production of large numbers of immune cells occurs around the same time.

Carrie-Anne Malinczak, Ph.D.

The researchers — led by Carrie-Anne Malinczak, Ph.D., now head of Nutritional Biology & Safety at Helaina — measured these markers in mice at five weeks and three months after the initial RSV infection and again after a reinfection with the virus. They focused on male mice because previous research has found that both male human infants and mice are more susceptible for severe RSV. Previous research has also shown there to be an increase in inflammatory cells after infection with RSV early in life.

Researchers in the current study found defects in the ability of the lungs to stretch and expand during breathing. Structural changes to the mice's lungs included an increase in alveoli size but fewer individual alveoli after RSV infection.

"These data indicate that the lungs of mice following an early-life RSV infection have a decreased lung function even at [three months] postinfection," the research team wrote. "Importantly, the structural defects of the early-life infected mice largely mimic the clinical setting where severe exacerbations are observed in children for several years following a severe early-life respiratory infection, especially RSV."

Researchers said the structural defects of the early-life infected mice mimic infection in human children. They said the mechanisms for these changes are "complex and associated with an inappropriate immune environment, specific cellular responses, and control of lung mesenchymal/epithelial cell maturation."

New Insights On Polymicrobial Infections In Chronic Lung Diseases

Chronic lung diseases are often accelerated and exacerbated by polymicrobial infections. An international study team led by MedUni Vienna has identified two types of these so-called dysbioses in cystic fibrosis. They display distinct ecology and are also likely to respond differently to treatment. The study was published in the journal Nature Communications.

Chronic lung diseases such as COPD, asthma or cystic fibrosis affect many people worldwide. In 2019, 454.6 million cases were registered worldwide. These diseases display a progressive loss of lung function and are associated with a high mortality rate. Polymicrobial infections of the respiratory tract, in which bacterial communities persist in the lungs for long time, constitute a major risk factor and are difficult to treat. These infections are often associated with recurrent, acute worsening of symptoms (exacerbations, "PEx"), which have a negative impact on the course of the disease.

A recent study led by Stefanie Widder from MedUni Vienna in collaboration with colleagues led by John J. LiPuma from the University of Michigan Medical School Ann Arbor has focused on the characterization of disease-associated bacterial communities ("dysbioses") in subjects with cystic fibrosis and investigated their ecological networks. The aim was to develop hypotheses that enable the development of more precise treatment strategies for people with chronic lung diseases.

Two different types of dysbiosis

To this end, sputum samples (mucus expectorated from the lung) were collected from people with cystic fibrosis over an extended period of time, sequenced and then analyzed using computational models by Stefanie Widder (Department of Medicine I, Division of Infection Biology, MedUni Vienna). Two antagonistic types of dysbiosis were discovered, which differ fundamentally in their organization: they either form hierarchical or stochastic networks. The structural differences of the microbiota have far-reaching consequences: Based on the sequencing data, it was shown that important pathogens such as Pseudomonas aeruginosa or Staphylococcus aureus only served as drivers of infection if located on top of the microbial hierarchy. In less structured microbiota, they showed more random dynamics, suggesting that they might be less decisive for the course of the infection.

Computer model predicts different responses to treatments

Moreover, the two types of dysbiosis are likely to respond differently to treatments. A simplified computer model that simulated the effect of antimicrobial drugs on pathogens predicted better efficacy with hierarchically organized microbiota. Both aspects are very relevant for patients and their medical care teams: "Our study reveals a data-based, causal relationship between PEx, microbial ecology and treatment success," explains study leader Stefanie Widder, "the findings form an important basis for further translational research into personalized management of dysbiosis, both in cystic fibrosis and in other obstructive pulmonary diseases."

---