key: cord-0712770-0yqh7t3e
authors: King, Christopher S.; Mannem, Hannah; Kukreja, Jasleen; Aryal, Shambhu; Tang, Daniel; Singer, Jonathan P.; Bharat, Ankit; Behr, Juergen; Nathan, Steven D.
title: How I Do It: Considering lung transplantation for patients with COVID-19
date: 2021-08-19
journal: Chest
DOI: 10.1016/j.chest.2021.08.041
sha: 25200e98cd107efc7d2cbf8af0602ec8c0025dca
doc_id: 712770
cord_uid: 0yqh7t3e

The COVID-19 pandemic has caused acute lung injury in millions of individuals worldwide. Some patients develop COVID-related acute respiratory distress syndrome (CARDS) and cannot be liberated from mechanical ventilation. Others may develop post-COVID fibrosis resulting in substantial disability and need for long-term supplemental oxygen. In both of these situations, treatment teams often inquire about the possibility of lung transplantation. In fact, lung transplantation has been successfully employed for both CARDS and post-COVID fibrosis in a limited number of patients worldwide. Lung transplantation following COVID infection presents a number of unique challenges that transplant programs must consider. In those with severe CARDS, the inability to conduct proper psychosocial evaluation and pre-transplant education, marked deconditioning from critical illness, and infectious concerns regarding viral re-activation are major hurdles. In those with post-COVID fibrosis, our limited knowledge about the natural history of recovery following COVID-19 infection is problematic. Increased knowledge of the likelihood and degree of recovery following COVID-19 acute lung injury is essential for appropriate decision making with regard to transplant. Transplant physicians must weigh the risks and benefits of lung transplant differently in a post-COVID fibrosis patient who is likely to remain stable or gradually improve in comparison to a patient with a known progressive fibrosing interstitial lung disease (fILD). It is clear that lung transplantation can be a life-saving therapeutic option for some patients with severe lung injury from COVID-19 infection. In this review, we discuss how lung transplant providers from a number of experienced centers approach lung transplantation for CARDS or post-COVID fibrosis.

COVID-19 has infected over 150 million people worldwide since the start of the pandemic. (1) Critical disease, characterized by respiratory failure, shock, and multi-organ system failure occurs in approximately 5% of infections, which equates to about 7.5 million individuals struck down by critical disease thus far. (2) Death rates amongst patients with critical COVID-19 infections are high, at more than 30% in most series. (3) A proportion of survivors from COVID-19 acute lung injury are left with residual lung disease resulting in the need for supplemental oxygen and impaired mobility. (4) The massive influx of critically ill patients has had profound impacts on healthcare systems throughout the world. The field of lung transplantation (LTx) has not been spared from this and has been affected in a myriad of ways as well. Many of the victims of critical COVID-19 lung injury are relatively young and previously healthy individuals with single organ dysfunction, so LTx is often considered as a salvage therapeutic option. Transplant centers have seen a large uptick in the number of requests for evaluation for LTx; often involving emotionally and intellectually challenging situations where patients do not meet traditional criteria for acceptable LTx recipients but have no other path forward to recovery. In this review, we will present two very different cases of patients affected by COVID who are referred for LTx evaluation. We will then discuss some common scenarios that can lead to referral for LTx evaluation and discuss issues that must be considered when performing transplant on patients with COVID-19.

A 62 year-old male presented to clinic for a LTx evaluation in October 2020 approximately 5 months after initially developing COVID-19. The patient was previously healthy, specifically with no known lung disease, until he was infected with SARS CoV-2 and required hospitalization. He was treated with remdesivir, steroids and toculizumab, but developed COVID-19 acute respiratory distress syndrome (CARDS). While intubation was avoided, he remained reliant on high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) with marked desaturations that limited his mobility. Given dysphagia and marked desaturation, the patient had a tracheostomy and percutaneous gastrostomy tube placed and was discharged to a long-term acute care facility following a 3 month hospitalization. The patient had been decannulated prior to returning to clinic but remained quite debilitated, having difficulty with activities of daily living and requiring four Liters (L) supplemental oxygen at rest and six L with J o u r n a l P r e -p r o o f ambulation. CT of the lungs ( Figure 1B ) obtained at the time of the clinic visit revealed diffuse ground glass opacities, upper lung peripheral consolidation and traction bronchiectasis which had progressed from a CT obtained at the time of admission ( Figure 1A ). Pulmonary function testing revealed a moderately severe restrictive defect (FVC 1.82 L (45%), FEV1 1.55L (50%). He was unable to tolerate diffusion capacity of the lung for carbon monoxide (DLCO) maneuver. The patient was referred to pulmonary rehabilitation and scheduled for follow-up in clinic in several months to assess for clinical improvement.

A 37 year-old female with no significant past medical history developed COVID-19 pneumonia with progressive respiratory failure. She was treated with remdesivir, dexamethasone, diuretics, and empiric antibiotics with no significant improvement. She was intubated and subsequently placed on venous-venous (VV) ECMO approximately twenty days after her initial symptoms. Her hospital course was complicated by ventilator associated Stenotrophomonas and methicillin-resistant Staph aureus (MRSA) pneumonia, for which she received appropriate antibiotics. Over time she was weaned off sedation to a point where she could be awake, interactive, and participate in physical therapy. However, her lung mechanics showed no significant improvement, and after eight weeks she remained on full support from both the ventilator and ECMO circuit. Her chest CT ( Figure 2 ) revealed upper lobe predominant pulmonary fibrosis and traction bronchiectasis along with areas of ground glass opacities throughout.

Despite the COVID pandemic generating a tremendous number of potential candidates for LTx, as well as significant interest and enthusiasm for use of LTx as a salvage option for residual COVID-19 lung disease, the actual number of transplants performed worldwide is fairly small. Although the exact number of transplants is not known, the available data give us some sense of the scope of LTx for COVID-19. A query of the United Network for Organ Sharing (UNOS) showed that as of April 30, 2021 only 78 LTx's carrying a recipient diagnosis of COVID-19 had been performed in the United States, 50 for CARDS and 28 for COVID fibrosis. (4) This number is likely lower than the true number of transplants, as UNOS implemented COVID diagnoses on October 28, 2020, and therefore LTx J o u r n a l P r e -p r o o f performed prior to that date would not be captured unless centers retroactively re-coded prior transplants. (5)

The European experience seems similar. As of April 23, 2021, the Eurotransplant consortium (responsible for organ allocation in Austria, Belgium, Croatia, Germany, Hungary, Luxemburg, the Netherlands, and Slovenia) reported only 21 patients transplanted for a diagnosis of COVID-19. (Personal communication -Juergen Behr). The relatively small number of LTx proportional to such a high number of potential recipients is likely multifactorial.

Health care systems overwhelmed by the pandemic may not have had adequate resources to provide the intensive support required in recipients. In fact, many transplant programs were placed on hold during the peak of the pandemic. Clinical uncertainty regarding best practices surrounding this new indication for LTx likely also contributed. Finally, many of the referred patients likely had significant relative contraindications to transplant that precluded their candidacy. Moving forward, it will be essential to review outcomes from the cohort of COVID-19 patients who were transplanted to ensure their outcomes are comparable to other indications for LTx and to identify predictors of success.

Should COVID-19 fibrosis be approached differently than other forms of fibrotic ILD?

It is likely that the COVID-19 pandemic will affect the management of fibrotic interstitial lung disease (fILD) for years to come. COVID-19 acute lung injury will be added to the differential diagnosis or contributory exposure for all fILD and assessing for a history of COVID-19 pneumonia will become a requisite standard during history taking. Indeed, we posit that any COVID-19 infection might emerge as a risk factor for the subsequent development of ILD, akin to burn-pit exposures and World Trade Center exposures which only became evident years later. These patients, particularly those more severely affected, are already being referred to ILD and LTx programs. However, the optimal approach in the evaluation and treatment of these patients is yet to be Based on the available data and extrapolating from other cause of ARDS, it is likely that the vast majority of patients with COVID-19 fibrosis will improve or remain stable. (12) The duration of time that one can expect ongoing recovery remains unclear. Anecdotally, the authors have observed ongoing improvement over the course of many months. However, patients should be closely followed as there may be a minority who develop progressive fibrosis, either from post-COVID fibrosis alone or exacerbation of a previously unrecognized fibrotic lung disease. For example, it is estimated that 2-7% of nonsmokers and 4-9% of smokers have interstitial lung abnormalities, with most of these likely going undiagnosed or without consequence in the absence of CT imaging of the chest. (13) How many of such cases are uncovered by an intercurrent COVID-19 infection and whether the existence of these lesions represent a risk factor for a more fibrotic response is uncertain. In such cases whether COVID is the cause or simply uncovers occult ILD is open to speculation.

At present, the authors approach to post-COVID fibrosis which is very similar to that taken for ILD in general. It starts first with a careful assessment for previously unrecognized fibrotic lung disease. (Table 1) The history should assess for dyspnea prior to the development of COVID-19. Patients should be queried about exposures both occupational and otherwise known to be associated with ILD, family history of ILD, and signs, symptoms, or history of connective-tissue disease. Chest imaging obtained prior to COVID infection, if available, should be carefully reviewed for signs of ILD. Baseline PFT, chest CT and six-minute walk test (6MWT) should be obtained.

Consideration can be given to obtaining connective-tissue disease serologies, particularly if signs or symptoms exist. Some centers advocate reviewing post-COVID fibrosis cases at a multi-disciplinary pulmonary meeting to get input regarding the optimal diagnostic and therapeutic strategy. Patients with any residual pulmonary sequelae should be referred to pulmonary rehabilitation, especially if significant debility exists. Given mounting data on potential benefit, a course of corticosteroids should be considered in patients with radiographic evidence of organizing pneumonia. (9, 14, 15) Patients should have repeat PFT and 6MWT performed on serial follow-up. needs to be ruled out as part of the standard transplant evaluation since these need to be factored into the patients overall transplant candidacy. In general in the United States, insurance coverage is required for adequate financial support to proceed with transplant. Advanced age also represents a contraindication for transplant. In general, patients being evaluated for LTx who require advanced life support and are in the midst of a prolonged hospitalization should be less than age 65, although exceptionally robust individuals older than this can be considered or a case by case basis. The age criteria provided here are somewhat arbitrary, but are generally agreed upon for post-COVID LTx given the relative lack of experience with this indication. As the experience with post-COVID transplantation grows, perhaps the acceptable age range will grow as well.

In general, all efforts should be made to wake patients up prior to transplantation to obtain consent for the procedure, provide education, assess interest, and to engage them in active rehabilitation. If mechanical ventilation and sedation requirements preclude mobilization and rehabilitation, then ECMO support should be strongly considered. All patients and their caregivers should undergo rigorous LTx education and evaluation by a multidisciplinary care team prior to transplantation.

This is often a particularly difficult question to answer and requires the best judgement of the lung transplant team. Patients should receive appropriate standard-of-care medical therapy for their COVID-19 infection to optimize the chances for recovery with adequate time allowed for lung recovery. Best clinical practices with regard to lung protective ventilation and negative fluid balance are essential to prevent potentiation of lung injury.

Although arbitrary, a minimum of four weeks' time for recovery has been suggested in the medical literature, unless a life-threatening complication which cannot be managed without LTx arises earlier. (22, 23) The authors agree that four weeks is considered an absolute minimum and more often wait for 8+ weeks before seriously considering transplant. Review of CT imaging may be helpful as well. Findings suggestive of irreversible change include traction bronchiectasis and subpleural fibrosis. Anecdotally, we have seen cases with CT evidence of "fibrosis" which has subsequently improved. On the other end of the spectrum, ground-glass infiltrates are commonly encountered early on and are typically due to an alveolar-filling process and hence regarded as potentially reversible. However, this radiographic pattern can also be due to early "fine fibrosis" which should be suspected in patients who are further out, especially if seen in the context of traction bronchiectasis or bronchiolectasis. If evidence of organizing pneumonia is present on CT scan, a trial of corticosteroids and possibly azithromycin is reasonable. CT scanning is also useful in assessing for other potentially treatable causes including pulmonary edema, pleural disease and bacterial pneumonia. Nosocomial infection is a potential cause of ongoing lung dysfunction as well and should be assessed for and treated prior to making a determination of irreversible lung disease. Multi-drug resistant bacterial infections were noted to complicate the course of many of reported patients transplanted for CARDS and likely contributed to the irreversible lung damage they developed. (23)

One major concern with transplantation of patients with COVID-19 is the potential impact of lingering active virus. The prolonged harboring of active virus has potential implications in patients with pre-existing ILD exacerbated by COVID-19 who have been managed with chronic immunosuppression. It is also conceivable that persistent virus may be fostered by therapy with corticosteroids or immunomodulators such as toculizumab. As such, a cautious approach to confirming clearance of COVID-19 is warranted. Bharat and colleagues advocated for two negative rt-PCR tests, obtained at least 24 hours apart, from bronchoalveolar lavage samples in intubated patients prior to proceeding with LTx. (22) For patients with no tracheostomy or endotracheal tube, two negative upper respiratory tract rt-PCR tests obtained at least 24 hours apart would be the minimum threshold the authors would require to proceed with LTx. (23) Due to persistent positive testing, this approach may result in delays in transplant, but seems to be a reasonable albeit conservative approach to adopt until further data is available on this issue.

The majority of patients with critical COVID-19 will have endured prolonged hospitalization and immobilization, compromised nutritional status from critical illness, and treatment with corticosteroids and neuromuscular blockade, all of which predispose to critical illness polyneuropathy/myopathy and marked deconditioning. Prior to transplant every effort should be made to optimize nutritional status and achieve a wakeful, interactive state where patients can participate meaningfully in the transplant process and rehabilitation. ECMO support may be J o u r n a l P r e -p r o o f required to achieve these goals. In exceptional circumstances, a patient with a normal baseline functional status and good potential for recovery post-LTx whose pulmonary status precludes rehabilitation prior to transplant could be considered. Whether rehabilitation potential and frailty present a contraindication to LTx must be interpreted in the context of the each patient's global clinical picture and rely on the clinical judgement of the multidisciplinary transplant team. In addition to their physical functional ability, their mental resilience is equally important in withstanding the acute psychological stress of transplantation, as well as the long-term commitment to a strict medical regimen. This is especially difficult for patient who were previously well prior to their COVID infection and who haven't had the time to accept or adapt psychologically to their new reality.

The experience with dual organ transplant for COVID-19 patients is limited. Acute kidney injury (AKI) is estimated to occur in approximately 35% of patients hospitalized with COVID-19, with 12-15% requiring renal replacement therapy. (28, 29) Mechanical ventilation is a risk factor for severe AKI. Given the potential reversibility of AKI in COVID-19, the appropriateness of proceeding with renal transplant in this setting in questionable. Some centers have elected to pursue LTX in patients with COVID-19 complicated by AKI requiring renal replacement therapy who were deemed to have a high likelihood of renal recovery. A lung-kidney transplant has been performed in a patient with lung and renal failure deemed irreversible. (30) One heart-lung transplant for COVID-19 in a patient with pre-existing cardiomyopathy has been reported. (31) To our knowledge, no lung-liver transplants for COVID-19 have been performed as of yet. While it is possible that dual organ transplant could be entertained in the future for highly select candidates, at this time, the authors feel that multi-organ dysfunction should preclude candidacy for LTx in the vast majority of candidates.

Given that the LTx recipient will be tested for and proven clear of COVID-19 infection prior to transplant, the operation need not be performed in a negative pressure environment. Surgical teams may consider wearing N-95 or equivalent masks and eye protection in addition to standard gown and gloves. Bilateral lung transplantation for J o u r n a l P r e -p r o o f COVID-19 has been recommended as many patients develop significant pulmonary hypertension. (24, 25) Additionally, explants from COVID-19 LTX recipients revealed cavitary areas of pneumonia that could serve as a nidus of infection if a single lung transplant was performed. (24) Single lung transplantation can be considered on a case by case basis, even in the presence of pulmonary hypertension, especially in patients who are in dire straits with a short window to receive a transplant. There may be added theoretic attraction to single lung transplants, since in some patients; this could serve as a "bridge to recovery" of the remaining native lung. Intra-operatively, surgical teams should be prepared for bleeding given the likelihood of pleural adhesions and platelets dysfunction in patients managed with pre-operative ECMO support. (25) Transplant centers undertaking these cases should be experienced in high acuity transplant with robust resources for extracorporeal support and post-operative rehabilitation. Our collective experience transplanting these patients is that their course and risk of specific posttransplant complications pulmonary or extra-pulmonary, such as acute kidney injury, is no different from a general transplant population. This is likely due these patients being closely vetted for end-organ dysfunction prior to acceptance.

The patient was treated with a course of corticosteroids and completed pulmonary rehabilitation. On follow-up six months after his initial hospitalization, his FVC had increased by approximately 100 mL to 1.9 L (50% predicted) and his 6MWT had increased by 75 meters to 316 m with decreased need for supplemental oxygen. He felt less dyspneic with activities of daily living. The decision was made to continue rehabilitation and follow-up in several months, but defer initiation of a lung transplant evaluation and assess for ongoing improvement.

In the setting of no significant clinical improvement despite maximum respiratory support, the patient underwent an expedited lung transplant evaluation. After ten weeks in the hospital, seven of which were on VV ECMO and mechanical ventilation, she received a bilateral lung transplantation. Of note, she had two negative COVID swabs and cleared COVID precautions per the hospital epidemiology team prior to being listed for transplant. She had a J o u r n a l P r e -p r o o f full recovery with minimal complications, and on post-operative day sixteen was discharged to an acute rehabilitation facility without any subsequent oxygen needs.

COVID-19 can result in severe, irreversible lung injury. In these cases, LTx may represent the only viable therapeutic option, albeit in a very small, highly select group of patients. This patient population presents a number of unique challenges for providers which require careful consideration. It is likely that COVID-19 associated lung disease will impact the field of ILD and LTx for years to come. Further study is required to determine the natural history of COVID-19-related lung disease. Questions to be addressed through future research include; which patients are likely to fully recover, who will be left with residual lung injury and who will progress to develop persistent or progressive fibrosis, requiring transplant consideration. Further study is also required to determine if outcomes from LTx for COVID are equivalent to other indications and if these patients are at risk for unique post-LTx complications including venous thromboembolism and neurocognitive issues. An

International Registry of COVID-related lung transplants could provide a foundation for expediting the answers to these and other emerging questions in this nascent area. Table 1 Considerations Prior to Transplant in Outpatients with post-COVID fibrosis Assess for evidence of pre-existing ILD  History: Symptoms prior to COVID-19 infection, family history of ILD, connective tissue disease history or signs/symptoms, occupational or other exposures associated with chronic hypersensitivity pneumonitis  Review available chest imaging from prior to COVID-19 infection  Consider connective tissue disease testing Obtain baseline PFTs, 6MWT, and imaging and monitor serially Consider a trial of corticosteroids Consider anti-fibrotic (pirfenidone or nintedanib) if evidence of progression Refer for pulmonary rehabilitation Transplant is reserved for severe debility failing to improve with time, medical therapy and rehabilitation or progressive disease Abbreviations: ILD = Interstitial lung disease; PFT= Pulmonary function testing; 6MWT = Six-minute walk test

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