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Original Clinical Science—General

Impact of COVID-19 on Lung Allograft and Clinical Outcomes in Lung Transplant Recipients: A Case-control Study

Permpalung, Nitipong MD, MPH1,2; Bazemore, Katrina MPH3; Chiang, Teresa Po-Yu MD, MPH4; Mathew, Joby DPT, MS3; Barker, Lindsay RN, BSN3; Nematollahi, Saman MD1; Cochran, Willa CRNP4; Sait, Afrah S. MD1; Avery, Robin K. MD1; Shah, Pali D. MD3

Author Information
doi: 10.1097/TP.0000000000003839
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Abstract

INTRODUCTION

The coronavirus disease 2019 (COVID-19) pandemic has markedly impacted the field of pulmonary disease and transplantation.1,2 Mortality from COVID-19 in solid organ transplant (SOT) recipients ranges from 4.4% to 20% among centers,3-9 but reports of other longer-term outcomes following hospital discharge remain limited. Lung transplant recipients (LTRs) are at risk of unique complications post–respiratory viral infections (RVIs) including allograft rejection and chronic lung allograft dysfunction (CLAD) stage progression.10-13 The data regarding COVID-19 outcomes in LTRs are very limited, as most large SOT cohorts contained only small numbers of LTRs and did not provide clinical outcomes specific to this patient population.4,8,9 Early in the pandemic, case series from France and New York reported mortality in LTRs at 15% and 34%, respectively; however, more contemporary follow-up incorporating current COVID treatment and an examination of outpatient outcomes are imperative to provide guidance to the clinical and scientific community.14,15

Community-acquired RVIs other than COVID-19 have been known to carry mortality rates of up to 10%–20% in LTRs in previous studies.10-13 Acute lung allograft rejection post-RVIs can occur in 5%–55% of LTRs depending on study year, definitions, and follow-up periods.13,16-18 Most concerning, RVIs are known to be a risk factor for CLAD with an incidence of CLAD stage progression at 20%–30% within 1 y post–community-acquired RVI.13,19,20 However, few studies have directly compared these rates of post viral-CLAD with the incidence of CLAD progression in uninfected LTRs. Our published works in LTRs have demonstrated that forced expiratory volume in 1 s (FEV1) decline at d 90 post-RVI was the main predictor for CLAD stage progression due to human metapneumovirus and parainfluenza virus, as well as a predictor for mortality from respiratory syncytial virus.12,13 In COVID-19, survival in LTRs has been reported, but other longer-term outcomes specific to this patient population including secondary infections, postviral lung function, and acute rejection remain unknown. To address these critical knowledge gaps, we performed a matched case–control study to evaluate lung allograft complications and clinical outcomes post COVID-19 in LTRs, a patient population highly vulnerable to lung allograft injury following SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2).

MATERIALS AND METHODS

This is a matched case–control study with 2 control LTR patients for each adult LTR diagnosed with COVID-19 by positive polymerase chain reaction from a respiratory specimen, together with respiratory symptoms, between March 2020 and January 2021 at The Johns Hopkins Hospital. The matching criteria for controls included patient’s age (within ±10 y) and year of lung transplantation, and the study population included both inpatients and outpatients. We selected time from transplant, with the intent that it would balance lung transplant relevant baseline lung function that naturally declines exponentially from time of transplant21,22 and baseline allograft rejection. We selected age with the intent to balance risk of baseline systemic comorbidities. The index dates for controls were the dates of COVID-19 diagnosis of their matched cases. Potential controls were excluded if they were diagnosed with other RVIs from 1 y before to 90 d after the index date but were not specifically excluded on the basis of other respiratory events. When > 2 potential control subjects met the above criteria, we selected those with closest follow-up time from transplant by year and then closest in age compared with the index case. Our small LTR sample size restricted the use of propensity matching or the number of variables we could match on. Moreover, matching on comorbidities will not allow us to examine the association between COVID-19 and lung allograft outcomes. All patients were followed up to 90 d after the index date. The study was approved by The Johns Hopkins Institutional Review Board.

Clinical Protocols

The center used basiliximab for routine induction and 3-drug immunosuppression with tacrolimus, prednisone, and mycophenolate mofetil as the preferred first-line maintenance. As part of this center’s management practice, LTRs were educated to contact their lung transplant team within 48 h of experiencing any respiratory or COVID-19 symptoms. During the COVID-19 pandemic, they underwent viral polymerase chain reaction screening within 2 d of reporting symptoms with nasopharyngeal swab, with 24-h result turnaround. LTRs with arterial oxygen saturation (SaO2) <94% or respiratory distress were instructed to present to the emergency room for further management without waiting for a viral test result. Nonhypoxic LTRs were considered for admission if they were likely to need antimicrobial therapies that could not be administered in the outpatient setting. During the COVID-19 pandemic, frequency of surveillance bronchoscopy was reduced due to infection control concerns. However, routine surveillance home spirometry, HLA-donor-specific antibodies (DSAs) every 3 mo in the first year, and then yearly thereafter were continued. For-cause bronchoscopies, formal spirometry, and HLA-DSA screening were performed with any LTRs exhibiting unexplained FEV1 decline ≥10%, suspected allograft dysfunction, or in the case of diagnostic uncertainty requiring tissue or bronchoalveolar lavage sampling. None of the patients had completed COVID-19 vaccination series at index date.

Treatment of COVID-19 at The Johns Hopkins Hospital has evolved over time with the emergence of evidence-based therapies and special consideration for immunocompromised hosts.2 In general, LTRs who were diagnosed with COVID-19 received remdesivir (inpatient), convalescent plasma (inpatient), and COVID-19-specific monoclonal antibodies (outpatient) based on emergency use authorization criteria, as these agents became available for clinical use. Dexamethasone was prescribed when LTRs required supplemental oxygen to maintain SaO2 ≥94%. Tocilizumab was considered when LTRs required high-flow oxygen while receiving dexamethasone or were within the first 24 h of intensive care. LTRs who were not at risk of immediate rejection often had antimetabolite immunosuppression held during the infectious period.23 At our center, inpatient LTRs with COVID-19 were routinely screened with inflammatory markers, serum fungal biomarkers, sputum culture, and cytomegalovirus (CMV) viral load. When LTRs were treated with dexamethasone or tocilizumab, we started mold-active azoles for fungal prophylaxis, and empiric antibiotics for secondary pneumonia. Bronchoscopy was performed if there was a concern for undiagnosed infection or allograft rejection. All LTRs remained on lifelong antiviral and Pneumocystis prophylaxis. After RVI episodes, pulmonary function tests were performed between d 60 and 90.

Data Collection and Study Definitions

Eligible cases and controls were identified through The Johns Hopkins Lung Transplant Database. Baseline characteristics and lung allograft function included patient’s comorbidities, transplant type, maintenance immunosuppression, history of rejection, and recent rejection treatment. Acute cellular rejection (ACR), acute antibody-mediated rejection (AMR), and CLAD were identified and staged based on formal spirometry values and according to the International Society for Heart and Lung Transplantation criteria.21,24-26

Upper respiratory tract infection (URTI) was defined as detection of SARS-CoV-2 with symptoms involving the upper respiratory tract (rhinorrhea, cough, sinus or nasal congestion, pharyngitis) without new oxygen requirement, pulmonary infiltrates on chest imaging, or decrease in FEV1 ≥10% at diagnosis compared with their baseline. Lower respiratory tract infection (LRTI) was defined as detection of SARS-CoV-2 with the presence of any of these parameters: new oxygen requirement, pulmonary infiltrates, need for mechanical ventilation, or decrease in FEV1 ≥10% at diagnosis compared with their baseline.12,13 We characterized the severity of COVID-19 using the World Health Organization COVID-19 severity scale, which ranges from 1 (ambulatory, no limitations) to 8 (death) and has previously been used as a metric of COVID-19 severity.27,28 Secondary bacterial and invasive fungal infections (IFIs) at or after the index date up to 90 d were defined according to standardized definitions in cardiothoracic transplant recipients and the European Organization for Research and Treatment of Cancer/Mycoses Study Group.29,30

Study Outcomes

Primary outcomes were 90-d all-cause mortality and 90-d readmission due to respiratory diseases. Secondary outcomes included the following variables for lung allograft function within 90 d after index date for controls: ACR, AMR, new DSA detection, and ≥10% decline in spirometry from their baseline preindex dates. We included all grades of ACR and AMR according to the International Society for Heart and Lung Transplantation criteria.24,25 Other outcomes included secondary bacterial and fungal infections as well as need of for-cause bronchoscopies.

Statistical Analyses

All statistical analyses were conducted with SAS OnDemand for Academics (SAS Institute, Cary, NC) and Stata/SE 15.1 (College Station, TX). Baseline characteristics, baseline lung allograft function, and clinical outcomes were analyzed to compare cases and controls. The chi-square test and Fisher exact were used to compare categorical and binary variables among the 2 groups. The Wilcoxon rank-sum test and T test were used to compare continuous variables among the 2 groups depending on data distribution.

Sensitivity Analyses

Because LTRs with COVID-19 and their controls were generally comparable regarding baseline characteristics and lung function, the analyses of primary outcomes of interest were unadjusted. However, to account for potential confounding, we performed sensitivity analyses by calculating a propensity score for LTRs with COVID-19 based on age, year of transplantation, and baseline CLAD stage ≥2 (yes/no) by the weighting-by-the-odds technique.9,31 The propensity score was converted to an odds scale (p1p) for all controls and a weight of 1 was applied for all LTRs with COVID-19. This assured comparable balance of age, year of transplantation, and baseline CLAD stage across both groups. We compared 90-d readmission, FEV1 decline ≥10%, for-cause bronchoscopy, secondary bacterial infection, and secondary fungal infection between cases and controls by using Poisson regression after applying the propensity score.

RESULTS

Baseline Characteristics and Lung Allograft Function

Twenty-four LTRs were diagnosed with COVID-19 during the study period and their 48 matched controls were identified. Their baseline characteristics are summarized in Table 1. There were no significant differences in their baseline characteristics with regard to age, sex, body mass index, race, underlying medical comorbidities, underlying lung disease before lung transplantation, lung transplant type, CMV serostatus, median duration from lung transplantation to index dates, and maintenance immunosuppression. Baseline lung allograft function and recent rejection treatment are summarized in Table 2. Cases and controls had similar proportion of CLAD stage ≥2 and similar rates of recent ACR, AMR, and new DSA detection within 180 d before index dates. At the time of COVID-19 diagnosis, 25% had CLAD stage 1, 8.3% had CLAD stage 2, 12.5% had CLAD stage 3, and 4.1% had CLAD stage 4. There were no statistically significant differences in recent rejection treatment and use of azithromycin for CLAD prophylaxis in the 2 groups.

TABLE 1. - Baseline patient characteristics
Variable Cases (n = 24), total (%) Controls (n =48), total (%) P
Age at diagnosis (y), median (IQR) 63.5 (39.5–67) 61.5 (43.5–71.5) 0.68
Male sex 10 (41.7) 19 (39.6) 0.87
BMI (kg/m2), median (IQR) 25.1 (21.2–30.3) 25.3 (22.1–28.2) 0.82
Race
 Caucasian 17 (70.8) 38 (79.2) 0.32
 African American 6 (25) 10 (20.8)
 Other 1 (4.2) 0 (0)
Underlying medical condition
 Diabetes mellitus 11 (45.8) 14 (29.2) 0.16
 Hypertension 14 (58.3) 30 (62.5) 0.73
 Coronary artery disease 6 (25) 13 (27.1) 0.85
 End-stage renal disease (on dialysis) 4 (16.7) 3 (6.3) 0.16
 Hypogammaglobulinemia 3 (12.5) 7 (14.6) 0.81
Underlying lung disease pretransplant
 Obstructive lung diseases 6 (25) 20 (41.7) 0.12
 Interstitial lung diseases 12 (50) 24 (50)
 Bronchiectasis 5 (20.8) 2 (4.2)
 Pulmonary vascular diseases 1 (4.2) 2 (4.2)
Lung transplant type
 Single lung 5 (20.8) 8 (16.7) 0.66
 Double lung 19 (79.2) 40 (83.3) 0.31
 Retransplant 0 (0) 2 (4.2)
Days from lung transplant to index date (d), median (IQR) 2109 (748.5–4751) 2106 (686–4785.5) 0.89
CMV status
 High risk (D+/R) 3 (13.1) 16 (33.3) 0.20
 Intermediate risk (D+/R+, D/R+) 13 (56.5) 21 (43.8)
 Low risk (D/R) 7 (30.4) 11 (22.9)
CMV reactivation within 90 d before index date 2 (8.3) 4 (8.3) >0.99
Maintenance immunosuppression
 Tacrolimus 23 (95.9) 42 (87.5) 0.26
 Everolimus 0 (0) 3 (6.3) 0.21
 Azathioprine 3 (12.5) 3 (6.3) 0.37
 Cyclosporine 0 (0) 5 (10.4) 0.10
 Mycophenolate 15 (62.5) 27 (56.25) 0.61
 Prednisone 24 (100) 48 (100)
BMI, body mass index; CMV, cytomegalovirus; D, donor; IQR, interquartile range; , negative; n, number; +, positive; R, recipient.

TABLE 2. - Baseline lung allograft function and recent rejection treatment before index dates
Variable Cases (n = 24), total (%) Controls (n = 48), total (%) P
Baseline PFT (±SD)
 FEV1 1.73 ± 0.72 1.97 ± 0.76 0.20
 FVC 2.59 ± 0.98 2.60 ± 0.79 0.97
Baseline CLAD stage ≥2 6/24 (25) 11/47 (23.4) 0.88
ACR ≥ A1 within 180 d before index date 1 (4.17) 0 (0) 0.15
AMR within 180 d before index date 2 (8.3) 4 (8.3) >0.99
HLA/DSA detection within 180 d before index date 3 (12.5) 7 (14.6) 0.81
Rejection treatment
 Augmented corticosteroids 2 (8.3) 4 (8.3) >0.99
 IVIG 2 (8.3) 9 (18.8) 0.25
 Rituximab 1 (4.2) 1 (2.1) 0.61
Receiving azithromycin prophylaxis 16 (66.7) 35 (72.9) 0.58
ACR, acute cellular rejection; AMR, acute antibody mediated rejection; CLAD, chronic lung allograft dysfunction; DSA, donor-specific antibody; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; n, number; PFT, pulmonary function test.

Clinical Trajectory Among COVID-19 Cases

Clinical course and COVID-19-specific therapies among cases are portrayed in Figure 1. At the time of COVID-19 diagnosis, 8 had URTI and 16 had LRTI. Median duration (interquartile range) from symptom onset to COVID-19 diagnosis was 2.5 (1–5) d. Among the 8 patients with URTI, 4 were successfully treated and monitored in an outpatient setting and 4 developed disease progression to LRTI requiring hospitalization later in the course. Among the 4 patients successfully treated in an outpatient setting, 3 received Bamlanivimab. All 16 patients with LRTI required hospitalization within 48–72 h of COVID-19 diagnosis.

FIGURE 1.
FIGURE 1.:
Clinical course and therapies among COVID-19-positive cases; Cont. O2, continued need for supplemental oxygen; CP, convalescent plasma; D, dexamethasone; FEV1 decline, forced expiratory volume decline ≥10% from baseline; mAb, monoclonal antibodies; R, remdesivir; Re-admit, readmission within 90 d of symptom onset; T, tocilizumab.

COVID-19-related parameters and COVID-19-specific therapies are summarized in Table 3. Among the 20 hospitalized patients, 4 received high-flow oxygen and 2 required mechanical ventilation. None required new dialysis or extracorporeal membrane oxygenation. Reduction of immunosuppression with mycophenolate discontinuation was the most common COVID-19-specific treatment (79.2%), followed by convalescent plasma transfusion (70.8%), remdesivir (45.8%), dexamethasone (41.7%), monoclonal antibody infusion in outpatient setting (33.3%), and tocilizumab (4.2%). Mean ± SD values of laboratory results at admission were as follow: white blood cell: 5.49 ± 2.1 × 103/µL, neutrophil count: 4.21 ± 2.1 × 103/µL, lymphocyte: count 0.77 ± 0.5 × 103/µL, C-reactive protein: 4.97 ± 5.8 mg/L, d-dimer: 1.39 ± 1.7 µg/mL, ferritin: 769.5 ± 1185.2 ng/mL, and interleukin-6: 31.46 ± 39.3 pg/mL.

TABLE 3. - COVID-19-related parameters and COVID-19-specific therapy
Variable Cases (n = 24), total (%)
Clinical parameters at diagnosis
 Classification of infection at diagnosis
  URTI (rhinorrhea, sore throat, or cough) 8 (25)
  LRTI (FEV1 decline ≥10%, new lung infiltrates or hypoxia) 16 (75)
 Duration of symptoms to diagnosis (d), median (IQR) 2.5 (1–5)
 Oxygen requirement at diagnosis
  Room air 16 (66.7)
  1–2 LPM 3 (12.5)
  >2 LPM 5 (20.8)
 Need mechanical ventilation at diagnosis 0 (0)
 WHO severity score at diagnosis, median (IQR) 3 (3–4)
 Maximum WHO severity score during admission,  median (IQR) 3 (3–4)
 Advanced life support therapy during admission
  High-flow oxygen 4 (16.7)
  Mechanical ventilation 2 (8.4)
Treatment-related parameters
 COVID-19-specific therapeutics
  Remdesivir 11 (45.8)
  Dexamethasone 10 (41.7)
  Convalescent plasma 17 (70.8)
  Tocilizumab 1 (4.2)
  Monoclonal antibody 8 (33.3)
  Mycophenolate discontinuation during period of infection 19 (79.2)
 Concurrent antimicrobial therapy
  Concomitant antibacterial agents 18 (75)
  Concomitant mold active agents 12 (50)
FEV1, forced expiratory volume; IQR, interquartile range; LPM, liter per minute; LRTI, lower respiratory tract infection; n, number; URTI, upper respiratory tract infection; WHO, The World Health Organization.

Clinical Outcomes

Clinical outcomes and lung allograft function are summarized in Table 4. Among 24 LTRs with COVID-19, there were 2 deaths during the study period. One died from COVID-19 and the other died from COVID-19-associated pulmonary aspergillosis (CAPA). Among controls, there was 1 death due to aspiration pneumonia with multiorgan failure. LTRs with COVID-19 had significantly higher readmission for respiratory exacerbation in 90 d after index date, compared with the controls (29.2% versus 10.4%, P = 0.04, respectively). Among the 7 LTRs with COVID-19 who were rehospitalized, 2 were due to volume overload and 5 were due to respiratory tract infection (3 with Pseudomonas pneumonia, 1 with mucormycosis, and 1 with CAPA). No control patients were hospitalized at time of index date but 5 were subsequently hospitalized within the 90-d follow-up window (due to CMV viremia, hemoptysis after a bronchoscopy, supraglottic mass, coronary artery disease, and S. viridans bacteremia).

TABLE 4. - Clinical outcomes and allograft function after index dates
Variable Cases (n = 24), total (%) Controls (n = 48), total (%) P
Clinical outcomes postinfection
 90-d all-cause mortality 2 (8.3) 1 (2.1) 0.21
 Readmission for respiratory exacerbation within 90 d 7 (29.2) 5 (10.4) 0.04
 For-cause bronchoscopy 8 (33.3) 6 (12.5) 0.04
  Within 7 d of index dates 2 (8.3) 1 (2.1)
  During 8–90 d after index dates 6 (25) 5 (10.4)
 Secondary infectious complications in 90 d, no. (%)
  Secondary bacterial infection 7 (29.2) 3 (6.3) 0.008
   Within 7 d of index dates 1 (4.2) 0 (0)
   During 8–90 d after index dates 6 (25) 3 (6.3)
  Secondary fungal infection 5 (20.8) 4 (8.3) 0.13
   Within 7 d of index dates 1 (4.2) 0 (0)
   During 8–90 d after index dates 4 (16.7) 4 (8.3)
  CMV reactivation 1/23 (4.2) 5 (10.6) 0.35
Allograft function after index dates
 ACR within 90 d, no. (%) 0/8 0/5
 AMR within 90 d, no. (%) 0/16 0/28
 New HLA-DSA detection within 90 d, no. (%) 0/16 0/28
 PFT after index dates
  FEV1 1.81 ± 0.71 1.88 ± 0.84 0.73
  FEV1 decline ≥10% from baseline 4/21 (19) 5/41 (12.2) 0.46
  FVC 2.67 ± 0.89 2.52 ± 0.90 0.53
  Interval in days from index date to PFT, median (IQR) 93 (69–108) 95(72–150) 0.31
ACR, acute cellular rejection; AMR, acute antibody mediated rejection; CMV, cytomegalovirus; DSA, donor-specific antibody; FEV1, forced expiratory volume; FVC, forced vital capacity; IQR, interquartile range; n, number; PFT, pulmonary function test.

For-cause bronchoscopies within 90 d were performed in 33.3% of LTRs with COVID-19 and 12.5% of controls (P = 0.04). Bronchoscopy was performed within 7 d of index date for 8.3% of cases versus 2.1% of controls, and during 8–90 d of index date for 25% of cases versus 10.4% of controls. HLA-DSA was checked in 16 of 24 (67%) cases and 28 of 48 (58%) control patients. No ACR, de novo HLA-DSA, or AMR were reported in the follow-up period in either group. LTRs with COVID-19 had higher incidence of secondary bacterial infections after index date, compared with controls (29.2% versus 6.3%, P = 0.008, respectively). Eighteen (75%) LTRs with COVID-19 were started on empiric antibiotics within 7 d of COVID-19 diagnosis, while no controls were started on antibiotics within 7 d of index dates. Seven LTRs with COVID-19 developed secondary bacterial pneumonia: 1 within 7 d and 6 during 8–90 d after COVID-19 diagnosis. Among these 7 patients, 5 were infected with Pseudomonas aeruginosa, 1 with Staphylococcus aureus, and 1 with Enterococcus faecalis. In comparison, 3 controls developed bacterial pneumonia within 90 d after index dates, 1 with P. aeruginosa, 1 with P. aeruginosa and Staphylococcus aureus, and 1 with Enterococcus coli, P. aeruginosa, and Achromobacter xylosoxidans. LTRs with COVID-19 developed higher incidence of secondary IFIs, compared with controls without RVIs, but the result was not statistically significant (20.8% versus 8.3%, P = 0.13, respectively). Among 5 LTRs with COVID-19 who developed IFIs, 3 developed CAPA, 1 was infected by Paecilomyces spp, and 1 developed mucormycosis. Four developed IFIs despite being on isavuconazole for antifungal prophylaxis in the aftermath of severe COVID-19 infection requiring treatment with augmented corticosteroids. FEV1 decline ≥10% from their baseline following acute infection date was found in 19% of LTRs with COVID-19, compared with 12.2% among control subjects (P = 0.46).

Sensitivity Analyses

After weighting, the incidence rate ratios of readmission (3.04 [1.06–8.71], P = 0.038), FEV1 decline ≥10% (1.61 [0.48–5.44], P = 0.45), for-cause bronchoscopy (2.99 [1.15–7.79], P = 0.025), secondary bacterial infection (5.08 [1.41–18.25], P = 0.013), and secondary fungal infection (2.59 [0.75–8.95], P = 0.13) were consistent with our main analyses. LTRs with COVID-19 were at higher risk for readmission, need of for-cause bronchoscopies, and developing secondary bacterial infection.

DISCUSSION

To the best of our knowledge, this is the first matched case–control study to evaluate lung allograft function following COVID-19 in LTRs, and one of the few studies to compare both pulmonary and secondary infectious outcomes with uninfected LTRs. To this end, we noted higher readmission rates, secondary infection, and more frequent bronchoscopy in the COVID-19 LTRs, compared with controls. We further observed that 24% of patients had significant decline in lung spirometry within 90 d of COVID-19.

Regarding lung allograft function post COVID-19, we observed no clinical ACR, AMR, or new DSA detection among cases or controls who underwent bronchoscopy with biopsy or had DSA checked. This appears distinct from findings in other RVIs from our center, where we have reported 3%–12% incidence of new HLA-DSA and 4%–6.5% incidence of ACR, in a similar proportion of patients who underwent the corresponding diagnostic testing.13 While our findings may underestimate the incidence of acute allograft rejection post COVID-19 due to reduced surveillance bronchoscopy, it is also possible that prompt antiviral therapy and concurrent steroids for moderate–severe COVID-19 cases may have mitigated the development of acute ACR. Approximately 20% of LTRs with COVID-19 developed FEV1 decline ≥10% from their baseline. This is consistent with the findings seen in other CLAD-associated RVIs, where we have reported >10% FEV1 decline within 90 d in 15%–23% of paramyxoviral infections.12,13 While future studies are underway to examine downstream CLAD incidence and to determine if this progression is in fact greater than natural decline of lung function among controls, our prior observations in paramyxoviral models raise concern that this subset of COVID-19 subjects with reduced lung function may be at highest risk of CLAD development and early 1-y mortality.12,13

The COVID-19-associated mortality in LTRs from our center is lower than the previously published reports of 15%–34% mortality of SARS-CoV-2-infected LTRs.14,15,32 We recognize various factors, including local incidence of infection and availability of COVID-specific treatments, could play a role in the heterogeneous mortality rates; however, both deaths in our study occurred in patients who received what is now considered first-line therapy for COVID-19 patients with hypoxia: remdesivir and corticosteroids. Further studies in larger cohorts are needed to validate whether the COVID-19 mortality rate in LTR is comparable or, in fact, increased from with that of non-RVI controls. Interestingly, recent work from our center showed no differences in mortality and length of stay among all SOT versus non-SOT patients hospitalized with COVID-19.9

Our study appears to be the first to our knowledge to examine secondary infections in concurrent or following COVID-19 infections in this population, a complication of critical importance given their therapeutic implication and associated risk of downstream CLAD.33,34 Infection with SARS-CoV-2 can lead to a robust inflammatory response. Compromised airway defense from viral infections in conjunction with increased dose of corticosteroids, a standard therapy of COVID-19 patients with hypoxemia, can increase risk of secondary infections regardless of host immune status.35-37 In our cohort, approximately 30% and 20% of LTRs with COVID-19 developed secondary bacterial pneumonia and secondary IFIs, respectively. This observed incidence of secondary bacterial infection was higher than previous reports at 1%–21% among all hospitalized patients with COVID-19.35,36,38,39 We recognize these variations could also be due to diagnostic bias toward performing bronchoscopies in LTRs, compared with other populations, and different definitions of infection. Our study is the first to report incidences of secondary IFIs post COVID-19 in LTRs. While the frequency of secondary IFIs after all RVIs in LTRs has not been well described, published data from our center showed that approximately 13% and 23% of LTRs had positive respiratory fungal isolates within 90 d post human metapneumovirus and parainfluenza virus infections, respectively, indirectly suggesting that the incidence of IFI after COVID-19 may be comparable.13 That said, our observed incidence of IFIs in the LTR cohort appears higher than the published incidences of CAPA among all-cause mechanically ventilated COVID-19 patients (5%–10%).37

Approximately 50% of LTRs with COVID-19 in our cohort actively received mold-active azoles for fungal prophylaxis during the study period. Remarkably, 4 of 5 patients developed breakthrough IFIs post COVID-19 while receiving isavuconazole prophylaxis. Although breakthrough IFIs have been reported among 3% LTRs and 5%–13% of hematologic malignancy/stem cell transplant patients receiving isavuconazole prophylaxis,40-44 our findings raised the concern that empiric isavuconazole may not be an optimal option in LTRs with severe COVID-19 requiring augmented corticosteroids therapy. This, in addition to high incidence of secondary bacterial infections, may support additional inquiry as to whether more frequent diagnostic bronchoscopy at time of COVID-19 infection may help and tailor antimicrobial strategies for secondary infections.

Limitations to this study include those inherent to retrospective design and small sample size to determine significance of select secondary outcomes. Nonetheless, this study’s robust clinical follow-up data acquired at a time when most outpatient clinical care was provided via telemedicine, and the inclusion of a concurrent RVI-negative matched controls group, which has not been commonly included in other studies of RVI-associated lung transplant outcomes, are notable strengths. These characteristics are of paramount importance in understanding sequelae of COVID-19 disease in the population that is at high risk of infection and irreversible loss of lung function. While the authors would like to have directly compared the post COVID-19 outcomes in LTRs with that of other RVIs, the marked paucity of other RVIs during the COVID-19 pandemic and the study period precluded this examination. Further studies with larger sample size and longer follow-up time are planned to understand late lung allograft complications post COVID-19, including CLAD stage progression, to investigate risk factors of secondary infections and the role of antimicrobial prophylaxis in at-risk LTRs.

In conclusion, LTRs with COVID-19 had >90% survival at 90 d, but were at high risk to develop secondary infections and experienced higher rates of rehospitalization and bronchoscopy, compared with uninfected LTR controls. Our study suggests that the majority of COVID-19-infected lung transplant individuals can have a successful recovery but may require vigilant monitoring for secondary infection and decline in spirometric lung function.

ACKNOWLEDGMENTS

Authors would like to thank all providers taking care of our LTRs at Johns Hopkins as well our lung transplant patients and their families.

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