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. 2021 Oct 6;16(10):e0257807. doi: 10.1371/journal.pone.0257807

COVID-19 in lung transplant recipients—Risk prediction and outcomes

Jan C Kamp 1,2,*, Jan B Hinrichs 2,3, Jan Fuge 1,2, Raphael Ewen 1, Jens Gottlieb 1,2
Editor: Robert Jeenchen Chen4
PMCID: PMC8494359  PMID: 34613977

Abstract

Patients after lung transplantation are at risk for life-threatening infections. Recently, several publications on COVID-19 outcomes in this patient population appeared, but knowledge on optimal treatment, mortality, outcomes, and appropriate risk predictors is limited. A retrospective analysis was performed in a German high-volume lung transplant center between 19th March 2020 and 18th May 2021. Impact of COVID-19 on physical and psychological health, clinical outcomes, and mortality were analyzed including follow-up visits up to 12 weeks after infection in survivors. Predictive parameters on survival were assessed using univariate and multivariate proportional hazards regression models. Out of 1,046 patients in follow-up, 31 acquired COVID-19 during the pandemic. 12 of 31 (39%) died and 26 (84%) were hospitalized. In survivors a significant decline in exercise capacity (p = 0.034), TLC (p = 0.02), and DLCO (p = 0.007) was observed at follow-up after 3 months. Anxiety, depression, and self-assessed quality of life remained stable. Charlson comorbidity index predicted mortality (HR 1.5, 1.1–2.2; p = 0.023). In recipients with pre-existing CLAD, mortality and clinical outcomes were inferior. However, pre-existing CLAD did not predict mortality. COVID-19 remains a life-threatening disease for lung transplant recipients, particularly in case comorbidities. Further studies on long term outcomes and impact on pre-existing CLAD are needed.

1. Introduction

Since the beginning of the ongoing worldwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, more than 172 million confirmed cases and more than 3.7 million deaths were documented by the World Health Organization (WHO) in the report of June 9, 2021 [1].

The clinical presentation of people infected by SARS-CoV-2 is termed as Coronavirus disease 2019 (COVID-19). Most patients (approximately 80%) suffer from mild to moderate symptoms and recover after the initial disease phase, which is dominated by symptoms and signs of viral response like fever, dry cough, and lymphopenia. However, a considerable amount of patients develop increasing host inflammatory response symptoms after the initial phase with dyspnea and hypoxemia up to life-threatening organ impairment like acute respiratory distress syndrome, shock, and cardiac failure [2]. Prolonged disease courses and persistent physical and psychological impairment after COVID-19 are well described in the general population [3] as well as in distinct pulmonary diseases [4].

COVID-19 in solid organ or lung transplant recipients was reported in cohort studies and case series [5–12] with a case fatality rate of 10–46%. There is a lack of knowledge about the preferred treatment strategy as well as long term physical and psychological outcomes in this patient population. Moreover little is known about the impact of COVID-19 on pre-existing chronic lung allograft dysfunction (CLAD).

Aim of this study was to contribute to the still limited knowledge on clinical outcomes in lung transplant (LTx) recipients with a confirmed infection by SARS-CoV-2. Moreover, potential predictors of mortality and psychological outcomes were analyzed as reliable data on these issues are still lacking.

2. Methods

2.1 Setting

A retrospective analysis was performed in a single high-volume lung transplant center. The LTx outpatients’ clinic actively follows 1,046 patients after unilateral, bilateral or combined lung transplantation by regular outpatient and telemedical visits. All patients received center-based blood samples (for cytomegalovirus and immunosuppressive drug monitoring) and telephonic advice to transplant-related issues as case management. Basically, all of our patients are encouraged to inform our outpatients’ clinic on occurring relevant health-related events like respiratory infections.

All patients fulfilled the following inclusion criteria: i) follow-up since lung transplantation in our outpatients’ clinic, ii) SARS-CoV-2 infection, confirmed by polymerase chain reaction-based assay until 13th March 2021, and iii) follow-up in our outpatients’ clinic 4–12 weeks after survived SARS-CoV-2 infection or death (i.e. after hospital discharge in inpatients / after end of symptoms in outpatients).

All SARS-CoV-2 infected outpatients were regularly followed after diagnosis by daily video consultations (Medflex GmbH, Konstanz, Germany) [13]. All LTx patients with COVID-19 hospitalized in other hospitals were managed by daily telephonic consultation with physicians on charge in these hospitals. Baseline parameters were derived by last available visit prior to infection. Comorbidity burden was assessed by the Charlson Comorbidity Index (CCI) [14]. This index includes several comorbid conditions which might alter the risk of mortality. A point value between 0 and 29 is calculated with a higher value indicating higher level of comorbidity.

Disease severity of SARS-CoV2 infection was assessed by the World Health Organization Ordinal Scale (WHO-OS) [15]. Non-hospitalized patients without / with limitation on activities were classified as “1” / “2”, hospitalized patients without / with conventional oxygen therapy requirement as “3” / “4”, patients with need of non-invasive ventilation or high flow oxygen therapy as “5”, patients with need of intubation and mechanical ventilation as “6”, patients in whom renal replacement therapy, administration of vasoactive drugs or extracorporeal membrane oxygenation therapy was required as “7”, and patients who died from acute SARS-CoV2 infection as “8”. In all patients who survived, follow-up parameters were assessed 4 to 12 weeks after infection. Observation period ended on 18th May 2021.

All patients provided written informed consent for the use of their data for scientific purposes. Approval was given by the local institutional review board (no. 2923–2015).

On on-site visits routine questionnaires, spirometry, chest X-ray, and routine laboratory testing incl. calcineurin inhibitor trough levels and cytomegalovirus-testing were performed. Pulmonary function testing and measuring of diffusing capacity for carbon monoxide (DLCO) was conducted according to current European Respiratory Society / American Thoracic Society standards [16, 17].

CLAD diagnosis and staging were conducted according to current International Society of Heart and Lung Transplantation recommendations [18].

During regular on-site follow-up all patients completed a self-reported questionnaire including need of medical aids (such as oxygen therapy, non-invasive ventilation, rollator, wheel chair, and feeding tube) and exercise capacity which is determined based on no. of flight of stairs.

Mental Health and quality of life (QoL) were assessed using the Euro Quality of Life 5 dimensions 5 levels questionnaire (EQ-5D-5L) [19] and the patient health questionnaire 4 (PHQ-4) [20]. The EQ-5D-5L has five sub scores in 5 dimensions ranging from 1 to 5 points and a QoL visual analogue scale (QoL-VAS) with a range from 0 (worst health one can imagine) to 10 (best health one can imagine). The PHQ-4 has 4 questions in two dimensions (anxiety and depression) ranging from 0 to 3 points, respectively. PHQ-4 scores are summed up in total and separately for generalized anxiety disorder (GAD, GAD-2) and major depressive disorder (MDD, PHQ-2). A GAD-2 or PHQ-2 score greater than 3 indicates signs of GAD or MDD, respectively.

2.2 Statistical analysis

We used IBM SPSS Statistics 27.0 (IBM Corp, Armonk, NY, USA) and Stata 13.0 (State Corp LP, College Station, Texas, USA) statistical software to analyze the data. Most continuous variables are shown as median and 25%–75% interquartile range (IQR). Only parameters from the EQ-5D-5L and PHQ-4 are shown as mean and standard deviation in case of small case numbers. Categorical variables are shown as numbers and percent (%). For comparisons of patient time points, Fisher’s exact test, Chi-square test, paired Wilcoxon-test, McNemar Bowkers test or paired t-tests were used as appropriate. Kaplan-Meier survival estimates were created for the whole group. To determine hazards of death proportional hazards regression models were created (one univariate and one multivariate model). All reported p-values are two sided and derived from paired data. P-values <0.05 were considered statistically significant.

3. Results

A total of 31 LTx recipients with confirmed infection by SARS-CoV-2 were included in this analysis (Fig 1). Patient characteristics at the onset of symptoms are shown in Table 1. Fifty-eight percent of the patients were female and median age was 54 (47.5/58) years. CCI was 4 (4/5.5) indicating a substantial burden of comorbid conditions and n = 14 (45%) patients suffered from preexisting CLAD. Until the end of the observation period additional 7 patients acquired SARS-CoV-2 infection but with insufficient follow-up (1 died).

Fig 1. Flow chart.

Fig 1

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SARS-CoV2, severe acute respiratory syndrome coronavirus 2.

Table 1. Patient characteristics at the onset of symptoms (31 patients).

Gender; n (%)

  • Female

  • 18 (58)
Age at diagnosis of SARS-CoV-2 infection 54 (47.5/58)
BMI at diagnosis of SARS-CoV-2 infection 22.3 (19.5/23.95)
Charlson Comorbidity Index at diagnosis of SARS-CoV-2 infection 4 (4/5.5)
Diagnosis leading to transplantation; n (%)

  • Interstitial lung disease

  • Emphysema

  • Cystic fibrosis / Primary ciliary dyskinesia

  • Pulmonary hypertension

  • Other

  • 14 (45)

  • 9 (29)

  • 4 (13)

  • 3 (10)

  • 1 (3)
Lung transplantation; n (%)

  • Unilateral

  • Bilateral

  • Combined heart and lung transplantation

  • 2 (6)

  • 28 (90)

  • 1 (3)
Duration from lung transplantation to onset of symptoms (years) 7.9 (3.2/12.9)
Primary immunosuppressive therapy; n (%)

  • Tacrolimus

  • Ciclosporine

  • 24 (77)

  • 7 (23)
Other immunosuppressive therapy; n (%)

  • Mycophenolate-mofetil

  • Everolimus

  • Azathioprine

  • Prednisolone

  • 25 (81)

  • 4 (13)

  • 2 (6)

  • 31 (100)
Preexisting CLAD; n (%) 14 (45)

  • Stage 1 / 2

  • Stage 3 / 4

  • 10 (32)

  • 4 (13)
CLAD therapy; n (% of CLAD patients)

  • Azithromycin

  • Montelukast

  • Extracorporeal photopheresis

  • 14 (100)

  • 6 (43)

  • 9 (64)
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Continuous variables are presented as median and 25% / 75%r quartiles; SARS-CoV-2, severe acute respiratory syndrome corona virus-2; BMI, body mass index; CLAD, chronic lung allograft dysfunction.

Median WHO-OS classification during the acute disease period was 4 (4/7) indicating predominantly severe disease courses and mortality was high (n = 12, 39%, Fig 2). Causes of death were respiratory failure from COVID-19 or from COVID-19 and progressive CLAD (n = 5, 42% and n = 3, 25%, respectively) as well as fatal complications following COVID-19 (necrotizing pancreatitis; n = 1; acute liver failure, n = 1; and septic shock, n = 2). Twenty-six (84%) patients were hospitalized due to dyspnea, n = 16 (61%); decrease in oxygen saturation, n = 6 (23%); diarrhoea, n = 1 (4%); or other reasons, n = 3 (12%). Median time from onset of symptoms to hospitalization was 7 (3/9) days and median duration of hospitalization was 19 (11/29) days. Median time from onset of symptoms to oxygen therapy / death was 8 (3/9) and 27 (12/48) days, respectively.

Fig 2. Survival after COVID-19.

Fig 2

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Kaplan-Meier survival estimate on 31 lung transplant recipients with confirmed SARS-CoV-2 infection.

Key characteristics of COVID-19 courses are presented in Table 2. In 18 (58%) patients 70 video consultations (median 3 per patient, 2/7.5) were performed since the onset of SARS-CoV-2 related symptoms. Of these patients, 2 were hospitalized immediately after the first video consultation and 11 following a later visit. Fifteen (58%) patients needed intensive care. Conventional oxygen therapy was required in all hospitalized patients (n = 26, 84%), high flow oxygen therapy in n = 3 (10%) patients, non-invasive ventilation in n = 5 (16%) patients, mechanical ventilation in 8 (26%) patients, and extracorporeal membrane oxygenation therapy in n = 4 (13%) patients. Twenty-two (71%) patients received dexamethasone, n = 5 (16%) patients received remdesivir, and n = 1 (3%) patient was treated with reconvalescent plasma. Cell-cycle inhibitors were withheld during hospitalization in all patients until discharge and thromboprophylaxis / anticoagulants were administered according to the treating physicians’ appraisal.

Table 2. Key characteristics of COVID-19 courses.

Hospitalization 26 (87)

  • ICU treatment

  • 15 (48)
Time from onset of symptoms to hospitalization (d), n = 26 7 (3/9)
Reasons for admission, n = 26

  • Dyspnea

  • Decrease in oxygen saturation, measured during video consultation

  • COVID-19-associated diarrhea

  • Other conditions, not associated with COVID-19

  • 16 (61)

  • 6 (23)

  • 1 (4)

  • 3 (12)
Duration of hospitalization (days) 19 (11/29)
Mortality 12 (39)
Cause of death, n = 12; n (% of deceased patients)

  • Respiratory failure from COVID-19 and (if applicable) progressive CLAD

  • Fatal complications following COVID-19

  • 8 (67)

  • 4 (34)
Time from onset of symptoms to death (days), n = 12 27.5 (12.5/48.25)
Time from onset of symptoms to oxygen therapy (days), n = 26 8 (3/9)
CLAD Progression; n (% of 14 CLAD patients)

  • Decline ≥10% in at least one of FEV1, TLC, and DLCO

  • Death from or following COVID-19

  • 6 (43)

  • 6 (43)
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Categorical variables are presented as n and percent unless stated otherwise; ICU, intensive care unit; COVID-19, Corona virus disease 19; FEV1, forced exhaled volume in 1 second; TLC, total lung capacity; DLCO, diffusing capacity for carbon monoxide.

Nineteen patients underwent 70 (median 3, 2/7) video consultations after infection. In n = 6 patients decrease in oxygen saturation to <92% without signs of dyspnea (so called “silent hypoxemia”) was detected 10 (10/12) days after onset of symptoms leading to hospital admission. In these 6 patients, duration of hospital stay was 17 (12/24) days and n = 4 (66%) patients needed intensive care treatment. In those patients who underwent more than 2 video consultations no trends in vital signs were detectable.

Follow-up results are displayed in Table 3. Forced expiratory volume in 1 second (FEV1) decline >10% was seen in 3 (16%) patients at follow-up. Total lung capacity (TLC) declined significantly (98, 94/102 vs. 86, 80/100; p = 0.02) as well as mean DLCO (66, 52.5/84 vs. 49, 44/59; p = 0.007). Exercise capacity, measured by no. of flight of stairs, worsened significantly (p = 0.034).

Table 3. Clinical outcomes in survivors, obtained 4–12 weeks after SARS-CoV-2 infection.

Baseline* Follow-Up** p-value
Time from baseline to symptom onset / Time from symptom onset to follow-up, n = 19 (days) 84 (13–175) 87 (69–143) n/a
FEV1, n = 19 (% baseline) 92 (80.5/96) 93 (74.5/100) 0.247
TLC, n = 15 (% baseline) 98 (94/102) 86 (80/100) 0.020
DLCO, n = 11 (% baseline) 66 (52.5/84) 49 (44/59) 0.007
QoL-VAS, n = 19 (points of 10) 7 (6/8.5) 8 (6.5/8) 0.938
Exercise capacity (no. of flight of stairs), n = 19, n (%) 0.034

  • >2

  • 2

  • 1

  • 0

  • 8 (42)

  • 6 (32)

  • 5 (26)

  • 0 (0)

  • 5 (26)

  • 6 (32)

  • 5 (26)

  • 3 (16)
Need of medical aids at follow-up, n = 19, n (%) n/a

  • Oxygen therapy

  • NIV therapy

  • Rollator

  • Wheel chair

  • Feeding tube

  • 2 (11)

  • 0 (0)

  • 5 (26)

  • 0 (0)

  • 1 (5)

  • 3 (16)

  • 0 (0)

  • 1 (5)

  • 4 (21)

  • 1 (5)
EQ-5D-5L, n = 19 (%) 88.0 ±14.3 80.8 ±21.4 0.055

  • Mobility (points)

  • Self-care (points)

  • Usual activities (points)

  • Pain / Discomfort (points)

  • Anxiety / Depression (points)

  • 1.4 ±0.8

  • 1.3 ±0.5

  • 1.6 ±0.8

  • 1.5 ±0.7

  • 1.5 ±0.8

  • 2.0 ±1.1

  • 1.5 ±0.8

  • 1.8 ±1.2

  • 1.8 ±1.2

  • 1.9 ±1.0

 0.066
0.096
0.236
0.163
0.033
PHQ-4, n = 19 (points) 2.4 ±2.5 2.7 ±2.8 0.261

  • PHQ-2 (points)

  • GAD-2 (points)

  • 1.0 ±1.1

  • 1.4 ±1.5

  • 1.6 ±1.5

  • 1.2 ±1.5

 0.090
0.305
PHQ-2—Depressive Disorder, n (%) 2 (11) 5 (26) 0.250
GAD-2—Anxiety Disorder, n (%) 3 (16) 3 (16) 1.000
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Continuous variables are presented as median and 25% / 75% inter quartile range (IQR) or mean and standard deviation as appropriate; categorical variables are presented as n and percent unless stated otherwise;

*Baseline was defined as last available visit prior to SARS-CoV-2 infection;

**Follow-up visits were conducted 4–12 weeks after survived SARS-CoV-2 infection;

COVID-19, Corona virus disease 19; ICU, intensive care unit; FEV1, forced exhaled volume in 1 second; TLC, total lung capacity; DLCO, diffusing capacity for carbon monoxide; QoL-VAS, quality of life, assessed by visual analogue scale; EQ-5D-5L, Euro-QoL 5 dimensions 5 levels questionnaire; PHQ-4, patient health questionnaire 4; PHQ-2, patient health questionnaire 2; GAD-2, generalized anxiety disorder questionnaire 2; CLAD, chronic lung allograft dysfunction.

Regarding the subgroup of LTx recipients with pre-existing CLAD (n = 14) there was a substantial deterioration in graft function. N = 6 (43%) of 14 patients died from or following COVID-19 and further n = 6 (43%) patients showed a decline ≥10% in at least one of FEV1, TLC, and DLCO at follow-up signaling CLAD progression. In survivors without pre-existing CLAD no new CLAD diagnoses were made at follow-up.

Quality of life as measured by EQ-5D-5L absolute value tendentially worsened (88 ±14.3 vs. 80.8 ±21.4, p = 0.055) which was mostly reflected by the subscores for mobility (p = 0.066) and anxiety / depression (p = 0.033). The PHQ-4 as well as its subscores (PHQ-2 and GAD-2) in absolute and categorical values did not change significantly. Self-reported QoL-VAS results remained unchanged.

Results of the univariate and multivariate analyses are shown in Table 4. Univariate analysis demonstrated no elevated hazard on sex, body mass index, chronic kidney disease, coronary heart disease, dyslipidemia, arterial hypertension, diabetes mellitus, pre-existing CLAD, established azithromycin therapy, % FEV1 predicted or % TLC predicted, and exercise capacity for mortality. Possible impact on mortality was found for age (Hazard Ratio, HR 1.1 (1.0–1.1); p = 0.029) and CCI (HR 1.5 (1.1–2.2); p = 0.023). A trend was visible for hemodialysis (HR 3.5 (0.9–13.1); p = 0.065) which was present in just 4 cases. Multivariate proportional hazards analyses testing for covariates age, CCI, and hemodialysis revealed no impact on mortality hazard for age and hemodialysis while CCI predicted mortality (HR 1.5 (1.1–2.2); p = 0.023).

Table 4. Results of univariate and multivariate linear regression analyses on predictive outcome parameters.

Item Univariate Multivariate
HR (95% CI); p-value HR (95% CI); p-value
Male Sex 0.7 (0.2–2.4); p = 0.590
Age 1.1 (1.0–1.1); p = 0.029
Body mass index 0.9 (0.8–1.1); p = 0.345
Chronic kidney disease 2.6 (0.3–20); p = 0.356
Hemodialysis 3.5 (0.9–13.1); p = 0.065
Coronary heart disease 1.5 (0.3–6.8); p = 0.613
Dyslipidemia 1.0 (0.3–3.2); p = 0.979
Arterial hypertension 2.8 (0.6–12.9); p = 0.182
Diabetes mellitus 1.2 (0.4–3.9); p = 0.802
CLAD 1.2 (0.4–3.8); p = 0.732
Charlson comorbidity index 1.5 (1.1–2.2); p = 0.023 1.5 (1.1–2.2); p = 0.023
% FEV1 predicted 1.0 (1.0–1.0); p = 0.138
% TLC predicted 1.0 (0.9–1.0); p = 0.152
Azithromycin therapy 1.1 (0.4–3.6); p = 0.842
Exercise capacity* 0.6 (0.3–1.2); p = 0.126
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HR, Hazard Ratio; CI, Confidence interval; CLAD, chronic lung allograft dysfunction; FEV1, forced exhaled volume in one second; TLC, total lung capacity;

*Exercise capacity was assessed based on no. of flight of stairs.

4. Discussion

We here report the clinical courses of a group of 31 LTx recipients from our institution diagnosed with SARS-CoV-2 infection. We determined the CCI independent risk factors for poor outcomes in LTx recipients with SARS-CoV-2 infection. Hospitalization rate was high and mostly due to COVID-19-associated dyspnea. More than half of all hospitalized patients needed intensive care indicating a high average disease severity. More than one third of our patients died.

Mortality rates from most recently published works were comparable. Saéz-Giménez et al. presented data on short-term outcomes of 44 LTx recipients with confirmed COVID-19 and hospitalization to one of six Spanish referral centers with a mortality rate of 39% [7]. Kates et al. found a mortality rate of 33% in 30 LTx recipients from the United States [9]. Coll et al. reported a mortality rate of 46% in 50 LTx recipients with COVID-19 from Spain [10]. Aversa et al. reported on 32 LTx recipients with COVID-19 from New York City with a mortality rate of 34% [11]. Further small case series on the outcomes of lung transplant recipients after COVID-19 revealed mortality rates between 10% and 25% [6, 8].

Long-term outcomes in LTx recipients with COVID-19 were published recently in a French cohort. Substantially lower mortality (14.3%) was found in 35 LTx recipients [5]. The difference in mortality between the French cohort and our patients might be explained by the sum of the following points: i) the minor amount of CLAD patients compared to our cohort (20% vs. 45%); ii) lower median values in age and body mass index (48.1 and 21.5 vs. 54 and 22.3, respectively); iii) the earlier observation period (March, 1 2020 to May, 19, 2020 compared with March 19, 2020 and May, 18, 2021). Most fatal cases from our cohort were diagnosed between November 2020 and February 2021 so a relation to the British / B.1.1.7 / alpha variant is not excludable what might contribute to the differing mortality rates [21].

Recently, a large registry study from the Unites States by Hady et al. was published [12]. Therein, 2,307 solid organ transplant recipients were propensity matched for demographics and comorbidities to a huge cohort from the general population. Interestingly, no significant differences regarding outcomes were found. However, LTx recipients were underrepresented in this cohort (4.7% of patients) and no survival estimate for this subgroup was stated. The authors suggest that increased risk for mortality in solid organ transplant recipients might be primarily explained by the higher burden of comorbidities. We agree that high morbidity should be an independent risk factor but nevertheless the required highly potent immunosuppressive therapy in lung transplant recipients as well as the limited respiratory reserve and the substantial CLAD prevalence even contribute to poor outcomes in these vulnerable patients. In our cohort, high comorbidity rate is reflected by the CCI.

One key experience from daily conducted video consultations was that many patients were in seemingly stable clinical condition after the onset of SARS-CoV-2 symptoms for up to 10 days. Following this, we observed a sudden respiratory deterioration or even decrease in oxygen saturation without shortness of breath rapidly leading to intensive care requirement in many cases. Asymptomatic decrease in oxygen saturation is a well described feature of COVID-19 termed as silent hypoxemia [22].

Pathomechanisms described recently might apply to lung transplant recipients as well [2]. Pulmonary embolism is a common feature of COVID-19 but in our cohort we did not observe any thromboembolic events. This might be explained by the late peak of cases when risk of thromboembolic events in COVID-19 was already well known and most patients received anticoagulants.

After hospital admission, we often observed prolonged lengths of stay (median 19, 11/29 days), especially in those patients who finally died (median time from onset of symptoms to death 27, 12/48 days).

These data considerably differ from those reported by Karagiannidis et al. in a large study on in-hospital mortality of patients from the German general population with COVID-19 [23]. In this work, in-hospital mortality was 22% (compared to 46% in our study) and hospital stays were significantly shorter (14 vs. 19 days) what might potentially be explained due to the therapeutics engaged in LTx recipients (e.g. exctracorporeal therapies) rather than in the general population. Moreover, half of all deaths occurred within 12 days after admission what is inconsistent with our data as described above.

Recently, Permpalung et al. reported on clinical outcomes after COVID-19 in a 1:2 matched case-control study with 24 SARS-CoV-2 infected and 48 non-infected LTx recipients. In that work, elevated risk for secondary infections and re-hospitalization was found within 90 days post COVID-19. However, no impact on CLAD or on the rate of acute cellular or antibody mediated rejections and was detected [24].

The incidence of SARS-CoV-2 infections in our patient-cohort during the observation period was similar to nationwide German incidence (Fig 3). However, it might be possible that the number of unreported / undetected cases were considerably higher in the general population. Considering the incidence and mortality in our LTx recipients over time a noticeable peak occurred between November 2020 and February 2021. Most confirmed cases and fatal outcomes arose from this time frame. As far as we know, no comprehensive sequencing of SARS-CoV-2 variants has been performed in our patients but it can be speculated that this cluster might be associated with the alpha variant B.1.1.7 which gained increasing national relevance during this period [22].

Fig 3. Incidence of SARS-CoV-2 infections in Germany.

Fig 3

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COVID-19 Pandemic subsumes the incidence in the German general population; COVID-19 Tx subsumes all confirmed SARS-CoV-2 infections in lung transplant recipients from our institution; those who deceased are shown black.

Follow-up diagnostics in survivors performed 4–12 weeks after terminated infection revealed significant lung function impairment and reduced exercise capacity. The relatively stable findings in FEV1 after COVID-19 are standing in contrast to infections caused by common community-acquired respiratory viruses which are known to cause a mean decline in FEV1 of approximately 15% after 28 to 90 days [25]. However, TLC and DLCO decreased significantly indicating a restrictive airway disease and interstitial alterations due to inflammatory and post-inflammatory processes.

The most important limiting single factor of long-term survival in LTx recipients is CLAD, responsible for >40% of deaths beyond the first year (17). It might be expected that LTx recipients with pre-existing CLAD are at particular high risk of poor outcome when suffering from COVID-19 as with other chronic respiratory disease (24). Almost half of CLAD patients died from or following COVID-19 and the same amount suffered from progressive deterioration in graft function at follow-up. Only 2 recipients (14%) with pre-existing CLAD showed stable findings at follow-up indicating a potential extremely vulnerable subgroup. In some patients decline in lung function was reflected by persistent alterations in chest computed tomography. As previously described by Messika et al. [5] radiologic imaging findings due to COVID-19 are comparable between LTx recipients and non-immunocompromised patients. However, it should be mentioned that there is a diagnostic uncertainty regarding the differentiation between progression of a preexisting CLAD with restrictive allograft syndrome or mixed phenotype according to current recommendations [18] and a (post-) COVID-19 pattern. Images from chest computed tomography in one of our LTx recipients with pre-existing CLAD before and after COVID-19 are presented in Fig 4.

Fig 4. Chest computed tomography findings pre and post COVID-19.

Fig 4

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Presentation of a 54-year-old male lung transplant recipient with pre-existing mixed phenotype chronic lung allograft dysfunction. A, B: High-resolution computed tomography (HR-CT) 4 months prior to COVID-19 infection. Axial slice showing distinct pleuroparenchymal infiltrates on the left side (arrow) and coronal slice showing streak densities in the basal parts of the lung as mild signs of CLAD. C, D: Axial HR-CT obtained 2 weeks after survived infection showing areas auf consolidation (arrows) mixed with ground glass opacities (arrow head). Images prior to COVID-19 were generated on a multidetector CT according to a standard protocol using a 64-row scanner (GE Lightspeed VCT, GE Healthcare, Chalfont St. Giles, United Kingdom). Either 100 kVp or 120 kVp tube voltage was used adjusted to the body mass index of the patient. Briefly, we used a detector collimation of 64 0.625 mm and a reconstructed slice thickness of 1.25 mm. High resolution CT images following COVID-19 were generated on a dual source 2x96-row MDCT (Siemens FORCE, Siemens Healthineers, Forchheim, Germany) (detector collimation: 192x0.7 mm, slice thickness: 1 mm, interval: 0.7 mm) and reconstructed in an appropriate kernel. COVID-19, Coronavirus disease 2019; CLAD, chronic lung allograft dysfunction; CT, computed tomography.

Today, there is still a lack on reliable mortality predictors for LTx recipients with imminent or confirmed SARS-CoV-2 infection. Messika et al. recently described a relationship between overweight and risk of death in this patient population [5]. Our analyses revealed the CCI as a marker of morbidity and the WHO-OS as a severity marker during COVID-19 as predictive markers on mortality before and during COVID-19, respectively. Certainly, the latter finding is not surprising but at least confirming the prognostic value of the WHO-OS in LTx recipients suffering from COVID-19. However, the CCI as an appropriate prognostic tool for this patient population is a very relevant finding and it would be worth to evaluate it in larger studies. Actually, these findings support the results of Hady et al. regarding the strong association between comorbidities and mortality in solid organ recipients [12].

None of our patients was vaccinated prior to infection. However, until the end of the observation period further LTx recipients were diagnosed with SARS-CoV-2 infections three of whom received their first vaccination, one with VaxZevria® (Astra Zeneca) and two with Comirnaty® (Biontech/Pfizer). There is concern about limited immune response to SARS-CoV-2 vaccines in transplant recipients [26]. Further studies are needed to evaluate efficacy of these vaccines and preferable dose regimens in these patients.

There are some limitations of our study. First the short observation period after terminated SARS-CoV-2 infection, second the small number of patients, third the monocentric design, and fourth the lack of a control group. Future studies are needed to analyze long-term survival after COVID-19 in LTx recipients, the influence on pre-existing CLAD, as well as the response to SARS-CoV-2 vaccinations in this patient population.

To date, many issues on COVID-19 in lung transplant recipients remain unanswered, especially the relevance of new virus variants and the benefit of future drug developments. More studies are needed to optimize treatment and vaccination strategies.

In conclusion, mortality and morbidity of COVID-19 in lung transplant recipients is high, especially in case of a pre-existing CLAD and significant co-morbidities. Future studies are needed to assess long-term influence on physical and psychological health and especially on the risk of CLAD.

Acknowledgments

We thank our coordinators from the transplant outpatients’ department, Linda Häsler, Anita Fuhrmann, and Bianca Rink for the helpful support during this project.

Abbreviations

CCI

Charlson Comorbidity Index

CLAD

chronic lung allograft dysfunction

COVID-19

Coronavirus disease 2019

DLCO

diffusing capacity for carbon monoxide

EQ-5D-5L

Euro Quality of Life 5 dimensions 5 levels questionnaire

FEV1

forced expiratory volume in 1 second

GAD

generalized anxiety disorder

HR

hazard ratio

IQR

interquartile range

LTx

lung transplantation

MDD

major depressive disorder

PHQ-4

patient health questionnaire 4

QoL

quality of life

SARS-CoV2

severe acute respiratory syndrome coronavirus 2

TLC

total lung capacity

WHO

World Health Organization

WHO-OS

World Health Organization Ordinal Scale

Data Availability

The data presented in this study are available only on reasonable request from the corresponding author or from the German Center for Lung Research (DZL) data warehouse. [Internet: “https://dzl.de/en/dzl-data-warehouse/”]. Contacts for data management requests: [Internet: “https://dzl.de/en/platforms/contact-central-biobanking-management/”]. General public deposition of patient data is restricted according to the written informed consent which has been given from all patients for the use of their data for scientific purposes. Approval was given by the local institutional review board at Hannover Medical School (no. 2923-2015).

Funding Statement

Dr. Kamp is supported by PRACTIS – Clinician Scientist Program of Hannover Medical School, funded by the German Research Foundation (DFG, ME 3696/3-1). www.dfg.de The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References

  • 1.World Health Organization. Coronavirus disease (COVID-19). Weekly epidemiological update on COVID-19–8 June 2021. [Internet]. https://www.who.int/publications/m/item/weekly-epidemiological-update-on-covid-19---8-june-2021 Accessed June, 06, 2021.
  • 2.Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant. 2020. May;39(5):405–407. doi: 10.1016/j.healun.2020.03.012 Epub 2020 Mar 20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Carfì A, Bernabei R, Landi F; Gemelli Against COVID-19 Post-Acute Care Study Group. Persistent Symptoms in Patients After Acute COVID-19. JAMA. 2020. Aug 11;324(6):603–605. doi: 10.1001/jama.2020.12603 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Park DH, Fuge J, Meltendorf T, Kahl KG, Richter MJ, Gall H, et al. Impact of Sars-CoV-2-Pandemic on mental disorders and quality of life in patients with pulmonary arteriaI hypertension. Front Psychiatry. 2021. Jun 24;12:668647. doi: 10.3389/fpsyt.2021.668647 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Messika J, Eloy P, Roux A, Hirschi S, Nieves A, Le Pavec J, et al. COVID-19 in Lung Transplant Recipients. Transplantation. 2021. Jan 1;105(1):177–186. doi: 10.1097/TP.0000000000003508 [DOI] [PubMed] [Google Scholar]
  • 6.Myers CN, Scott JH, Criner GJ, Cordova FC, Mamary AJ, Marchetti N, et al. COVID-19 in lung transplant recipients. Transpl Infect Dis. 2020. Dec;22(6):e13364. doi: 10.1111/tid.13364 Epub 2020 Jul 22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Saez-Giménez B, Berastegui C, Barrecheguren M, Revilla-López E, Los Arcos I, Alonso R, et al. COVID-19 in lung transplant recipients: A multicenter study. Am J Transplant. 2021. May;21(5):1816–1824. doi: 10.1111/ajt.16364 Epub 2020 Nov 7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Verleden GM, Godinas L, Lorent N, Van Bleyenbergh P, Dupont L, Delcroix M, et al. COVID-19 in lung transplant patients: A case series. Am J Transplant. 2020. Nov;20(11):3234–3238. doi: 10.1111/ajt.16212 Epub 2020 Aug 29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Kates OS, Haydel BM, Florman SS, Rana MM, Chaudhry ZS, Ramesh MS, et al. COVID-19 in solid organ transplant: A multi-center cohort study. Clin Infect Dis. 2020. Aug 7:ciaa1097. doi: 10.1093/cid/ciaa1097 Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Coll E, Fernández-Ruiz M, Sánchez-Álvarez JE, Martínez-Fernández JR, Crespo M, Gayoso J, et al. COVID-19 in transplant recipients: The Spanish experience. Am J Transplant. 2021. May;21(5):1825–1837. doi: 10.1111/ajt.16369 Epub 2020 Nov 10. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Aversa M, Benvenuto L, Anderson M, Shah L, Robbins H, Pereira M, et al. COVID-19 in lung transplant recipients: A single center case series from New York City. Am J Transplant. 2020. Nov;20(11):3072–3080. doi: 10.1111/ajt.16241 Epub 2020 Sep 5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Hadi YB, Naqvi SF, Kupec JT, Sofka S, Sarwari A. Outcomes of Coronavirus Infectious Disease -19 (COVID-19) in Solid Organ Transplant Recipients: A Propensity Matched Analysis of a Large Research Network. Transplantation. 2021. Feb 5. doi: 10.1097/TP.0000000000003670 Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Kayser MZ, Valtin C, Greer M, Karow B, Fuge J, Gottlieb J. Video Consultation during the Covid-19 pandemic: A single center’s experience with lung transplant recipients. Telemed J E Health. 2020. Oct 14. doi: 10.1089/tmj.2020.0170 Online ahead of print. [DOI] [PubMed] [Google Scholar]
  • 14.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–83. doi: 10.1016/0021-9681(87)90171-8 [DOI] [PubMed] [Google Scholar]
  • 15.World Health Organization. Clinical management of COVID-19: interim guidance. May; 2020; [Internet]. https://www.who.int/publications/i/item/clinical-management-of-covid-19s Accessed June, 09, 2021.
  • 16.Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, et al. Standardisation of spirometry. Eur Respir J. 2005. Aug;26(2):319–38. doi: 10.1183/09031936.05.00034805 [DOI] [PubMed] [Google Scholar]
  • 17.Graham BL, Brusasco V, Burgos F, Cooper BG, Jensen R, Kendrick A, et al. 2017 ERS/ATS standards for single-breath carbon monoxide uptake in the lung. Eur Respir J. 2017. Jan 3;49(1):1600016. doi: 10.1183/13993003.00016-2016 Erratum in: Eur Respir J. 2018 Nov 22;52(5). [DOI] [PubMed] [Google Scholar]
  • 18.Verleden GM, Glanville AR, Lease ED, Fisher AJ, Calabrese F, Corris PA, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment—A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019. May;38(5):493–503. doi: 10.1016/j.healun.2019.03.009 [DOI] [PubMed] [Google Scholar]
  • 19.Euro QoL Group. Euro Qol—a new facility for the measurement of health-related quality of life. Health Policy. 1990. Dec;16(3):199–208. doi: 10.1016/0168-8510(90)90421-9 [DOI] [PubMed] [Google Scholar]
  • 20.Löwe B, Wahl I, Rose M, Spitzer C, Glaesmer H, Wingenfeld K, et al. A 4-item measure of depression and anxiety: validation and standardization of the Patient Health Questionnaire-4 (PHQ-4) in the general population. J Affect Disord. 2010. Apr;122(1–2):86–95. doi: 10.1016/j.jad.2009.06.019 Epub 2009 Jul. [DOI] [PubMed] [Google Scholar]
  • 21.Public Health England. Investigation of novel SARS-CoV-2 variant: variant of concern 202012/01, technical briefing 3. London, United Kingdom: Public Health England; 2020. [Internet]. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/950823/Variant_of_Concern_VOC_202012_01_Technical_Briefing_3_-_England.pdf Accessed June, 11, 2021.
  • 22.Simonson TS, Baker TL, Banzett RB, Bishop T, Dempsey JA, Feldman JL, et al. Silent hypoxaemia in COVID-19 patients. J Physiol. 2021. Feb;599(4):1057–1065. doi: 10.1113/JP280769 Epub 2021 Jan 4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Karagiannidis C, Mostert C, Hentschker C, Voshaar T, Malzahn J, Schillinger G, et al. Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study. Lancet Respir Med. 2020. Sep;8(9):853–862. doi: 10.1016/S2213-2600(20)30316-7 Epub 2020 Jul 28. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Permpalung N, Bazemore K, Chiang TP, Mathew J, Barker L, Nematollahi S, et al. Impact of COVID-19 on Lung Allograft and Clinical Outcomes in Lung Transplant Recipients: A Case-Control Study. doi: 10.1097/TP.0000000000003839 Published online ahead of print. [DOI] [PubMed] [Google Scholar]
  • 25.Vandervest KM, Zamora MR. Respiratory viral infections post-lung transplantation. Curr Respir Care Rep. 2012;1(3):162–167. doi: 10.1007/s13665-012-0017-x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Miele M, Busà R, Russelli G, Sorrentino MC, Di Bella M, Timoneri F, et al. Impaired anti-SARS-CoV-2 Humoral and Cellular Immune Response induced by Pfizer-BioNTech BNT162b2 mRNA Vaccine in Solid Organ Transplanted Patients. Am J Transplant. 2021. May 31. doi: 10.1111/ajt.16702 Epub ahead of print. [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Robert Jeenchen Chen

9 Aug 2021

PONE-D-21-23993

COVID-19 in lung transplant recipients - risk prediction and outcomes

PLOS ONE

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Reviewer #1: The subject included in the manuscript is of the utmost importance for broad medical community. Firstly, COVID-19 is the novel disease of unknown long-term consequences. Secondly, undoubtedly it will be present in population for many years, if not decades.

Therefore every report sheds a new light on the condition we will be facing in the years to come.

It is reviewer satisfaction to be able to congratulate the Authors. The forwarded paper is meticulous, comprehensive, and precise. It is astounding that out of more than 1000 LTx individuals, solely more then 30 have gotten ill.

Definitely this indicates accurate measures introduced to prevent them from being infected, some of them you have mentioned in the manuscript.

I am quite aware of the leading role of the Hannover Medical School in Europe in lung transplantation. Therefore I got impression the COVID-19 is not affecting seriously this population. It is reassuring message, which perhaps might be more openly emphasized.

In the discussion section you have made an extensive comparison with other LTx centers.

Generally speaking reading this manuscript has been a teachable moment.

Reviewer #2: Thank you for submititng this retrospective analysis of one of the largest cohort in europe in COVID period.

The paper is well written. Statistics were performed rigorously

Can you support few precision

1 can you explain why recent lung transplant seems to be less affected and the high proportion of preexisting CLAD. Is a particularity of your global cohort ?

2 in discussion line 290 : "hospital stays were significately shorter". This result may be explain due to the therapeutics engaged in lung transplant patient (dialysis - ECMO) and not in the general population.

3 line 346 you assay that the lack of control group. Can you develop this point. You can realize propensive score with your cohort, especially on CLAD

**********

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Reviewer #1: No

Reviewer #2: Yes: geoffrey Brioude

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PLoS One. 2021 Oct 6;16(10):e0257807. doi: 10.1371/journal.pone.0257807.r002

Author response to Decision Letter 0

16 Aug 2021

Rebuttal letter – Response to Reviewers

Reviewer #1:

The subject included in the manuscript is of the utmost importance for broad medical community. Firstly, COVID-19 is the novel disease of unknown long-term consequences. Secondly, undoubtedly it will be present in population for many years, if not decades. Therefore every report sheds a new light on the condition we will be facing in the years to come. It is reviewer satisfaction to be able to congratulate the Authors. The forwarded paper is meticulous, comprehensive, and precise. It is astounding that out of more than 1000 LTx individuals, solely more then 30 have gotten ill. Definitely this indicates accurate measures introduced to prevent them from being infected, some of them you have mentioned in the manuscript. I am quite aware of the leading role of the Hannover Medical School in Europe in lung transplantation. Therefore I got impression the COVID-19 is not affecting seriously this population. It is reassuring message, which perhaps might be more openly emphasized. In the discussion section you have made an extensive comparison with other LTx centers. Generally speaking reading this manuscript has been a teachable moment.

Comment #1:

Thank you very much for your appreciative comments. We are very pleased about this kind feedback.

You suggested giving a little more emphasis on the small amount of lung transplant recipients from our institution affected by COVID-19. In fact, approximately 4 percent of our recipients have been infected by SARS-CoV-2 during the observation period what is comparable to the numbers in the German general population. However, the estimated number of unreported / undetected cases might be considerably higher in the general population so we added the following sentence to our discussion:

Lines 283-284: The incidence of SARS-CoV-2 infections in our patient-cohort during the observation period was similar to nationwide German incidence (figure 3). However, it might be possible that the number of unreported / undetected cases were considerably higher.

Reviewer #2:

Thank you for submititng this retrospective analysis of one of the largest cohort in europe in COVID period. The paper is well written. Statistics were performed rigorously. Can you support few precision:

Comment #2:

We thank you for the valuable comments which helped to improve the manuscript. We have addressed all your comments below and provided explanations where information was requested.

1) can you explain why recent lung transplant seems to be less affected and the high proportion of preexisting CLAD. Is a particularity of your global cohort ?

Thank you for these questions. Chronic lung allograft dysfunction (CLAD) is the most important limiting single factor of long-term survival after lung transplantation, accounting for >40% of deaths beyond the first year.1,2 The amount of lung transplant recipients with pre-existing CLAD in our work seems not to be unexpectedly high as CLAD is a major issue in these patients. Almost one third of our reciepints alive are affected with CLAD. As presented in figure 3, the incidence trend of SARS-CoV-2 infections in our cohort was very similar to that from the German general population.

We added a sentence to the manuscript to highlight the relevance of CLAD in lung transplant recipients:

Lines 302-303: The most important limiting single factor of long-term survival in LTx recipients is CLAD, responsible for >40% of deaths beyond the first year (17).

1) Verleden GM, Glanville AR, Lease ED, Fisher AJ, Calabrese F, Corris PA, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019 May;38(5):493-503. doi: 10.1016/j.healun.2019.03.009. Epub 2019 Apr 3. PMID: 30962148.

2) Van Herck A, Frick AE, Schaevers V, Vranckx A, Verbeken EK, Vanaudenaerde BM, et al. Azithromycin and early allograft function after lung transplantation: A randomized, controlled trial. J Heart Lung Transplant. 2019 Mar;38(3):252-259. doi: 10.1016/j.healun.2018.12.006. Epub 2018 Dec 14. PMID: 30686699.

2) in discussion line 290 : "hospital stays were significately shorter". This result may be explain due to the therapeutics engaged in lung transplant patient (dialysis - ECMO) and not in the general population.

Thank you for this comment. We added this potential explanation to the discussion section:

Lines 271-274: In this work, in-hospital mortality was 22% (compared to 46% in our study) and hospital stays were significantly shorter (14 vs. 19 days) what might potentially be explained due to the therapeutics engaged in LTx recipients (e.g. exctracorporeal therapies) rather than in the general population.

3) line 346 you assay that the lack of control group. Can you develop this point. You can realize propensive score with your cohort, especially on CLAD

Thanks again for this important consideration and the excellent statistical discussion point. The patient cohort affected by COVID-19 is rather small. We agree that this is a limitation for all forms of multivariate analyses used in small sample sizes. We have recognized propensity score matching as an in-vogue method but we must at the same time acknowledge inherent limitations of this method. Indeed, we discussed to use this method beforehand instead of traditional covariate adjustment. After statistical advice and following recent guidance for statistical reporting we decided against using propensity score matching.3 No change in the revised manuscript regarding this point.

3) Harhay MO, Donaldson GC. Guidance on Statistical Reporting to Help Improve Your Chances of a Favorable Statistical Review. Am J Respir Crit Care Med. 2020;201(9):1035-1038. doi: 10.1164/rccm.202003-0477ED.

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Decision Letter 1

Robert Jeenchen Chen

13 Sep 2021

COVID-19 in lung transplant recipients - risk prediction and outcomes

PONE-D-21-23993R1

Dear Dr. Kamp,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

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Comments to the Author

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Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

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Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: (No Response)

Reviewer #2: Tak you for this answer.

All the comments were discussed and appropriate modifications done.

No further modifications

**********

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Reviewer #1: No

Reviewer #2: Yes: Brioude Geoffrey

Acceptance letter

Robert Jeenchen Chen

15 Sep 2021

PONE-D-21-23993R1

COVID-19 in lung transplant recipients - risk prediction and outcomes

Dear Dr. Kamp:

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    Data Availability Statement

    The data presented in this study are available only on reasonable request from the corresponding author or from the German Center for Lung Research (DZL) data warehouse. [Internet: “https://dzl.de/en/dzl-data-warehouse/”]. Contacts for data management requests: [Internet: “https://dzl.de/en/platforms/contact-central-biobanking-management/”]. General public deposition of patient data is restricted according to the written informed consent which has been given from all patients for the use of their data for scientific purposes. Approval was given by the local institutional review board at Hannover Medical School (no. 2923-2015).

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