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Original Clinical Science—General

COVID-19 in Lung Transplant Recipients

Messika, Jonathan MD, PhD1,2,3; Eloy, Philippine PharmD4,5; Roux, Antoine MD, PhD3,6,7; Hirschi, Sandrine MD8; Nieves, Ana MD9; Le Pavec, Jérôme MD, PhD10,11,12; Sénéchal, Agathe MD13; Saint Raymond, Christel MD14; Carlier, Nicolas MD15; Demant, Xavier MD16; Le Borgne, Aurélie MD17; Tissot, Adrien MD18; Debray, Marie-Pierre MD19; Beaumont, Laurence MD6; Renaud-Picard, Benjamin MD8; Reynaud-Gaubert, Martine MD, PhD9; Mornex, Jean-François MD, PhD13,20; Falque, Loïc MD14; Boussaud, Véronique MD15; Jougon, Jacques MD, PhD16; Mussot, Sacha MD10,11,12; Mal, Hervé MD, PhD1,2; for the French Group of Lung Transplantation

Author Information
doi: 10.1097/TP.0000000000003508

Abstract

INTRODUCTION

In the time of the worldwide coronavirus disease 2019 (COVID-19) pandemic, comorbidities significantly affect prognosis.1-3 Among comorbidities, immunosuppression has scarcely been reported. Nevertheless, a concern was internationally raised for solid organ transplantation (SOT) recipients,4 and reports emerged from various areas.5-17 From these reports, a few observations can be drawn: the clinical presentation, severity, and outcomes are heterogenous, as in the general population1,2,18; coinfections or coisolations of other pathogens might appear at the onset of symptoms19; and clear management of the immunosuppressive maintenance regimen and antiviral treatments during the episode must be set up.17,20,21

Besides immunosuppression, lung transplantation (LT) recipients are particularly scrutinized because the main injury of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is respiratory, patients sometimes have impaired respiratory function,22 and clinical presentation may be altered by local factors. The first case reports of COVID-19 pneumonia in LT recipients described an uneventful evolution: some patients were hospitalized with low-flow oxygen,8,17 and others remained at home.9 Moreover, published series of SOT recipients with COVID-19 described a small number of LT recipients.9,13,15,16 Nevertheless, no comprehensive study has described COVID-19 manifestations in LT recipients.

We aimed to identify LT patients presenting COVID-19 in all French LT centers and describe their clinical presentation, characteristics, and outcome (including intensive care unit [ICU] admission), with associated risk factors.

MATERIALS AND METHODS

Setting and Study Subjects

We conducted a retrospective, multicenter cohort study in the 11 French LT centers. All adult LT recipients with a biologically confirmed or highly suspected SARS-CoV-2 infection who were followed in 1 of these centers from March 1 to May 19, 2020 were enrolled. The study was approved by the Institutional Review Board of the Société de Pneumologie de Langue Française (CEPRO 2020-015). According to French law, the patients (or their proxies) were informed of the study, its purpose and objectives and did not object to the collection of their data.

Data Collection

Study data were collected anonymously and managed by physicians and research teams by use of an electronic data capture tool23 (see Figure S1, SDC, http://links.lww.com/TP/C46). Demographic data collected included sex and age. Type of LT (single or double lung, combined organs), date of LT, and the underlying diagnosis were recorded. Type and stage of chronic lung allograft dysfunction before the episode were defined.22 Comorbid conditions and type of current or recent immunosuppressive therapies were recorded. Data were collected on clinical, biological, and CT findings at COVID-19 diagnosis, type of sample positive for SARS-CoV-2, community- or hospital-acquired type of episode, and the coisolation of a pathogen or the occurrence of a superinfection. Patients were followed after the episode until May 19, 2020, when the data collection system was frozen.

Outcome

The primary endpoint was death at follow-up. Secondary endpoints were ICU admission, need for invasive mechanical ventilation, time elapsed from (1) LT to COVID-19 diagnosis, (2) the first symptoms to COVID-19 diagnosis, (3) the first symptoms to hospital admission, (4) the first symptoms to ICU admission, and (5) the first symptoms to mechanical ventilation onset and COVID-19 complications.

Definitions

Diagnosis of SARS-CoV-2 infection was ascertained by a positive SARS-CoV-2 result on real-time RT-PCR assay1 of a respiratory sample or highly suspected in an LT recipient presenting the association of clinical presentation of COVID-19, typical chest CT-scan pattern,24 and no alternative diagnosis during the study period.

Chronic kidney disease was defined by estimated glomerular filtration rate <60 mL/min/1.73 m2.25 Fever was defined as corporeal temperature >37.8°C. A hospital-acquired COVID-19 episode was defined for patients who had been admitted 5 days or more before the first symptom(s), and healthcare-associated COVID-19 was defined for patients who lived in a nursing home or extended-care facility or who received chronic dialysis. Other episodes were considered community-acquired. A typical chest CT-scan pattern was defined according to Salehi et al,24 and chest CT-scans were centrally reviewed and scored by a skilled radiologist (MPD). Extension of pneumonia was considered minimal with the pulmonary injury representing <10% of the pulmonary field, moderate with 10%–25%, extensive with 25%–50%, severe with 50%–75%, and critical with >75%.

The need for ICU admission and occurrence of thromboembolic disease, acute respiratory distress syndrome,26 and acute kidney injury27 were considered COVID-19 complications, and data on overdose of calcineurin inhibitors were collected.

Statistical Analysis

Continuous variables are described with median and interquartile range (IQR) unless otherwise indicated. Categorical variables are described with number (%). For analysis of factors associated with mortality or ICU admission, univariate analyses assessed associations between outcomes and demographic characteristics, comorbidities, and treatments with a logistic regression model. Variables with P < 0.20 in univariate analysis were tested in multivariate models. Mann-Whitney test was used for analysis of continuous variables and chi-square or Fisher exact test as appropriate for categorical variables. All tests were 2-tailed, and P < 0.05 was considered statistically significant. Statistical analysis was performed with R v4.0.1.

RESULTS

Diagnosis of Infection

We report the cases of 35 patients from the 11 French LT centers who experienced COVID-19 during the study period. Diagnosis was ascertained by a positive RT-PCR test for SARS-CoV-2 in 30 (85.7%) patients and was highly suspected in 5 (14.3%).

Demographics and Comorbid Conditions

Main demographic characteristics are reported in Table 1. Median age was 50.4 (IQR, 40.6–62.9) years, and 16 (45.7%) patients were female. In total, 28 (80%) patients had double LT, 7 single LT (20%; 5 right, 2 left), and none cardiopulmonary transplantation. Time from LT was 38.2 (6.6–78.3) months. Two patients had received another solid organ transplant (1 kidney, 1 liver).

TABLE 1. - Demographics and comorbid conditions
Total (n = 35) ICU (n = 13) Hospital ward (n = 18) Outpatients (n = 4) Survivors (n = 30) Nonsurvivors (n = 5)
Age, y 50.4 (40.6–62.9) 59.7 (47.9–63.2) 45.5 (40.3–61.0) 40.9 (33.4–52.3) 48.1 (40.5–63.0) 58.1 (50.4–60.5)
Gender, M/F 19/16 8/5 7/11 4/0 16/14 3/2
BMI, kg/m2 21.5 (20.3–22.6) 23.8 (20.4–27.4) 21.0 (20.2–24.8) 21.0 (20.4–21.4) 21.0 (20.2–24.0) 25.9 (25.6–27.4)
 <25 25 (71.4) 7 (53.8) 14 (77.8) 4 (100) 24 (80) 1 (20)
 ≥25 to <30 10 (28.6) 6 (46.2) 4 (22.2) 0 6 (20) 4 (80)
 ≥30 0 0 0 0 0 0
Type of LT, n (%)
 Single lung 7 (20) 2 (16.7) 4 (22.2) 1 (25) 6 (20) 1 (20)
 Double lung 28 (80) 11 (84.6) 14 (77.8) 3 (75) 24 (80) 4 (80)
 Heart-lung 0 0 0 0 0 0
Indication for LT
 Obstructive pulmonary disease 12 (34.3) 3 (23.1) 7 (38.9) 2 (50) 11 (36.7) 1 (20)
 Interstitial lung disease 9 (25.7) 7 (53.8) 2 (11.1) 2 (50) 5 (16.6) 4 (80)
 Cystic fibrosis 11 (31.4) 2 (15.7) 7 (38.9) 0 11 (36.7) 0
 Pulmonary arterial hypertension 1 (2.9) 0 1 (5.6) 0 1 (3.3) 0
 Graft-vs-host pulmonary disease 1 (2.9) 0 1 (5.6) 0 1 (3.3) 0
 Lymphangioleiomyomatosis 1 (2.9) 1 (7.7) 0 0 1 (3.3) 0
Age at LT—y 48.1 (35.0–59.8) 55.4 (45.8–62.4) 40.8 (35.0–59.4) 32.7 (30.4–40.4) 44.3 (35.0–59.7) 56.8 (49.6–59.9)
Comorbid conditions
 Recipient of another solid organ, n (%) 3 (8.6) 1 (7.7) 2 (11.1) 0 3 (10) 0
 Liver 1 (2.9) 0 1 (5.6) 1 (3.3)
 Kidney 1 (2.9) 1 (7.7) 0 1 (3.3)
CLAD, n (%) 7 (20) 3 (23.1) 3 1 (25) 6 (20) 1 (20)
CLAD stage, n (%)
 Stage 1 4 (11.4) 2 (14.4) 2 (11.1) 0 3 (10) 1 (20)
 Stage 2 2 (5.7) 1 (7.7) 0 1 (25) 2 (6.7)
 Stage 3 1 (2.9) 0 1 (5.6) 0 1 (3.3)
Bronchial complications, n (%) 6 (17.1) 3 (23.1) 3 (16.7) 3 (75) 4 (13.3) 2 (40)
 Stable bronchial stenosis 2 (5.7) 0 2 (11.1) 2 (50) 2 (6.7) 2 (40)
 Bronchial interventions in the last 3 mo 4 (11.4) 3 (23.1) 1 (5.6) 1 (25) 2 (6.7)
 Chronic arterial hypertension, n (%) 15 (42.9) 6 (46.2) 6 3 (75) 13 (43.3) 2 (40)
 Incl. requiring treatment with renin-aldosterone blockers 10 (28.6) 5 (38.5) 4 1 (25) 9 (30) 2 (40)
Chronic renal failure, n (%) 14 (40) 4 (30.8) 8 (47.1) 2 (50) 15 (50) 1 (20)
 Incl. requiring renal replacement therapy 1 (2.9) 0 1 (5.6) 0 1 (3.3) 0
 Median eGFR (mL/min/1.73m2) 63.0 (43.0–90.0) 76.5 (53.8–90.0) 65.0 (39.0–77.0) 47.5 (30.5–67.5) 62.0 (42.0–83.3) 90.0 (63.0–90.0)
Ongoing treatment before COVID-19 episode, n (%)
 Calcineurin inhibitor 35 (100) 13 (100) 18 (100) 4 (100) 30 (100) 5 (100)
 Antimetabolite 29 (82.9) 10 (76.9) 15 (83.3) 4 (100) 25 (83.3) 4 (80)
 Oral corticosteroids 33 (94.3) 13 (100) 17 (94.4) 3 (75) 28 (93.3) 5 (100)
 (median dose) 8.8 (5.0–11.3) 10.0 (9.4–19.4) 7.5 (5.0–10.0) 7.5 (7.3–8.8) 7.5 (5.0–12.5) 10 (7.5–10.0)
 mTOR inhibitor 7 (20) 3 (23.1) 3 (16.7) 1 (25) 6 (20) 1 (20)
 Azithromycin 15 (42.9) 4 (30.8) 9 (50) 2 (50) 14 (46.7) 1 (20)
 Inhaled corticosteroids 4 (11.4) 3 (23.1) 0 1 (25) 2 (6.7) 2 (40)
 Inhaled ß2-receptor agonist 7 (20) 4 (30.8) 1 (5.6) 2 (50) 5 (16.7) 2 (40)
 Insulin 10 (28.6) 4 (30.8) 5 (27.8) 1 (25) 8 (26.7) 2 (40)
Intensification of immunosuppression therapy during the last 6 mo, n (%) 7 (20) 5 (38.5) 2 (11.1) 0 6 (20) 1 (20)
 Induction therapy 3 (8.6) 1 (7.7) 2 (11.1) 3 (10) 0
 Intravenous corticosteroid pulses 7 (20) 5 (38.5) 2 (11.1) 6 (20) 1 (20)
 Rituximab infusion 1 (2.9) 1 (7.7) 0 1 (3.3) 0
 Plasmapheresis 2 (5.7) 2 (15.4) 0 1 (3.3) 0
 Bortezomib 0 0 0 0 0
Time from the last intensification therapy, d 89.0 (5.0–140.0) 7.0 (3.0–89.0) 162.5 (154.2–170.8) 115.0 (78.3–154.3) 111.5 (24.5–143.0) 7
Time from LT, mo 38.2 (6.6–78.3) 9.6 (4.5–98.9) 44.6 (16.5–66.8) 59.6 (24.7–114.9) 43.0 (7.0–86.3) 9.6 (7.2–16.3)
Data are median (interquartile range) unless otherwise indicated.
BMI, body mass index; CLAD, chronic lung allograft dysfunction; COVID-19, coronavirus disease 2019; eGFR, estimated glomerular filtration rate by Chronic Kidney Disease Epidemiology Collaboration; ICU, intensive care unit; LT, lung transplant; mTOR, mammalian target of rapamycin.

Chronic lung allograft dysfunction had been diagnosed in 6 (17.1%) patients; 6 had bronchial complications (17.1%), 4 of whom required interventional endoscopic procedure within 3 months before COVID-19 onset. All but 1 patient (97.1%) received calcineurin inhibitor therapy before COVID-19 onset. Most (n = 33) received daily oral corticosteroids at a median dose of 8.75 (5.0–11.25) mg/d prednisone or equivalent, and 15 (42.9%) were on azithromycin before the episode.

Seven patients (20%) had undergone an intensification of their immunosuppression regimen in the last 6 months (median time from intensification to COVID-19 onset 89.0 [5.0–140.0] d). This intensification always included high-dose corticosteroid pulses, associated with another therapy for 5 (induction therapy in 3; plasmapheresis in 2; and 1 who also received rituximab infusion).

Characteristics of COVID-19

SARS-CoV-2 infection was most often community-acquired (25 [71.4%] patients); hospital-acquired in 7 (20%), including 1 who was already in the ICU at the time of diagnosis; and healthcare-associated in 3 (8.6%).

The manifestations of COVID-19 are summarized in Table 2. Median time from the first symptoms to diagnosis was 4.0 (1.0–7.0) days. Fever was the first and most frequent sign, occurring in 25 (71.4%) patients, followed by cough (n = 19; 54.3%). Diarrhea occurred in 11 (31.4%) patients and acute renal failure in 4 (11.4%). A chest CT-scan was performed at a median of 4 (1–7) days after first symptoms in 25 (71.4%) patients: 1 had no abnormalities (despite a positive RT-PCR result in a respiratory sample). The main findings were ground-glass opacities in 24 (92.3%) patients. Extension of pneumonia was considered minimal in 6 (23.1%), moderate in 9 (36%), and extensive or severe in 9 (34.6%). None had pulmonary extension >75%.

TABLE 2. - Clinical, radiologic, and laboratory findings of 35 lung transplant patients at COVID-19 diagnosis
Total n = 35 ICU n = 13 Hospital ward n = 18 Outpatients n = 4 Survivors n = 30 Nonsurvivors n = 5
Time from LT (mo) 38.2 (6.6–78.3) 9.6 (4.5–98.9) 44.6 (16.5–66.8) 59.6 (24.7–114.9) 43.0 (7.0–86.3) 9.6 (7.2–16.3)
Settings of COVID-19 acquisition, n (%)
 Community-acquired 25 (71.4) 6 (46.2) 15 (83.3) 4 (100) 23 (76.7) 2 (40)
 Hospital-acquired 7 (20) 5 (38.5) 2 (11.1) 0 5 (16.7) 2 (40)
 Healthcare-associated 3 (8.6) 2 (15.4) 1 (5.6) 0 2 (6.7) 1 (20)
Signs and symptoms
 Fever 25 (71.4) 10 (76.9) 13 (72.2) 2 (50) 21 (70) 4 (75)
 Cough 19 (54.3) 6 (46.2) 11 (61.1) 2 (50) 17 (56.7) 2 (40)
 Dyspnea 15 (42.9) 9 (69.2) 4 (22.2) 2 (50) 11 (36.7) 4 (75)
 Expectoration 12 (34.3) 4 (30.8) 8 (44.4) 0 10 (33.3) 2 (40)
 Diarrhea 11 (31.4) 2 (15.4) 8 (44.4) 1 (25) 10 (33.3) 1 (20)
 Headache 12 (34.3) 2 (15.4) 9 (50) 1 (25) 12 (40) 0
 Myalgia 13 (37.1) 3 (23.1) 8 (44.4) 2 (50) 13 (43.3) 0
 Acute renal failure 4 (11.4) 2 (15.4) 2 (11.1) 0 3 (10) 1 (20)
 Asthenia 16 (45.7) 7 (53.8) 8 (44.4) 1 (25) 15 (50) 1 (20)
Chest CT-scan findings
No abnormalities, n (%) 1 (3.8) 0 1 (7.1) 0 1 (4.8) 0
Extension of abnormalities, n (%)
 Minimal or <10% 6 (23.1) 0 6 (42.8) 0 5 (23.8) 1 (20)
 Moderate or 10%–25% 9 (36.0) 4 (40.0) 5 (35.7) 1 7 (23.3) 2 (40)
 Extensive or 25%–50% 7 (26.9) 4 (40.0) 2 (14.3) 0 5 (23.8) 2 (40)
 Severe or 50%–75% 2 (7.7) 2 (20.0) 0 0 2 (9.5) 0
 Critical or >75 0 0 0 0 0
Radiological pattern, n (%)
 Ground-glass opacities 24 (92.3) 10 (100) 13 (86.7) 1 (100) 19 (90.5) 5 (100)
 Incl. with crazy paving 7 (26.9) 4 (40.0) 3 (20.0) 1 (100) 6 (28.6) 1 (20)
 Consolidations 12 (46.2) 6 (60.0) 5 (33.3) 1 (100) 9 (42.9) 3 (60)
 Single-sided abnormalities, n (%) 3 (11.5) 0 3 (20.0) 0 2 (9.5) 1 (20)
 Bilateral abnormalities, n (%) 22 (84.6) 10 (100) 11 (73.3) 1 (100) 18 (85.7) 4 (80)
Laboratory findings at diagnosis
 PaO2/FiO2 278.6 (162.8–357.7) 187.5 (100.0–319.0) 357.7 (275.4–429.5) 319.0 (186.2–375.0) 179.9 (118.1–187.5)
 White cell count, per mm3 6085 (4720–9425) 5840 (4100–9400) 6200 (5180–9800) 5650 (5425–5875) 6100 (4655–9450) 4580 (3910–7030)
 <4000, n (%) 5 (17.9) 3 (23.1) 2 (15.4) 2 (100) 4 (17.4) 1 (20)
 ≥4000 to ≤10 000, n (%) 19 (67.9) 8 (61.5) 9 (50) 16 (69.7) 3 (60)
 >10 000, n (%) 4 (14.3) 2 (15.4) 3 (69.2) 3 (13.0) 1 (20)
Lymphocyte count, per mm3 790 (585–1200) 670 (515–925) 1100 (780–1750) 1185 (877–1495) 985 (713–1635) 560 (500–600)
 <800, n/total, n (%) 14 (51.9) 8 (66.7) 5 (38.5) 1 (50) 9 (40.9) 5 (100)
 >800, n/total, n (%) 13 (44.8) 4 (33.3) 8 (61.5) 1 (50) 13 (59.1)
Creatinine, µmol/L 104.0 (84.0–154.0) 92.0 (81.0–141.0) 122.0 (88.4–170.2) 185.0 (144.5–225.5) 112.5 (84.8–154.3) 96.0 (81.0–141.0)
 >133, n/total, n (%) 12 (41.4) 5 (38.5) 6 (42.9) 1 (50) 10 (41.7) 2 (40
C-reactive protein, mg/L 67.0 (25.0–126.0) 88 (38–126) 49 (24.3–131.3) 4.4 (3.5–5.2) 49.0 (21.8–99.0) 147 (67–177)
Procalcitonin, ng/mL 0.22 (0.12–0.41) 0.15 (0.07–0.23) 1.53 (0.27–6.09) NA 0.23 (0.13–0.34) 0.22 (0.15–1.50)
 <0.1, n/total, n (%) 3 (27.3) 3 (42.9) 0 2 (25.0) 1 (33.3)
 ≥0.1 to <0.25, n/total n (%) 4 (36.4) 3 (42.9) 1 (25.0) 3 (37.5) 1 (33.3)
 ≥0.25 to <0.5, n/total n (%) 1 (9.1) 0 1 (25.0) 1 (12.5) 0
 ≥0.5 ng/mL, n/total n (%) 3 (27.3) 1 (14.3) 2 (50.0) 2 (25.0) 1 (33.3)
Creatine kinase 40 (32.0–86.8) 60.0 (31.0–93.0) 37.5 (32.8–70.5) 39.0 39.5 (32.0–55.0) 115.0 (57.0–206.2)
Serum ferritin, µg/L 1156 (570–2200) 1156 (573–1658) 1292 (382–2325) NA 1163 (571–2065) 841.0 (704.5–2052.5)
Incl. >300 µg/L, n (%) 13 (100) 9 (100) 4 (100) 10 (100) 3 (100)
D-dimer, ng/mL 991.5 (495.5–1592.0) 743 (633–1824) 1240 (215–1357) NA 991.5 (578.5–1441.8) 1294 (852–1736)
 ≤500, n (%) 3 (25.0) 1 (14.3) 2 (40.0) 2 (22.2) 1 (50)
 >500 to ≤1000, n (%) 3 (25.0) 3 (42.9) 0 3 (33.3) 0
 >1000, n (%) 5 (41.7) 2 (28.6) 3 (60.0) 4 (44.4) 1 (50)
Data are median (interquartile range) unless otherwise indicated.
A chest CT-scan was performed for 25 (71.4%) patients (10 finally admitted in the ICU), after a median time of 4 (1–7) d from diagnosis; PaO2/FiO2 ratio was available for the 17 patients who underwent blood-gas analysis, 6 ward patients, 13 survivors and 4 nonsurvivors; white blood cell count for 28 patients, 13 ICU patients, 13 ward patients and 2 outpatients, 23 survivors and 5 nonsurvivors; lymphocyte count for 27 patients, 12 ICU patients, 13 ward patients, 2 outpatients, 22 survivors and 5 nonsurvivors; creatinine level for 29 patients, 13 ICU patients, 14 ward patients, 2 outpatients, 24 survivors and 5 nonsurvivors; C-reactive protein level for 29 patients, 13 ICU patients, 14 ward patients, 2 outpatients, 24 survivors and 5 nonsurvivors; procalcitonin level for 11 patients, 7 ICU patients, 4 ward patients, no outpatient, 8 survivors, 3 nonsurvivors; ferritine level for 13 patients, 9 ICU patients, 4 ward patients, no outpatient, 10 survivors, 3 nonsurvivors; D-dimer level for 12 patients, 7 ICU patients, 5 ward patients, no outpatient, 10 survivors and 2 nonsurvivors; creatine kinase level for 14 patients, 9 ICU patients, 4 ward patients, 1 outpatient 10 survivors, and 4 nonsurvivors.
COVID-19, coronavirus disease 2019; ICU, intensive care unit; NA, not available.

The main biological features at first hospital admission are in Table 2. Seven (20%) patients had a respiratory bacterial coisolation at diagnosis, documented on the initial respiratory sample (Pseudomonas aeruginosa, n = 5; Streptococcus pneumoniae, n = 1; and Corynebacterium sp., n = 2). Two had a viral coisolation: cytomegalovirus reactivation in 1 and rhinovirus/enterovirus sampled in the respiratory tract in 1. Finally, Aspergillus sp. was isolated from a single respiratory sample from 1 patient.

Treatment Settings

Four (11.4%), 25 (71.4%), and 6 (17.1%) patients were exclusively cared for as outpatients, primarily hospitalized in the general ward, and primarily cared for in the ICU, respectively (Figure 1). Among the 25 patients primarily hospitalized in the general ward, 7 (28.0%) were secondarily cared for in the ICU. Overall, 13 (37.1%) patients were admitted to the ICU, including 1 who was already in the ICU at the time of diagnosis. For the 12 patients who were not in the ICU at diagnosis, ICU admission occurred after a median of 13.0 (5.5–14.8) days from the onset of symptoms and 1.0 (0–4.0) days from hospital admission for the 8 with COVID-19 acquired outside the hospital.

FIGURE 1.
FIGURE 1.:
Flowchart of the cohort. Among the 35 lung transplant recipients with COVID-19, 4 were cared for as outpatients. Twenty-five were treated in the respiratory ward, including 7 who were secondarily admitted in the ICU; 6 were initially treated in the intensive care unit, including 1 who acquired COVID-19 in the ICU. In total, 30 were alive after a median follow-up of 50 (41.0–56.5) d. COVID-19, coronavirus disease 2019; ICU, intensive care unit.

Immunosuppression Management

For 13 (37.1%) patients, the antimetabolite therapy was discontinued, with an increase in corticosteroids in 7, combined with withdrawal of the mammalian target of rapamycin (mTOR) inhibitor in 1 and withdrawal of calcineurin inhibitor in 1. Two (5.7%) others had a withdrawal of the mTOR inhibitor without any antimetabolite therapy change: 1 had increased corticosteroids dosage, and 3 only increased corticosteroids dosage. The 11 (31.4%) patients with an increase in corticosteroids dosage received a median dose of 100 (40–125) mg/d of prednisone or equivalent.

Management of Specific Infection

Eleven (31.4%) patients received at least 1 specific treatment intended to treat the SARS-CoV-2 infection: hydroxychloroquine for 9 (25.7%); remdesivir for 2; and lopinavir-ritonavir association for 2. Of note, 2 patients received 2 different treatments (remdesivir followed by chloroquine or lopinavir-ritonavir followed by remdesivir). All 15 (42.9%) patients who received azithromycin before COVID-19 continued it, and 2 additional patients received azithromycin associated with hydroxychloroquine (ie, 17 [48.6%] patients overall received azithromycin).

Outcomes and Complications

Survival was 85.7% (n = 30) after a median follow-up of 50 (41.0–56.5) days. Five patients died (14.3%; 95% CI, 5.4-31.0), due to multiorgan failure and acute respiratory distress syndrome in 4, and 1 was not admitted to the ICU because of limitation of therapeutic effort.

Among the 25 patients primarily hospitalized in the general hospital ward, 22 (88.0%) received low-flow oxygen therapy. Among the 13 patients (37.1%; 95% CI, 21.9-55.1) in the ICU, 5 received noninvasive respiratory support (ie, nasal high-flow oxygen therapy only, because no patient received continuous positive pressure or noninvasive ventilation), 7 (53.8%) received invasive mechanical ventilation, 4 had prone positioning, and 1 had veno-venous extracorporeal membrane oxygenation. Four received catecholamine infusion and 5 (38.5%) renal replacement therapy.

Three of the 7 patients with invasive ventilation died. At the end of follow-up, 6 patients remained hospitalized, including 4 in the ICU.

During follow-up, a thrombotic event occurred in 4 patients (3 with pulmonary embolism and 1 arterial embolic manifestation of the lower limb due to an intracardiac thrombus). Twelve (34.3%) patients had at least 1 pulmonary superinfection (11 bacterial and 1 fungal). Two had bacteremia during follow-up (detailed in Table 3).

TABLE 3. - Treatments and outcomes
Total n = 35 ICU n = 13 Hospital ward n = 18 Outpatients n = 4 Survivors n = 30 Nonsurvivors n = 5
Withdrawal of calcineurin inhibitor 1 (2.9) 0 1 (5.5) 0 1 (3.3) 0
Withdrawal of antimetabolite 13 (37.1) 7 (53.8) 6 (33.3) 0 11 (36.7) 2 (40)
Tapering of oral corticosteroids 0 0 0 0 0
Withdrawal of mTOR inhibitor 3 (8.6) 1 (7.7) 2 (11.1) 0 2 (6.7) 1 (20)
Antiinflammatory management
 Continuation or initiation of azithromycin 17 (48.6) 4 (30.7) 10 (55.6) 3 (75) 16 (53.3) 1 (20)
 High-dose corticosteroid 12 (31.4) 7 (53.8) 4 (22.2) 0 8 (26.7) 3 (75)
 Dose (prednisone equivalent, mg) 100 (50–125) 120 (90–125) 50 (35.0–76.3) 70.0 (35.0–106.3) 125 (122.5–125)
Antiinterleukin 6 treatment, n (%)
 Tocilizumab 1 (2.9) 1 (7.7) 0 0 1 (3.3) 0
 Sarilumab 1 (2.9 1 (7.7) 0 0 1 (3.3)
Antiinterleukin 1 treatment—anakinra n (%) 2 (5.7) 2 (15.4) 0 1 (3.3) 1 (20)
Specific infection management
 Lopinavir-ritonavir 2 (5.7) 2 (15.4) 0 0 2 (6.7) 0
 Hydroxychloroquine 9 (25.7) 3 (23.1) 5 (27.8) 1 (25) 8 (26.7) 1 (20)
 Remdesivir 2 (5.7) 2 (15.4) 0 0 2 (6.7) 0
Organ failure management
 Low-flow oxygen, n (%) 22 (69.9) 9 (69.2) 13 (72.2) 0 18 (60) 4 (75)
 High-flow nasal cannula, n (%) 5 (14.3) 5 (38.5) 0 0 3 (10) 2 (40)
 Noninvasive mechanical ventilation, n (%) 0 0 0 0 0 0
 Invasive mechanical ventilation, n (%) 7 (20) 7 (53.8) 4 3 (60)
 Length, d 10.5 (9.0–13.5) 10.5 (9.0–13.5) 9 (9.0–22.0) 12 (8.5–13.0)
1 (3.3) 3 (60)
 Incl. prone positioning 4 (11.4) 4 (30.8)
ECMO, n (%) 1 (2.9) 1 (7.7) 1 (3.3) 0
 Length, d 6 6 6
Renal replacement therapy 5 (14.3) 4 (33.3) 1 (5.5) 3 (10) 2 (40)
 Length, d 3 (2.5–21) 6.5 (2.3–26.5) 3 10 (3.0–32.0) 2.5 (2.0–3.0)
Catecholamine infusion 4 (11.4) 4 (30.8) 1 (3.3) 3 (60)
 Length, d 8.5 (5.3–11.8) 8.5 (5.3–11.8) 3 11.0 (8.5–12.5)
Bacterial superinfection, n (%) 11 (31.4) 5 (41.7) 6 (33.3) 0 9 (30) 2 (40)
 Pneumonia 11 (31.4) 5 (41.7) 6 (33.3) 0 9 2 (40)
 Bacteremia 2 (5.7) 2 (15.4) 0
Fungal superinfection, n (%) 1 (2.9) 0 1 (5.6) 0 0
Complications
Calcineurin inhibitor overdose, n (%) 9 (25.7) 7 (58.3) 2 (11.1) 0 7 (23.3) 2 (40)
ARDS, n (%) 9 (25.7) 9 (69.2) 5 (16.7) 4
 Worst PaO2/FiO2 68.0 (50.0–142) 68.0 (50.0–142) 142.0 (50.0–148.0) 62.0 (51.5–92.0)
Pulmonary embolism, n (%)
 Time from onset of illness to pulmonary embolism 3 (8.6) 3 (23.1) 0 0 2 (6.7) 1 (20)
Other embolic manifestationa 1 (2.9) 0 0 1 (25) 1 (3.3) 0
Renal failure, n (%) 4 (11.4) 2 (15.4) 2 (11.1) 0 4 (13.3)
Outcomes
 Death, n (%) 5 (14.3) 4 (30.8) 1 (5.6) 0
 Length of ICU stay, d 11.5 (5.5–20.3) 11.5 (5.5–20.3) 12.5 (5.5–37.8) 9.0 (4.5–12.8)
 Length of follow-up, d 50 (41.0–56.5) 49.0 (24.0–57) 49.5 (42.3–55.8) 54 (46.5–55.0) 52.5 (46.5–57.0)
Data are median (interquartile range) unless otherwise indicated.
Bacterial pulmonary superinfection were due to: Pseudomonas aeruginosa (n = 6), Streptococcus pneumoniae (n = 1), Methicillin-susceptible Staphylococcus aureus (n = 2), Haemophilus influenzae (n = 1), Enterobacter sp (n = 1), Corynebacterium sp. (n = 1), Stenotrophomonas maltophilia (n = 1); Bacteremia was caused by Enterococcus sp (n = 1), and Pseudomonas aeruginosa (n = 1); Fungal superinfection was due to Aspergillus fumigatus; worst PaO2/FiO2 was obtained for 7 patients
who underwent invasive mechanical ventilation, 4 survivors, and 3 nonsurvivors.
aOne patient had arterial embolic manifestation with lower-limb ischemia.
ARDS, acute respiratory distress syndrome; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; mTOR, mammalian target of rapamycin.

Risk Factors for Death and ICU Admission

The 5 nonsurvivors had undergone LT at a median of 9.6 (7.2–16.3) months before the COVID-19 diagnosis, including 3 during the previous 12 months. For 2, the postoperative period was complicated by bronchial issues, requiring bronchial intervention in the previous 3 months; 1 patient with LT 87 months before had had bronchiolitis obliterans syndrome grade 1; and 1 patient who had double LT 52 days before received intravenous corticosteroid pulses and plasmapheresis at 9 and 7 days, respectively, before diagnosis.

Univariate exploratory analysis is summarized in Figures 2 and 3 (and Table S1, SDC, http://links.lww.com/TP/C46). Odds of death were increased with only overweight status (ie, body mass index ≥25 and <30 kg/m2) (OR, 16.0 [1.5–170.6], P = 0.02). No other characteristics were significantly associated with ICU admission or death. Intensification of immunosuppression therapy in the last 6 months was associated but not significantly with ICU admission (OR, 6.25 [1.00–39.1], P = 0.08). On multivariate analysis, no other risk factor was significantly associated with death or ICU admission.

FIGURE 2.
FIGURE 2.:
Forest plot of death outcome. Plots represent point estimate of odds ratio for each risk factor and lines their 95% confidence interval. CI, confidence interval; COVID-19, coronavirus disease 2019; LT, lung transplantation.
FIGURE 3.
FIGURE 3.:
Forest plot of ICU admission outcome. Plots represent point estimate of odds ratio for each risk factor and lines their 95% confidence interval. CI, confidence interval; COVID-19, coronavirus disease 2019; ICU, intensive care unit; LT, lung transplantation.

DISCUSSION

We report here the first national series of LT patients with SARS-CoV-2 infection in the 11 French LT centers. For the 35 LT recipients who had proven or highly suspected COVID-19 during the study period, the presentation was severe for most, with hospitalization in 31 (88.6%). COVID-19 was responsible for death in 5 (14.3%) patients, after a median follow-up of 50.0 (41.0–56.5) days.

As described in nonimmunocompromised hosts,1,2 COVID-19 clinical presentation was consistent with a viral pulmonary infection, with fever (in 25; 71.4%), cough (in 19, 54.3%), and sputum production (in 12; 34.3%). Other symptoms of viral infection such as headache (in 12; 34.3%) or diarrhea (in 11; 31.4%) were also present, as in larger series with unbiased recruitment.1,2

CT-scan findings were consistent with those described in nonimmunocompromised individuals.24 In single-LT patients, the challenge of the CT-scan interpretation involves detecting ground-glass opacities on the native lung. Our series included 7 single-lung transplanted patients, 1 showing bilateral involvement. The native lung might be difficult to analyze, because ground-glass opacities might occur in the native lung as a manifestation of interstitial lung disease, for example. Or, conversely, when the parenchyma is destructed by emphysema, the pattern of viral infection might be missing. In our series, despite these limitations, bilateral involvement was indeed detected.

Although 4 (11.4%) patients received treatment on an outpatient basis, in LT hosts, COVID-19 might have a dreadful course: the crude hospital mortality reached 14.2%, because 5 patients died during their hospital stay after a median follow-up of 15 (7.0–15.0) days and 6 patients remained hospitalized at the end of follow-up.

Significant risk factors for death in COVID-19 are scarce. An increased risk for markedly severe COVID-19 was previously described in ICU populations,28,29 and the increased risk of death with overweight was evidenced in previously published studies.30 The median body mass index of our LT patients was not high (21.5 kg/m2), and only 10 were overweight, all with BMI <30 kg/m2. Nevertheless, odds of death were increased with overweight status. Recent intensification of immunosuppression was not found associated with poor prognosis of COVID-19 course.

Our results agree with those from the largest series of SOT recipients with COVID-19.10 Akalin et al reported a single-center cohort of 36 kidney transplant recipients: 8 (22.2%) had received treatment as outpatients, and 11 (39%) received mechanical ventilation. Mortality reached 28% at a median follow-up of 21 days. The mortality rate of our cohort seems lower. To date, COVID-19 infection in LT recipients has been sparsely described: a first report of an LT recipient was recently published8; the evolution was uneventful because the patient required supplemental nasal oxygen therapy at 1 to 2 L/min. Another series of 4 SOT recipients9 described 1 LT recipient with COVID-19, who despite having comorbid conditions (eg, chronic lung allograft dysfunction and chronic renal failure), showed resolution with simple home supportive care. Hoek et al13 reported a single-center series of 23 SOT recipients, 3 with LT. Data on prognosis for these patients are unfortunately unavailable. Finally, Yi et al16 reported a single-center series of 21 SOT recipients with COVID-19, including 2 with LT. Only 14 (66.7%) of these required inpatient management; 7 were admitted in the ICU. The median follow-up reached 18 (13–30) days, and at follow-up, only 1 patient had died, and 4 were still in the ICU.

Management of SOT patients with COVID-19 remains based on expert opinion. A consensus approach was derived from the guidelines of 22 transplant societies.31 A medium-strength recommendation to decrease immunosuppression was proposed, as advocated by 9 of the societies. The guidelines from the French Transplant Society32 were not included in the previous consensus approach,31 but they advocated different strategies according to the severity of the condition. In all cases, a modification of the antimetabolite therapy (a decrease if outpatient care is possible or an interruption with need for hospitalization) is suggested, as is withdrawal of the mTOR inhibitor with acute respiratory failure. No definite attitude stems from recent case reports, toward neither immunosuppressive treatment withdrawal nor antiviral treatments.5-16

In our series, no definite strategy was adopted: antimetabolite withdrawal was the most frequent immunosuppression therapy modification (in 13 of 29 patients, 44.8% of the patients under antimetabolites before COVID-19). Antimetabolite withdrawal was not restricted to only patients with severe disease because 6 hospital-ward patients had a withdrawal of antimetabolite therapy. The second most frequent modification was an increase in corticosteroids regimen, in 11 (31.4%) patients. These findings agree with the reported strategies in other SOT recipients.5-14,16

Collateral damage of COVID-19 pandemics has been reported all over the world and has been described early in its course.33 It includes reduced available ICU beds resulting from the need for admission of critically ill COVID-19 patients, the transformation of operating theaters into intensive care beds, the decrease in donation organs, and the risk of nosocomial transmission of SARS-CoV-2 to a newly transplanted recipient. In our series, 4 patients acquired COVID-19 in the 3 months following LT: 3 had a nosocomial COVID-19, not donor-derived, and the fourth had a healthcare-associated infection.

Limitations

Although retrospective, this report is likely complete because all French LT centers participated, and missed cases are unlikely. Actually, LT patients are used to getting in touch with their LT center in case of any intercurrent event and therefore informed their LT center of their infection. Nevertheless, our study was not designed to measure the incidence of COVID-19 in the French cohort of LT recipients. Moreover, some asymptomatic cases might have occurred, and we might have underestimated the burden of COVID-19 in LT recipients. We acknowledge that the cohort described here is of limited size but therefore assume that all data on French symptomatic COVID-19 infections in LT patients have been collected. The absence of a control group (eg, nonimmunocompromised hosts, or nonlung SOT recipients) prevents us from comparing the outcomes of COVID-19. Still, our study aimed at describing the course of COVID-19 in LT recipients.

Finally, our study lacked long-term follow-up of outcomes, including graft outcome. These outcomes remain to be explored.

CONCLUSIONS

This first comprehensive multicenter series of 35 LT recipients with COVID-19 shows a diverse prognosis. The presentation was severe, requiring hospitalization in most cases. Overall mortality was 14.3%. Death rate in the ICU was 30.7%. Overweight was significantly associated with odds of death. Long-term outcomes remain to be investigated.

ACKNOWLEDGMENTS

The authors wish to thank all the investigators from the French Group of Lung Transplantation: Dr Vincent Bunel, Dr Gaelle Weisenburger, Dr Tiphaine Goletto, Dr Chahine Medraoui, Dr Cendrine Godet, Dr Armelle Marceau, Pr Pierre Mordant, Dr Arnaud Roussel, Dr Quentin Pellenc, Dr Pierre Cerceau, Pr Yves Castier, Pr Romain Sonneville, Pr Jean-François Timsit, Pr Lila Boudma, Dr Etienne de Montmollin, Dr Sandrine Boudinet, Dr Aurélie Gouel, Dr Brice Lortat-Jacob, Dr Sylvain Jean-Baptiste, Dr Enora Atchade, Dr Sebastien Tanaka, Dr Aurélie Snauwert, Dr Parvine Tashk, Dr Alexy Tran-Dinh, Dr Julie Macey, Dr Claire Bon, Dr Hadrien Roze, Dr Arnaud Germain, Dr Arnaud Rodriguez, Dr Matthieu Thumerel, Dr Charlotte Roy, Dr Sylvie Colin de Verdiere, Dr Clément Picard, Dr Olivier Brugière, Dr Sandra de Miranda, Dr Dominique Grenet, Dr Abdul Hamid, Dr François Parquin, Dr Benjamin Zuber, Dr Charles Cerf, Pr Chirstophe Pison, Dr Pierrick Bedouch, Dr Amandine Briault, Dr Margaux Feger, Dr Rebecca Hamidfar, Dr Helene Pluchart, Dr Arnaud Fedi, Dr Hubert Gheerbrant, Dr Nader Chebib, Dr Claire Merveilleux du Vignaux, Dr Gaëlle Dauriat, Dr Isabelle Danner, Dr Emmanuel Eschapasse, Dr Philippe Lacoste, Dr Thierry Lepoivre, Dr Jean-Christian Roussel, Pr R. Kessler, Dr A. Schuller, Dr T. Degot, Dr M. Porzio, Dr M. Riou, Dr S. Freudenberger, Pr P.E. Falcoz, Dr A. Olland, Dr O. Helms, Dr F. Levy, Pr O. Collange, Dr L. Jazaerli, Dr A. Essaydi, Dr Marlène Murris, Dr Berengere Coltey, Dr Nadine Dufeu, Dr Benjamin Coiffard, Dr Clarisse Gautier, Dr Jean-Baptiste Rey, Dr Pascal-Alexandre Thomas, Dr Geoffrey Brioude, Dr Xavier-Benoit D’journo, Dr Delphine Trousse, Dr Jean-Marie Forel, Pr Laurent Papazian, Pr Marc Leone, and Dr Aude Charvet.

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