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Corresponding author. Gautam George, MD, Division of Pulmonary and Critical Care Medicine, Jane and Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, 211 S 9th St, Philadelphia, PA 19107, United States.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been associated with acute respiratory distress syndrome (ARDS) and in some cases with pulmonary fibrosis. There is limited information regarding the long-term outcomes of patients who develop severe COVID-19 infection and subsequent pulmonary fibrosis. We present a patient with severe ARDS due to COVID-19 who required prolonged extra-corporeal oxygenation support and eventually recovered significant lung function. This case is unique because the patient survived one of the longest reported runs on extra-corporeal membrane oxygenation without requiring lung transplantation. Further, our patient developed severe parenchymal and airway distortion but ultimately resolved pulmonary fibrosis many months into the hospitalization. In addition to our detailed case discussion, we will provide a focused review on pulmonary fibrosis post COVID-19.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appeared in late 2019 in Wuhan, China, and was declared a global pandemic by the World Health Organization in March 2020. Approximately 5% of patients with COVID-19 develop critical illness such as acute respiratory distress syndrome (ARDS) and the mortality rate of patients with ARDS is 45%, increasing to 59% in those that receive invasive mechanical ventilation.
Treatment options include anti-virals, corticosteroids, and immunomodulation; but the mainstay of ARDS management continues to be supportive care with lung-protective ventilation. When mechanical ventilation is not sufficient, extra-corporeal membrane oxygenation (ECMO) is utilized in select cases to provide respiratory support.
A minority of patients on ECMO develop refractory respiratory failure and pulmonary fibrosis and may be considered for lung transplantation. SARS-CoV-2 along with other viral infections leading to ARDS have been associated with persistent radiographic and physiologic abnormalities that are suggestive of the development of pulmonary fibrosis.
Patients with interstitial lung diseases and pulmonary fibrosis are generally not considered to be candidates for ECMO unless as a bridge to lung transplantation. In the setting of severe ARDS where radiographic and physiologic features of pulmonary fibrosis are apparent, it is generally thought that recovery is only possible with lung transplantation. However, there is uncertainty regarding the clinical course of these patients, and this makes it challenging to determine when advanced therapies such as ECMO and lung transplantation should be considered and will be beneficial.
We present a 35-year-old man with severe ARDS from COVID-19 requiring prolonged ECMO therapy who developed radiographic features of pulmonary fibrosis, but eventually was successfully liberated from ventilator support and discharged from the hospital. This case describes the progression of COVID-19 lung destruction from initial development to the point of significant lung recovery at one-year follow up. We describe available literature on the potential benefits of prolonged ECMO in this setting and COVID-19 associated pulmonary fibrosis.
A 35-year-old man with a history of type 1 diabetes mellitus presented to an affiliate community hospital with a four-day history of subjective fevers, malaise, dry cough, and shortness of breath. On presentation he was afebrile, normotensive, tachycardic, tachypneic and profoundly hypoxemic with an initial oxygen saturation of 51% on room air. Initial chest x-ray showed widespread parenchymal opacification of bilateral lung fields with air bronchograms and low lung volumes. Computed tomography with angiography (CTA) was performed which ruled out pulmonary embolism but revealed diffuse bilateral lung consolidation (Figure 1). COVID-19 was diagnosed after a nasopharyngeal swab revealed the SARS-COV-2 virus. Endotracheal intubation was immediately performed, and patient was initiated on mechanical ventilation with lung protective parameters. Inhaled epoprostenol was added for refractory hypoxia and norepinephrine was started for vasopressor support. Due to the severity of respiratory failure with worsening hypoxemia and evidence of pneumo-mediastinum, he was transferred to our institution for ECMO evaluation. The patient was initiated on veno-venous (VV)-ECMO on day 2 of hospitalization with a 22 Fr right femoral venous drainage cannula and 18 Fr right internal jugular venous return cannula. He was anticoagulated with ultra-fractionated heparin. He received one dose of tocilizumab as an off-label intervention on day 4 of hospitalization and a ten-day course of dexamethasone. He developed additional pulmonary complications during his hospitalization including bacterial pneumonia and pneumothorax requiring tube thoracostomy. Follow-up CT chest on day 35 (Figure 2) showed markedly diminished consolidation now changing to ground glass opacities with dilated small airways. Due to persistent high ECMO requirements (Table 1), a referral for lung transplantation was made however this could not to be pursued due to socio-economic barriers. Supportive care and lung protective ventilation were continued with eventual improvement in hemodynamic and respiratory support. On hospital day 90, after 89 days of continuous VV-ECMO, he was decannulated and ECMO support was discontinued. Follow up CT chest on day 112 (Figure 3) showed development of right upper lobe honeycomb lung but resolution of consolidation. He required ventilatory support until hospitalization day 137 after which he tolerated oxygen supplementation by tracheal mask. After 160 days of hospitalization, the patient was discharged to a subacute rehabilitation facility with oxygen therapy via nasal cannula. Approximately one year after discharge, the patient underwent re-imaging of his chest when he had presented to the emergency room for an unrelated problem. Repeat chest imaging (Figure 4) showed improvement in cystic changes, bronchiectasis, and linear subpleural fibrosis. He continues to do well and is independent of his activities of daily living and requires supplementation by low flow oxygen by nasal cannula.
Table 1Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation settings.
In this case report we highlight the successful use of prolonged VV-ECMO (p-ECMO) to support acute respiratory failure in a patient who developed radiographic features of COVID-19 associated pulmonary fibrosis. Our case describes one the longest runs of VV-ECMO for COVID-19 related ARDS. Additionally, we have follow-up one year after initial presentation, which showed significant clinical improvement and the evolution of radiographic changes in COVID-19 related pulmonary fibrosis.
SARS-CoV-2 is one of multiple coronaviruses which have been associated with development of pulmonary fibrosis.
Three-month follow-up of patients with severe SARS-CoV-1 infection has shown that imaging consistent with pulmonary fibrosis is common (62%) though there is limited data on functional status regarding these patients.
Specifically looking at SARS-CoV-2 infection, medium-term (6 month) follow up imaging findings after severe COVID-19 show traction bronchiectasis, parenchymal banding, and honeycombing in approximately one-third of patients.
In one study, one year-follow up of patients that survived severe COVID-19 still showed significant DLCO reduction that was not improved when compared to values at three-month follow up, suggesting persistent physiologic abnormalities after initial infection.
Patients who undergo mechanical ventilation, had more severe initial illness, had higher lactate dehydrogenase levels on admission, and those with shorter leukocyte telomere length were more likely to developed signs of pulmonary fibrosis at 4 month follow up.
In patients with features suggestive of organizing pneumonia after initial hospitalization, steroid therapy has demonstrated a modest improvement in pulmonary function tests (FVC improvement of 9.6%) and radiological improvement.
In sum, pulmonary fibrosis has been shown to occur after COVID-19 and current literature has established persistent radiographic and physiologic abnormalities in survivors after COVID-19. In some cases, there is improvement in these abnormalities over time. We do not have a precise way to quantify the probability of developing pulmonary fibrosis after severe COVID-19, but disease severity and patient characteristics maybe associated with an increase in incidence.
In select patients with severe COVID-19 and persistent ARDS, concerning imaging such as traction bronchiectasis and cystic change are thought to represent irreversible lung injury. These patients are thought to be poor candidates for native lung recovery and lung transplantation is considered. In the pre-COVID-19 era, patients with pulmonary fibrosis after recovery from ARDS have shown near normal pulmonary function at long term follow up.
These patients may have significant functional limitation, but this is thought to be largely because of critical illness associated weakness rather than intrinsic pulmonary injury. It is unclear if ARDS associated with COVID-19 is similar, but as this case demonstrates, lung recovery even in the setting of severe ARDS and pulmonary fibrosis is possible.
Seminal studies have established ECMO as an important option for patients with severe but reversible respiratory failure.
Due to the lack of reversibility seen in most cases of interstitial lung disease exacerbations, many centers do not use ECMO in this setting unless it is a bridge to lung transplantation. In severe, highly destructive forms of ARDS the likelihood for long-term respiratory disability is a greater concern and consideration for lung transplantation is undertaken. ECMO therapy can be used as a bridging therapy in this scenario, although consensus has not been reached on indications or optimum duration of this therapy Of 94 ECMO centers surveyed, 37% defined prolonged ECMO (p-ECMO) as 14-21 days, 30% as 21-28 days, and 28% as greater than 28 days.
Once the threshold of p-ECMO is reached, it is hypothesized that native lung failure may not be reversible due to fibro-proliferative changes and further ECMO support may not lead to the eventual goal of liberation from respiratory support without lung transplantation. Our patient recovered a significant degree of lung function after 89 days on ECMO and was able to be liberated from respiratory support without lung transplantation. We hypothesize that patient and treatment specific factors played an important role in our patient's favorable outcome. This includes his young age, which likely associated with longer telomeres and conferred greater lung regenerative capacity and, early initiation of ECMO and lung protective ventilator strategies. Regardless of mechanisms, our case illustrates that severe parenchymal disease and radiographic evidence of pulmonary fibrosis post-COVID does not signify irreversible lung destruction, and continuing ECMO support may help in bridging patients on a path to lung recovery. Additionally, our patient's functional recovery after prolonged ECMO argues against early and indiscriminate referral of severe COVID pneumonias to lung transplantation programs, which is a comforting finding given the scale and impact of this pandemic on society.
In conclusion, this case demonstrates recovery from persistent ARDS in a case of severe COVID-19 with radiographic features of pulmonary fibrosis. It is also one of the longest reported runs on VV-ECMO for this condition and we propose that p-ECMO be considered as an alternative to lung transplantation in select patients.
All authors reviewed the case and contributed to the final manuscript.
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Consent was obtained from patient to publish case report.
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Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.