key: cord-0857056-amozdz0y
authors: Cattel, Francesco; Giordano, Susanna; Bertiond, Cecilia; Lupia, Tommaso; Corcione, Silvia; Scaldaferri, Matilde; Angelone, Lorenzo; De Rosa, Francesco Giuseppe
title: Use of exogenous pulmonary surfactant in acute respiratory distress syndrome (ARDS): Role in SARS-CoV-2-related lung injury
date: 2021-02-28
journal: Respir Physiol Neurobiol
DOI: 10.1016/j.resp.2021.103645
sha: a57959e911b26f43290e7f600a5f476d5d5a0276
doc_id: 857056
cord_uid: amozdz0y

Several pre-clinical and clinical trials show that exogenous pulmonary surfactant has clinical efficacy in inflammatory lung diseases, especially ARDS. By infecting type II alveolar cells, COVID-19 interferes with the production and secretion of the pulmonary surfactant and therefore causes an increase in surface tension, which in turn can lead to alveolar collapse. The use of the pulmonary surfactant seems to be promising as an additional therapy for the treatment of ARDS. COVID-19 causes lung damage and ARDS, so beneficial effects of surfactant therapy in COVID-19-associated ARDS patients are conceivable, especially when applied early in the treatment strategy against pulmonary failure. Because of the robust anti-inflammatory and lung protective efficacy and the current urgent need for lung-supportive therapy, the exogenous pulmonary surfactant could be a valid supportive treatment of COVID-19 pneumonia patients in intensive care units in addition to the current standard of ARDS treatment

Acute Respiratory Distress Syndrome (ARDS) is a syndrome characterized by cardiogenic or noncardiogenic respiratory failure, mild, moderate, or severe oxygenation impairment [1] .

Pathophysiologically, there is observed damage to the capillary endothelium and alveolar epithelium. It can also occur fluid accumulation in the alveolar space, reduced lung compliance, imbalanced lung ventilation flow ratio, decreased lung volume, and refractory dyspnea [1] [2] .

Dysfunction of the alveolar epithelium determines an alteration of the surface tension with consequent harmful gas exchange and lung lesions. During the mechanism of dysfunction of the alveolar epithelium, an important role is related to alveolar cells called type I and II. Type II contain secretory granular organelles fused with the cell membranes. These organelles, called lamellarbodies, produce pulmonary surfactant andt is excreted into the alveolar space [3] . If type II is damaged, production and secretion of pulmonary surfactant to the alveolar space will be considerably reduced and, consequently, lung ventilation flow [4] .

One of the most significant issues related to SARS-CoV-2 infection is its ability to affect the respiratory system: because of the high viral tropism for lung epithelial cells, it can colonize and replicate within type II cell [3] . By infecting type II, COVID-19 interposes with the production and secretion of the pulmonary surfactant and therefore causes an increase in surface tension, leading to alveolar collapse. The tendency towards lung collapse is countered by inspiratory movement; however, inspiration simultaneously causes pressure in the interstitial space.

This phenomenon causes inflammatory liquids and molecules from the bloodstream to be called into the interstitial space, causing the onset of interstitial pneumonia and possibly acute respiratory distress syndrome (ARDS) [4] .

During the pandemic, Gattinoni et al. [5] have proposed two different phenotypes of COVID-19 patients, with different pathophysiology and progression. Type 1, "nonARDS", patients had radiological features of SARS-CoV-2 pneumonia with almost regular respiratory system compliance, and severe hypoxemia is primarily due to high intrapulmonary shunting [5] . On the other hand, Type 2 subjects are affected by severe ARDS with low compliance value [5] .

Theoretically, type 2 phenotype is due to the disease's natural evolution and initial respiratory management, according to Gattinoni et al. and non-ARDS type may transit to ARDS-type by selfinflicted or ventilator-induced lung injury [5] . Interestingly, Schousboe et al., starting from Gattinoni's hypothesis, compared ARDS in SARS-CoV-2 to neonatal respiratory distress syndrome, caused by surfactant deficiency, suggesting an assessment of surfactant levels to the evaluation of COVID-19 patients [6] .

Because there are no specific antiviral treatments against SARS-CoV-2, barring the recent approval of remdesivir [7] , it is necessary to find alternative supportive symptomatic treatments to prevent ARDS and pulmonary failure, among the most common causes of COVID-19 mortality [8] .

This work aims to summarize the current evidence on the use of exogenous pulmonary surfactant in Seventy-four articles met the search criteria applied (Figure 1 ). Of these, 60 titles appeared to be relevant to pulmonary surfactant use in ARDS and 14 titles were excluded because they were not focused on the medical application of exogenous pulmonary surfactant. An additional thirty articles were then excluded after abstract review. Thirty articles were found to support the clinical efficacy of the exogenous surfactant in inflammatory lung diseases.

The use of exogenous surfactant in the treatment of ARDS has been investigated in several trials. Some of these studies support its use however, otherhave shown that there is no significant improvement. Nine articles were found to support the clinical efficacy of the exogenous surfactant in inflammatory lung diseases: i) Two of them are pre-clinical trials on animals (rabbits and lambs) [4, 9] ; ii) three describe clinical trials on infants and children, two of which are meta-analyses [10-11] and a comparative study [12] ; iii) three are meta-analyses [13-15] describing the results obtained from several randomized clinical trials on adults; iv) one article is a retrospective casecontrol pilot study [16] Ttwo articles were found to not support the exogenous surfactant's clinical efficacy in inflammatory lung diseases to improve mortality and oxygenation for adult ARDS patients [2, 17] .

Pre-clinical trials on animals showed how exogenous surfactant use resulted in improved lung function and decreased pulmonary oedema.

The first trial is a comparative study [4] of two pulmonary surfactants, rSP-C33Leu (surfactant protein C analogue) and Curosurf® (poractant alfa), used to reduce pulmonary inflammation as a model of ARDS in rabbits (Table 1) . After induction of ARDS, 23 animals were allocated randomly to three groups: a) control group, n=7: no surfactant treatment; b) treatment with Curosurf®, n=8; or c) treatment with rSP-C33Leu surfactant, n=8 [4] . Both preparations were administered with two intratracheal boluses, and the rabbits were subsequently ventilated for the next three hours [4] . In the control group, an air bolus was given instead of surfactant [4] . After treatment, the animals were set in a prone position, and physiological data were recorded every 30min, considering blood gases and respiratory parameters [4] . Both surfactant preparations improved lung function and decreased inflammation, level of pro-inflammatory cytokines and formation of pulmonary oedema. Curosurf® showed better efficacy in improving lung parameters than rSP-C33Leu [4].

The second study [9] , performed on preterm lambs, compares Curosurf® with Synsurf®, a synthetic surfactant. In this randomized controlled trial (six lambs/group), the pharmacological substances have been dispensed at 100mg/kg; normal saline was administered to the control group Preterm infants have immature lungs that produce an inadequate amount of surfactant to decrease the surface tension between air and alveoli and are more likely to develop ARDS, so they need respiratory support [10] . The use of an exogenous pulmonary surfactant in intubated infants immediately after birth or after developing ARDS reduced the occurrence of pneumothorax, pulmonary interstitial emphysema and neonatal mortality [10] [11] .

In a study of 60 infants [12] , the use of intubation, mechanical ventilation and administration of pulmonary surfactant (experimental group, n=30) is compared with the use of intubation and mechanical ventilation only (control group, n=30). PaO2, PaCO2 and PaO2/FiO2 values were measured before and after treatment [12] . The PaO2 level in both groups continually increased with the duration of time, starting from before treatment, then six hours after treatment and 12 h after treatment, and was highest at 24 h after treatment [12] . The PaCO2 level in both groups continually J o u r n a l P r e -p r o o f decreased with time, starting from before treatment, then six hours after treatment and12 h after treatment, and was lowest at 24 h after treatment [12] . The ratio of PaO2/FiO2 in the observational group and the control group continually increased with the duration of time, starting from before treatment, six hours after treatment and 12 h after treatment, and was highest at 24 h after treatment [12] . The results show that levels of all parameters improved in the two groups, and the improvement effect in the experimental group was better than in the control group [12] . Another but new drug is Solnatide, a synthetic peptide composed of 16 amino acids normally found in nature, understudy for the treatment of ARDS (Table 1) 

Solnatide deactivates the pulmonary sodium ion channels (ENaC), thus accelerating the dissolution of alveolar edema. Besides, Solnatide inhibits the production of reactive species of oxygen (ROS).

The drug reduces the level of myosin light chain (MLC) phosphorylation, thus protecting and restoring the integrity of the barrier of endothelial and epithelial cells. It has no pro-inflammatory activity and does not lead to increased chemokine production or increased infiltration of neutrophils [21] . A clinical study evaluated the local and systemic safety of multiple sequential ascending doses of Solnatide inhaled for seven days orally [21] . This is a phase IIb, randomized, placebo-controlled, double-blind, dose-escalation study. Patients in this trial had moderate to severe pulmonary permeability edema and ARDS. This trial reviewed the potential efficacy endpoints for a future phase III study (NCT03567577) [21] . Solnatide deactivates the pulmonary sodium ion channels The release of the surfactant into the alveolar space is the result of a mechanism of exocytosis that involves the membranes of the lamellar bodies which fuse with the membranes of the epithelial cells [10] [11] . In lungs, the surfactant reservoir is represented by a structure called tubular myelin inside which phospholipids and surfactant proteins, particularly SP-A, both assemble; tubular myelin plays an essential role the alveolar breathing process and improves the insertion of lipids into the air-liquid interface [10] [11] . During the breathing process, high pressures in low lung volumes favour the desorption of surfactant lipids. A portion of desorbed lipid follows the following steps: it is recycled by type II cells, endocytosed through multivesicular bodies and finally stored in lamellar bodies and secreted. Other elements of the surfactant can be recovered in tubular myelin through an extracellular process; macrophages absorb the rest for degradation [10] [11] .

Several pre-clinical and clinical trials show that exogenous pulmonary surfactant has clinical efficacy in inflammatory lung diseases, especially ARDS [4, [9] [10] [11] [12] [13] [14] [15] . Pre-clinical trials on rabbits and lambs show that pulmonary surfactants improve lung function and reduce inflammation, production of pro-inflammatory cytokines, and pulmonary oedema, leading to significant improvement in oxygenation [4, 9] . Clinical trials on infants show that using an exogenous pulmonary surfactant in J o u r n a l P r e -p r o o f intubated infants immediately after birth or after developing ARDS significantly reduces the occurrence of pneumothorax, pulmonary interstitial emphysema and neonatal mortality and improves the levels of oxygen parameters [10] [11] . Randomised clinical trials on adults show that the administration of pulmonary surfactant improves oxygenation during the first 24 h after treatment and appears to reduce the duration of ventilation. The use of this preparation in adults is not associated with reduced mortality or reduced ventilation duration. However, several studies have reported how surfactant administration has not been shown to improve mortality [2] and oxygenation for adult ARDS patients [2, 17] .

There is no convincing proof that surfactant in COVID-19 patients is dysfunctional [22] . However, indirect evidence indicates that surfactant disorders play a significant part theoretically in COVID-19 lung dysfunction [23] [24] [25] [26] . We know that SARS-CoV-2 infects the type II alveolar surfactant cells Further studies are needed in adults to obtain conclusive results. However, since ARDS are among the complications of COVID-19, the use of exogenous surfactant or Solnatide can be hypothesized for the treatment of this viral infection.

There are no conflicts of interest to report for any authors.

J o u r n a l P r e -p r o o f

Endothelial Damage in Acute Respiratory Distress Syndrome

Covid-19, Type II Alveolar Cells and Surfactant

Lung Surfactant for Pulmonary Barrier Restoration in Patients With COVID-19 Pneumonia. Front Med (Lausanne)

Synthetic surfactant with a recombinant surfactant protein C analogue improves lung function and attenuates inflammation in a model of acute respiratory distress syndrome in adult rabbits

COVID-19 pneumonia: ARDS or not? Crit Care