The COVID-19 pandemic that began in December 2019 was declared a global pandemic by the World Health Organization in March 2020. Patients with malignancies, particularly those with hematological malignancies, are highly susceptible to pneumonia and mortality following COVID-19 infection (1, 2) owing to anticancer therapy or malignancy itself. The mortality rate related to COVID-19 among patients with hematological malignancy is very high, reportedly 30% to 40% (3–5). However, these results are mostly based on hospitalized patients and were from the early period of the COVID-19 pandemic when the virus was more aggressive and medical resources were scarcer. Since that time, a considerable number of patients with cancer have experienced COVID-19 infection out of hospital and the mortality rate has decreased owing to weakened virulence of the causative virus, SARS-CoV-2, as well as better accessibility to anti-COVID-19 drugs. However, related reports are rare regarding outcomes among patients with cancer who develop COVID-19 infection.

Lymphoma is the most prevalent hematologic malignancy. Previous studies have primarily focused on identifying the mortality risk factors among patients with lymphoma following COVID-19 infection (1, 6). Reportedly, older age, cancer type, therapy, and complications are associated with mortality owing to COVID-19 infection among patients with lymphoma (4, 7). There is scant research examining the pneumonia incidence and associated risk factors within this patient cohort. China removed most COVID-19 quarantine measures in December 2022. Most individuals in China experienced their first COVID-19 infection between December 2022 and February 2023. We conducted a questionnaire survey targeting patients with lymphoma to investigate their experiences with COVID-19 infection and pneumonia occurrence during the epidemic wave involving the SARS-CoV-2 Omicron variant. This effort will help hematologists to recognize high-risk patients and improve preventive measurements.

Before exploring the relationship between lymphoma patients and COVID-19 patients with viral pneumonia, the pneumonia-related adverse reactions during the treatment process should also be taken into account. Interstitial pneumonia is a lethal complication in lymphoma patients undergoing chemotherapy. A retrospective study found that the incidence of interstitial pneumonia was 3.9% (7/287) in patients with HL and 2.4% (76/1925) in patients with NHL (12). Furthermore, an analysis of the Chinese subgroup in the Phoenix study revealed that, compared to the R-CHOP group, combining the BTK inhibitor ibrutinib with R-CHOP increased the incidence of pneumonia-related adverse reactions from 2.1% to 9.7% (13). A study on the pulmonary adverse effects caused by the anti-CD20 monoclonal antibody rituximab reported that among all side effects, the incidence of pulmonary diseases may be the highest (14).

COVID-19 has been endemic since 2019, and the virulence of the virus has decreased substantially. However, patients with lymphoma remain at high risk for COVID-19 infection and subsequent pneumonia. Evidence from previous studies suggests that patients with cancer remain susceptible to comorbidity and mortality if infected with COVID-19, despite having received full vaccination (15, 16). Patients with lymphoma, especially those receiving anti-CD20 therapy, have poor or no vaccine response compared with healthy controls (17, 18). A meta-analysis reported a response rate of 64% for patients with hematologic malignancies following complete COVID-19 vaccination (19). Moreover, the response rates vary among specific types of lymphoma, with 91% for HL but only 58% for aggressive NHL and 61% for indolent NHL (19). Although most patients with NHL have been fully vaccinated, they remain susceptible to COVID-19 infection and developing pneumonia. The vaccination rate in our study was 67%; however, the protective effect against infection was found to be very limited. The vaccination-related findings seem contradictory. Vaccination can provoke an immune response; however, for patients with underlying diseases such as lymphoma, particularly those who have undergone chemotherapy or immunotherapy, the immune function may be significantly impaired, which can lead to dysregulation of the immune response and make them more susceptible to pneumonia. Indeed, we compared the differences in age, gender, lymphoma type, treatment received, and remission status between patients who received the vaccine and those who did not. We found that among vaccinated patients, a higher proportion were currently active therapies (59.5%) ( Supplementary Table 1 ). Therefore, the increased pneumonia rate among vaccinated patients may be due to the fact that most patients were in the treatment process, leading to a decline in immune function. Additionally, vaccination may lead to increased healthcare engagement and monitoring among patients, which could mean that vaccinated patients are more frequently diagnosed with pneumonia, regardless of whether the vaccine truly affects the incidence.

Patients who received their last anti-CD20 treatment within 3 months of vaccination had a much lower response rate of 16% (18). These findings indicate that patients with HL exhibit a superior vaccine response compared with those who have NHL. This observation may potentially explain the lower incidence of pneumonia among patients receiving anti-PD-1 therapy; most individuals in this study who underwent such treatment were diagnosed with HL. Although our results suggest that anti-PD-1 therapy may have protective effects, the small sample size does pose a significant limitation to the generalizability of our findings. Further exploration in larger studies and meta-analyses is needed to validate our findings and better understand the true impact of anti-PD-1 therapy.

During the early stage of the COVID-19 pandemic, mortality was reported to be as high as 20%–40% among patients with cancer (6, 7, 9); therefore, the risk factors reported in previous studies for this population were nearly all for mortality. Older age, disease progression, indolent NHL, and aggressive NHL have been reported as risk factors for mortality in hematological malignancies (4, 7). Among hospitalized patients, cardiovascular disease, a lack of disease remission, active treatment, and CAR T-cell therapy are independently associated with mortality (20). Anti-CD20 treatments have also been found to independently influence prolonged viral detection among patients with hematologic malignancies (HR=3.64, 95% CI 1.44–8.97) (20). However, an Italian study reported that anti-CD20 therapy did not affect survival because this type of therapy does not impair cellular responses (9).

The mortality associated with COVID-19 was vastly decreased in our study compared with that in previous reports (6, 7, 9). This is partly because of increased access to antiviral drugs and decreased virulence of SARS-CoV-2. In a cohort of 308 pediatric patients with leukemia or lymphoma, 36% developed COVID-19 and only 6% patients developed severe disease (21). But the incidence of pneumonia was still high. Therefore, during the later stages of the COVID-19 pandemic, it is crucial to prioritize vigilance regarding pneumonia rather than just focusing on mortality. We found that anti-CD20 therapy and a lack of remission were related to a higher risk of pneumonia after infection with COVID-19, which was coincident with the mortality risk factors reported previously (22). A past study reported that the BTK inhibitor ibrutinib may provide protection against lung injury in patients with COVID-19 because it reduces proinflammatory and chemoattractant cytokines (23). However, that study lacked a large sample, and only included six patients with Waldenström macroglobulinemia who were receiving ibrutinib. In our study, BTK inhibitor was an independent risk factor for the occurrence of pneumonia after COVD-19 infection.

BTK inhibitors also increased common pneumonia by previous studies (13, 24, 25). In a multicenter, open-label phase II study assessing the efficacy and safety of ibrutinib in previously treated marginal zone lymphoma (MZL), grade 3-4 pneumonia was the most common adverse event (26). Additionally, an analysis of the Chinese subgroup in the Phoenix study found that the incidence of pneumonia-related adverse reactions increased from 2.1% to 9.7% when comparing the BTK inhibitor ibrutinib combined with R-CHOP to the R-CHOP group (13). In studies involving zanubrutinib for various B-cell malignancies, serious treatment-emergent adverse events included pneumonia at a rate of 11% (27). Furthermore, a phase II clinical study found that the incidence of grade ≥3 pneumonia in patients treated with acalbrutinib for mantle cell lymphoma was 5% (28). A pharmacovigilance study based on the FAERS database revealed that infection-related adverse reactions, such as pneumonia associated with ibrutinib and acalbrutinib, were among the most common safety signals linked to high mortality associated with these two BTK inhibitors (24).

Research shows that weighted gene co-expression network analysis combined with the explainable artificial intelligence algorithm LIME can comprehensively characterize the transcriptional changes in bronchial epithelial cells (including primary human bronchial epithelial cells and transformed alveolar cells) during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and identify new hub gene features such as PGLYRP4 and HEPHL1 (29). Therefore, future studies can focus on the integration of COVID-19, SARS-CoV-2, bronchial epithelial cells, and transcriptomic analysis in lymphoma patients, especially regarding the gene networks associated with pneumonia risk when using BTK inhibitors or anti-CD20 therapies.

The present research was a retrospective study conducted at a single center. In terms of demographic characteristics, our study population primarily consisted of patients aged 43 to 64 years, with males accounting for 52.91% and females for 47.09%. Among the patients, 91.8% had NHL, while approximately 8.2% had HL. This is consistent with the overall incidence rates reported in a study on the burden of lymphomas in China in 2016. The study estimated that there were 6,900 new cases of HL and 68,500 cases of NHL in China. NHL has a higher incidence in the age group of 40 to 70 years, while the incidence of HL gradually increases after the age of 45, with males having a higher incidence than females (30). Further confirmation of our findings in large-scale multicenter cohort studies is warranted.

Our findings indicated that during the Omicron era of COVID-19, approximately 24% of our patients with lymphoma were found susceptible to developing pneumonia following viral infection, but with low mortality. Patients receiving BTK inhibitors, those undergoing active therapy, and those without disease remission exhibited a higher risk for developing pneumonia. So, for lymphoma patients, particularly those with B-cell non-Hodgkin lymphoma, especially those receiving BTK inhibitors or anti-CD20 therapy, it is recommended to implement personalized protective measures. This includes maintaining good hygiene practices during periods of high COVID-19 prevalence, providing education about the risks of COVID-19 and pneumonia, and encouraging patients to seek medical attention promptly when relevant symptoms arise.