key: cord-0718741-3ppc5vep
authors: Heching, Moshe; Lev, Shaul; Shitenberg, Dorit; Dicker, Dror; Kramer, Mordechai R.
title: Surfactant for Treatment of ARDS in COVID-19 Patient
date: 2021-01-22
journal: Chest
DOI: 10.1016/j.chest.2021.01.028
sha: 63a5673fc1cf8ab274fc38f4ac47457a2d9ca2a0
doc_id: 718741
cord_uid: 3ppc5vep

Patients with coronavirus disease 2019 (COVID-19) suffer from severe respiratory symptoms consistent with acute respiratory distress syndrome (ARDS). The clinical presentation of ARDS in COVID-19 is often atypical, as COVID-19 patients exhibit a disproportionate hypoxemia as compared to a relatively preserved lung mechanics. This pattern is more similar to neonatal respiratory distress syndrome (RDS) secondary to surfactant deficiency, which has been shown to benefit from exogenous surfactant. We present our experience with exogenous surfactant treatment in a COVID-19 patient suffering from COVID-19 related ARDS. The patient responded with improved oxygenation, and we believe surfactant was the catalyst for the successful extubation and clinical improvement of the patient.

Patients hospitalized with coronavirus disease 2019 (COVID-19) suffer from severe respiratory symptoms consistent with acute respiratory distress syndrome (ARDS). To date, despite various trials and medication regimens, no treatment has emerged as significantly efficacious in the treatment of patients with severe respiratory failure secondary to COVID-19, though some treatments have shown early promise. 1, 2 It is has been observed that COVID-19 patients suffering from severe respiratory distress can present with an atypical form of ARDS, exhibiting significant discrepancy between their severe hypoxemia and their relatively preserved lung mechanics. 3 This pattern is more similar to neonatal respiratory distress syndrome (RDS) secondary to surfactant deficiency, which has been shown to benefit from exogenous surfactant. 4 We present our experience with exogenous surfactant treatment in a COVID-19 patient suffering from respiratory failure.

A 48 year old male non-smoker, with prior medical history of hyperlipidemia and prediabetes, was admitted to the hospital after four days of fever, dry cough and exertional dyspnea. On presentation, he had speech dyspnea, was febrile (39.5 Celsius) and tachycardic (109 bpm). Oxygen saturation (SaO2) at room air was 94%, with normal venous blood gas, mild hyponatremia (126) and lymphopenia (0.8). Chest x-ray showed mild bibasilar opacities ( Figure 1A ). COVID-19 test was positive. Patient was initially treated with azithromycin, hydroxychlroquine and ceftriaxone, with azithromycin replaced by lopinavir/ritonavir as patient did not improve. Repeat chest x-ray demonstrated worsening bilateral opacities ( Figure 1B ) and due to worsening respiratory status, patient was admitted to the ICU, with a single dose of tocilizumab replacing lopinovir/ritonavir. Patient continued to desaturate despite non-invasive respiratory support and was intubated on day 3 of hospitalization, placed on ARDS protocol, including extended proning. Despite full respiratory support, patient's ratio of arterial oxygen partial pressure (PaO2 in mmHg) to fractional inspired oxygen (FiO2) continued to decline and on day 6 of hospitalization he was placed on extracorporeal membrane oxygenation (ECMO). Patient remained stable but did not improve on ECMO for 5 days. On day 11 of hospitalization, patient was administered five ampules of 6 ml surfactant (Calfactant, 35 mg/ml phospholipid suspension), determined based on 20 mg phospholipids/kg of lean body weight, similar to dosing in a prior adult surfactant treatment trial which demonstrated clinical improvment. 5 The surfactant was administered via tracheobronchial suction catheter passed through the endotracheal tube with the distal suction tip positioned above the carina, and then dispersed directly into the lungs. The patient was sequentially turned right side down and then left side down immediately subsequent to administration. Prior to administration, SaO2 was 89% on FiO2 100%, PaO2/FiO2 was 148 and compliance was measured at 31 mL/cmH2O. Subsequently, PaO2/FiO2 improved to 185 after 18 hours and 231 after 36 hours (Graph 1), at which point patient was weaned from ECMO. Patient was extubated the following day, and was discharged eight days later.

While COVID-19 patients with severe respiratory symptoms can suffer from ARDS consistent with the Berlin criteria, 6 the clinical presentation of acute respiratory distress in COVID-19 is often atypical. 7 COVID-19 patients exhibit a disproportionate hypoxemia as compared to a relatively preserved compliance and lung mechanics, a pattern more similar to RDS observed in premature infants who lack sufficient capacity to produce endogenous surfactant. 3 SARS-CoV-2 has affinity for the angiotensin converting enzyme receptor 2 (ACEr2) and predominantly damages cells expressing ACEr2 including type II alveolar cells, the source of lung surfactant. 8 Damage to the type II alveolar cells markedly decreases the J o u r n a l P r e -p r o o f production of surfactant, which is necessary for effective gas exchange, leading to increased surface tension, alveolar flooding and atelectasis. 9 As such, a common pathophysiological feature of COVID-19 patients with acute respiratory distress is dysfunction of the endogenous surfactant system, similar to the pathophysiology of RDS. Administration of exogenous pulmonary surfactant is an effective treatment of premature infants with RDS due to insufficient surfactant production. 4 Although exogenous surfactant therapy has proven to be an effective treatment for RDS, no similar current effective therapy exists for patients with ARDS. Prior trials of surfactant administration to adults suffering from ARDS have generally disappointed, 10 with the majority showing no benefit, 11 though a minority have demonstrated improvement in oxygenation and time to extubation. 12 However, as noted, the pathophysiology of alveolar epithelial cell damage due to COVID-19 does not follow a classical pattern of ARDS; lung mechanics and compliance can be preserved, despite severe hypoxemia. 13 Further, other notable distinctions between classical ARDS and respiratory failure due to COVID-19 include the discrepancy between symptoms and radiological presentation, delayed timing of respiratory failure from disease onset in COVID-19, and the direct involvement of ACERr2 in the infiltration of COVID-19.

The preferential targeting of COVID-19 for ACEr2, and consequently type II alveolar cells, implies a pivotal role of surfactant deficiency in the hypoxemic lung injury caused by COVID-19. Beyond the critical role surfactant plays in maintaining surface tension and preserving gas exchange, surfactant also exhibits anti-inflammatory properties, reducing the expression of various cytokines, 14 resulting in decreased lung inflammation and damage. 15 Accordingly, due to the similarities between neonatal RDS and COVID-19 induced respiratory distress, surfactant administration has been proposed as a potential treatment for COVID-19. 3, 16, 17 More specifically, COVID-19 damages the type II alveolar cells, inhibiting production of surfactant. The reduction in natural surfactant in the lung leads to alveolar collapse and atelectasis, which as the process progresses, reduces the dynamic compliance of the lung, as observed in our patient who was administered surfactant at a relatively late stage of his infection. This is further exacerbated by an observed failure of the hypoxic pulmonary vasoconstriction mechanism in COVID-19, which combined with alveolar collapse secondary to surfactant loss and lung edema, results in a substantial portion of the cardiac output perfusing non-aerated lung tissue, increasing intrapulmonary shunting. 18 Restoration of surfactant would lower surface tension, reduce atelectasis and intrapulmonary shunting, and improve gas exchange, as well as counter-balance the pro-inflammatory effects of Our experience with surfactant administration to a COVID-19 patient, while limited, is informative. The patient responded to surfactant with improved oxygenation, leading we believe to his clinical improvement, and providing the catalyst that lead to weaning from ECMO and extubation. While it has been posited that surfactant administration would be more efficacious in ARDS if administered earlier in the course of the disease, prior to patients already having suffered substantial lung damage, similar benefits can be observed even during the refractory weaning phase of COVID-19 disease. 3, 16 Further studies can assist to determine the optimal timing and means of administering surfactant. For example, deposition of surfactant into the distal periphery of the lung under atelectic conditions may be improved through aerosolizing the surfactant, potentially decreasing the particle size, allowing for more distal distribution to the periphery of the lung. Additionally, sampling of surfactant levels in patients may provide further insight into the pathophysiology of COVID-19 ARDS and potentially identify patients who can benefit from surfactant administration. 20 Future clinical J o u r n a l P r e -p r o o f trials, some of which are underway (ClinicalTrials.gov Identifiers: NCT04389671, NCT04384731, NCT04362059, NCT04375735, NCT04502433), will further elucidate the potential benefits of surfactant administration in COVID-19.

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Figure 1-Chest x-ray of patient on admission (A) and after respiratory decline (B and C)