A total of 172 patients who underwent LTx at TUH were included in the study. Among them, 39 patients were diagnosed with COVID-19, resulting in an accumulated incidence of COVID-19 among LTx recipients in Japan of 22.7% (39/172) as of November 2023. Of the 39 patients, 9 (23%) developed COVID-19 pneumonia (CP +), while 30 did not exhibit pneumonia (CP-), as summarized in Table 1. The representative CT images on CP + are shown in Fig. 1. The clinical course of the nine LTx recipients with CP + is summarized as follows:

Chest CT findings of lung transplant recipients before and after COVID-19 pneumonia. Representative images include: A a male in his 50s, 3 years post left single LTx for idiopathic pulmonary fibrosis; B a male in his 50s, 11 years post bilateral LTx for Eisenmenger syndrome; C a female in her 60s, 8 years post bilateral LTx for pulmonary alveolar proteinosis; D a male in his 30s, 3 years post bilateral LTx for Eisenmenger syndrome; E a male in his 50s, 4 years post left single LTx for chronic obstructive pulmonary disease; F a female in her 50s, 5 years post left single LTx for lymphangioleiomyomatosis (LAM); G a female in her 50s, 9 years post bilateral LTx for LAM; H a female in her 20s, 4 years post living-donor lobar LTx for pulmonary arterial hypertension; and I a female in her 50s, 12 years post right single LTx. COVID-19: Coronavirus disease 2019 and LTx: lung transplant;

Case 1 A 53-year-old male underwent left single LTx for idiopathic pulmonary fibrosis 3 years ago (Figure 1-A). He had received four doses of an mRNA vaccine and one set of tixagevimab/cilgavimab (T/C). On the 6th day after fever onset, he was diagnosed with COVID-19 and initially received symptomatic treatment. By the 10th day, he developed progressive respiratory failure; a chest CT scan revealed extensive lung infiltrates on the graft. Despite intubation, extracorporeal circulation, and treatment with remdesivir, antibacterial agents, and steroid pulse therapy, his hypoxemia did not improve. He passed away on the 27th hospital day.

Case 2 A 58-year-old male underwent bilateral LTx for Eisenmenger syndrome 11 years ago (Figure 1-B). He had received three doses of the mRNA vaccine and one dose of T/C. One day after symptom onset, he tested positive for SARS-CoV-2 and was treated with remdesivir for 5 days at our center. Two weeks after discharge, he experienced a relapse of fever; a CT scan revealed diffuse ground-glass opacities in all lung lobes. Mycophenolate mofetil (MMF) was discontinued, and he received additional remdesivir for 10 days and dexamethasone. He was discharged on the 15th hospital day.

Case 3 A 63-year-old female underwent bilateral LTx for pulmonary alveolar proteinosis 8 years ago (Figure 1-C). She had received four doses of an mRNA vaccine but not T/C. She developed a fever and tested positive for SARS-CoV-2 on the same day. With no initial drop in lung function, she was treated with molnupiravir, leading to defervescence. However, on the 9th day, she experienced a relapse with a drop in lung function; chest CT revealed pneumonia, and she was hospitalized to receive remdesivir for 5 days. On the 13th day, she continued to experience loss of appetite and weight loss. MMF was discontinued, and she was re-administered remdesivir for 5 days along with dexamethasone. She was discharged 2 months after hospitalization.

Case 4 A 36-year-old male underwent bilateral LTx for Eisenmenger syndrome 3 years ago (Figure 1-D). He had received two doses of an mRNA vaccine but not T/C. After his family was diagnosed with COVID-19, he developed a fever 2 days later. Despite testing positive for SARS-CoV-2, his lung function remained stable, and he was initially managed with antipyretics, resulting in clinical improvement. On the 21st day, he visited the hospital due to feeling unwell. A CT scan revealed consolidation in the left lower lobe, and he was hospitalized and treated with sotrovimab and remdesivir. He improved and was discharged after 6 days of hospitalization.

Case 5 A 53-year-old male underwent left single LTx for chronic obstructive pulmonary disease 4 years ago (Figure 1-E). He had received two doses of an mRNA vaccine but not T/C. He developed a fever and tested positive for SARS-CoV-2. Unable to receive antiviral treatment at that time, he followed symptomatic treatment. Fourteen days after symptom onset, he visited the hospital because of shortness of breath; a chest CT scan revealed pneumonia on the graft. He was treated with remdesivir and improved swiftly.

Case 6 A 53-year-old female underwent left single LTx for lymphangioleiomyomatosis (LAM) 5 years ago (Figure 1-F). She had received four doses of an mRNA vaccine but not T/C. After contracting COVID-19, she was treated with molnupiravir but did not improve. Six days after symptom onset, a CT scan revealed graft pneumonia, requiring treatment with remdesivir upon admission. Despite the worsening of chronic kidney disease, she was discharged 2 months after hospitalization.

Case 7 A 50-year-old female underwent bilateral LTx for LAM 9 years ago (Figure 1-G). She had received six doses of an mRNA vaccine but not T/C. She developed a fever, tested positive for SARS-CoV-2, and was prescribed molnupiravir. By the 5th day, her symptoms had not improved. Although her lung function was stable, a CT scan revealed pneumonia, leading to hospitalization on the same day. She was treated with remdesivir for 10 days, leading to swift improvement. On the 18th hospital day, her symptoms relapsed. She was then treated with ensitrelvir and discharged on the 24th hospital day.

Case 8 A 23-year-old female underwent living-donor LTx for pulmonary arterial hypertension 4 years ago (Figure 1-H). As a post-transplant complication, she developed chronic graft infection with Stenotrophomonas maltophilia and had several hospitalizations due to exacerbations. She had not received an mRNA vaccine or T/C. She was diagnosed with COVID-19, and a CT scan revealed bronchitis and pneumonia. It was unclear whether this was an exacerbation of pre-existing bronchitis or a new finding due to COVID-19, so she was treated with ceftazidime and remdesivir, to which S. maltophilia was sensitive. Following treatment, her fever subsided and lung function returned to baseline.

Case 9 A 57-year-old female underwent right single LTx 12 years ago (Figure 1-I). She had received four doses of an mRNA vaccine and one set of T/C. Ten days after developing a fever, she was diagnosed with COVID-19. A chest CT scan revealed pneumonia on the graft, and she was treated with remdesivir and dexamethasone. During her hospitalization, she developed acute kidney dysfunction, leading to severe uremia. Despite various treatments, she passed away 4 months after contracting COVID-19.

Overall, the median age of LTx recipients who developed COVID-19 pneumonia was 53 years (interquartile range [IQR] 50–57), which was slightly higher compared to those without pneumonia, with a median age of 45 years (IQR 39–58). No significant differences were observed in sex distribution, type of lung transplant, or underlying disorders between the CP + and CP- groups. Notably, none of the patients in the CP + group had received an mRNA vaccine prior to transplantation. Following transplantation, both groups received mRNA vaccination, with no discernible difference in immunization rates (88.8% vs. 73.3%).

Regarding the blood concentrations of immunosuppressants, the area under the curve (AUC0-12) for MMF in the CP + group showed a trend toward being higher (median AUC 38.4 µg·hr/mL vs. AUC 29.0 µg·hr/mL) compared to the CP- group. However, there were no significant differences observed in the trough concentration of tacrolimus (median trough 8.2 ng/mL vs. 8.8 ng/mL) between the two groups. While there was a tendency toward a higher proportion of comorbid DM in the CP + group (33.3% vs. 3.3%), no significant differences were noted in the prevalence of CKD (0% vs. 6.7%) or CLAD (22.2% vs. 26.8%) between the two groups, respectively.

The treatment experience is summarized in Table 2. Overall, the median time since LTx to COVID-19 diagnosis was 8 years (IQR 4–11). There was a delay in initiating antiviral therapy in the CP + group, with a median duration of 6 days from the date of infection, compared to within 1 day in the CP- group. Only one patient was infected during the period when the Delta variant was predominant in Japan, while all other cases occurred during the period marked by the dominance of the Omicron variant. All nine patients with COVID-19 pneumonia received hospital treatment, including administration of remdesivir and antibiotics. Among LTx recipients diagnosed with COVID-19, a total of four patients succumbed to the illness, with 2 (22.2%) in the CP + group and 2 (6.7%) in the CP- group. Additionally, relapse was observed in 5 patients (55.5%), all of whom were in the CP + group. Conversely, a decline in forced expiratory volume in one second (FEV1) at 30 days showed no significant difference between the groups.