Standards for the care of people with cystic fibrosis; establishing and maintaining health.

This is the second in a series of four papers updating the European Cystic Fibrosis Society (ECFS) standards for the care of people with CF. This paper focuses on establishing and maintaining health. The guidance is produced using an evidence-based framework and with wide stakeholder engagement, including people from the CF community. Authors provided a narrative description of their topic and statements, which were more directive. These statements were reviewed by a Delphi exercise, achieving good levels of agreement from a wide group for all statements. This guidance reinforces the importance of a multi-disciplinary CF team, but also describes developing models of care including virtual consultations. The framework for health is reinforced, including the need for a physically active lifestyle and the strict avoidance of all recreational inhalations, including e-cigarettes. Progress with cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy is reviewed, including emerging adverse events and advice for dose reduction and interruption. This paper contains guidance that is pertinent to all people with CF regardless of age and eligibility for and access to modulator therapy.

Insulin-like growth factor-1 replacement therapy after extremely premature birth: An opportunity to optimize lifelong lung health by preserving the natural sequence of lung development.

The past decades have seen markedly improved survival of increasingly immature preterm infants, yet major health complications persist. This is particularly true for bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, which has become the most common sequelae of prematurity and a significant predictor of respiratory morbidity throughout childhood as well as adult life, neurodevelopmental disability, cardiovascular disease, and even death. The need for novel approaches to reduce BPD and related complications of prematurity has never been more critical. Thus, despite major advances in the use of antenatal steroids, surfactant therapy, and improvements in respiratory support, there is a persistent need for developing therapeutic strategies that more specifically reflect our growing understanding of BPD in the post-surfactant age, or the "new BPD." In contrast with the severe lung injury leading to marked fibroproliferative disease from the past, the "new BPD" is primarily characterized by an arrest of lung development as related to more extreme prematurity. This distinction and the continued high incidence of BPD and related sequelae suggest the need to identify therapies that target critical mechanisms that support lung growth and maturation in conjunction with treatments to improve respiratory outcomes across the lifespan. As the prevention of BPD and its severity remains a primary goal, we highlight the concept from preclinical and early clinical observations that insulin-like growth factor 1 (IGF-1) can potentially support the natural sequence of lung growth as a replacement therapy after preterm birth. Data supporting this hypothesis are robust and include observations that low IGF-1 levels persist after extremely preterm birth in human infants and strong preclinical data from experimental models of BPD highlight the therapeutic benefit of IGF-1 in reducing disease. Importantly, phase 2a clinical data in extremely premature infants where replacement of IGF-1 with a human recombinant human IGF-1 complexed with its main IGF-1 binding protein 3, significantly reduced the most severe form of BPD, which is strongly associated with multiple morbidities that have lifelong consequences. As physiologic replacement therapy of surfactant heralded the success of reducing acute respiratory distress syndrome in preterm infants, the paradigm has the potential to become the platform for discovering the next generation of therapies like IGF-1, which becomes deficient after extremely premature birth where endogenous production by the infant is not sufficient to maintain the physiologic levels adequate to support normal organ development and maturation.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Effect of Nitric Oxide via Cardiopulmonary Bypass on Ventilator-Free Days in Young Children Undergoing Congenital Heart Disease Surgery: The NITRIC Randomized Clinical Trial.

Importance: In children undergoing heart surgery, nitric oxide administered into the gas flow of the cardiopulmonary bypass oxygenator may reduce postoperative low cardiac output syndrome, leading to improved recovery and shorter duration of respiratory support. It remains uncertain whether nitric oxide administered into the cardiopulmonary bypass oxygenator improves ventilator-free days (days alive and free from mechanical ventilation). Objective: To determine the effect of nitric oxide applied into the cardiopulmonary bypass oxygenator vs standard care on ventilator-free days in children undergoing surgery for congenital heart disease. Design, Setting, and Participants: Double-blind, multicenter, randomized clinical trial in 6 pediatric cardiac surgical centers in Australia, New Zealand, and the Netherlands. A total of 1371 children younger than 2 years undergoing congenital heart surgery were randomized between July 2017 and April 2021, with 28-day follow-up of the last participant completed on May 24, 2021. Interventions: Patients were assigned to receive nitric oxide at 20 ppm delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care cardiopulmonary bypass without nitric oxide (n = 685). Main Outcomes and Measures: The primary end point was the number of ventilator-free days from commencement of bypass until day 28. There were 4 secondary end points including a composite of low cardiac output syndrome, extracorporeal life support, or death; length of stay in the intensive care unit; length of stay in the hospital; and postoperative troponin levels. Results: Among 1371 patients who were randomized (mean [SD] age, 21.2 [23.5] weeks; 587 girls [42.8%]), 1364 (99.5%) completed the trial. The number of ventilator-free days did not differ significantly between the nitric oxide and standard care groups, with a median of 26.6 days (IQR, 24.4 to 27.4) vs 26.4 days (IQR, 24.0 to 27.2), respectively, for an absolute difference of -0.01 days (95% CI, -0.25 to 0.22; P = .92). A total of 22.5% of the nitric oxide group and 20.9% of the standard care group developed low cardiac output syndrome within 48 hours, needed extracorporeal support within 48 hours, or died by day 28, for an adjusted odds ratio of 1.12 (95% CI, 0.85 to 1.47). Other secondary outcomes were not significantly different between the groups. Conclusions and Relevance: In children younger than 2 years undergoing cardiopulmonary bypass surgery for congenital heart disease, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days. These findings do not support the use of nitric oxide delivered into the cardiopulmonary bypass oxygenator during heart surgery. Trial Registration: anzctr.org.au Identifier: ACTRN12617000821392.

Early Physiological and Adrenal Effects of Budesonide Mixed with Surfactant in Large Observational Preterm Cohort Study.

BACKGROUND: The combination of surfactant and budesonide has been shown to decrease BPD rates and severity. Budesonide may be released systemically from lungs, and the effects on the immature adrenal glands are not known. OBJECTIVE: The aim of this study was to determine if adrenal suppression rates are higher in preterm infants receiving budesonide with surfactant compared to surfactant alone. METHODS: A retrospective chart review of 608 infants ≤1,250 g received intubation for surfactant therapy from 2013 through 2020. In August 2016, budesonide was added to surfactant for these infants. Indicators of adrenal suppression, including mean blood pressures, plasma electrolyte levels, hydrocortisone use, and the use of vasoactive medications, were analyzed for the first 14 days after birth. Respiratory variables, biochemical signs of adrenal insufficiency, and neonatal morbidities were analyzed. RESULTS: There was no difference in hydrocortisone administration in the first 14 days between infants receiving budesonide with surfactant (n = 314) or surfactant alone (n = 294) (23% vs. 19%, p = 0.38). Budesonide exposed infants received hydrocortisone 3 days later than surfactant only infants (median DOL 5 vs. 2, p < 0.001). Infants receiving budesonide had higher blood pressures, required less dopamine (19% vs. 39%, p < 0.001) and dobutamine (2% vs. 6%, p = 0.02). Budesonide exposed infants were discharged home after a shorter NICU stay (85 days vs. 94 days, p = 0.02) and at a younger gestational age (39 vs. 40 weeks, p = 0.001). CONCLUSIONS: The use of surfactant and budesonide does not alter the rate of hydrocortisone use, but does delay the timing of treatment initiation and decreases the use of vasoactive medications.

Effects of ivacaftor on systemic inflammation and the plasma proteome in people with CF and G551D.

BACKGROUND: Ivacaftor is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator for people with CF and the G551D mutation. We aimed to investigate the biology of CFTR modulation and systemic effects of CFTR restoration by examining changes in circulating measurements of inflammation and growth and novel proteins with ivacaftor treatment. METHODS: Blood samples from 64 CF subjects with G551D-CFTR were analyzed for inflammatory and growth-related proteins at baseline, 1 and 6 months after ivacaftor initiation. In 30 subjects, plasma was assayed for 1,322 proteins using the SomaScan proteomic platform at baseline and 6 months post-ivacaftor. Correlations with clinical outcomes were assessed. MEASUREMENTS AND MAIN RESULTS: Significant reductions in high mobility group box-1 protein (HMGB-1), calprotectin, serum amyloid A, and granulocyte colony-stimulating factor (G-CSF), and an increase in insulin-like growth factor (IGF-1) occurred 1 month after ivacaftor. This treatment effect was sustained at 6 months for HMGB-1 and calprotectin. Correcting for multiple comparisons in the proteomic analysis, 9 proteins (albumin, afamin, leptin, trypsin, pancreatic stone protein [PSP], pituitary adenylate cyclase-activating polypeptide-38, repulsive guidance molecule A [RGMA], calreticulin, GTPase KRas) changed significantly with ivacaftor. Proteins changing with treatment are involved in lipid digestion and transport and extracellular matrix organization biological processes. Reductions in calprotectin and G-CSF and increases in calreticulin, and RGMA correlated with improved lung function, while increasing IGF-1, leptin and afamin and decreasing PSP correlated with increased weight. CONCLUSIONS: Ivacaftor led to changes in inflammatory, lipid digestion, and extracellular matrix proteins, lending insights into the extrapulmonary effects of CFTR modulation.

Corticosteroids in the prevention and treatment of infants with bronchopulmonary dysplasia: Part II. Inhaled corticosteroids alone or in combination with surfactants.

This paper is the second in a two-part State-of-the-Art series that reviews the latest relevant clinical trials investigating the short-term and long-term effects of corticosteroids in the prevention and treatment of bronchopulmonary dysplasia (BPD). Inhaled postnatal corticosteroids demonstrate low systemic bioavailability and rapid systemic clearance with high pulmonary deposition and were expected to reduce the incidence of BPD with reduced adverse effects, however, increased rate of mortality in the neonatal period and at the 18-24 months follow-up was observed. In a milestone study, intratracheal instillation of corticosteroids combined with surfactant decreased the incidence of BPD without increasing the mortality or the long-term neurodevelopmental adverse outcomes. However, subsequent trials using different types of surfactants, different surfactant to budesonide ratio, different time of the drug administration for infants with different severity of respiratory distress syndrome could not reproduce all the beneficial effects. Future perspectives for the identification of premature infants at high risk of BPD and the prevention or treatment of established BPD are discussed.

Función pulmonar: función pulmonar en fibrosis quística / Lung function in cystic fibrosis

La fibrosis quística (FQ) es una enfermedad hereditaria autosómica recesiva, causada por la mutación del gen que codifica la proteína CFTR (cystic fibrosis transmembrane conductance regulator), afecta varios órganos, pero la enfermedad pulmonar es la primera causa de morbimortalidad. El diagnóstico a través del screening neonatal (SNN) y los nuevos tratamientos moduladores del CFTR han aumentado el interés por pesquisar y monitorizar la función pulmonar antes del inicio de los síntomas para lograr un tratamiento adecuado y oportuno con una mejor calidad de vida. Existen numerosas formas de medir la función pulmonar según la edad, colaboración y recursos disponibles. En este artículo se resumen las pruebas clásicas y las más novedosas, como técnicas de imágenes, en la búsqueda de marcadores precoces de daño pulmonar, herramientas con los que cada centro de fibrosis quística debiera contar en la era de tratamientos moduladores del CFTR, que están cambiando el pronóstico de los pacientes con esta enfermedad.

Cystic fibrosis (CF) is an autosomal recessive inherited disease, caused by mutation of the gene encoding the CFTR protein (cystic fibrosis transmembrane conductance regulator), affects several organs, but lung disease is the first cause of morbidity and mortality. Diagnosis through neonatal screening (NNS) and new CFTR modulating treatments have increased interest in screening and monitoring lung function before the onset of symptoms to achieve adequate and timely treatment with a better quality of life. There are numerous ways to measure lung function based on age, collaboration, and available resources. This article summarizes the classic and the most innovative tests, which have emerged from imaging techniques in the search for early markers of lung damage, tools that each cystic fibrosis center should have in the era of CFTR modulating treatments, which are changing the prognosis of patients with this disease.

Early experience of nintedanib in COVID-19 ARDS-related pulmonary fibrosis: a case series.

The current COVID-19 pandemic has spread like wildfire worldwide and has affected millions of people. The novel corona virus mainly affects the lungs leading to life threatening disease like acute respiratory distress syndrome (ARDS). The aftermath of the disease in form of pulmonary fibrosis is upcoming cause of further increase in morbidity and mortality. Nintedanib is an oral antifibrotics with proven role in idiopathic pulmonary fibrosis, however its use in COVID-19 related pulmonary fibrosis has not been studied. We report our early experience of use of nintedanib in COVID-19 related pulmonary fibrosis.

Comparative outcomes in patients receiving pirfenidone or nintedanib for idiopathic pulmonary fibrosis.

BACKGROUND: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. In France, pirfenidone and nintedanib are only reimbursed for documented IPF, with similar reimbursement criteria with respect to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in multidisciplinary discussion. RESEARCH QUESTION: The data of the comprehensive French National Health System were used to evaluate outcomes in patients newly treated with pirfenidone or nintedanib in 2015-2016. STUDY DESIGN AND METHODS: Patients aged < 50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. All-cause mortality, acute respiratory-related hospitalisations and treatment discontinuations up to 31 December 2017 were compared using a Cox proportional hazards model adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period. RESULTS: During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical contacts prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.8; 95% confidence interval [CI] 1.3-2.6), a greater risk of acute respiratory-related hospitalisations (HR 1.3; 95% CI 1.0-1.7) and a lower risk of treatment discontinuation at 12 months (HR 0.7; 95% CI 0.6-0.9). INTERPRETATION: This observational study identified potential differences in outcome under newly prescribed antifibrotic drugs, deserving further explorations.

Surfactant protein D and bronchopulmonary dysplasia: a new way to approach an old problem.

Surfactant protein D (SP-D) is a collectin protein synthesized by alveolar type II cells in the lungs. SP-D participates in the innate immune defense of the lungs by helping to clear infectious pathogens and modulating the immune response. SP-D has shown an anti-inflammatory role by down-regulating the release of pro-inflammatory mediators in different signaling pathways such as the TLR4, decreasing the recruitment of inflammatory cells to the lung, and modulating the oxidative metabolism in the lungs. Recombinant human SP-D (rhSP-D) has been successfully produced mimicking the structure and functions of native SP-D. Several in vitro and in vivo experiments using different animal models have shown that treatment with rhSP-D reduces the lung inflammation originated by different insults, and that rhSP-D could be a potential treatment for bronchopulmonary dysplasia (BPD), a rare disease for which there is no effective therapy up to date. BPD is a complex disease in preterm infants whose incidence increases with decreasing gestational age at birth. Lung inflammation, which is caused by different prenatal and postnatal factors like infections, lung hyperoxia and mechanical ventilation, among others, is the key player in BPD. Exacerbated inflammation causes lung tissue injury that results in a deficient gas exchange in the lungs of preterm infants and frequently leads to long-term chronic lung dysfunction during childhood and adulthood. In addition, low SP-D levels and activity in the first days of life in preterm infants have been correlated with a worse pulmonary outcome in BPD. Thus, SP-D mediated functions in the innate immune response could be critical aspects of the pathogenesis in BPD and SP-D could inhibit lung tissue injury in this preterm population. Therefore, administration of rhSP-D has been proposed as promising therapy that could prevent BPD.

A delayed diagnosis of atypical immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A case report.

INTRODUCTION: Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is a rare monogenic autoimmune disease, which is caused by mutations in the forkhead box protein 3 gene, can affect various systems. The typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases. However, some atypical phenotypes can easily be misdiagnosed clinically. PATIENT CONCERNS: A 9-year-and-7-month old patient suffered from recurrent wheezing, hematochezia, and eczematous dermatitis at the age of six months, but did not have any manifestations of autoimmune endocrinopathy. The patient was treated with glucocorticoids for more than six years, and he developed bronchiectasis. DIAGNOSIS: Whole exome sequencing revealed a hemizygous pathogenic mutation c.1010G>A, p. (Arg337Gln) in Forkhead box protein 3 gene (NM_014009.3). INTERVENTIONS: The patient was treated with oral mycophenolate mofetil combined with inhaled budesonide formoterol for six months after diagnosis. OUTCOMES: The respiratory symptoms of the patient seemed to be controlled but eczematous dermatitis progressed, which led the patient to give up the treatment. CONCLUSION: Early diagnosis and treatment of IPEX are crucial. Lung injury may be a major problem in the later stages of atypical IPEX, and mycophenolate mofetil seems to control the respiratory symptoms, but could induce significant skin side effects.

The problem of postoperative respiratory depression.

WHAT IS KNOWN AND OBJECTIVE: Postsurgical recovery is influenced by multiple pre-, intra- and perioperative pharmacotherapeutic interventions, including the administration of medications that can induce respiratory depression postoperatively. We present a succinct overview of the topic, including the nature and magnitude of the problem, contributing factors, current limited options, and potential novel therapeutic approach. COMMENT: Pre-, intra- and perioperative medications are commonly administered for anxiety, anaesthesia, muscle relaxation and pain relief among other reasons. Several of the medications alone or in joint-action can be additive or synergistic producing respiratory depression. Given the large number of surgical procedures that are performed each year, even a small percentage of postoperative respiratory complications translates into a large number of affected patients. WHAT IS NEW AND CONCLUSION: Due to the large number of surgeries performed each year, and the variety of medications used before, during, and after surgery, the occurrence of postoperative respiratory depression is surprisingly common. It is a significant medical problem and burden on hospital resources. There is a need for new strategies to prevent and treat the acute and collateral problems associated with postoperative respiratory depression.

Contemporary Role and Regulation of Over-the-Counter Sinonasal Medications.

OBJECTIVE: Numerous pharmaceutical options are available over-the-counter (OTC) for the relief of sinonasal symptoms. Patients typically utilize these drugs in an unsupervised manner, without appreciation of their relative efficacy or potential for adverse effects. This review covers the scope and regulation of the OTC drug market, the pros and cons of OTC availability, and specific concerns that surround the most common classes of OTC sinonasal drugs. Suggestions are provided for the improvement of patient care and public health. DATA SOURCES: MEDLINE publications and market reports. REVIEW METHODS: Literature review. CONCLUSIONS: Some of the most commonly used OTC sinonasal remedies, including decongestants and first-generation antihistamines, are less effective than alternative drugs and pose potential safety concerns. IMPLICATIONS FOR PRACTICE: Clinicians should advocate to their patients for the appropriate use of alternative agents, such as intranasal corticosteroids and newer-generation antihistamines, and discourage the unsupervised use of oral and topical decongestants. Furthermore, health care practitioners should encourage dialogue with their patients about the use of OTC sinonasal remedies, with the goals of optimizing individual health and health care delivery.

Real-life experiences in a single center: efficacy of pirfenidone in idiopathic pulmonary fibrosis and fibrotic idiopathic non-specific interstitial pneumonia patients.

BACKGROUND: Pirfenidone is the first antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF) and it is used in the treatment of other interstitial pneumonias, such as unclassifiable interstitial lung disease (ILD) and connective tissue-related ILD. This study examined the efficacy of pirfenidone in patients with IPF and fibrotic idiopathic non-specific interstitial pneumonia (f-iNSIP). METHODS: In a retrospective real-life study, 67 IPF and 24 f-iNSIP patients were enrolled and classified into a pirfenidone group and a non-antifibrotic group. The level of forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLco) at baseline, 6, 12 and 24 months were recorded. The level of KL-6 in serum was detected by chemiluminescence enzyme immunoassay (CLEIA). The prognosis and safety outcomes were collected from patients. RESULTS: In IPF patients, pirfenidone decreased the mean change of FVC and DLco, and decreased the proportion of patients with a ⩾10% decline in FVC or a ⩾15% decline in DLco compared with the non-antifibrotic group. There was no difference in the mean change of FVC and DLco between smokers and non-smokers who received pirfenidone treatment. There was an improvement in progression-free survival, defined as the time to the first occurrence of acute exacerbation or death related to pulmonary fibrosis. Moreover, the ratio of patients who experienced acute exacerbation and death related to pulmonary fibrosis was lower in the pirfenidone group. There was no change in lung function and prognosis between the pirfenidone and non-antifibrotic groups in f-iNSIP patients. The KL-6 level slightly decreased after 1 year of pirfenidone treatment but not significantly. Gastrointestinal and skin-related adverse events were most common, and four patients ceased treatment due to the side effects. CONCLUSIONS: Pirfenidone safely reduced disease progression by improving the lung function and progression-free survival in IPF patients, with acceptable side effects. The efficacy of pirfenidone on f-iNSIP was not significant, suggesting the need for further studies.The reviews of this paper are available via the supplemental material section.

Peptides: Prospects for Use in the Treatment of COVID-19.

There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.

Prognostic significance of forced vital capacity decline prior to and following antifibrotic therapy in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease (ILD). Currently, two antifibrotic drugs are available for reducing forced vital capacity (FVC) decline in IPF. However, many pulmonologists wait before initiating treatment, especially when IPF patients have stable disease. This study aimed to investigate the impact on survival outcome of FVC decline and a slow rate of FVC decline prior to and following treatment with these two antifibrotic drugs. METHODS: Out of the 235 IPF patients treated with antifibrotic therapy that were screened, 105 cases were eligible, who then underwent physiological evaluation at 6 months prior to and following antifibrotic therapy. Clinical characteristics and prognostic outcomes were compared among groups, and prognostic factors were evaluated using a Cox proportional hazards analysis. RESULTS: In terms of %FVC decline prior to the therapy and a slow rate of FVC decline, there was no significant difference between stable and worsened groups and responder and non-responder groups, respectively. On the other hand, in terms of %FVC decline (decline >5%) following antifibrotic therapy, the stable/improved group had significantly better prognosis than the worsened group. Prognostic analysis revealed that a stable/improved status following antifibrotic therapy [HR: 0.35 (0.15-0.87)] was significantly associated with a better prognosis. CONCLUSIONS: Concerning the FVC decline prior to and following antifibrotic therapy and a slow rate of FVC decline, only the FVC decline following the therapy is associated with a greater survival outcome. An early treatment decision may thus be beneficial for IPF.The reviews of this paper are available via the supplemental material section.

Rational use of mucoactive medications to treat pediatric airway disease.

Many airway diseases in children, notably bronchiolitis, cystic fibrosis (CF), non-CF bronchiectasis including primary ciliary dyskinesia, pneumonia, and severe asthma are associated with retention of airway secretions. Medications to improve secretions clearance, the mucoactive medications, are employed to treat these diseases with varying degrees of success. This manuscript reviews evidence for the use of these medications and future directions of study.

Non-specific protection from respiratory tract infections in cattle generated by intranasal administration of an innate immune stimulant.

Alternatives to antibiotics for prevention of respiratory tract infections in cattle are urgently needed given the increasing public and regulatory pressure to reduce overall antibiotic usage. Activation of local innate immune defenses in the upper respiratory tract is one strategy to induce non-specific protection against infection with the diverse array of viral and bacterial pathogens associated with bovine respiratory disease complex (BRDC), while avoiding the use of antibiotics. Our prior studies in rodent models demonstrated that intranasal administration of liposome-TLR complexes (LTC) as a non-specific immune stimulant generated high levels of protection against lethal bacterial and viral pathogens. Therefore, we conducted studies to assess LTC induction of local immune responses and protective immunity to BRDC in cattle. In vitro, LTC were shown to activate peripheral blood mononuclear cells in cattle, which was associated with secretion of INFγ and IL-6. Macrophage activation with LTC triggered intracellular killing of Mannheimia hemolytica and several other bacterial pathogens. In studies in cattle, intranasal administration of LTC demonstrated dose-dependent activation of local innate immune responses in the nasopharynx, including recruitment of monocytes and prolonged upregulation (at least 2 weeks) of innate immune cytokine gene expression by nasopharyngeal mucosal cells. In a BRDC challenge study, intranasal administration of LTC prior to pathogen exposure resulted in significant reduction in both clinical signs of infection and disease-associated euthanasia rates. These findings indicate that intranasal administration of a non-specific innate immune stimulant can be an effective method of rapidly generating generalized protection from mixed viral and bacterial respiratory tract infections in cattle.

Utilization trends of respiratory medication in premature infants discharged on home oxygen therapy.

BACKGROUND: Roughly half of all extremely preterm infants will be diagnosed with bronchopulmonary dysplasia (BPD), and a third will be discharged on home oxygen therapy (HOT). To date, there have been no studies that have examined the relationship between respiratory medication utilization in infants with BPD on HOT. METHODS: The recorded home oximetry trial was a multicenter, randomized trial comparing two home oxygen management strategies in premature infants. Infants were enrolled at first outpatient pulmonary or neonatal intensive care unit (NICU) follow-up visit with a pulmonary component. Respiratory medication prescriptions and dosage were collected from time of enrollment through 6 months after HOT discontinuation. Patients were seen monthly while on HOT and at 1, 3, and 6 months after successful discontinuation. RESULTS: During protocol visits, 174 (89%) infants had respiratory medications documented. Respiratory medication use was higher at initial follow-up visit compared with NICU discharge and decreased at the final 6-month follow-up visit. Infants who received inhaled steroids (IS) before weaning had mean HOT duration of 138 days (range: 24-562 days); infants who received IS after weaning had shorter mean HOT duration (55 days, range: 21-264). In time-to-event analysis the no IS group and the postwean group differed significantly (χ21 = 8.1; P = .004). NICU clinics gave a total of 35 prescriptions to 43 patients, an average of 0.8 per patient, while the pulmonary clinics gave 837 prescriptions to 153 patients, or 5.5 per patient (P < .0001). CONCLUSION: Respiratory prescribing patterns for infants on HOT are highly variable. Utilization of IS was not associated with shorter duration of HOT.