THE OUTLOOKS FOR THE SURFACTANT REPLACEMENT THERAPY OF COVID-19 INDUCED RESPIRATORY DISTRESS SYNDROME IN CHILDREN

Nearly 6.5 million people have died worldwide from the COVID-19 pandemic. Improvement of pediatric patients survival depends on the continued provision of basic health services to women and children all over the world. The world scientific community must start more scientific clinical investigations and receive more data in order to know the impact of COVID-19 on children's health and mortality, and to ensure that children and adolescents do not die from preventable events. Such trends in the spread of morbidity and mortality from COVID-19 require an interdisciplinary approach as soon as possible to further contain the spread of the disease and prevent complications in order to improve the quality of life. Insufficiently studied molecular changes in lung morpho-biology due to the action of COVID-19 complicate its clinical treatment. An in-depth genetic mechanisms investigation during pathogenetic disorders caused by virus can help in the development of new treatment methods, in particular, the use of surfactant drugs as a component of basic therapy. Recently, it became known that COVID-19-associated lung damage is characterized by typical pathophysiological changes for RDS. Diffuse alveolar damage occurs due to edema of the interstitium, the formation of hyaline membranes, as well as the proliferation of fibroblasts at the stage of recovery. When COVID-19 affects the lungs, surfactant synthesis is dysregulated, as viral proteins suppress the expression of regulatory genes. Changes during the reparation process also lead to loss of surfactant function. Surfactant replacement therapy can be an alternative in the treatment of patients with COVID-19associated lung damage, there are a number of studies that prove the effectiveness of such therapy in other infections. COVID-19 can be especially dangerous for children with chronic lung disease, congenital malformations, previously undiagnosed genetic defects in the surfactant production system. However, timely use of surfactant replacement therapy can prevent one of the worst complications during mechanical ventilation - air leakage syndrome. © Yu.I.Chernyavska, V.I. Pokhylko, Z.I. Rossokha, S.M. Tsvirenko, N.I. Hasiuk, 2022.

Pulmonary Surfactant: A Unique Biomaterial with Life-saving Therapeutic Applications.

Pulmonary surfactant is a complex lipoprotein mixture secreted into the alveolar lumen by type 2 pneumocytes, which is composed by tens of different lipids (approximately 90% of its entire mass) and surfactant proteins (approximately 10% of the mass). It is crucially involved in maintaining lung homeostasis by reducing the values of alveolar liquid surface tension close to zero at end-expiration, thereby avoiding the alveolar collapse, and assembling a chemical and physical barrier against inhaled pathogens. A deficient amount of surfactant or its functional inactivation is directly linked to a wide range of lung pathologies, including the neonatal respiratory distress syndrome. This paper reviews the main biophysical concepts of surfactant activity and its inactivation mechanisms, and describes the past, present and future roles of surfactant replacement therapy, focusing on the exogenous surfactant preparations marketed worldwide and new formulations under development. The closing section describes the pulmonary surfactant in the context of drug delivery. Thanks to its peculiar composition, biocompatibility, and alveolar spreading capability, the surfactant may work not only as a shuttle to the branched anatomy of the lung for other drugs but also as a modulator for their release, leading to innovative therapeutic avenues for the treatment of several respiratory diseases.

A recipe for a good clinical pulmonary surfactant.

The lives of thousands premature babies have been saved along the last thirty years thanks to the establishment and consolidation of pulmonary surfactant replacement therapies (SRT). It took some time to close the gap between the identification of the biophysical and molecular causes of the high mortality associated with respiratory distress syndrome in very premature babies and the development of a proper therapy. Closing the gap required the elucidation of some key questions defining the structure-function relationships in surfactant as well as the particular role of the different molecular components assembled into the surfactant system. On the other hand, the application of SRT as part of treatments targeting other devastating respiratory pathologies, in babies and adults, is depending on further extensive research still required before enough amounts of good humanized clinical surfactants will be available. This review summarizes our current concepts on the compositional and structural determinants defining pulmonary surfactant activity, the principles behind the development of efficient natural animal-derived or recombinant or synthetic therapeutic surfactants, as well as a the most promising lines of research that are already opening new perspectives in the application of tailored surfactant therapies to treat important yet unresolved respiratory pathologies.

Advances in the Pharmacological Management of Pediatric Acute Respiratory Distress Syndrome.

INTRODUCTION: Noninvasive mechanical ventilation is the main supportive measure used in patients with pediatric ARDS (PARDS), but adjunctive pharmacological therapies (corticosteroids, inhaled nitric oxide [iNO], surfactant replacement therapy and neuromuscular blocking drugs) are also used, although limited data exists to inform of this practice. AREAS COVERED: The authors review the current challenges in the pharmacological management of PARDS and highlight the few certainties currently available. EXPERT OPINION: Children with PARDS must not be treated as young adults with ARDS, essentially because children's lungs differ substantially from those of adults and PARDS occurs in children differently than ARDS in adults. Pharmacological treatments available for PARDS are relatively few and, since there is great uncertainty about their effectiveness also because of the extreme heterogeneity of this syndrome, it is necessary to conduct large clinical trials using currently available definitions and considering recent pathobiological knowledge. The aim is to identify homogeneous subgroups or phenotypes of children with PARDS that may benefit from the specific pharmaceutical approach examined. It will be then necessary to link endotypes and outcomes to appropriately target therapies in future trials, but this will be possible only after it will be possible to identify the different PARDS endotypes.

Surfactant therapy for COVID-19 related ARDS: a retrospective case-control pilot study.

BACKGROUND: COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. METHODS: We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. RESULTS: Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. CONCLUSIONS: Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.