Abstract
It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19. The management of a lung transplantation (LTx) program and the therapeutic strategies to adapt the immunosuppressive regimen and antiviral measures is a major issue in the COVID-19 era, but little is known about worldwide practice. We sent out to 180 LTx centers worldwide in June 2020 a survey with 63 questions, both regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 LTx recipients. We received a total of 78 responses from 15 countries. Among participants, 81% declared a reduction of the activity and 47% restricted LTx for urgent cases only. Sixteen centers observed deaths on waiting listed patients and eight centers performed LTx for COVID-19 disease. In 62% of the centers, COVID-19 was diagnosed in LTx recipients, most of them not severe cases. The most common immunosuppressive management included a decreased dose or pausing of the cell cycle inhibitors. Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. Most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to treat LTx recipients with COVID-19.
KEYWORDS: antibiotic: antiviral, clinical research / practice, immunosuppression / immune modulation, immunosuppressive regimens, infection and infectious agents - viral, infectious disease, lung transplantation / pulmonology, recipient selection, waitlist management
Abbreviations: ARDS, acute respiratory distress syndrome;; LTx, lung transplantation
1. BACKGROUND
A novel coronavirus, SARS-CoV-2, causing a severe acute respiratory syndrome with its disease designated as COVID-19, emerged in December 2019 and is now a global pandemic.1 It is unknown if solid organ transplant recipients are at higher risk for severe COVID-19 and the specific role of the immunosuppression in the disease. Lung transplantation (LTx) recipients are a specific group in this population, especially due to the generally increased risk of respiratory infections.2
At this time a proven and specific therapy against COVID-19 disease is lacking, and there are no specific guidelines from experts or transplant societies regarding the management of LTx in this era.3 , 4 We hypothesized that most physicians in charge of a LTx program will propose a specific strategy to protect and give the maximum chance of recovery in case of infection.
This survey aims to assess the management of LTx programs in the era of COVID-19 and therapeutic strategies against COVID-19.
2. METHODS
We designed a survey consisting of 63 questions regarding the management of a LTx program in the COVID-19 era and the therapeutic strategies to treat COVID-19 lung transplant recipients. After general questions on local practice, we asked for the impact of the COVID-19 pandemic on patients waiting for LTx and the LTx activity (restriction of the lung transplant surgery, quantification of the reduction of the activity, perioperative and follow-up management of LTx recipients). We asked physicians for the possibility of transplanting a COVID-19 patient with refractory lung failure or chronic lung sequelae. We also brought up the management of the immunosuppressive regimen and the therapeutic regimens against COVID-19 in LTx recipients with mild, moderate, or severe forms (Data S1).
Mild case (Case 1) was defined as a confirmed case of COVID-19 LTx recipient by throat-swab PCR with classical symptoms (fever, cough, myalgia, fatigue) but no respiratory failure or hypoxemia. Moderate case (Case 2) consisting of a confirmed case of COVID-19 LTx recipient by throat-swab PCR with classical symptoms (fever, cough, myalgia, fatigue) with mild respiratory failure and confirmed hypoxemia (requiring O2 therapy at 2-4L/min) but no respiratory distress or sepsis. Severe case (Case 3) consisting of a confirmed case of COVID-19 LTx recipient by throat-swab PCR with initial classical symptoms (fever, cough, myalgia, fatigue) who deteriorates with severe respiratory failure and severe hypoxemia requiring hospitalization in ICU for mechanical ventilation.
The survey was developed by two transplant teams (Marseille, France; Homburg, Germany) in May 2020. The survey was approved by the Institutional Review Board of the French learned society for respiratory medicine -Société de Pneumologie de Langue Française (SPLF) - CEPRO 2020-026 and the Ethics Committee of the Landesärztekammer Saarland (Germany). We used a mailing list of LTx physicians from 180 centers in 35 countries as published elsewhere.5 In June 2020, the survey was sent to the mailing list with a personal link to an internet service provider (SurveyMonkey Inc., San Mateo, CA; www.surveymonkey.com). A reminder was sent every 7 days for 3 weeks.
Graphical illustrations were performed with the public software R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria).
3. RESULTS
3.1. Centers participating in the survey
We received 78 responses from 15 countries, mostly from Western Europe (n = 45) and the USA (n = 24; Figure 1). Five respondents did not specify the information on their centers. The description of the LTx centers is summarized in Table 1.
FIGURE 1.
World map representing the lung transplant centers answering the survey. The map was generated with the public R software using the “maps” package. Red dots represent the centers participating in the survey. Gray areas depict countries participating in the survey [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 1.
Description of the lung transplant centers and the impact of the COVID-19 on lung transplant programs
| Question | Answers | n (%) |
|---|---|---|
| What is the main indication for lung transplant in your program? | ||
| ILD | 43 (55) | |
| COPD | 24 (31) | |
| CF | 5 (6) | |
| PH | 1 (1) | |
| No predominant disease | 5 (6) | |
| No answer | 0 (0) | |
| What kind of lung transplant procedures were performed in 2019 in your center? | ||
| Unilateral | 50 (64) | |
| Bilateral | 77 (99) | |
| Heart–Lung | 14 (18) | |
| No answer | 0 (0) | |
| During the last 5 years, how many lung transplantations have been performed per year at your center on average? | ||
| 0-10 | 9 (12) | |
| 11-20 | 18 (23) | |
| 21-40 | 19 (24) | |
| 41-60 | 21 (27) | |
| >60 | 11 (14) | |
| No answer | 0 (0) | |
| How many patients undergo follow-up after lung transplant at your center? | ||
| 0-50 | 8 (10) | |
| 51-100 | 11 (14) | |
| 101-200 | 18 (23) | |
| 201-300 | 16 (21) | |
| >300 | 23 (29) | |
| No answer | 2 (3) | |
| Did the COVID–19 pandemic lead to one of more of the following measures? | ||
| Moratorium for new admissions to the waiting list | 4 (5) | |
| Restriction of lung tranplantations performed to urgent cases | 37 (47) | |
| Restriction of new admissions to the waiting list to urgent cases | 11 (14) | |
| Periodical shutdown of the transplant program | 4 (5) | |
| None of these measures | 21 (27) | |
| No answer | 1 (1) | |
| If the program was reduced, what was the approximal reduction ? | ||
| Less than 10% | 1 (1) | |
| 11%-25% | 14 (18) | |
| 26%-50% | 20 (26) | |
| 51%-75% | 8 (10) | |
| 76%-100% | 17 (22) | |
| No reduction at all | 15 (19) | |
| No answer | 3 (4) | |
| Did you observe deaths on waiting list due to COVID–19? | ||
| No | 60 (77) | |
| Yes | 16 (20) | |
| No answer | 2 (3) | |
| Did you ever consider lung transplantation in a listed patient tested positive for COVID–19? | ||
| No | 69 (88) | |
| Yes | 8 (10) | |
| No answer | 1 (1) | |
| Did you separate patients post-LTx from COVID–19 patients on another ICU in order to minimize the risk of SARS-CoV–2 infection? | ||
| No | 9 (12) | |
| Yes | 66 (85) | |
| No answer | 3 (4) | |
| Did you separate treating staff for LTx and COVID–19 patients on the ICU (or the ICUs) in order to minimize the risk of SARS-CoV–2 infection? | ||
| No | 22 (28) | |
| Yes | 54 (69) | |
| No answer | 2 (3) | |
| Did you screen donor and recipient prior to the procedure in order to minimize the risk of SARS-CoV–2 infection? | ||
| No | 0 (0) | |
| Yes | 76 (97) | |
| No answer | 2 (3) | |
| Did you expand follow-up intervals in order to minimize the risk of SARS-CoV–2 infection? | ||
| No | 12 (15) | |
| Yes | 60 (77) | |
| No answer | 6 (8) | |
| Did patients request to expand follow-up intervals in order to minimize the risk of SARS-CoV–2 infection? | ||
| No | 12 (15) | |
| Yes | 60 (77) | |
| No answer | 6 (8) | |
| Did you utilize telemedical approaches instead of regular follow-up visits during the SARS-CoV–2 pandemic? | ||
| No | 8 (10) | |
| Yes | 64 (82) | |
| No answer | 6 (8) | |
| Did you observe cases of COVID–19 among recipients during follow-up? | ||
| No | 25 (32) | |
| Yes | 48 (62) | |
| No answer | 5 (6) | |
| Number (between January 2020 and April 2020) | 1 [0-4] | |
| Number requiering MV (between January 2020 and April 2020) | 0 [0-1] | |
| Number of death (between January 2020 and April 2020) | 0 [0-0] | |
| Based on your experience with COVID–19 in lung transplant recipients: are lung transplant recipients more prone to critical illness than average COVID–19 patients? | ||
| Less prone | 18 (23) | |
| More prone | 17 (22) | |
| Equally prone | 31 (40) | |
| No answer | 12 (15) | |
Abbreviations: CF, cystic fibrosis; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung diseases; LTx, lung transplantation; PH, pulmonary hypertension.
3.2. Impact of the COVID-19 pandemic on the lung transplant program
Responses on the impact of the COVID-19 pandemic on the LTx activity, waiting list patients, and LTx recipients are summarized in Table 1.
Most centers restricted LTx to urgent cases (47%). Only 19% of the centers did not observe a reduction of the LTx activity. The number of LTx performed from January to April was significantly reduced in 2020 as compared with 2019 in the centers participating in the survey ( Figure 2, median decrease number of LTx estimated by paired samples Wilcoxon rank test at –3.5; 95% CI, –4.5 to –2.0; P < .001). A median note of 75/100 (interquartile range, 64–98) was reported by the centers to agree that the COVID-19 pandemic affected the LTx program.
FIGURE 2.
Number of lung transplantations performed from January to April in 2019 and 2020
Only 20% of the centers observed deaths on waiting list patients. In the postoperative phase of a LTx, most centers separated treating staff (69%) and LTx recipients (85%) from COVID-19 patients on another ICU in order to minimize the risk of SARS-CoV-2 infection. The majority of the centers has been faced with COVID-19 LTx recipients (62%) for a total of 226 infected LTx recipients. Only a few required mechanical ventilation (42 recipients in total) or died (17 centers having observed 30 deaths in total). Centers considered COVID-19 LTx recipients less or equally prone (63%) to critical illness than average COVID-19 patients. A median note of 98/100 (interquartile range, 77–100) was reported by the centers to agree that they had enough test capacity to provide COVID-19 testing for their transplant patients.
3.3. Indication of LTx in COVID-19 patients
Most centers would not consider COVID-19–positive patients for LTx (63%). However, six centers (8%) declared having performed LTx as a rescue for patients with COVID-19 acute respiratory distress syndrome (ARDS; Table 2). A median note of 59/100 (interquartile range, 32–75) was reported by the centers to agree that refractory COVID-19 patients should be considered as potential candidates for salvage LTx. A median note of 59/100 (interquartile range, 50–70) was reported by the centers to agree that COVID-19 patients with post-ARDS fibrosis will be a cohort with a high need for LTx in the future ( Figure 3).
TABLE 2.
Consideration of lung transplantation in COVID-19 patients
| Question | Answers | n (%) |
|---|---|---|
| Would you transplant COVID–19–positive patients from… | ||
| Invasive ventilatory assist | 1 (1) | |
| Extracorporeal Membrane Oxygenation (ECMO) | 6 (8) | |
| Both | 16 (21) | |
| Only unassisted | 4 (5) | |
| Would not consider COVID–19–positive patients for lung transplant at all | 49 (63) | |
| No answer | 2 (3) | |
| Did your center do a rescue lung transplantation in a patient with COVID–19–ARDS ? | ||
| No | 71 (91) | |
| Yes | 6 (8) | |
| No answer | 1 (1) | |
| When do you consider a patient eligible for LTx with COVID–19? | ||
| rtPCR negative in nasopharyngeal swab | 7 (9) | |
| rtPCR negative in BAL within 72 h | 9 (12) | |
| 2 x rtPCR negative in nasopharyngeal swab within 72 h | 13 (17) | |
| 2 x rtPCR negative in BAL within 72 h | 19 (24) | |
| Negativity from viable virus | 8 (10) | |
| COVID–19 lung transplant not an option | 21 (27) | |
| No answer | 1 (1) | |
Abbreviations: rtPCR, retro-transcriptase polymerase chain reaction.
FIGURE 3.
Questions regarding the indication of a lung transplant in COVID-19 patients. The dots represent the individual response. The boxplot corresponds to the median with the interquartile range (distance between the first and third quartiles); the lower and upper whiskers extend from the hinge to the lowest and highest (respectively) values that are within 1.5 x IQR of the hinge. LTx, lung transplantation
3.4. Management of the immunosuppressive regimen in COVID-19 lung transplant recipients
The most common immunosuppressive management included no change for calcineurin and mTOR inhibitors, and decrease dose or stop for cell cycle inhibitors especially for moderate or severe forms of COVID-19 for these latter. Corticosteroids were increased in severe cases especially ( Figure 4). Management of the immunosuppressive regimen was not adapted according to patient characteristics, blood peripheral immune markers, nor recipient immunological risk in the majority of the responses whatever the severity of the COVID-19 ( Table 3).
FIGURE 4.
Management of immunosuppressive therapy in recipients infected by the SARS-CoV-2. Red bars are the strategies the most frequently adopted. Orange bars are the second most frequent strategies adopted. Decrease if >5 mg = decrease if >5 mg/day of prednisone dose equivalent. Cyclo, cyclosporine; Tacro, tacrolimus; MMF, mycophenolate mofetil; Aza, azathioprine; CNI, calcineurin inhibitors; CCI, cell cycle inhibitors [Color figure can be viewed at wileyonlinelibrary.com]
TABLE 3.
Patient characteristics, immune markers, immunological risk, and adaptation of the immunosuppressive regimen in recipients with COVID-19
|
Case 1: mild COVID–19 recipient |
Case 2: moderate COVID–19 recipient |
Case 3: severe COVID–19 recipient |
||
|---|---|---|---|---|
| Question | Answers | n (%) | n (%) | n (%) |
| Adaptation according to patient characteristics: | ||||
| No | 45 (58) | 43 (55) | 43 (55) | |
| Age | 14 (18) | 16 (21) | 17 (22) | |
| Gender | 1 (1) | 3 (4) | 3 (4) | |
| Underlying disease | 11 (14) | 11 (14) | 13 (17) | |
| BMI | 8 (10) | 8 (10) | 9 (12) | |
| Othera | 7 (9) | 5 (6) | 3 (4) | |
| Adaptation according to blood peripheral immune markers: | ||||
| No | 46 (59) | 43 (55) | 41 (53) | |
| Total lymphocytes | 12 (15) | 18 (23) | 15 (19) | |
| T lymphocytes | 7 (9) | 4 (5) | 8 (10) | |
| CD4+ T lymphocytes | 6 (8) | 8 (10) | 11 (14) | |
| B lymphocytes | 2 (3) | 2 (3) | 2 (3) | |
| NK cells | 0 (0) | 1 (1) | 1 (1) | |
| Lymphocyte function tests | 2 (3) | 2 (3) | 3 (4) | |
| Otherb | 1 (1) | 1 (1) | 1 (1) | |
| According to recipient immunological risk and clinical history: | ||||
| Adaptation whatever the past medical history | 38 (49) | 46 (59) | 54 (69) | |
| No adaptation if recent (only) acute cellular or humoral rejection | 26 (33) | 19 (24) | 11 (14) | |
| No adaptation if acute cellular or humoral rejection (even if ancient) | 12 (15) | 10 (13) | 8 (10) | |
| No adaptation if chronic lung allograft dysfunction (CLAD) | 12 (15) | 10 (13) | 8 (10) | |
| Otherc | 1 (1) | 0 (0) | 0 (0) | |
Case 1 = based on patient condition (n = 1); based on comorbidities and clinical conditions (n = 1); if AIFELL score 6 with 4 or more point: risk of bad evolution increased (n = 1); leucopenia (n = 1); based on lung function (n = 1); based on symptoms severity (n = 1). Case 2 = baseline lung function (n = 1); based on patient condition (n = 1); based on comorbidities and clinical conditions (n = 1); if AIFELL score 28 with 4 or more point: risk of bad evolution increased (n = 1); time of transplant (n = 1). Case 3 = based on patient condition (n = 1); based on comorbidities and clinical conditions (n = 1); depends if other infection (n = 1).
Cases 1, 2, and 3 = eosinophil count (n = 1).
Case 1 = if AIFELL score 29 with 4 or more point: risk of bad evolution increased (n = 1).
3.5. Therapeutic strategies to fight SARS-CoV-2 in lung transplant recipients
Remdesivir, hydroxychloroquine, and azithromycin were the most proposed antiviral strategies. In severe forms of COVID-19 especially, an anti-inflammatory therapy was proposed with corticosteroids at 1 mg/kg/d of prednisone dose equivalent (21%) or anti-IL6 therapy (26%). A prophylactic dose of antithrombotic therapy was mostly proposed whatever the severity of the COVID-19 ( Table 4).
TABLE 4.
Therapeutic strategies to treat recipients with COVID-19
| Case 1: mild COVID–19 recipient |
Case 2: moderate COVID–19 recipient |
Case 3: severe COVID–19 recipient |
||
|---|---|---|---|---|
| Question | Answers | n (%) | n (%) | n (%) |
| Do you propose an antiviral therapy to your patient? | ||||
| No | 25 (32) | 16 (21) | 11 (14) | |
| Remdesivir | 26 (33) | 32 (41) | 39 (50) | |
| Ribavirin | 1 (1) | 2 (3) | 1 (1) | |
| Ribavirin +Interferon | 0 (0) | 1 (1) | 0 (0) | |
| Favipiravir | 0 (0) | 0 (0) | 0 (0) | |
| Lopinavir-Ritonavir | 1 (1) | 5 (6) | 4 (5) | |
| Ribavirin +Interferon+ Lopinavir-Ritonavir | 2 (3) | 1 (1) | 2 (3) | |
| Darunavir | 0 (0) | 0 (0) | 0 (0) | |
| Umifenovir | 0 (0) | 0 (0) | 0 (0) | |
| Oseltamivir | 0 (0) | 0 (0) | 1 (1) | |
| (Val)ganciclovir | 0 (0) | 0 (0) | 2 (3) | |
| Chloroquine | 0 (0) | 1 (1) | 2 (3) | |
| Hydroxychloroquine | 3 (4) | 4 (5) | 5 (6) | |
| Chloroquine +Azithromycine | 2 (3) | 1 (1) | 3 (4) | |
| Hydroxychloroquine +Azithromycine | 6 (8) | 11 (14) | 11 (14) | |
| Azithromycine | 9 (12) | 10 (13) | 10 (13) | |
| Othera | 5 (6) | 5 (6) | 5 (6) | |
| No answer | 13 (17) | 12 (15) | 12 (15) | |
| Do you propose an anti-inflammatory therapy? | ||||
| No | 37 (47) | 30 (38) | 19 (24) | |
| Corticosteroids (0.5 mg/kg/d prednisone dose equivalent) | 8 (10) | 8 (10) | 4 (5) | |
| Corticosteroids (1 mg/kg/d prednisone dose equivalent) | 6 (8) | 14 (18) | 16 (21) | |
| Corticosteroids (2 mg/kg/d prednisone dose equivalent) | 3 (4) | 4 (5) | 6 (8) | |
| Corticosteroids (>2 mg/kg/d prednisone dose equivalent) | 1 (1) | 3 (4) | 6 (8) | |
| Anti-IL1 therapy (eg, Anakinra) | 2 (3) | 1 (1) | 4 (5) | |
| Anti-IL6 therapy (eg, Tocilizumab) | 7 (9) | 5 (6) | 20 (26) | |
| Convalescent plasma | 10 (13) | 7 (9) | 17 (22) | |
| Otherb | 4 (5) | 5 (6) | 7 (9) | |
| No answer | 13 (17) | 14 (18) | 12 (15) | |
| If no sign of thrombotic complication, do you propose an antithrombotic therapy? | ||||
| No (neither prophylactic nor therapeutic) | 4 (5) | 6 (8) | 4 (5) | |
| Prophylactic dose systematically | 35 (45) | 36 (46) | 27 (35) | |
| Prophylactic dose, only if a high-risk recipient | 8 (10) | 2 (3) | 0 (0) | |
| Prophylactic double dose systematically | 4 (5) | 14 (18) | 17 (22) | |
| Prophylactic double dose, only if a high-risk recipient | 3 (4) | 4 (5) | 3 (4) | |
| Therapeutic dose systematically | 4 (5) | 5 (6) | 13 (17) | |
| Therapeutic dose, only if a high-risk recipient | 6 (8) | 6 (8) | 8 (10) | |
| No answer | 11 (14) | 12 (15) | 12 (15) | |
Case 1 = consider switch from cyclosporine to tacrolimus; maintain tacrolimus dose sufficiently high (n = 1); leronlimab (n = 1); convalescent plasma (n = 1); only in the case of clinical trial (n = 1); we did both (ie, remdesivir and hydroxychloroquine +azithromycin); we did not know what arm our one recipient got randomized to placebo vs remdesivir (n = 1). Case 2 = leronlimab (n = 1); remdesivir in case of therapy failure with hydroxychloroquine +azithromycin (n = 1); only in the case of clinical trial (n = 1); plus intravenous antibiotic therapy if CRP >20 (n = 1), inclusion in Discovery trial, or hydroxychloroquine if not and O2 requirement >3L/min, plus biantibiotherapy including a macrolide (n = 1). Case 3 = tocilizumab (n = 1); aciclovir (n = 1), Discovery trial (n = 1); only in the case of clinical trial (n = 1); plasma therapy (n = 1).
Case 1 = hydroxychloroquine (n = 1); increase steroids if ARDS (n = 1); patient already in therapy with steroids (n = 1); plasma therapy in study if possible (n = 1). Case 2 = hydroxychloroquine (n = 1); steroid stress dose 15-20 mg/d, depending on patient weight (n = 1); increase steroids if ARDS (n = 1); plasma therapy in study if possible (n = 1), only in late phase if no concomitant bacterial infection (n = 1). Case 3 = intravenous immunoglobulins (n = 1); increased steroids +plasma if available in study (n = 1); steroid stress dose 15-20 mg/d, depending on patient weight (n = 1); steroids as prospective protocol DHYSCO (n = 1); according to inflammatory state (n = 1); double dose steroids for stress in the acute phase. ARDS dosage after 14d (n = 1); double the used corticoid dose (to prevent adrenal insufficiency, if low blood pressure, I would recommend higher dose [n = 1]).
3.6. Practice according to small- and large-volume centers
Large- and small-volume centers were defined as an activity of more or less than 40 LTx a year. Management of lung transplantation during the COVID-19 era was not different according to small- and large-volume centers (Table S1). Large-volume centers were faced with a higher absolute number of COVID-19 cases during the study period (January to April 2020). The difference could probably be due to a higher volume of recipients they followed up in their centers.
The management of the immunosuppression regimen in COVID-19 LTx recipients was not different in small- and large-volume centers. Large-volume centers used more frequently the association hydroxychloroquine plus azithromycin as an antiviral therapy to treat COVID-19 LTx recipients, whatever the severity (Table S2).
4. DISCUSSION
This international survey aimed to investigate the impact of the COVID-19 pandemic on global LTx activity. The main findings of our study were the following: (1) most participating centers’ LTx programs were affected during the early phase of the COVID-19 pandemic and were required to implement changes in their standard practice; (2) whether COVID-19 patients are candidates for LTx is controversial; and (3) most participating centers proposed specific antiviral regimens for COVID-19–positive LTx recipients, whereas substantial changes in the immunosuppressive regimen were mostly limited to severe cases.
The COVID-19 pandemic rapidly spread worldwide in early 2020 and the first cases of COVID-19 in LTx recipients have already been reported from centers all over the world.7, 8, 9, 10, 11, 12, 13, 14, 15 Due to their generally increased vulnerability to viral infections, immunocompromised patients were considered to be at high risk for critical courses of COVID-19. We, therefore, hypothesized that LTx providers changed their standard practice in order to prevent COVID-19 transmission in LTx recipients (especially in the early postoperative phase) and developed individual strategies to treat COVID-19 infections in LTx recipients.
In 2003, the SARS pandemic already led to temporary shutdowns of transplant centers in affected regions.16 Recently, in the United States, the numbers of LTx performed and LTx waiting list additions in April 2020 were decreased by approximately 40% and 34%, respectively, compared to January and February 2020.17 At the same time, deaths on the LTx waiting list increased by approximately 12%.17 Similar observations have been made in European countries hit by the pandemic such as France.18 The results from our present study underline the significant impairment of global LTx activity with a vast majority of 81% of the participating centers reporting a decrease in their LTx numbers between January and April 2020. Some centers even decided to periodically shut down their programs or stop new admissions to the waiting list. However, it is not clear whether the reduction of the centers’ activity was rather due to an active decision by the LTx providers in order to protect LTx candidates from severe infections, or due to external factors such as shortage of staff, equipment, donors, or ICU capacity.
Although long-term effects of SARS-CoV-2 infection are unknown today, it can be assumed that survivors of COVID-19 may be at risk of developing pulmonary fibrosis similar to patients with ARDS from other causes.19 First cases of LTx in patients with end-stage COVID-19 pneumonia undergoing intensive care including extracorporeal membrane oxygenation support but without ongoing replicative viral infection have recently been reported.20 , 21 Results from our present study indicate that there is currently no consensus on how to deal with end-stage lung disease caused by COVID-19. Criteria for eligibility of COVID-19 patients for LTx have yet to be defined but should probably be considered only in a very selected group of patients with COVID-19-related ARDS.22
Although early considerations judged transplant recipients to be more prone to severe courses of COVID-19 due to their chronically immune-incompetent state, there are also considerations that immunosuppression might be protective against fatal disease.23 The inflammatory response to SARS-CoV-2 might be attenuated in transplant recipients8 , 24 and their risk for mortality due to COVID-19 does not seem to be excessively increased.15 , 25 , 26 This was supported by the results of our present study, with a majority of survey participants reporting favorable courses in LTx recipients. Most participating experts estimate the risk of LTx recipients to develop severe COVID-19 equally or lower than that of the general population.
It has been suggested that, on the one hand, calcineurin inhibitors (tacrolimus and cyclosporine) exert a favorable disease-modifying effect.3 Based on preliminary data from the RECOVERY trial, corticosteroids have even been proposed as a therapeutic strategy improving outcomes in COVID-19.27 On the other hand, cell cycle inhibitors (such as mycophenolate mofetil) may have adverse effects in coronavirus infection, and published reports suggested stopping these drugs in infected transplant recipients.15 , 25 Compatible with these recommendations, the typical immunosuppressive regimen for COVID-19–affected LTx recipients included only punctual changes in immunosuppressive medication. Calcineurin inhibitors and mTOR inhibitors were typically continued, whereas cell cycle inhibitors were reduced or even stopped in moderate to severe COVID-19. Severe cases were typically treated with increased doses of corticosteroids.
In the natural absence of evidence-based specific antiviral approaches in the setting of a pandemic with a new infectious agent, the antiviral therapies used by the participating LTx centers mainly were based on remdesivir, hydroxychloroquine, and azithromycin, thus mirroring the general therapy attempts in this phase of the pandemic. The anti-inflammatory and immunomodulatory effects of azithromycin have been applied in LTx recipients long before the current pandemic to treat chronic lung allograft dysfunction with response rates of approximately 40%28; it is, therefore, a standard component of LTx medications for many LTx recipients. Since SARS-CoV-2 may possibly induce allograft dysfunction (such as infections with other coronaviruses), azithromycin may also have a distinctive role in LTx recipients with COVID-19. Abundant use of azithromycin in a general population with a consequent shortage of the substance should be seen critically with regard to its importance in post-LTx care.
In our practice (specifically in France where the number of cases was high during the study period, and hospitals saturated by COVID-19 patients), after a periodical shutdown and a dramatic decrease in LTx procedures during the study period that have been restricted to urgent cases only, a normal activity resumed in May 2020. At the early stage of the pandemic, swab testing was restricted to severe symptomatic COVID-19–suspected cases. Now, systematic donors and recipients testing for SARS-CoV-2 allows us to continue safely. Recipients in the early postoperative phase are isolated in a dedicated intensive care unit. Social distancing is now largely followed among patients, staff, and the general population. Personal protective equipment for staff and recipients was lacking at the early phase of the pandemic when the number of cases boomed. Now our hospitals are sufficiently supplied.
Telemedicine has been largely used in our centers during the study period to screen most severe complications after LTx. However, most routine monitoring such as systematic radiology or bronchoscopy have been postponed and we now face an important increase in activity (increased number of outpatients and inpatients for LTx monitoring) and difficulties managing new transplant patients and catch-up recipients with the consequence of late diagnosis of complications. We now test all recipients on the first day of their hospitalization or at each outpatient follow-up to ensure a safe activity. In case of another significant sustained spike in COVID-19 cases, we would probably try to maintain normal activity as much as possible with all safety measures in place (testing, protective personal equipment, distancing). In our experience, restriction of LTx procedures and remote recipient follow-up have led to an increased activity to catch-up the usual routine monitoring. This situation questions the risk of late diagnosis of post-LTx complications with potential significant consequences on long-term allograft outcome.
In conclusion, most of the centers have been affected by the COVID-19 pandemic and proposed an active therapeutic strategy to cure LTx recipients with COVID-19. Considering the ongoing pandemic, there is an urgent need for LTx providers to develop strategies to safely perform LTx procedures and after treatment in order to limit direct and indirect impairment of the prognosis of potential and actual LTx recipients. Appropriate protocols as proposed by some centers may thus help LTx centers to reestablish the ability to act.29 , 30
ACKNOWLEDGMENTS
We would like to thank all participants of this study who responded to the survey and made possible the collection of these data. All respondents agreed to participate in the survey and consented that the results of the study would be analyzed anonymously. Five participants declined to be cited as collaborators. All other participants gave voluntarily their names and the name of their center and consented to be disclosed as a collaborator as listed below: Selim M Arcasoy, MD (Columbia University Irving Medical Center, Charleston, South Carolina, USA); John-David Aubert, MD (Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland); David Bennett, MD (Azienda Ospedaliera Universitaria Senese, Siena, Italy); Alessandro Bertani, MD (Division of Thoracic Surgery and Lung Transplantation, IRCCS ISMETT, Palermo, Italy); Geoffrey Brioude, MD (Aix-Marseille University, Marseille, France); Marie Budev, MD (Cleveland Clinic, Cleveland, Ohio, USA); Stefania Camagni, MD (Hospital Papa Giovanni XXIII, Bergamo, Italy); Richard Daly, MD (Mayo Clinic, Rochester, New York, USA). Alejandro Da Lozzo, MD (Hospital Italiano de Buenos Aires, Buenos Aires, Argentina); Göran Dellgren, MD (Sahlgrenska University Hospital, Gothenburg, Sweden); Xavier Demant, MD (Hôpital Haut Lévêque, Pessac, France); Daniel Dilling, MD (Loyola University Chicago, Stritch School of Medicine, Chicago, Illinois, USA); Xavier Benoit D’Journo, MD (Aix-Marseille University, Marseille, France); Patrick Evrard, MD (CHU UCL Mont- Godinne, Yvoir, Belgium); Maria Elisa Uribe Echevarria, MD (Hospital Italiano de Cordoba, Cordoba, Argentinia); Reda Girgis, MD (Spectrum Health, Grand Rapids, Michigan, USA); Alice L Gray, MD (University of Colorado Hospital, Aurora, Colorado, USA); Mark Greer, MD (Hannover Medical School, Hannover, Germany); Denis Hadjiliadis, MD (Penn Medicine, Philadelphia, Pennsylvania, USA); René Hage, MD (University Hospital Zurich, Zurich, Switzerland); Matthias Hecker, MD (University of Giessen, Giessen, Germany); Sandrine Hirschi, MD (Hôpitaux Universitaires de Strasbourg, Strasbourg, France); Stephen Huddleston, MD (University of Minnesota, Minneapolis, Minnesota, USA); Christopher King, MD (Inova Fairfax Hospital, Falls Church, Virginia, USA); Julia Klesney-Tait, MD (University of Iowa Hospitals and Clinics, Iowa City, USA); Nikolaus Kneidinger, MD (Department of Internal Medicine V, Ludwig-Maximillians-University Munich, Member of the German Center for Lung Research [DZL], Munich, Germany); Christiane Knoop, MD (CHU Erasme, Brussels, Belgium); Achim Koch, MD (University Hospital Essen, Essen, Germany); Bartosz Kubisa, MD (Pomeranian Medical University of Szczecin, Szczecin, Poland); Jasleen Kukreja, UCSF Medical Center, San Francisco, California, USA); Johanna M Kwakkel-van Erp, MD (UZA, Antwerpen, Belgium); Aurélie Le Borgne, MD (Service de Pneumologie, Hôpital Larrey, Toulouse, France); Karl Lemström (Helsinki University Hospital, Helsinki, Finland); Deborah Levine, MD (University of Texas, San Antonio, Texas, USA); Robert Levy, MD (Vancouver General Hospital, Vancouver, Canada); Sandra Lindstedt, MD (Lund University Hospital, Lund, Sweden); Robert Lischke, MD (University Hospital Motol, Prague, Czech Republic); Monica, Loy, MD (Azienda Ospedaliera Padova, Padova, Italy); George Makdisi, MD (Tampa General Hospital, Tampa, Florida, USA); Ochman Marek, MD (Śląskie Centrum Chorób Serca, Zabrze, Poland); Archer Kilbourne Martin, MD (Mayo Clinic, Jacksonville, Florida, USA); Stephen McKellar, MD (University of Utah, Salt Lake City, Utah, USA); Federica Meloni, MD (Policlinico San Matteo Foundation, Pavia, Italy); Paolo Mendogni, MD (Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy); Olaf Mercier, MD (Hôpital Marie Lannelongue, Le Plessis Robinson, France); Jonathan Messika, MD (Hôpital Bichat, Paris, France); Eduardo Minambres, MD (Marqués de Valdecilla University Hospital, Santander, Spain); Takuro Miyazaki, MD (Nagasaki University Hospital, Nagsaki, Japan); Victor Monforte, MD (Hospital Vall d`Hebron, Barcelona, Spain); Pierre Mordant, MD (CHU Bichat Claude Bernard, Paris, France); Joshua Mooney, MD (Stanford Hospital, Stanford, California, USA); Miroslaw Necki, MD (Śląskie Centrum Chorób Serca, Zabrze, Poland); Anna Nolde, MD (Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany); Gian Maria Paganelli, MD (S.Orsola-Malpighi Hospital, Bologna, Italy); Luca Paoletti, MD (Medical University of South Carolina, Charleston, SC, USA); Joseph Pilewski, MD (University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA); Andres Pelaez, MD (University of Florida Health, Gainesville, Florida, USA); Michael Perch, MD (Rigshospitalet, Copenhagen, Denmark); Benjamin Renaud-Picard, MD (Hôpitaux Universitaires de Strasbourg, Strasbourg, France); Ivan Robbins, MD (Vanderbilt University Medical Center, Nashville, USA); Macé M Schuurmans, MD (University Hospital Zurich, Zurich, Switzerland); Harish Seethamraju, MD (Montefiore Medical Center, Bronx, New York, USA); Takeshi Shiraishi, MD (Fukuoka University Hospital, Fukuoka, Japan); Zeglen Slawomir, MD (Medical University of Gdańsk, Gdańsk, Poland); Paola Soccal, MD (Geneva University Hospitals, Geneva, Switzerland); Heather Strah, MD (University of Nebraska Medical Center, Omaha, Nebraska, USA); Alexy Tran Dinh, MD (CHU Bichat, Paris, France); Rade Tomic, MD (Northwestern University, Chicago, USA); Federico Venuta, MD (University of Rome, Rome, Italy); Geert M. Verleden, MD (University Hospitals Leuven, Leuven, Belgium); Robin Vos, MD (University Hospitals Leuven, Leuven, Belgium).
DISCLOSURE
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.