Surfactant replacement therapy as promising treatment for COVID-19: an updated narrative review

Abstract Patients with COVID-19 exhibit similar symptoms to neonatal respiratory distress syndrome. SARS-CoV-2 spike protein has been shown to target alveolar type 2 lung cells which synthesize and secrete endogenous surfactants leading to acute respiratory distress syndrome in some patients. This was proven by post-mortem histopathological findings revealing desquamated alveolar type 2 cells. Surfactant use in patients with COVID-19 respiratory distress syndrome results in marked improvement in respiratory parameters but not mortality which needs further clinical trials comparing surfactant formulas and modes of administration to decrease the mortality. In addition, surfactants could be a promising vehicle for specific drug delivery as a liposomal carrier, which requires more and more challenging efforts. In this review, we highlight the current reviews and two clinical trials on exogenous surfactant therapy in COVID-19-associated respiratory distress in adults, and how surfactant could be a promising drug to help fight the COVID-19 infection.


Introduction
COVID-19 is an encapsulated, single-stranded, positive-sense RNA virus that can cause serious illnesses due to its broad-ranging tropism [1,2]. Severe COVID-19 represents viral pneumonia caused by SARS-CoV-2 infection, which results in acute respiratory distress syndrome (ARDS) [3]. ARDS is characterized by lung inflammation and pulmonary edema. SARS-CoV-2 virus mainly attacks alveolar cells type 2, whereupon it induces apoptosis, cell damage, and decreased pulmonary surfactant synthesis [4] ( Figure  1). Angiotensin-converting enzyme 2 (ACE2) is recognized as playing a significant role in host-virus interaction. However, new gene-ontology investigations have revealed that alveolar type 2 (AT2) cells represent 83% of lung cells expressing the ACE2 gene, and the progressive damage of AT2 limits surfactant production [5]. Pathogens are thought to be opsonized by pulmonary surfactant, which makes it easier for cells of the innate immune system to phagocytose them [6]. It may be most beneficial if preventative measures and a combination of medicines are available for people who are already infected. Numerous existing medications, such as anti-inflammatory agents, have been evaluated in response to the pressing need to stop the COVID-19 epidemic [7].
There are currently just a few trials that describe the possibility of using exogenous surfactants as adjuvant therapy for COVID-19-associated ARDS in a limited number of patients [8,9]. Using exogenous surfactant improved static lung compliance and oxygenation and had the propensity to lower mortality rates. This study will briefly discuss the role of surfactants and the effectiveness of exogenous surfactant therapy in treating neonatal and adult respiratory distress syndrome. In addition, we aim to review the planning and analysis of clinical trials on exogenous surfactant therapy for COVID-19.

SARS-CoV-2 mechanism
SARS-CoV-2 is thought to target alveolar type-II cells, the lung cells in charge of producing surfactant, similar to SARS-CoV. Inflamed cells emit endogenous chemicals that trigger Toll-like receptor activation, inflammatory mediators, and inflammation synthesis. Along with the surfactant's continued decline brought on by the demise of these type II pneumocytes, these effects (and possibly the increased activity of secretory phospholipase A2 [sPLA2]) [10,11] promote pulmonary edema, a hallmark of COVID-19. Pulmonary edema, in turn, leads to ARDS ( Figure 2).
Early on, the pulmonary failure brought on by COVID-19 appears to be very different from other forms of ARDS [12,13]. For instance, many COVID-19 patients first exhibit hypoxemia with sustained lung compliance, referred to as the L-type presentation provided by phosphatidylcholine. L-type patients frequently change into the second or H-type clinical presentation, nevertheless. Only after significant phosphatidylcholine depletion and mass destruction of AT2 cells, which show high elastance and low compliance, will the surfactant's ability to reduce surface tension be lost [13,14]. Consequently, only the H-type reproduces the lung characteristics of premature children with low surfactant production.
Exogenous surfactant administered via the lungs is predicted to counteract this chain of events in a variety of ways ( Figure 3), including (i) restoring surfactant levels to protect against increased surface tension in the lung, (ii) limiting the production of damage-associated molecular patterns (DAMPs) from activating the innate immune system to minimize inflammation and inflammatory damage by suppressing the activation of toll-like receptors [15], and (iii) reducing pulmonary edema through the combination of the first two actions.
Finally, excessive inflammation is linked to the hypercoagulopathy that is occasionally observed in COVID-19 individuals (e.g., notably elevated C-reactive protein and D-dimer levels). As a result, phosphatidylglycerol's capacity to block PAMP-and DAMP-induced sequelae may likewise lessen these COVID-19 effects.

Structure and uses of surfactant
The most prevalent surfactant component is lipids, as it contains a high amount of dipalmitoylphosphatidylcholine (DPPC), the most abundant phospholipid in surfactant and the most important in reducing surface tension, and phosphatidylglycerol that indicates lung maturity [16][17][18]. The surfactant also contains two small hydrophobic proteins, surfactant proteins (SP)-C and SP-B, which enable the lipids to adsorb and spread rapidly into the air-liquid interface. Without these proteins, lipids do not move out from their assembly origin into the interface [19][20][21]. The other two oligomeric proteins, SP-A and SP-D, have immunomodulatory properties by binding to innate immunity receptors and helping in cytokine production, which are hydrophilic [21,22]. DPPC allows the surfactant to reach maximal packing due to its saturated acyl chains, which can have an entirely straight conformation as opposed to other unsaturated acyl chains. Phosphatidylinositol and phosphatidylglycerol are the most prevalent anionic phospholipids in surfactants. They are considered cofactors that form selective interactions with the hydrophobic cationic groups of SP-C and SP-B to catalyze their specific function. Cholesterol amounts are highly variable, but a high percentage of cholesterol may indicate pathological conditions such as ARDS [23,24]. However, it is still unclear whether  high cholesterol is a consequence or a cause of a maleficent surfactant system. Recently, it has been thought that limited amounts of cholesterol are still important for unique interactions with hydrophobic proteins [25,26]. The basic compositional structure of surfactant requires saturated/unsaturated proportions of anionic phospholipids, DPPC, hydrophobic proteins, and cholesterol. Pathological conditions leading to a defect in these components worsen surfactants' performance. The surfactant can be extracted by bronchoalveolar lavage in animals, and the whole material coating both upper and distal airways can be collected. Suppose extraction is done by bronchoscopy in patients. In that case, the material obtained will be just from the area washed, the cells of the material are removed, and the rest is centrifuged to yield the surfactant, which consists of 80% phospholipids, 10% proteins such as SP-C and SP-B, and 10% neutral lipids [27]. Calfactant, from calf lung, contains normal amounts of cholesterol and works well in surfactant replacement therapy of premature babies [28][29][30]. Production of enough amounts of hydrophobic proteins is considered the most challenging step in making synthetic surfactants. Naturally originated clinical surfactants are limited in amount and may contain pathogenic antigens, so they are difficult to standardize; this means that hydrophobic protein production by the recombinant system is the future to look for. Amounts of recombinant human SP-C have already been produced and used in clinical trials in contrast with recombinant SP-B, which still cannot be produced [31][32][33][34]. Table 1 represent available surfactant preparations and their composition.
Surfactant replacement therapy in treating COVID-19 is an essential case of interest whose results have been promising. Many trials are ongoing in the meantime, indicating improvement of outcomes in patients with COVID-19, as it is known to have antagonism to type 2 pneumocytes whose destruction results in decreased amounts of surfactant and worse prognosis COVID-19 patients [8,35,36].

Clinical uses of exogenous surfactant Exogenous surfactant as a carrier
The concept that surfactants may be used as a delivery vehicle for pulmonary medicines and other chemicals was inspired by the efficacy of exogenous surfactant therapy in neonatal respiratory distress syndrome (NRDS) and the known physicochemical features of surfactants that allow them to diffuse through the lung [37,38]. The fundamental idea is that exogenous surfactant, when coupled, will make it easier to carry a substance to the far reaches of the lung. Surfactant has been employed as a drug carrier in preterm infants at risk of developing bronchopulmonary dysplasia (BPD) [39][40][41].

Exogenous surfactant in BPD
BPD, a chronic lung disease, is more likely to develop in premature newborns, especially those who experience prolonged ventilation and high oxygen demands. In two carefully controlled clinical trials, the efficacy of an exogenous surfactant, Survanta ® , in combination with budesonide, as compared with the efficacy of the surfactant alone in preventing the development of BPD in preterm newborns [40,42]. A detailed evaluation and meta-analysis of the data from the two clinical trials revealed that BPD incidence was decreased by intra-tracheal injection of budesonide-surfactant mixtures (RR: 0.57; 95%CI: 0.43-0.76, NNT = 5) [43,44]. Before recommending it as routine therapy, additional sizable clinical trials are also necessary due to the lack of rigorous clinical trials. However, these trials offer the first evidence of the theory underlying the clinical application of a surfactant-drug combination and call for further research into the viability of applying this strategy to other medications addressing other clinical diseases like pneumonia and ARDS. Vitamin D has the counterintuitive effect of lessening the severity of COVID-19 based on the up-to-date umbrella review [45], despite the initial inconsistency in the results, which could be explained by genetic polymorphisms in several genes associated with vitamin D metabolisms such as CYP2R1 rs10741657, DHCR7/NADSYN rs12785878, carriers of CYP2R1 GG and DHCR7/NADSYN TG+GG genotypes, and DBP polymorphisms rs4588 and rs7041 [46]. Although vitamin D induces the expression of ACE2, which indeed promotes the binding of the virus, it prevents pulmonary vasoconstriction response in COVID-19 cases. Vitamin D may suppress renin activity, lessening angiotensin II production and producing less vasoconstriction [47]. The minimum optimal plasma target of 25-hydroxyvitamin D to be reached in the preventive setting would be ≥30 ng/ml, for which it is necessary to administer high doses of cholecalciferol, also concerning the basal levels of the patient, up to 4000 IU/day [48][49][50]. Therefore, according to these recommendations, co-administering vitamin D with surfactants may increase its beneficial effect, especially for groups with a higher risk of COVID-19 and vitamin D deficiency.

Exogenous surfactant in NRDS
NRDS significantly contributed to infant mortality until the mid-1980s, when exogenous surfactant therapy was created [51,52]. It has been demonstrated that intratracheal administration of a pure form of animal surfactants to vulnerable patients significantly increases survival, as reported in network meta-analysis of randomized controlled trials. Hence, the exogenous surfactant remains the preferred therapy in neonatal intensive care units [53,54]. (I) Two are preclinical trials on animals, which explain how surfactant improves lung function and decreases pulmonary edema. The first trial is a comparative study of two pulmonary surfactants, rSP-C33Leu (surfactant protein C analog) and Curosurf ® (protectant alfa); improved lung function and reduced inflammation were seen with both surfactant preparations [56]. The second study compares Curosurf ® with Synsurf ® . Both surfactant preparations ameliorated the oxygenation (significant increase in PaO2/FiO2 ratio) [57].
(II) Three studies describe clinical trials on infants and children, two of which are meta-analyses [58,59] have demonstrated that pneumothorax, pulmonary interstitial emphysema, and neonatal mortality were all decreased when an exogenous pulmonary surfactant was administered.
A comparative study compared the administration of pulmonary surfactant in intubated and mechanically ventilated infants (experimental group, n=30) and the use of intubation and mechanical ventilation only (control group, n=30), and the findings demonstrate that all parameter values improved in both groups, with the experimental group seeing more improvement than the control group [60].
(III) Two meta-analyses [53,61] describe the results of several randomized clinical studies. The results in the first 24 h following therapy showed that pulmonary surfactant usage increased oxygenation and reduced the duration of ventilation in adults with ARDS or acute lung disease.
(IV) According to two studies [62,63], exogenous surfactants do not improve adult ARDS patients' oxygenation or mortality while treating inflammatory lung diseases. Another meta-analysis concluded that using exogenous surfactants may improve oxygenation with a pooled mean change of 13.18 mmHg, standard error of 8.23 mmHg; 95% CI: 2.95, 29.32, but not mortality. It was surprising considering the changes in surfactant functions in ARDS patients, and the explanation was that rather than dying from respiratory failure, patients with ARDs typically pass away from the underlying disease's multi-organ system collapse. Another possibility is that the ideal surfactant recipe has not yet been discovered [64]. It is worth mentioning that ARDS is accompanied by augmented sPLA2 activity in the lungs. sPLA2 degrades the phospholipids of surfactants, including phosphatidylglycerol [11]. In addition to raising surface tension and decreasing lung compliance, a surfactant function deficit may also worsen pulmonary edema [65,66]. It is important to note that the ideal surfactant preparation composition and source may vary depending on whether CARDS or NRDS is being treated. First off, despite the fact that their presence can contribute to a more effective treatment of CARDS, none of the therapeutic surfactants currently available to prevent NRDS contain the hydrophilic proteins SP-A and SP-D. Through the binding of their CRD to the glycosylated spike protein, SP-A and SP-D may aid in the removal of SARS-CoV-2 [24]. It is worth mentioning that potential disease-causing factor, as auto-IgA prevents lung surfactant from reducing surface tension. This might compromise the pulmonary air sacs' ability to stabilize themselves, causing alveolar collapse and inadequate oxygen exchange [67].

COVID-19
The trials of feasibility and safety of using exogenous pulmonary surfactant showed no direct evidence that surfactant is dysfunctional in the lungs of COVID-19 patients. Type II alveolar cells infected by SARS-CoV-2 could not properly secrete the endogenous surfactant [36,62,63,68,69]. Figure 4 shows the positive effect of surfactant replacement therapy.
Recently, several authors have undertaken ongoing studies to hypothesize exogenous surfactant value in COVID-19 patients [10]. Prospective case-control research [35], one of the most recent investigations on the subject, split the patients into surfactant (n=33) and control (n=32) groups. A daily dose of 150-300 mg inhaled surfactant was given to the surfactant group. Many clinical outcomes and the oxygenation parameters were examined, and as a result, the surfactant group's oxygenation index (PaO2/FiO2) significantly increased. Additionally, compared with the control group, considerably fewer patients in the surfactant group were transferred to the intensive care unit and placed in mechanical ventilation. However, mortality did not differ significantly between the groups. Overall, the early findings supported the need for additional research on inhaled surfactant treatment for COVID-19, including randomized controlled clinical trials.
Piva et al. did a retrospective study on seven patients affected by COVID-19 in the case of ARDS compared with 14 individuals who were similar to them in disease characteristics and were given supportive treatment for ARDS simultaneously. Patients with surfactant installed in their small bronchi via bronchoscopy showed no signs of severe decompensation. This study reported a not statistically significant 28-day mortality reduction in the surfactant group. Nevertheless, a favorable safety profile and feasibility of administration without increased risk of infection to medical staff are observed. Future trials may be needed to confirm surfactant efficacy by this route on mortality and morbidity [70].
Infasurf ® was given to a COVID-19 patient who was critically unwell at a dosage of 20 mg/kg, according to a report by Heching et al. [8]. A tracheobronchial suction catheter that was inserted through the endotracheal tube was used to administer surfactant into the lungs directly. Following an improvement in oxygenation after 18 h, which continued to improve after 48 h, the patient was taken off from extracorporeal membrane oxygenation and extubated [8]. Busani et al. [9] described giving Curosurf ® to five seriously ill patients with pneumonia associated with COVID-19 and poor lung compliance. Soon after the start of invasive mechanical breathing, patients had intratracheal intubation and were administered surfactant for one month at a dose of 30 mg/kg [9]. According to the results, four patients' oxygen levels improved after an hour, and all patients' oxygen levels improved after 6 h. Also, despite the included patients' critical condition, a survival rate of 80% over 30 days was seen [9]. Many clinical trials are ongoing on only surfactant supplementation without budesonide or other steroids, e.g., NCT04362059 or NCT04375735 via different drug delivery System [71,72]. However, in vitro investigations show that budesonide improves budesonide diffusion over an air-liquid interface without affecting the surfactant's effectiveness [73,74]. Animal studies supported the findings of human studies by showing that budesonide had a longer half-life in the lung than budesonide alone, was more evenly distributed in the alveoli when combined with surfactant than when combined with saline, and reduced lung inflammation without impairing the physiological response to surfactant treatment [75,76]. Table 2 illustrates ongoing trials investigating surfactants' role in COVID-19 management.

Failure of surfactant therapy
Surfactant therapy fails to lower mortality in individuals with ARDS for two primary reasons: First, compared to the edematous, exogenous surfactant-stimulated lungs of preterm newborns, which are known to enhance lung compliance by causing exogenous surfactant to dissolve in water. Even when they are sick, adult lungs still have aerated parts. Because adult lungs typically lack a liquid lining, it is difficult for the surfactant to breakdown in water and ultimately reach the adult lung's targeted area due to its structural characteristics. In addition, compared to newborn lungs, adult lungs have a more extended airway branching system through which surfactants must travel to reach their intended destinations. Second, the exogenous surfactant loses its surface-active effect even when supplied to the desired disease location. When they travel to the alveoli, the contents of the airways exhibit a range of compositional, physical,  [79] chemical, and anomalies in varying degrees. Exogenous surfactants' surface-active characteristics may change due to their contents [80]. Only the newborn's need for oxygen therapy is currently used to determine whether surfactant treatment is necessary. Recent recommendations recommend beginning surfactant therapy as soon as possible for patients who need nCPAP of at least 6 cmH 2 O and a FiO 2 of at least 0.3. Some evidence suggest that lung ultrasound score, as opposed to FiO 2 , better assures prompt surfactant treatment in premature patients, [81,82] and also in early detection of ventilatory associated pneumonia since fluctuations in lung ultrasound scores are correlated with illness severity and progression in adult patients with COVID-19-associated ARDS [83].

Regulation of surfactant proteins by the proinflammatory cytokines
Activating the proteolytic and oxidative pathways may harm the surfactant complex, resulting in problems including acute respiratory distress syndrome. The collagen-containing C-type lectins or collections include the lectins SP-A and SP-D related to surfactant and the lining of the airways. They act as an opsonin for some bacteria and viruses by aggregating respiratory viruses and microbial binding components [28].

Surfactant-based prophylaxis against COVID-19
Coronavirus preferentially attacks type 2 pneumocytes which secrete surfactant resulting in dyspnea and ARDS following viral infection. Surfactant contains several proteins named SP-A, SP-B, SP-C, SP-D, and SP-B stabilizes the lipid coat during respiration. On the other hand, SP-C modulates the compression of lipid coating with decompression during expiration [6]. Scheme of alveolar collapse caused by surfactant impairment due to COVID-19. Pulmonary surfactant also works in host defense against viruses as it works as a barrier to extruding viral invasion by increasing mucociliary transport mechanisms. Also, surfactant components directly interact with respiratory viruses inhibiting their proliferation through stimulating opsonization, inactivation, and agglutination [84,85]. Surfactant phospholipids interact with specific receptors to decrease proinflammatory cytokines, and proteins like SP-A and SP-D act on the host immune response, enhancing viral clearance. Exogenous surfactant showed positive results in treating meconium aspiration syndrome, which has a very similar pathophysiology to COVID-19 as it enhanced oxygenation and its anti-inflammatory effects enhanced wound repairing of damaged alveoli to prevent COVID-19-associated ARDS [64] could be added to SRT. Additionally, SP-A and SP-D are important markers for alveolar collapse which is a very common SARS-CoV-2 infection [86] SARS-CoV-2 enters the body through the lungs via the binding of viral spike protein with ACE-2 receptor. SARS-CoV-2 enters the body primarily through the nose and mouth, with some entrance through the eyes. The virus that entered through these routes can be rendered inactive using a surfactant-based gargle or any other tool filled with surfactant ( Figure 5). Gargles and mouthwashes could benefit more if added antiviral drugs, proteases, astringents (protein precipitants). Using surfactants for lung and tracheal infections was not linked to cilia damage. The use of surfactants will stop the virus from attaching via its spike glycoproteins. A virus can be destroyed by interfering with the spike glycoprotein surfactant [15]. Surfactants are considered a physiological barrier to viral infections and function in innate host defense during infections [85]. According to studies, lung surfactant inhalation was linked to a reduction in respiratory illnesses. The antiviral activity is mainly caused by the lipid component [87,88]. Phospholipids found in surfactants play a part in preventing virally induced inflammation and infection [89]. Moreover, the protein component has antiviral properties. By preferential SARS coronavirus spike glycoprotein identification and subsequent activation of macrophages [90,91]. Lately, the use of bear bile to combat COVID-19 has been suggested. Bile salts, which can act as surfactants, are present in bile [92,93].

The recent promising treatment of COVID-19
Since the first coronavirus epidemic was discovered, no particular and potent antiviral medication or vaccine has been granted approval for the treatment of coronavirus infections. Currently, COVID-19 is mostly treated symptomatically, with supportive care as required. However, a range of therapeutic options are being investigated such as remdesivir and lopinavir, convalescent plasma therapy, phytochemicals, lianhuaqingwen, chloroquine and hydroxychloroquine, and herbal medications [94][95][96]. Recent studies showed that niclosamide provides distinct advantages over other drugs currently being investigated in the COVID-19 space because it can act as an immunomodulator as well as an anti-bacteriostatic agent [97]. In vitro studies on interferon-α, an antiviral medication routinely used to treat hepatitis, demonstrated that it inhibits SARS-CoV-2 replication. Arbidol, an antiviral medication, has also been reported to have anti-SARS-CoV-2 action [98]. In addition to antiviral drugs, several treatments are being explored [99]. Monoclonal antibodies are being developed as a potential treatment option that can neutralize the virus and prevent it from infecting healthy cells. Immunomodulatory drugs, such as corticosteroids, are also being used to manage severe cases by reducing inflammation and preventing an overactive immune response. Furthermore, vaccines have emerged as a crucial tool in combating COVID-19 [98]. Multiple vaccines have been developed and authorized for emergency use around the world. These vaccines work by stimulating an immune response against SARS-CoV-2, providing protection against infection or reducing its severity if contracted [100].

Nanoparticle-mediated surfactant therapy in patients with severe COVID-19
Nanotechnology can be used to lessen the negative effects of surfactants and enhance their therapeutic impact. Nanotechnology is used, for example, to enhance the target specificity of surfactant capsules by improving the bioactivities of the encapsulated compounds, reducing side effects, and increasing their solubility and stability. The ability to target surfactants to certain lung areas and extend resistance time in the body are two of the key benefits of employing nanoparticles to distribute surfactants. A wide range of nanomaterials is based on polymer nanoparticles, lipid nanoparticles, inorganic nanoparticles, drug conjugates, and viral nanoparticles [101]. These nanoparticles can have surfactants physically enclosed inside them or covalently coupled to them. An important recent example is that lipid nanoparticles are utilized as mRNA vehicles in BioNTech/Pfizer's BNT162b2 and Moderna's mRNA-1273 vaccines.
The surfactant-loaded nanoparticles may be injected intravenously. For instance, surfactants can be loaded into poly lactic-glycolic acid nanoparticles or liposomes coated with polyethylene glycol (PEG). The PEG-coated nanoparticles can have longer blood circulation after intravenous injection to delay the rapid clearance of the administered surfactant by macrophages. As a result, surfactants' negative effects can be reduced while their effectiveness can be increased thanks to nanoparticles [80]. Hydrophilic nanoparticles will more readily bind to SP-A and SP-D, resulting in particle opsonization and improved uptake by AMs and lung dendritic cells [102,103]. Moreover, it is possible to inhale the surfactant-loaded nanoparticles. Though local pulmonary delivery of nanomedicines has many benefits, it can also be hampered by the lung's numerous extracellular and intracellular barriers, which can prevent siRNA delivery. The destiny of inhaled nanoparticles is generally difficult to predict because it depends on a number of factors. Along with particle-related characteristics like mean mass aerodynamic diameter (MMAD), hydrophobicity, and charge, there are patient-related characteristics like breathing habits and lung anatomy, physiology, and pathology to consider. The highly branching structure of the lungs, where the fate of aerosolized particles after inhalation therapy would significantly rely on their MMAD, is an essential anatomical barrier to pulmonary siRNA delivery [24,104,105]. Surfactants are often delivered to the airways or lung periphery rather than the particular sites of lung injury, which presents a challenge when they are inhaled. According to Dames and colleagues, the surfactant can be loaded in magnetic aerosol droplets to address this issue. Superparamagnetic iron oxide nanoparticles are present in aerosol droplets. A magnetic field can collect aerosol droplets in a particular lung region after inhalation [106]. Additionally, it is anticipated that the side effects of surfactants would be lessened since it interferes less with other organs and tissues. They can therefore be administered both for therapy and as a preventative measure. Bromhexine, on the other hand, blocks transmembrane protease, serine 2 (TMPRSS2). It is thought that inhibiting effective viral entry against SARS-CoV-2 requires TMPRSS2. The first human body-based preliminary exploratory randomized-controlled clinical trial on bromhexine hydrochloride tablets (BHT) to treat COVID-19 was carried out by Wepon Pharmaceutical Group Co. Ltd. based on this supposition. The study's findings illustrated the advantages of employing BHT from various angles. BHT therapy had few negative side effects while somewhat reducing lung damage. So, clinical testing has shown that bromhexine is effective against COVID-19 [107]. Wu et al. concluded in their study that nanoparticle-medicated surfactant treatment will increase lung compliance and oxygenation by distributing surfactant to targeted lung areas, eventually reducing mortality. Since they can accommodate RNA molecules to increase their stability and improve their intracellular release efficacy, nanoparticles have considerably accelerated the development of RNA therapies over the past few decades [108]. A recent example is the use of lipid nanoparticles as mRNA vehicles in the vaccines BNT162b2 by BioNTech/Pfizer and mRNA-1273 by Moderna [109]. Future clinical trials that assess the effectiveness of nanoparticle-mediated surfactant therapy for patients with COVID-19 ARDS are supported by the success of nanoparticles in the treatment of disease and the development of the COVID-19 vaccine, as well as the positive outcomes of clinical studies of surfactant therapy on COVID-19 patients [80]. Small interfering RNA (siRNA) can be used to address acute respiratory viral infections as it targets both viral and host-related proteins responsible for the infection's severity and contagion. These siRNA molecules are encapsulated into nanoparticles and need cytosolic delivery to act on their target proteins; however, many intra and extracellular barriers prevent their efficient cytosolic delivery. Depending on the administration technique and lung disease circumstances, exogenous surfactants maintain varying surface-active functions. In order to replace the endogenous surfactant and perform as expected, exogenous surfactants must be administered and delivered to the targeted lung regions with intact or well-preserved surface-active characteristics [80]. This is where the pulmonary surfactant's role comes in place. Raemdonck and his co-workers stated that exogenous pulmonary surfactant could be used to promote cytosolic siRNA delivery by polymeric nanomedicines [110,111]. The surfactant may be inactivated with a high presence of plasma proteins in airspaces when the blood-gas barrier function is disrupted [106]. There is a need for more effective administration of intact exogenous surfactants with high surface-active characteristics. By delivering surfactant complexes to the areas of the lung that require surfactant the most, nanoparticles have the potential to address these problems, hence reducing ventilator-induced lung injury and mortality.

Conclusion
For almost four decades, surfactants have been known to treat neonatal respiratory distress syndrome and hyaline membrane disease. Several studies have been conducted to evaluate the use of surfactants in acute respiratory distress syndrome and respiratory distress associated with COVID-19. These studies have demonstrated a positive impact on oxygenation, hospital and intensive care unit stay duration, and the need for mechanical ventilation. However, the limited number of studies, small sample size, unavailability of ongoing trial results, and terminated trials weaken the evidence supporting the standard use of surfactants in adults with COVID-19-associated respiratory distress. Additionally, surfactants have been found to help the innate immune system fight the COVID-19 virus. Surfactants also have the potential to act as liposomal carriers or helpers for certain molecules, drugs, or antivirals to target affected tissue, which presents an excellent area for future research.