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Lung recovery with prolonged ECMO following fibrotic COVID-19 acute respiratory distress syndrome

  • Abdul W Kazi
    Affiliations
    Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, United States
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  • Ross Summer
    Affiliations
    Division of Pulmonary and Critical Care Medicine, Jane and Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
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  • Baskaran Sundaram
    Affiliations
    Department of Radiology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
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  • Gautam George
    Correspondence
    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.
    Affiliations
    Division of Pulmonary and Critical Care Medicine, Jane and Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, United States
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Published:December 16, 2022DOI:https://doi.org/10.1016/j.amjms.2022.12.008

      Abstract

      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.

      Keywords

      Introduction

      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.
      • Wu C
      • Chen X
      • Cai Y
      • et al.
      Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China.
      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.
      • Guler SA
      • Ebner L
      • Aubry-Beigelman C
      • et al.
      Pulmonary function and radiological features 4 months after COVID-19: first results from the national prospective observational Swiss COVID-19 lung study.
      ,
      • So M
      • Kabata H
      • Fukunaga K
      • Takagi H
      • Kuno T.
      Radiological and functional lung sequelae of COVID-19: a systematic review and meta-analysis.
      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.

      Case presentation

      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.
      Fig 1
      Fig. 11a (axial) and 1b (coronal) obtained on day 1. Extensive bilateral consolidation (arrow) and air bronchograms as well as bilateral pneumothoraces and pneumomediastinum.
      Fig 2
      Fig. 22a (axial) and 2b (coronal) obtained on day 37. There is decrease in consolidation but gradual increase in fibrotic change as evidenced by traction bronchiectasis and cystic change (arrow).
      Table 1Extracorporeal membrane oxygenation (ECMO) and mechanical ventilation settings.
      ECMO DayECMO FiO2 (%)ECMO Sweep (L/min)ECMO Flow (L/min)Ventilator FiO2 (%)Tidal Volume Set (cc)Tidal volume cc/kg/IBWPlateau Pressure (cm H20)Driving Pressure (cm H20)PC Setting
      18034.9503005.272412N/A
      1010084.21001021.79301515
      2010075.080751.32261415
      3010073.9702223.9291415
      409063.7502364.15261410
      50100113.4501923.38271212
      605063.4501602.81271212
      705073.7403706.52412N/A
      804053.8403305.82818N/A
      89210.53.4504207.383224N/A
      Fig 3
      Fig. 33a (axial) 3b (coronal) obtained on day 115. Decrease in consolidation with an increase in fibrotic change as evidenced by traction bronchiectasis, cystic changes and honeycomb appearance (arrow).
      Fig 4
      Fig. 44a (axial) and 4b (coronal) obtained approximately 1 year and 5 months from initial presentation (day 550). Decrease in fibrotic change as evidenced by decrease in cystic changes and honeycomb appearance (arrow points toward areas of lung that previously showed honeycomb change).

      Discussion

      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.
      • Farghaly S
      • Badedi M
      • Ibrahim R
      • et al.
      Clinical characteristics and outcomes of post-COVID-19 pulmonary fibrosis: a case-control study.
      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.
      • Antonio GE
      • Wong KT
      • Hui DSC
      • et al.
      Thin-section CT in patients with severe acute respiratory syndrome following hospital discharge: preliminary experience.
      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.
      • Han X
      • Fan Y
      • Alwalid O
      • et al.
      Six-month follow-up chest CT findings after severe COVID-19 pneumonia.
      ,
      • Huang C
      • Huang L
      • Wang Y
      • et al.
      6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.
      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.
      • Wu X
      • Liu X
      • Zhou Y
      • et al.
      3-month, 6-month, 9-month, and 12-month respiratory outcomes in patients following COVID-19-related hospitalisation: a prospective study.
      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.
      • McGroder CF
      • Zhang D
      • Choudhury MA
      • et al.
      Pulmonary fibrosis 4 months after COVID-19 is associated with severity of illness and blood leucocyte telomere length.
      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.
      • Myall KJ
      • Mukherjee B
      • Castanheira AM
      • et al.
      Persistent post–COVID-19 interstitial lung disease. An observational study of corticosteroid treatment.
      There is very limited investigation into the role of anti-fibrotic agents for post-COVID fibrosis.
      • Marwah V
      • Choudhary R
      • Malik V
      • Pemmaraju A
      • Peter D.
      Early experience of nintedanib in COVID-19 ARDS-related pulmonary fibrosis: a case series.
      There are multiple clinical trials currently underway to evaluate anti-fibrotic agents in this disease, although existing evidence suggests many patients recover independent of such treatments.
      • Mylvaganam RJ
      • Bailey JI
      • Sznajder JI
      • Sala MA.
      Recovering from a pandemic: pulmonary fibrosis after SARS-CoV-2 infection.
      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.
      • Herridge MS
      • Tansey CM
      • Matté A
      • et al.
      Functional disability 5 years after acute respiratory distress syndrome.
      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.
      • Peek GJ
      • Mugford M
      • Tiruvoipati R
      • et al.
      Efficacy and economic assessment of conventional ventilatory support versus extracorporeal membrane oxygenation for severe adult respiratory failure (CESAR): a multicentre randomised controlled trial.
      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.
      • Lepper PM
      • Barrett NA
      • Swol J
      • et al.
      Perception of prolonged extracorporeal membrane oxygenation in Europe: an EuroELSO survey.
      And the Extracorporeal Life Support Organization (ELSO) has most recently defined p-ECMO as continuous support for more than 28 days.
      • Conrad SA
      • Broman LM
      • Taccone FS
      • et al.
      The extracorporeal life support organization maastricht treaty for nomenclature in extracorporeal life support. A position paper of the extracorporeal life support organization.
      Long ECMO runs have been reported in non-COVID ARDS and pediatric patients, with durations as long as 265 days, but there are very few reports on runs with the outcome of native lung recovery.
      • Wiktor AJ
      • Haft JW
      • Bartlett RH
      • Park PK
      • Raghavendran K
      • Napolitano LM.
      Prolonged VV ECMO (265 days) for ARDS without technical complications.
      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.

      Conclusions

      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.

      Authors' contributions

      All authors reviewed the case and contributed to the final manuscript.

      Ethics approval and consent to participate

      Consent was obtained from patient to publish case report.

      Source of funding

      None.

      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.

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