Background

Immune checkpoint inhibitors (ICIs) are commonly used to treat lung cancer, either alone or in combination with chemotherapy and radiotherapy [1, 2]. While ICIs enhance immune function against tumor cells [3, 4], they also carry the risk of immune-related adverse events (irAEs) affecting multiple organs through immunological mechanisms [5]. The incidence of these events varies based on ICI type, dosage, and treatment duration. Immunotherapy-related pneumonitis is a common irAE affecting up to 3%~19% of lung cancer patients treated with ICIs [6,7,8].

The COVID-19 pandemic has created significant disruptions in healthcare and social and economic systems worldwide [9]. Cancer patients face heightened risks of hospitalization and mortality from the disease due to age-related declines in immune function and immunosuppression from chemotherapy and radiation therapy [10,11,12,13]. IrAEs may contribute to these risks by inducing cytokine dysregulation, which can parallel the cytokine storm observed in some cases of COVID-19-induced acute respiratory distress syndrome [14,15,16,17]. Previous studies suggest that COVID-19 vaccines are safe for cancer patients receiving anti-PD-1 treatment and that ICIs do not worsen outcomes in cancer patients with COVID-19 [18,19,20,21,22]. Some studies have evaluated the safety and efficacy of ICIs in lung cancer patients with COVID-19 infection [23, 24]. The Omicron variant has presented a new challenge to Chinese healthcare systems and care of cancer patients due to its persistent spread in the end of 2022. However, the impact of irAEs in lung cancer on the incidence of Omicron variant COVID-19 pneumonia remains obscure.

Therefore, this cross-sectional study seeks to investigate the association between irAEs and COVID-19 pneumonia in lung cancer patients infected with the Omicron variant in China. By understanding the impact of irAEs on COVID-19 pneumonia incidence, we can improve the management and monitoring of these patients during the ongoing pandemic.

Methods

Design and patients

This cross-sectional study was conducted at the Second Affiliated Hospital of Nanchang University in China between December 8, 2022 and February 1, 2023, during the Omicron variant epidemic. We reviewed lung cancer patients diagnosed with COVID-19, who received at least one cycle of immune checkpoint inhibitors (ICIs), including programmed cell death protein 1 (PD-1)/pro-programmed death-ligand 1 (PD-L1) inhibitors, either as monotherapy or combination therapy at our institution. All enrolled patients had confirmed lung cancer by pathology and COVID-19 diagnosis through reverse transcriptase-polymerase chain reaction (RT-PCR) using nasopharyngeal swabs. Patients diagnosed solely on the basis of rapid antigen testing were excluded. This study adhered to the Declaration of Helsinki principles and followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines [25]. The institutional ethics committees of the Second Affiliated Hospital of Nanchang University approved the study protocol.

Data collection

We collected data on patient characteristics, including age, sex, tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status score at the time of COVID-19 infection, previous treatment history, ICI-related data, irAE-related data, and routine blood tests. The Common Terminology Criteria of Adverse Events (version 5.0) was utilized to grade irAE at its peak severity [5]. Solid tumor TNM staging was based on the AJCC staging system’s eighth edition. COVID-19 pneumonia diagnosis was confirmed via chest computed tomography (CT) scans, and patients were categorized based on the NCCN Guidelines for cancer-related infections as having mild, moderate, severe, or critical COVID-19 severity [26].

Statistical analysis

We used R software (version 3.6.3) to analyze all data. Categorical variables were reported as frequency and percentage, while continuous variables were expressed as mean ± standard deviation. Groups were compared using independent sample t-tests or analysis of variance (ANOVA). Univariate and multivariate logistic regression analyses were conducted to evaluate the connection between immune-related adverse events (irAEs) and COVID-19 pneumonia incidence; Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. Statistical significance was defined as P < 0.05.

Results

Patient characteristics

We excluded 46 patients with non-lung cancer, leaving 326 patients diagnosed with both lung cancer and COVID-19 infection for further investigation. Out of these, 133 patients who did not receive immune checkpoint inhibitor (ICI) treatment were excluded, resulting in a total of 193 patients enrolled in the study. Of these, 72 patients (37.30%) experienced immune-related adverse events (irAEs), while 121 patients (62.70%) did not belong to the irAEs group (Fig. 1). Table 1 presents patients’ baseline demographics, clinical, and biochemical characteristics. The median age for the non-irAEs group was 64.55 years, with 85.95% being male. The irAEs group had a median age of 62.83 years, with 86.11% male. Among the entire cohort, 26 patients (13.47%) developed COVID-19 pneumonia, while six (3.11%) progressed to severe cases after COVID-19 infection. We observed a higher incidence rate of COVID-19 pneumonia in the irAEs group compared to the non-irAEs group (27.78% vs. 4.96%, P < 0.01). Furthermore, the irAEs group had a higher incidence rate of different COVID-19 pneumonia grades (P < 0.01).

Fig. 1
figure 1

Flowchart of patient selection. Abbreviations: COVID-19, coronavirus disease 2019; ICIs, Immune checkpoint inhibitors; irAEs, Immune-Related Adverse Events

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Table 1 Baseline characteristics of all enrolled patients
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Profiles of irAEs

Table 2 showed the types of irAEs in the 72 lung cancer patients. A total of 104 irAE trips were documented after immune checkpoint inhibitor (ICI) treatment. Most common types of irAEs were dermatitis/rash (33.65%), thyroiditis (23.08%), pneumonitis (22.12%), hepatitis (8.65%), colitis (7.69%), and other types (3.85%) in the 72 lung cancer patients. For patients who had multisystem irAEs, the highest grade was considered a priority. Most irAEs were mild, with grade 1 accounting for 50.00% and grade 2 accounting for 29.81%. Eleven patients experienced grade 3 or grade 4 irAEs. No severe (grade 5) irAEs were reported after ICI therapy, with only one patient experiencing grade 1 myocarditis.

Table 2 The types of irAEs in lung cancer patients
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Association between irAEs and COVID-19 pneumonia

As shown in Table 3, in the univariate analysis, irAEs (OR = 7.37, 95%CI: 2.80, 19.43; P<0.01) and lymphocyte count (OR = 0.37, 95%CI: 0.15, 0.89; P = 0.03) were associated with a higher incidence of developing COVID-19 pneumonia after infection. However, we did not find a significant association between all-grade irAEs and COVID-19 pneumonia (OR = 1.00, 95%CI: 0.30, 3.29; P = 1.00). In the multivariate analysis, the incidence of COVID-19 pneumonia remained significantly associated with irAEs (OR = 9.56, 95%CI: 2.21,41.33; P = 0.0025) and lymphocyte count (OR = 0.35, 95%CI: 0.14, 0.9; P = 0.0033). Comorbidities (OR = 2.38, 95%CI: 0.76, 7.49; P = 0.14), chemotherapy (OR = 0.64, 95%CI: 0.18, 2.28; P = 0.49), targeted therapy (OR = 2.24, 95%CI: 0.46,10.84; P = 0.32), and anti-angiogenic therapy (OR = 0.73, 95%CI: 0.15, 3.54; P = 0.70) were not significantly associated with COVID-19 pneumonia.

Table 3 Univariate and multivariate analyses for risk factors associated with COVID- 19 pneumonia
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Discussion

COVID-19 infection can cause immune dysregulation, leading to excessive inflammation and high levels of pro-inflammatory cytokines [27, 28]. This study examines the impact of Omicron variant COVID-19 on lung cancer patients in China receiving ICIs. Specifically, we conducted a cross-sectional analysis of patients diagnosed between December 2022 and February 2023. Our results confirm that lung cancer patients who develop irAEs while receiving ICIs suffer a higher risk of Omicron variant COVID-19 pneumonia.

There has been growing concern about the potential for unopposed T-cell activation and downstream cytokine excess resulting from the convergence of ICIs treatment toxicity and COVID-19 in cancer patients [28, 29]. In line with this view, our study found that lung cancer patients who developed irAEs while receiving ICIs had a significantly higher incidence of COVID-19 pneumonia compared to those without irAEs (27.78% vs. 4.96%, P < 0.01). It has been suggested that patients who experience irAEs are those who can mount a more robust reconstitution of anticancer immunity [30]. As a result, lung cancer patients receiving ICIs who become infected with COVID-19 may face a higher risk of immune hyperactivation and cytokine storm. Our multivariate analysis revealed that the development of irAEs was significantly associated with a higher incidence rate of COVID-19 pneumonia. Interestingly, previous studies have yielded conflicting results. For example, Mengni Guo et al. reported that COVID-19 infection may pose a risk of severe irAEs in cancer patients receiving ICIs [24]. On the other hand, a registry for thoracic cancers did not find a significant impact of ICIs on COVID-19 outcomes [31, 32]. A New York study reported that prior ICIs therapy was associated with an increased risk of severe respiratory illness and hospitalization among COVID-19 patients [33]. In contrast, a US study of 25 patients found no association between ICIs therapy and COVID-19-related outcomes [20]. Likewise, a prospective study of 44 patients showed that ICIs therapy within 4 weeks of COVID-19 diagnosis trended toward reducing the risk of COVID-19 mortality [34]. Furthermore, a study involving 41 lung cancer patients found no significant association between ICIs therapy and an increased risk of COVID-19 mortality [35]. Differences in cancer types, COVID-19 variants and patient characteristics may account for these discrepancies. However, in our study, we observed a significant difference in the incidence of COVID-19 pneumonia between different grades of irAEs in the univariate analysis. In the multivariate analysis, no difference was observed. This may be attributed to the relatively low number of irAE events, especially in the Grade 3–4 category.

Our study also found that the absolute lymphocyte count was significantly associated with a higher incidence rate of COVID-19 pneumonia (OR = 0.36, 95%CI: 0.14, 0.94; P = 0.04). Prior research has established that reduced CD4+/CD8 + T cells and lymphocyte count are associated with severe COVID-19 [29] and mortality [36]. Meanwhile, the mechanisms leading to irAEs include the expansion of intertumoral and peripheral T-cell receptor repertoire, as well as the mobilization of large numbers of T cells [37]. These findings suggest that there may be an immunological link between irAEs and COVID-19 pneumonia in lung cancer patients, but further mechanistic studies are needed to fully elucidate this relationship.

While our study has limitations - including its retrospective design and small sample size - it provides valuable real-world data from a Chinese institution during a specific timeframe. What’s more, our study specifically focused on lung cancer patients used ICIs. This focus was chosen because distinguishing immunotherapy-related pneumonitis from COVID-19 pneumonia when both occur simultaneously can be challenging, and CT scanning is often necessary for tumor evaluation and monitoring adverse reactions. Our analysis was limited to the Omicron variants (BA.2 and BA.5), and given the emergence of new strains, more investigation is needed to explore the association between irAEs and COVID-19 infection outcomes in cancer patients. Nonetheless, our findings underscore the importance of close monitoring and timely intervention for lung cancer patients receiving ICIs who contract COVID-19.

Conclusion

In conclusion, our study firstly evaluated the impact of irAEs on COVID-19 pneumonia incidence in lung cancer patients receiving ICI therapy. We found that patients who developed irAEs were at higher risk of contracting Omicron variant COVID-19 pneumonia. This highlights the importance of increased vigilance for COVID-19 infections in this patient population, along with closer monitoring, including timely chest CT scans, and potentially more aggressive treatment if necessary.