EXPERIMENTAL AND CLINICAL TRANSPLANTATION

The severe acute respiratory syndrome coronavirus 2 pandemic has dramatically changed medical practices worldwide. These changes have been aimed both to reallocate resources toward fighting the novel coronavirus and to prevent its transmission during nonurgent medical and surgical interventions. Heart and lung transplantation could not be an exception, as most transplant centers have either restricted their activity to only urgent, lifesaving procedures or stopped these surgical procedures for various periods of time depending on the local virus epidemiology. The effect of this infection on the immunosuppressed heart and lung transplant recipient is still questionable; however, there are limited reports suggesting that there is no increased risk of transmission or more severe disease course compared with that shown in the general population. Transplant organizations have disseminated early recommendations as a guidance in a yet evolving situation. Finally, data suggest that lung transplant could potentially serve as an ultimate, lifesaving procedure for COVID-19-related end-stage respiratory failure in carefully selected patients.

Key words : Coronavirus, Immunosuppression, Pandemic, SARS-CoV-2, Severe acute respiratory syndrome

The novel coronavirus pandemic (coronavirus disease 2019 or COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in December 2019 in Wuhan, China and has since spread rapidly throughout the world. The full spectrum of the clinical manifestations and complications associated with COVID-19 is yet to be elucidated. Current data suggest that men are more commonly affected (60% of cases), and the median age of presentation is approximately 50 years.^1-3 Most patients (80%) are asymptomatic or present with mild disease. However, hospitalized patients may develop severe or critical disease, sepsis, and death. Indeed, Guan and associates³ reported that serious illness occurs in 16% of the cases.⁴The clinical presentation typically consists of fever (> 80%), dry cough (> 60%), and fatigue (> 40%), whereas other commonly reported symptoms include headache, sore throat, neurological symptoms, gastrointestinal manifestations, and anosmia.^2,3,5 In addition, COVID-19 has been associated with a high risk of acute respiratory disease, venous thromboembolism, and intensive care unit (ICU) admission.^2,6-10

Strict measures have been applied worldwide, including social distancing, minimization of public transport, and house quarantine to deescalate the outbreak and to “flatten the curve.” At the same time, the widespread application of these measures, combined with an overwhelming need for ICU beds and allocation of human resources in the fight against the pandemic, has resulted in the suspension of elective surgical procedures.¹¹

Respiratory viral infections commonly affect transplant recipients as consequences of long-term immunosuppression and comorbidities.^12-14Transplant recipients who acquire COVID-19 can have comorbidities that predispose to severe disease.^14,15 In addition, transplant recipients with COVID-19 have high rates of hospitalization, ICU admission, and adverse events.^15,16 This situation constitutes an unprecedented and yet unresolved problem in the field of heart and lung transplantation.

Transplant Practice Recommendations During the COVID-19 Outbreak
Transplant programs have been modified in almost all countries, and each country has developed its own algorithm for donor and recipient testing, selection, and operation.¹⁷

The Transplant Infectious Disease Society recommends against the use of organs from donors with unspecified respiratory failure or those who have been in contact with suspected or confirmed COVID-19 cases. Similarly, organ donors who had visited high-risk areas or those who had been in close contact with suspected or confirmed COVID-19 cases were initially excluded from donation for 14 to 28 days according to the American Society of Transplantation (AST).¹⁵ The AST currently suggests testing of donors with nucleic acid test (NAT) within 3 days of procurement. Donors with active SARS-CoV-2 infection, positive NAT test performed during preoperative assessment, or resolution of COVID-19 symptoms less than 28 days before transplant should not be considered as candidates for organ procurement. If the NAT test is not available, AST strongly recommends against lung transplant in the presence of intermediate epidemiologic risk factors for COVID-19.¹⁸

Ιn the United Kingdom, all donors must be tested with nose and throat swab, endotracheal aspirate, and blood SARS-CoV-2 polymerase chain reaction (PCR) testing. Again, resolution of symptoms for more than 28 days before procurement and subsequent negative PCR tests are required for organ procurement from donors with previous SARS-CoV-2 infection. In addition, a chest computed tomography scan may reveal signs of SARS-CoV-2 infection even in asymptomatic patients or in patients with negative tests, and its implementation as a preoperative test has also been proposed.¹⁹ Similar guidelines have been published by the International Society for Heart and Lung Transplantation, which suggests that all donors should be tested with nasopharyngeal swabs or preferably with deep tracheal aspiration or bronchoalveolar lavage (BAL), if the latter can be safely performed.²⁰ In Italy, BAL sample PCR is also preferred over nasopharyngeal swabs as the preoperative donor testing method. Notably, BAL testing is associated with a high risk of transmission to health care workers; it also requires properly trained personnel who can perform bronchoscopies, which may further overwhelm the health care system, especially during this period of severe shortages of resources.¹⁷

Organization of Surgical Activities and Precautions in the COVID-19 Era
The number of surgical interventions, including heart and lung transplant procedures, has generally decreased and is restricted to absolutely emergent lifesaving procedures.²¹ Current data mostly apply to adult transplant recipients, as the pediatric population has been less affected by the SARS-CoV-2 infection.²² A national survey (79.3% response rate) conducted in the United States between March 24 and March 31, 2020, reported that only 6 of 32 (18.8%) heart transplant programs and 5 of 27 (18.5%) lung transplant programs continued to operate without any restrictions. Most heart transplant programs restricted their activity to severe cases, and many lung transplant programs prioritized cases according to the lung allocation score.²³ In the United Kingdom, 2 major lung transplant programs were temporarily suspended, whereas heart programs had significantly limited the number of procedures.¹⁹ On the other hand, an early study from Italy reported that activities in heart and lung transplant programs were minimally influenced by the COVID-19 pandemic. The investigators compared the transplant activity between February 24 and March 22, 2020, versus during the same time period since 2015, and they did not observe significant differences in the number of transplants. However, this period included only the beginning of the outbreak, prior to the peak of the pandemic, and these findings should be considered with caution.²⁴ Furthermore, data from France suggested a significant reduction in lung transplants during the COVID-19 outbreak. Specifically, only 2 lung transplants were performed between March 17 and April 7, 2020 compared with 31 procedures performed during the same period in 2019.²⁵ In addition, Loupy and colleagues²⁶ reviewed solid-organ transplant activity in France and the United States between February 28 and April 3, 2020 and reported an inverse association between the increasing number of SARS-CoV-2 cases and the number of deceased donor transplant procedures. This decrease was more significant for lung than for heart transplants.²⁶

The prevention and control of hospital-related COVID-19 spread are of paramount importance. The outpatient follow-up of transplant recipients has been modified, and telehealth approaches, cessation of nonurgent visits, and minimization of consultations have been applied.²⁷ In addition, health care workers involved in the transplant process and the management of transplant patients have received special training on transmission control and prevention methods.^23,28 Furthermore, transplant research activities have decreased in several countries. Cessation of outpatient clinics and decreased or reallocated funding to COVID-19 research projects were some of the reported reasons.²⁹

Immunosuppression and SARS-CoV-2 Infection
The long-term need of immunosuppression in solid-organ transplant recipients has been proposed as a major cause of prolonged viral shedding, prolonged hospitalization, higher rate of adverse events, and increased mortality. The risk of transmission to donors, recipients, family members, and health care professionals constitutes another major concern.30 Our knowledge about the management of COVID-19 infection in transplant patients is still naive, with the first reports of COVID-19 pneumonia management in immunosuppressed renal and heart transplant recipients published in March 2020.^31,32 Reports from other solid-organ transplant procedures have suggested increased risks of severe disease and increased mortality in immunosuppressed transplant recipients with COVID-19. Akalin and colleagues³³ reported a 21-day mortality rate of 28% in 36 renal transplant patients who tested positive for SARS-CoV-2. The authors pointed out the need of decreasing the doses of immunosuppressive medications, as most patients (70%) had decreased number of circulating CD3 and CD4 lymphocytes.³³

However, the role of immunosuppressive drugs in the course of COVID-19 has yet to be determined. The host immune response seems to play an important role in the pathogenesis of the SARS-CoV-2 infection. In patients with severe or critical COVID-19, the viral infection elicits an excessive immune response, the so-called “cytokine storm,” which leads to multiorgan failure. Interleukin 6 seems to play a pivotal role in this dysregulated immune process and provides an appealing treatment target.³⁴ Interleukin 17 and complement activation are also implicated in excessive immune responses, and both have been proposed as therapeutic targets.³⁵ Therefore, immunosuppression could be a double-edged sword, since it can theoretically lead to both increased transmissibility and prolonged viral shedding or to a milder host immune response and less tissue damage. In emerging data from the randomized controlled RECOVERY trial, dexamethasone reduced mortality by 35% in patients requiring mechanical ventilation.³⁶ Dexamethasone might soon be implemented into the standard treatment regimens for COVID-19. Lastly, previous data from the SARS and MERS coronavirus outbreaks have shown that immunosuppression is not associated with a higher incidence of severe disease.^37,38

General Considerations in Heart and Lung Transplant Recipients
Because heart and lung transplant recipients commonly require pre- and always posttransplant admission to the ICU, several issues may arise for both uninfected transplant recipients and nontransplant SARS-CoV-2-positive patients. These include (1) the increased risk of transmission from SARS-CoV-2-positive patients to transplant recipients, (2) the limited availability of ICU beds for transplant recipients and candidates because of high numbers of SARS-CoV-2-positive severe and critically ill patients, and (3) even if not transplanted, some heart or lung transplant candidates may still require ICU admission due to disease progression.³⁹

Among donated organs, lungs seem to carry the highest risk in terms of transmission. Blood and stool transmission is possible but is less commonly reported.^2,40 It has been shown that SARS-CoV-2 is most commonly isolated from the respiratory tract and that the angiotensin-converting enzyme 2 (ACE-2) receptors facilitate viral entry to the cells, whereas reports from animal models have suggested that ACE-2 mediates a protective role in acute lung injury.⁴¹ Both heart and lung transplant and the associated hemodynamic changes that follow these major operations may alter the expression of ACE-2 receptors in the lung parenchyma. Thus, the immunologic response and the severity of the COVID-19 may differ in heart and lung recipients.⁴²

Early Reports and Outcomes in Heart Transplant Recipients
The first 2 cases of SARS-CoV-2 infection in heart transplant recipients were reported by Li and associates in China.⁴³ The first patient had received a heart transplant 17 years previously and was on long-term immunosuppression with tacrolimus and mycophenolate mofetil. He gradually deteriorated both clinically and radiologically and required oxygen supplementation, cessation of immunosuppression, and treatment with intravenous human gamma-globulin and methylprednisolone for 5 days. The patient responded to treatment, and regular immunosuppression regimen was reinitiated 12 days later, without any signs of graft rejection. The patient remained afebrile for 20 days, with resolution of symptoms and improvement of radiographic findings at discharge. The second patient had milder disease, and neither oxygen nor immunosuppression modification was required.⁴³

A mild case of SARS-CoV-2 infection was reported in a heart transplant recipient at 4 months posttransplant by Decker and colleagues.⁴⁴ The symptoms resolved without immunosuppression cessation, but prolonged viral shedding at repeated nasopharyngeal swabs was noted.⁴⁴ Similarly, Mathies and colleagues⁴⁵ 77-year-old heart transplant recipient who had been successfully treated with hydroxychloroquine, oxygen supplementation, mycophenolate mofetil discontinuation, and tacrolimus to sirolimus replacement, due to concerns of potential lung toxicity.

In pediatric heart transplant recipients, SARS-CoV-2 infection has also been reported.^46,47 A mild, self-limited course of disease was reported in all patients, with none requiring ICU admission or any type of respiratory support. Discontinuation of mycophenolate mofetil was decided in 1 patient, whereas the remainder continued with regular immunosuppression regimens with good outcomes.^46,47

COVID-19 has been reported in combined heart-kidney transplant recipients who presented with mild symptomatology.^48,49 Only 1 patient required transient oxygen supplementation, and both patients were managed with adjustments to their immunosuppression regimens with clinical improvement and no signs of acute rejection.^48,49

In a study from Spain, the authors retrospectively reviewed 18 transplant patients, including 4 heart transplant recipients. The overall fatality rate in this study was 27.8%, including in 1 heart transplant recipient. Notably, 1 heart transplant recipient was admitted to the ICU, whereas another presented with diarrhea in addition to fever, cough, and shortness of breath.⁵⁰ Pereira and colleagues retrospectively reviewed 90 SARS-CoV-2-positive solid-organ transplant recipients, including 9 heart and 3 heart-kidney recipients, of whom 4 developed severe disease with ICU admission and intubation.⁵¹

In a retrospective study from Ren and colleagues⁵² of 87 heart transplant recipients to determine their risk of infection, 57 had travelled or had been in contact with people of the endemic area of Wuhan, China, but none had been in contact with confirmed or suspicious COVID-19 cases. Most of the study group had taken adequate precautious measures, with no SARS-CoV-2 infection eventually reported, suggesting that this group might not be more susceptible than the general population.⁵² However, the small study sample size renders larger epidemiologic studies essential to estimate the risk of infection in this population.

Early Reports and Outcomes in Lung Transplant Recipients
Current investigations on the clinical course of COVID-19 and predisposing risk factors in lung transplant recipients are relatively scarce. Myers and colleagues⁵³ reported 8 SARS-CoV-2-positive lung transplant recipients with clinical presentation varying between mild disease (3 patients) and fatal disease during the immediate postoperative period (2 patients). Immunosuppression management included cessation of nucleotide analogs, titration of calcineurin inhibitor doses, and increased corticosteroid doses. In addition, 2 patients received remdesivir, 2 patients received tocilizumab (interleukin 6-receptor antagonist), and 1 patient received anakinra (interleukin 1-receptor antagonist) and intravenous immunoglobulin.⁵³ Similarly, a severe SARS-CoV-2 infection in the immediate postoperative period was reported by Keller and associates⁵⁴ in a patient who required prolonged intubation and hemodialysis due to acute kidney injury.

Early reports from Italy by Morlacchi and colleagues⁵⁵ included 4 lung transplant recipients with COVID-19 at time points beyond 40 months posttransplant. Two of the patients had generally mild courses of disease, 1 patient required a prolonged hospital admission, and 1 patient died as a result of progressively worsening disease. Immunosuppression management included azathioprine discontinuation and increased corticosteroid doses, whereas all patients received high doses of low-molecular-weight heparin and mechanical ventilation.⁵⁵ A severe clinical course of COVID-19 in lung recipients was also reported by Cozzi and associates,⁵⁶ whereas Aigner and associates⁵⁷ presented a relatively mild case of SARS-CoV-2 infection in a lung transplant recipient with minimal supplemental oxygen requirements and no adjustments in the patient’s immunosuppressive regimen. Lastly, Pereira and associates⁵¹ reported a 41% incidence of severe disease (mechanical ventilation, ICU admission, or death) in 17 lung transplant recipients with COVID-19.

Lung transplant may also be considered as a last therapeutic option for patients with severe COVID-19-related end-stage respiratory failure, that is, when all other treatment options have failed. Han and colleagues reported 2 cases of therapeutic lung transplant in patients with severely compromised pulmonary function following SARS-CoV-2 infection.⁵⁸ Both patients received optimal supportive care, including antiviral medication, methylprednisolone, and extracorporeal membrane oxygenation with mechanical ventilation. However, the disease progressed to end-stage respiratory failure requiring lung transplant.⁵⁸ Chen and colleagues also attempted therapeutic lung transplant.⁵⁹ In their 3 patients, all presented with irreversible fibrosis-related acute respiratory distress syndrome, secondary to SARS-CoV-2 infection, and bilateral lung transplant was decided as an ultimate rescue treatment, with 2 of 3 patients surviving upon publication. The authors also stressed the need of close B-type natriuretic peptide monitoring due to elevated pulmonary artery pressure. This may be the result of left heart failure, probably secondary to the effect of COVID-19 on the heart.⁵⁹

It is crucial to balance the benefits and risks of heart and lung transplant during pandemic outbreaks. Because the role of immunosuppression is still questionable and COVID-19 is currently considered a multisystemic disease, immunosuppression after transplant should be managed on a case-by-case basis. Current reports support the adjustment of immunosuppressive regimens as a common approach in the management of COVID-19 in transplant recipients. Despite the risk of increased wait list mortality, temporary cessation of heart and lung transplants in areas heavily affected by COVID-19 and regulated continuation in less affected areas are considered as the most viable options. Lung transplant has been proposed as an ultimate therapeutic approach to irreversible and resistant COVID-19-related respiratory failure. Lastly, potential lung transplant recipients should be carefully selected because of the ethical implications associated with candidate prioritization.

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