Low Mortality Associated with COVID-19 Infection in Lung Transplant Recipients at a Single Center

Rahul F. Gomez ^{1, *}, Aarya Kafi ¹, Gordon Yung ¹, Saima Aslam ², Christine M. Lin ¹, Travis Pollema ³, Eugene Golts ³, Kamyar Afshar ¹

1. Division of Pulmonary and Critical Care Medicine, University of California San Diego Medical Center, La Jolla, CA, USA

2. Division of Infectious Disease and Global Public Health, University of California San Diego Medical Center, La Jolla, CA, USA

3. Division of Cardiovascular and Thoracic Surgery, University of California San Diego Medical Center, La Jolla, CA, USA

* Correspondence: Rahul F. Gomez

Academic Editor: Haval Shirwan

Special Issue: Lung Transplant

Received: October 15, 2023 | Accepted: April 18, 2024 | Published: April 28, 2024

OBM Transplantation 2024, Volume 8, Issue 2, doi:10.21926/obm.transplant.2402213

Recommended citation: Gomez RF, Kafi A, Yung G, Aslam S, Lin CM, Pollema T, Golts E, Afshar K. Low Mortality Associated with COVID-19 Infection in Lung Transplant Recipients at a Single Center. OBM Transplantation 2024; 8(2): 213; doi:10.21926/obm.transplant.2402213.

© 2024 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

1. Introduction

To date, the severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) global pandemic has been responsible for over 650 million cases and 6.5 million deaths worldwide [1]. Lung transplant recipients (LTR) are at particularly high risk for complications from coronavirus disease 2019 (COVID-19) due to their immunocompromised status and by virtue of the lung being the primary site of infection. Available data on the short-term effect of COVID-19 in lung transplant recipients remains limited [2,3,4]. As the pandemic has progressed, several new viral variants have emerged, with several time periods dominated by different variants, demarcating viral ‘eras’. The outcomes associated with the various viral variant eras of COVID-19 in LTRs are not well characterized.

Mortality rates for LTRs who contracted COVID-19 infection ranged from 8-39% in observational case series [2,4,5,6,7,8,9,10,11,12,13] In fact, current literature reports up to 8 times higher mortality rates associated with COVID in recipients of solid organ transplants, when compared to the general population [14]. Most of the observational studies on LTR with COVID-19 are from the earlier COVID-19 variant eras of the pandemic at which point treatment modalities were substantially more limited than there are available today. Currently available literature document short term follow ups and allograft dysfunction after COVID-19 infection has not been reported. Several community acquired respiratory viral infections, such as respiratory syncytial virus (RSV), are associated with an increased risk of acute cellular rejection (ACR) and chronic allograft rejection (CLAD) but such data regarding COVID-19 is lacking [15]. The initial management goal of LTRs with COVID-19 infection is to allow for adequate degree of cellular immunity to combat infection while minimizing the risk of increased allogeneic response triggering allograft rejection.

Our aim in this study is to expand the current understanding of disease progression among LTRs with COVID-19 and characterize outcomes, based on COVID-19 viral variant eras, vaccination status and the use of pre- and post-exposure therapies.

2. Methods

All LTR aged 18 years or older who had confirmed infection with a positive polymerase chain reaction (PCR) for SARS-CoV-2 in an inpatient or outpatient setting between June, 2020 and September, 2022 were retrospectively reviewed for descriptive observation at the University of California, San Diego. This study was reviewed and approved by the Institutional Review Board (IRB #210245). Informed consent was waived due to the retrospective nature of the study. This study complies with the LIDSEN Journals’ ethics guidelines.

Patient demographic data, including age, co-morbidities, type and timing of transplantation, and type of immunosuppression were documented. Symptoms at time of diagnosis and outcomes including hospitalization, changes in lung function, and mortality were characterized. Radiographic findings at the time of diagnosis of COVID-19, modifications to immunosuppression, vaccinations, and treatment for COVID-19 were characterized. If hospitalized, the level of care, degree of supplemental oxygen requirement or mechanical ventilatory support and length of stay were recorded. Therapeutic drug levels were determined according to our UCSD lung transplant protocols unless a different goal was specified by a lung transplant provider in the last clinical note prior to COVID-19 infection.

Patients had spirometry done approximately 6 weeks post COVID-19 infection. If there was evidence of a significant decline in spirometry, persistent respiratory symptoms or non-resolving infiltrates on chest imaging then patients were referred for flexible fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy to assess for rejection or superimposed infection. Spirometry data for all patients were reviewed to ensure all data met American Thoracic Society criteria for pulmonary function testing [16]. Diagnosis of chronic lung allograft dysfunction (CLAD) was determined based on the ISHLT guidelines with an assessment of the spirometry values and computed tomographic (CT) images of the chest [17]. Determination of radiographic opacities was based on the final read made by the attending radiologist. Pathologic grading of rejection was based on the working formulation for the standardization of nomenclature in the diagnosis of lung transplant rejection as determined by the pathologist based on the ISHLT guidelines [18].

Unfortunately, routine viral sequencing is not common practice, so exact data on viral variant within our patient population was not obtainable. However, utilizing widely recognized dates of dominant variant timelines, supported by Center for Disease Control (CDC) data, we delineated viral “variant eras” based on the date of positive PCR test. Based on CDC data, we identified three COVID-19 variants dominated during our study period. The wild-type COVID-19 variant served as the dominant species between June 2020 and May 2021. The Delta variant dominated from June 2021 until December 2021, and was followed by the Omicron variant from January 2022 until the completion of the study period in September 2022 [19,20].

In the United States, the Food and Drug Administration (FDA) released the first COVID-19 Vaccination Emergency Use Authorization on December 11, 2020, with the Advisory Committee on Immunization Practices of the CDC releasing guidelines for vaccination of all persons over the age of 16 on the same date. On September 22, 2021, the CDC would go on to release recommendations for people to receive a booster dose, in addition to the primary series of vaccinations.

2.1 Comorbidity Definitions

Our patients’ comorbidities were diagnosed utilizing commonly observed definitions. For chronic kidney disease (CKD), we utilized the Kidney Disease Improving Global Outcomes (KDIGO) definition of CKD. Our heart failure patients met current American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the diagnosis. We defined obesity as a body mass index equal to or greater that 30 kg/m², in accordance with World Health Organization guidelines. The Eighth Joint National Committee (JNC 8) guidelines were utilized for hypertension diagnosis and current American Diabetes Association guidelines for the diagnosis of diabetes mellitus.

2.2 Statistical Analysis

Demographic characteristics as well as baseline measurements were reported as counts with percentages, or median with interquartile range of measurements for categorical values with continuous variables. Statistical significance of impacts on outcomes including hospitalization and mortality were determined by performing Mann Whitney U tests for continuous variables and Chi Square analyses for categorical variables. The change in spirometry results were compared with pre-COVID baselines utilizing Paired Wilcox testing. All statistical analyses were performed using R 4.2.2 software. A p value less than 0.05 was utilized as the cut off to reject the null hypothesis.

3. Results

3.1 Patient Characteristics

Among 236 total LTR, 72 (30.5%) were identified in the study period with confirmed COVID-19 with baseline characteristics as noted in Table 1. The median age was 53.5 years old, 62.5% were men, and 54.2% were Caucasian. The majority (77.8%) had undergone bilateral lung transplantation with the most common indication being restrictive lung disease (43.1%). Nearly half of the LTR had primary systemic hypertension. Most patients (67.1%) had a sick contact prior to onset of illness. Median forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were 2305 mL and 2955 mL, respectively, prior to diagnosis of COVID-19. The median time from the date of lung transplantation to infection was 1260 days. Utilizing the statistical analyses outlined above, the relationship between these patient characteristics with hospitalization and mortality were analyzed, however no statistically significant relationships were observed.

Table 1 Demographics

3.2 Clinical Characteristics of COVID-19 and Treatment

The most common presenting symptoms were cough (47.2%), dyspnea (29.2%) and fever (23.6%). Over a quarter of patients (26.4%) were asymptomatic and were incidentally diagnosed during screening prior to procedures (Table 2). Radiographic abnormalities were noted in half of the patients (54.2%), while the remaining did not have any changes from their baseline at time of COVID-19 diagnosis. Bilateral infiltrates were seen in 23.6%, while 19.4% had ground glass opacities and 9.7% with focal consolidations. Radiographic changes were based on CT Chest findings when available (47.2% of patients), the remaining patients findings were based from chest X-Ray results. All results represent the final radiographic read from an attending radiologist. Over a third of the patients (37.5%) were admitted; including 7/27 (25.9%) requiring intensive care unit (ICU) admission requiring 100% FiO₂ via High-Flow Nasal Canula or Mechanical Ventilation at some point during their hospitalization. One patient additionally required venovenous extracorporeal membrane oxygenation (vvECMO).

Table 2 Clinical Characteristics (n = 72).

3.3 Superimposed Infections

A minority of patients (9.7%) had confirmed superimposed bacterial pneumonias: Pseudomonas aeruginosa (n = 4), Staphylococcus aureus (n = 2), Achromobacter xylosoxidians (n = 1). All but one patient sick enough to warrant ICU admission were treated with empiric antibiotics regardless of confirmation of superimposed bacterial infection.

3.4 Medical Management

Prior to onset of COVID-19, 73.6% patients had received at least one vaccination dose (Table 3). Of these patients, 32.1% received 1 or 2 doses, and the remaining 67.9% received 3 or 4 doses of vaccine. Of those vaccinated, 62.3% received the Elasomeran vaccine, 35.8% received the Tozinameran vaccine, and 1.9% received a combination of both vaccines. Additionally, 18.1% of patients received pre-exposure prophylactic therapy (PrEP) with Tixagevimab/cilgavimab (Table 3), all of whom had previously been vaccinated. The majority of patients had their antimetabolite (mycophenolate mofetil or azathioprine) dose reduced (18.1%) or held (43.1%), although this was not protocolized, and was dependent on the clinical judgement of the provider. When compared to the treatment options utilized in the management of COVID-19 patients in prior viral variant eras, the COVID-19 Omicron variant era saw a rise in the prevalence of monoclonal antibody (mAb) therapies including Casirivimab/Imdevimab, Bebtelovimab and Sotrovimab. Overall, our population of LTRs saw 59.7% treated monoclonal antibody (mAb) therapy. In addition to mAb therapy, 15.3% were treated with intravenous dexamethasone, and 26.4% received Remdesivir. At 93.1%, the vast majority of patients had therapeutic immunosuppression levels at time of diagnosis (Table 4). In general, the use of Remdesivir was recommended in patients hospitalized for COVID-19 without contraindications for the medication, and steroids were recommended in patients suffering from hypoxic respiratory failure due to COVID-19, but ultimately their use was dependent on clinical judgement of the provider.

Table 3 Vaccination and Pre-infection Prophylaxis (n = 72).

Table 4 Treatments (n = 72).

3.5 Outcomes and Survival

Of the total population, 84.7% (72 LTR) underwent follow up spirometry 1-2 months after infection. The median drop in FEV1 and FVC within 1-2 months after COVID-19 infection was 140 mL and 25 mL, respectively. This represented a drop in percentage of predicted FEV1 of 4.84% and in FEV1 of 0.64%. Those with the largest drop in FVC and FEV1 were patients who were either found to have new bilateral infiltrates on chest imaging, or those requiring admission to ICU. 70.8% of patients completed follow up spirometry at 3 months post-infection. Median reduction in FVC was slightly larger at 75 ml, while median FEV1 measurements dropped by only 55 ml. This correlated with a drop in percentage of predicted FEV1 of 2.69% and in FVC of 3.03%. Notably, only the drop in FEV1 at 3 months was found to be statistically significant with a p-value of 0.022 (Table 5, Figure 1).

Table 5 Outcomes and Survival (n = 72).

Figure 1 Changes in Spirometry.

Persistent infiltrates were found in 23.6% of patients 6 weeks after infection, and a total of 3 (4.2%) patients were definitely diagnosed with acute cellular rejection (ACR) after COVID-19 infection based on transbronchial biopsy results. One patient was diagnosed with presumptive ACR given the risk for pneumothorax was high while intubated and on mechanical ventilation after a negative bronchoalveolar lavage cultures and improvement with empiric pulse dose methylprednisolone. The other two were diagnosed with ISHLT minimal grade (A1) acute cellular rejection based on transbronchial biopsy. All three patients had therapeutic CNI levels at the time of their diagnosis of ACR.

There were three deaths during the study period due to progressive CLAD and respiratory failure. Of the three deaths, two were felt to be secondary to COVID-19 infection and occurred in patients who were on baseline supplemental oxygen with preexisting CLAD. The one remaining death was attributed to failure to thrive and worsening comorbidities, occurring over several months after resolution of COVID-19. 12 patients contracted COVID-19 within the first year post lung transplant. Of these, eight required hospitalization, with only one of these requiring ICU admission.

When considering patient symptoms, 45.3% of symptomatic patients required hospitalization, as compared to 15.8% of asymptomatic patients, reaching statistical significance (p-value 0.023). No asymptomatic patients required ICU admission, or suffered mortality, as compared to 13.2% and 5.7%, respectively, of symptomatic patients. This did not reach statistical significance (Table 6).

Table 6 Outcome Based on Presence of Symptoms.

Another consideration when stratifying outcomes, is the presence of interventions such as vaccination status, PrEP and use of mAb. Looking first at vaccination status, 34% of vaccinated patients required hospitalization, while 5.7% suffered mortality, however this was not a significant impact. PrEP did result in a significantly lower rate of hospitalization at 7.7% (p-value 0.014), although despite a 0% mortality rate, this did not reach statistical significance. The most notable impact was seen from mAb therapy, which resulted in statistically significant decreases in both hospitalization at 20.9% in mAb recipients, compared to 62% in those without (p-value 0.001), as well as mortality at 0% as compared to 10.3% in those without mAb (p-value 0.031) (Table 7).

Table 7 Outcomes Based on Vaccination, PrEP and mAb.

As far as the use of other treatment modalities, including Remdesivir and Steroids, these were used exclusively in patients who were hospitalized, so no meaningful statistical data could be drawn from their implication on hospitalization rates. Also, all 3 patients who suffered mortality were receiving Remdesivir at the time, and 2 of them were receiving both steroids and Remdesivir. Steroids were used in 11 patients, 10 of whom also received Remdesivir. Because of this significant overlap, no statistically meaningful conclusions could be drawn from the use of these agents when compared to each other. In addition, there was one patient who received mAb, Remdesivir and steroids, one patient who received mAb and Remdesivir, and one who received mAb and Steroids, none of whom suffered mortality. There was no other overlap in these populations. Finally, there were 12 patients who received no therapies. This population had had 0 deaths and 2 hospitalizations, however did not reach statistical significance in hospitalizations (p 0.077) or mortality (p 0.429).

3.6 COVID Variant Eras

Among the study population, 25% had COVID-19 during the “Wild Type era”, 10.8% during the “Delta era”, and 54.2% occurred during the “Omicron era”. Of these eras, the Wild Type and Delta eras represented the highest incidence of hospitalization at 50% and 46.7%, respectively, as compared to only 28.2% hospitalization rate in the Omicron era. However, no statistically significant differences in risk for hospitalization, ICU admission or death were appreciated among the different variant eras (Table 8).

Table 8 Variant Eras (n = 72).

4. Discussion

Our single center observational study of LTR with COVID-19 showed low mortality rates across three viral variant eras by taking aggressive measures to modify immunosuppression and monitoring for allogenic responses. In addition to low mortality rates, our population demonstrated minimal spirometric changes at 1-2 months and at 3 months post-infection. We found that the ACR and mortality rates were significantly lower than what is reported widely in the literature [4,21,22,23,24,25]. While we could not isolate any significant characteristics predictive of improved outcomes, these findings may be attributable to a combination of expedient recognition and treatment of COVID-19 as well as high rates of vaccination prior to infection [26,27], use of prophylactic and treatment monoclonal antibody therapies, and decreasing virulence in predominant COVID-19 variants in the community at the time of this study.

Interestingly, 26.4% patients remained asymptomatic and nearly half did not have any radiographic findings associated with COVID-19 infection. Of these asymptomatic patients, 10 received 3 or more doses of vaccine, 5 had received Tixagevimab/cilgavimab and 4 patients were within 1 year of their lung transplantation. During the later pandemic, nasopharyngeal COVID PCR testing was compulsory prior to procedures, leading to the detection of many asymptomatic cases. We intentionally included these cases to help ascertain whether even asymptomatic infection may be associated with allograft dysfunction.

4.1 Hospitalization and Mortality

Our overall population demonstrated a mortality rate of only 4.2%, which remains significantly lower than the mortality rates between 8-39% currently reported in literature [5,6,7,21,25,28]. This is despite the particularly vulnerable nature of LTR owing to increased risk of transplant rejection in the setting of viral pneumonias [15], as well as the necessity of immunosuppression and lower pulmonary reserve. In fact, in a multicenter study of solid organ transplant recipients diagnosed with COVID-19, Heldman et al found a Hazard Ratio of 1.5 in 28-day all-cause mortality in LTR compared to even other solid organ transplant recipients [29]. The most influential factor in decreasing mortality rates at our center was the administration of mAb therapy, resulting in a statistically significant drop in both hospitalization and mortality. In fact, the mortality rate decreased from 10.3% in patients who did not receive mAb, to 0% in those who did. Additionally, similar to the report from Gottlieb et al our population did not see a significant decline in mortality due to PrEP, however contrary to their results, PrEP did benefit our cohort’s hospitalization rates [30]. Our low mortality rate of 4.2% may also have been influenced by a combination of multiple factors, including the evolution of the dominant strain of COVID-19 from Delta and wild-type to Omicron with a lower associated virulence, as well as earlier testing and more frequent testing of asymptomatic patients, and early mAb therapy use in our cohort. Unfortunately our population size limited any statistically significant findings in variation of mortality among variants, comorbidities or demographics.

Although most of our patients had mild COVID-19 and did not require supplemental oxygen, we still had a 37.5% admission rate. Due to reports of high mortality among LTRs early in the pandemic, our lung transplant group practiced caution and admitted most patients with positive COVID-19 tests and concerning respiratory symptoms early in the pandemic. The decision to hospitalize patients was heavily influenced by the presence of symptoms, as illustrated by a statistically significant difference in hospitalization rates of asymptomatic (15.8%) vs symptomatic patients (45.3%). While this cautious approach may have confounded the hospitalization rates, it likely improved survival outcomes.

4.2 Viral Variant Eras

Utilizing the predominating viral variant at the time of the positive viral PCR test, we differentiated patients into three variant eras: “Wild type”, “Delta”, and “Omicron”. Among these variant eras, our study revealed that while the majority of confirmed infections occurred during the Omicron era (54.2%), there was no statistically significant difference in risk for mortality, ICU admission or hospitalization across viral variant eras.

Previous publications have shown mortality rates of 25%-34% in LTR during the wild-type and Delta variant eras [3], while Hum et al. reported a mortality rate of 12% specifically in Omicron variant era [31]. This would suggest, despite higher transmissibility in the Omicron variant widely reported in the literature, the virulence appeared lower. While this may have accounted for our lower mortality rate when compared to other studies, this subgroup analysis performed on our population did not yield any statistically significant differences in mortality.

4.3 Spirometry

Although there was a median reduction observed in both FEV1 and FVC, the only statistically significant decrease in lung function was recorded in FEV1 at three months after infection. With a median decrease of 55 mL, this decline likely signals the development of some element of airway obstruction over 3 months following the initial infection. Overall, the recorded decreases may be accounted for by the large drop in spirometry observed in patients who required ICU admission and supplemental oxygen, as well as those found to have bilateral parenchymal opacifications on imaging studies at the time of infection. By comparison, Roosma et al. found that at three months following infection, both FEV1 and FVC declined by 138 and 233 mL, respectively, and still significantly reduced at 6 months [32]. Once again, our data suggest a less detrimental post-infectious response, in line with more recently published data from Touilloux et al. [33].

4.4 Rates of Organ Transplant Rejection

Additionally our study looked at rates of ACR, which is infrequently studied or reported in other similar literature [4,21,22,23,24,25]. Other respiratory viruses have shown a strong association with acute rejection, particularly RSV (75% in early RSV, 38% in late RSV) [15,34]. Characterizing the downstream effects of COVID-19 is vital to post-transplant care as ACR is a risk factor for both chronic lung allograft dysfunction and mortality.

The incidence of ACR after COVID-19 in our cohort was very low at 4.2%, possibly explained by the small percentage of symptomatic patients who were less than 1 year post lung transplant, as these patients are at greatest risk for acute rejection. Median time after transplant for our infected patients was nearly 3.5 years.

4.5 Limitations and Future Directions

This study has several limitations. The sample size is small and involves a single center. It is also retrospective in nature, and there were a large number of asymptomatic patients included. Follow up time was limited and most patients (51/72) did not undergo bronchoscopy for surveillance of ACR and CLAD. The intermediate and long term outcomes of COVID-19 on LTR merit further investigation to optimize post-COVID-19 management in this at risk patient population.

This would benefit from further multi-center studies to delineate factors that contribute to hospitalization, mortality, ACR and CLAD. Particular attention should be paid to rates of immunization, mAb utilization, and viral variants, as these all represent understudied areas. While the future prevalence of COVID-19 is uncertain, further research in COVID-19 effects on LTR may help elucidate how to approach other Community Acquired Respiratory Virus infections.

5. Conclusions

We found a lower mortality in our single center cohort of 72 LTRs when compared to the currently available literature. We found that FEV1 and FVC volumes were also largely unchanged, and the occurrence of ACR and CLAD was rare. We attribute these favorable outcomes to the use of pre-exposure prophylactic therapy, monoclonal antibody therapy, early hospitalization and high rates of vaccination.

Nonstandard Abbreviations

Author Contributions

A.K. and K.A. designed the study. R.G. and A.K. collected the data and wrote the manuscript. R.G. performed the statistical analysis and designed the figures and tables. All authors performed revisions and provided critical feedback in the editing of this manuscript.

Competing Interests

The authors of this manuscript have no conflicts of interest as described by the OBM Transplantation Journal.