Abstract
The objective of this study is to examine the general characteristics, clinical manifestations, laboratory findings, and imaging features of patients with lung adenocarcinoma who develop influenza pneumonia while undergoing immunotherapy. A retrospective analysis was conducted on the clinical data of 48 patients with lung adenocarcinoma and pulmonary infections who received immunotherapy as a stand-alone treatment between September 2022 and September 2024 at the Affiliated Hospital of North China University of Science and Technology. Clinical characteristics of patients with concurrent influenza pneumonia were assessed. When compared with the non-influenza pneumonia group, patients in the influenza pneumonia group demonstrated significantly more severe systemic symptoms, elevated urea nitrogen levels, reduced platelet counts, decreased serum albumin levels, lower Prognostic Nutritional Index values, and higher prevalence of bilateral and multilobed lung involvement. Chest imaging frequently revealed ground glass opacities, reticular patterns, and the “crazy paving” sign. Additionally, this group exhibited higher CURB-65 scores and an increased need for intensive care unit admission, with all comparisons yielding p values <0.05. Hypotension emerged as a potential factor influencing mortality in both groups (odds ratio = 9.094, p = 0.041). Among the 19 patients with lung adenocarcinoma and influenza pneumonia, 89.5% had coinfections with other pathogens. Gram-negative bacterial infections were the most common (64.7%), with Klebsiella pneumoniae subspecies, Pseudomonas aeruginosa, and Haemophilus parainfluenzae identified as the leading pathogens. Fungal infections, primarily involving Aspergillus species, accounted for 23.5% of cases. General characteristics, clinical manifestations, laboratory findings, and imaging features are essential references for the diagnosis and management of lung adenocarcinoma complicated by influenza pneumonia. Particular attention should be directed to blood pressure fluctuations, with careful monitoring of low blood pressure, especially when accompanied by bacterial infections.
Introduction
Malignant tumors, including cancer, have become a significant global public health concern, posing a substantial threat to human health. According to the 2024 Global Cancer Statistics Report, nearly 20 million new cancer cases and 9.7 million cancer-related deaths were reported worldwide in 2022. Approximately 1 in 5 individuals will be diagnosed with cancer during their lifetime, with cancer-related mortality rates of approximately 1 in 9 for men and 1 in 12 for women. Among the various types of cancer, lung cancer remains one of the most prevalent and deadliest, with nearly 2.5 million new cases reported in 2022, accounting for 12.4% of all global cancer diagnoses. Lung cancer also remains the leading cause of cancer-related deaths worldwide (Bray et al., 2024).
Globally, cancer surveillance data from 185 countries indicate that China ranks 65th for age-standardized cancer incidence rates and 13th for age-standardized cancer mortality rates, both surpassing the global average. Data from the National Cancer Center of China further highlight lung cancer as the most common malignancy among Chinese men and the leading cause of cancer-related deaths in both men and women. Notably, lung cancer deaths in China account for ∼40% of the global total, underscoring the severe public health burden of lung cancer in the country (Qiu et al., 2021).
From a pathological and therapeutic standpoint, lung cancer is classified into two primary types: non-small cell lung cancer (NSCLC) and small cell lung cancer. NSCLC accounts for the majority of lung cancer cases, with 40–55% diagnosed as lung adenocarcinoma, a subtype of NSCLC. In many regions, adenocarcinoma has surpassed squamous cell carcinoma as the most common form of lung cancer (General Office of National Health Commission of the People’s Republic of China, 2022). Recent advancements in lung cancer treatment, including molecular targeted therapies and immunotherapy, have significantly reduced lung cancer mortality rates (Siegel et al., 2023). Despite these advancements, key challenges remain in maximizing survival rates, prolonging life expectancy, and improving the quality of life for patients.
Although T cell activation has traditionally been considered unrelated to increased infection risk, emerging evidence challenges this assumption. Recent meta-analyses and clinical observations indicate that patients receiving programmed cell death protein 1/programmed death-ligand 1 inhibitors face a heightened risk of immune-related pneumonia and a higher incidence of infectious pneumonia compared with those undergoing chemotherapy or placebo (Su et al., 2019). These findings underscore the need for close monitoring of infection-related complications during immunotherapy.
Influenza, a common acute respiratory disease, has caused several global pandemics, contributing significantly to morbidity and mortality. Seasonal influenza-related respiratory diseases are responsible for an estimated 290,000–650,000 deaths annually (Iuliano et al., 2018). Patients with underlying conditions, such as malignancies, diabetes, cardiovascular diseases, and chronic pulmonary disorders, are particularly vulnerable to influenza pneumonia due to compromised immune function (Chinese Medical Association Respiratory Branch, 2016; Feng et al., 2014). Among these populations, patients with lung cancer are especially at risk due to advanced age, comorbidities, and immunosuppressive states (Longbottom et al., 2016; Li et al., 2014; Liang et al., 2020). Studies indicate that these patients are more likely to develop severe or critical pneumonia following the influenza virus, which significantly affects their prognosis (Yang et al., 2020).
Kunisaki et al. reported an influenza infection rate of 21–33% among patients with cancer, with associated mortality rates ranging from 11% to 33%, emphasizing the substantial risks faced by this population (Kunisaki and Janoff, 2009). Given these findings, timely clinical interventions for patients at high risk are essential to reduce complications and mortality.
This study explores the clinical characteristics of patients diagnosed with lung adenocarcinoma and influenza pneumonia undergoing immunotherapy. By analyzing clinical data from 48 patients, the study provides valuable insights to inform treatment strategies and improve patient outcomes. The results are presented as follows.
Materials and Methods
Study participants
Clinical data from 48 patients diagnosed with lung adenocarcinoma and pulmonary infections who received immunotherapy alone between September 2022 and September 2024 at the Affiliated Hospital of North China University of Science and Technology were included in the analysis. Patients diagnosed with accompanying influenza pneumonia were categorized into the case group, while those with non-influenza pneumonia were assigned to the control group. A retrospective analysis was conducted.
Diagnostic, inclusion, and exclusion criteria
Diagnostic criteria
Diagnostic criteria for lung cancer: A definitive diagnosis of lung adenocarcinoma was confirmed based on cytological or pathological examination. Diagnostic criteria for influenza virus infection: According to the Guidance of Diagnosis and Treatment for Influenza (2020) (Diagnosis and treatment of influenza, 2021), the diagnosis of influenza virus infection was based on the following criteria: (i) Clinical manifestations consistent with influenza virus infection. (ii) At least one of the following microbiological findings: (a) Positive influenza virus nucleic acid test. (b) Positive influenza antigen test. (c) Positive influenza virus culture isolation. (d) A fourfold or greater increase in influenza virus-specific IgG antibody levels in paired acute and convalescent sera. Clinical diagnostic criteria for pneumonia: In accordance with the Guidance of Diagnosis and Treatment for Chinese Adult Community-Acquired Pneumonia (2016), pneumonia was diagnosed when patients met one or more of the following criteria: (a) New onset of cough, expectoration, or exacerbation of preexisting respiratory symptoms, with or without purulent sputum, chest pain, difficulty breathing, or hemoptysis. (b) Fever. (c) Physical signs indicative of lung consolidation and/or wet rales. (d) Peripheral blood leukocyte count 10 × 109/L or <4 × 109/L, with or without a nuclear left shift in the white blood cell differential. (e) Chest imaging revealing newly appearing patchy infiltrates, lobar or segmental consolidation, ground glass opacities, or interstitial changes, with or without pleural effusion.
Diagnosis was confirmed following the exclusion of other conditions such as pulmonary tuberculosis, lung tumors, noninfectious interstitial lung diseases, pulmonary edema, atelectasis, pulmonary embolism, eosinophilic pneumonia, and pulmonary vasculitis.
Inclusion criteria
Patients with a confirmed diagnosis of lung adenocarcinoma established through cytological or pathological examination, who received immunotherapy as the sole treatment modality. Patients meeting the diagnostic criteria for pneumonia as defined by the relevant clinical guidelines. Patients with comprehensive and standardized clinical data.
Exclusion criteria
Age <18. Patients with an uncertain diagnosis or incomplete baseline data. Patients with lung cancer complicated by other pulmonary conditions, including chronic obstructive pulmonary disease, bronchiectasis, lung abscess, bronchial asthma, active pulmonary tuberculosis, interstitial lung diseases, or obstructive sleep apnea syndrome. Patients with lung cancer complicated by severe cardiovascular diseases, autoimmune disorders, long-term oral glucocorticoid use, or hematologic malignancies. Patients with lung cancer complicated by checkpoint inhibitor-associated pneumonitis, radiation pneumonitis, or obstructive pneumonia.
Methods
This study involved comprehensive collection and analysis of clinical data from 48 patients. The data encompassed demographic data, medical history, clinical symptoms, findings from physical examinations, associated complications, laboratory test results within 24 h of admission, chest imaging features, and prognostic outcomes. Relevant composite indices were derived from the collected data, including the following: Neutrophil-to-lymphocyte ratio (NLR): Calculated as the neutrophil count/lymphocyte count. Systemic immune-inflammation index (SII): Calculated as (platelet count × neutrophil count)/lymphocyte count (Hu et al., 2014). Prognostic Nutritional Index (PNI): Calculated as (10 × serum albumin value) + (0.005 × lymphocyte count) (Buzby et al., 1980). C-reactive protein–albumin–lymphocyte (CALLY) index: Calculated as (serum albumin value × lymphocyte count)/(C-reactive protein [CRP] × 10) (Müller et al., 2021).
Statistical analysis
The data were processed using Excel software and SPSS version 27.0. Quantitative data following a normal distribution were analyzed using the t-test, while the Mann–Whitney U test was used for quantitative data that did not meet the normality assumption. Categorical data were analyzed using the chi-squared test. A p-value of <0.05 was considered indicative of statistical significance. Statistically significant variables identified through univariate analysis were further analyzed using binary logistic regression to determine factors associated with mortality in both patient groups.
Results
General data
This study included 48 patients diagnosed with lung adenocarcinoma and pulmonary infection who were treated exclusively with immunotherapy. No statistically significant differences were observed between the two groups with respect to age, body mass index, gender, smoking history, or comorbidities, including hypertension, diabetes, coronary heart disease, and gastroesophageal reflux disease (p > 0.05). For further details, refer to Table 1.
Comparison of General Conditions Between the Two Patient Groups
BMI, body mass index; CHD, coronary heart disease; GRD, gastroesophageal reflux disease.
Physical signs, clinical symptoms, and complications
The influenza pneumonia group exhibited a significantly higher average body temperature (p = 0.019) and lower blood pressure (p = 0.025) when compared with the non-influenza pneumonia group. Systemic symptoms, including fever, chills/shivering, and headache, were more prominent in the influenza pneumonia group (p < 0.05). For more details, see Table 2. No significant differences were identified between the two groups in terms of complications.
Comparison of Signs, Clinical Symptoms, and Complications Between the Two Patient Groups
p < 0.05.
p < 0.01.
Laboratory examination results
The influenza pneumonia group demonstrated significantly lower platelet counts (p = 0.001), serum albumin levels (p = 0.035), and PNI (p = 0.034) compared with the non-influenza pneumonia group. In contrast, blood urea nitrogen levels were significantly higher (p = 0.000) in the influenza pneumonia group, as depicted in Table 3.
Comparison of Laboratory Examination Results Between the Two Patient Groups
p < 0.05.
p < 0.01.
ALB, albumin; A/G, albumin/globulin ratio; ALT, alanine aminotransferase; AST, aspartate transaminase; BUN, blood urea nitrogen; CTnI, cardiac troponin I; CALLY index, C-reactive protein–albumin–lymphocyte index; CRP, C-reactive protein; Cr, creatinine; CK, creatine kinase; CK-MB, creatine kinase-MB; ESR, erythrocyte sedimentation rate; HGB, hemoglobin; hs-CRP, hypersensitive C-reactive protein; K, kalium; LDH, lactate dehydrogenase; LYM, lymphocyte; MON, monocyte; Na, sodium; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NEU, neutrophil; NLR, neutrophil–lymphocyte ratio; PaO2, partial pressure of oxygen in arterial blood; PaCO2, partial pressure of carbon dioxide in arterial blood; PLT, platelet; PH, potential of hydrogen; P/F, oxygenation index; PCT, procalcitonin; PNI, Prognostic Nutritional Index; RBC, red blood cell; SaO2, oxygen saturation in arterial blood; SAA, serum amyloid A; SII, systemic immune-inflammation index; WBC, white blood cell count.
Chest imaging results
Patients with concurrent influenza pneumonia were more likely to exhibit infection involving multiple pulmonary lobes (78.95%, p = 0.035). Additionally, bilateral lung lobe involvement was more prevalent in the influenza pneumonia group (73.68%, p = 0.049). Chest computed tomography findings in the influenza pneumonia group more frequently revealed ground glass opacities (68.42%, p = 0.003), reticular patterns (42.11%, p = 0.032), and the “crazy paving” sign (26.32%, p = 0.022) compared with the non-influenza pneumonia group, as shown in Table 4.
Comparison of Chest Imaging Results Between the Two Patient Groups
p < 0.05.
p < 0.01.
Prognosis
The influenza pneumonia group exhibited a significantly higher CURB-65 score (p = 0.010) and an increased need for intensive care unit (ICU) admission (p = 0.027) as depicted in Table 5. To further examine factors associated with mortality, variables with statistically significant differences identified through univariate analysis were included as covariates in a binary logistic regression model. Presence or absence of influenza infection and hypotension were coded as “1” and “0,” respectively. Hypotension was identified as a potential factor influencing mortality in both groups (odds ratio = 9.094, p = 0.041), with statistical significance (p < 0.05). See Table 6 for more details.
Comparison of Prognosis Between the Two Patient Groups
p < 0.05.
p < 0.01.
ICU, intensive care unit.
Logistic Regression Analysis of Factors Affecting Mortality Between the Two Patient Groups
Pathogens in patients with lung adenocarcinoma with influenza pneumonia
Among the 19 patients diagnosed with lung adenocarcinoma and influenza pneumonia, 17 cases involved concurrent infections with other pathogens. Gram-negative bacterial infections were identified in 11 patients (64.7%), with the most common pathogens being Klebsiella pneumoniae subspecies, Pseudomonas aeruginosa, and Haemophilus parainfluenzae. Fungal infections were observed in four cases (23.5%), primarily involving Aspergillus species. Additionally, gram-positive bacterial infections were detected in two cases (11.8%), including one case of Staphylococcus aureus. Refer to Table 7 for more details.
Pathogen Proportions in Patients with Lung Adenocarcinoma and Influenza Pneumonia
Pathogens in non-influenza pneumonia group
Among the 29 patients with non-influenza pneumonia, microbiological analysis identified pathogens in 72.4% of cases. Gram-negative bacteria (e.g., K. pneumoniae, P. aeruginosa) accounted for 38.1%, while gram-positive bacteria (e.g., Streptococcus pneumoniae) were detected in 28.6%. Fungal infections (e.g., Candida spp.) were observed in 47.6% of patients. Notably, viral pathogens (e.g., respiratory syncytial virus) were identified in 23.8% of cases.
Discussion
Despite significant advancements in the treatment of NSCLC over the past two decades, which have resulted in notable improvements in survival outcomes, the overall cure and survival rates for lung adenocarcinoma remain low. Cancer-related inflammation and malnutrition, increasingly recognized as common conditions among patients with cancer, are known to profoundly affect tumor progression and prognosis (Alwarawrah et al., 2018; Han et al., 2023).
In recent years, several studies have highlighted relationships between specific markers derived from routine blood tests or biochemical examinations and cancer prognosis. For instance, Cedrés et al. demonstrated the prognostic value of the NLR in NSCLC, with lower NLR values correlating with longer overall survival (Cedrés et al., 2012). Similarly, Zhong et al. identified a significant association between elevated SII and poorer overall survival (Zhong et al., 2017). Sun et al., through a meta-analysis, reported worse overall survival in patients with low PNI values, while Liu et al., in a study of 1,864 patients with NSCLC, observed significantly reduced overall survival among those with lower CALLY index values compared with patients with higher CALLY index values (Sun et al., 2014; Liu et al., 2023).
The findings of this study further support these observations, revealing that patients with concurrent influenza pneumonia have significantly lower PNI and serum albumin levels compared with those with non-influenza pneumonia. These results indicate a compromised immune and nutritional status in this patient group, which may negatively impact the long-term prognosis of patients with lung cancer (Wang et al., 2024; Raymond et al., 2022).
Patients with lung adenocarcinoma typically exhibit weak immune function, which increases their susceptibility to severe or critical pneumonia after an influenza infection (Garmendia et al., 2023; Weng et al., 2019). Research has revealed that the influenza virus uses various mechanisms to suppress the innate immune response of the host, thereby heightening the risk of bacterial invasion into the lower respiratory tract (Aliberti et al., 2021).
One such mechanism involves damage to the respiratory mucosal barrier by the influenza virus, which impairs its bacterial clearance function. This damage can result in the retention of respiratory secretions within the bronchioles, creating an environment conducive to bacterial adhesion and proliferation. The virus also stimulates excessive secretion of fibrin and mucin within the bronchi, leading to local congestion and edema that may cause airway obstruction (Khan et al., 2021).
Additionally, the virus can injure epithelial cells in the alveolar walls and endothelial cells in the capillaries, resulting in thickening of the alveolar septa (Huang and Tang, 2021). These changes impair normal gas exchange and diminish the ability of the lung to clear bacteria effectively (Rosli et al., 2025; Zou et al., 2019). In later stages of infection, the influenza virus further suppresses the intrinsic immune response of the lungs, reducing antimicrobial activity and facilitating bacterial adhesion and invasion (Metzger and Sun, 2013; Jia et al., 2017).
These combined effects significantly increase the susceptibility of patients with lung adenocarcinoma to severe secondary bacterial infections following influenza infection.
The incidence of bacterial coinfections in severe influenza cases increased, complicating pulmonary infections in patients with lung adenocarcinoma, worsening their prognosis, and making treatment more challenging (Martin-Loeches et al., 2017). Although precise prevalence data on influenza combined with bacterial infections are limited, estimates from the U.S. virus monitoring system indicate that between 1976 and 2009, an average of 66,324 deaths annually were attributed to coinfections, with the highest mortality rates observed among individuals aged 65 years and older (Chertow and Memoli, 2013).
In China, comprehensive reports on influenza-related bacterial coinfections remain scarce. However, a study by Zheng et al. on 72 cases of severe H1N1 influenza in 2009 reported elevated neutrophil percentages in 22 patients, indicative of bacterial coinfections (Zheng and Zhou, 2010). Similarly, Wang et al. analyzed 69 cases of influenza pneumonia between 2014 and 2018 and found that 40.6% of patients had secondary bacterial infections (Wang et al., 2020). Prior research had identified bacterial coinfections as independent risk factors for mortality in patients with influenza, with common pathogens including Streptococcus pneumoniae, P. aeruginosa, S. aureus, Aspergillus species, and H. influenzae (Martin-Loeches et al., 2017; Brundage, 2006; Petersdorf et al., 1959).
In this study, laboratory findings from patients diagnosed with lung adenocarcinoma and influenza pneumonia also demonstrated increased neutrophil percentages. Microbiological analysis of lower respiratory tract specimens revealed that 17 out of the 19 patients (89.5%) had coinfections with other pathogens. Among these, gram-negative bacterial infections were the most prevalent, affecting 11 patients (64.7%). The most common gram-negative pathogens were K. pneumoniae subspecies (three cases), P. aeruginosa (two cases), and H. parainfluenzae (two cases). Fungal infections, exclusively caused by Aspergillus species, were identified in four cases (23.5%). Gram-positive bacterial infections were detected in two cases (11.8%), including one case of S. aureus. These findings align with those reported by Martin-Loeches et al. (2017).
Conclusion
In summary, compared with the non-influenza pneumonia group, patients with influenza pneumonia exhibited higher body temperatures, more pronounced systemic symptoms, elevated blood urea nitrogen levels, and lower platelet counts. Imaging findings commonly indicated bilateral lung involvement, including ground glass opacities, reticular patterns, and the “crazy paving” sign. Additionally, these patients demonstrated higher CURB-65 scores and a greater need for ICU admission, underscoring the importance of proactive treatment adjustments and timely interventions. Close monitoring of blood pressure, particularly to prevent hypotension, is crucial for improving survival outcomes in this patient population.
However, the findings from this study should be interpreted with caution due to its limitations. As a single-center study excluding patients with influenza treated in outpatient or emergency settings, potential sample selection bias and the relatively small sample size may have introduced limitations in the statistical analysis.
Authors’ Contributions
W.L.: Conception and design of the research, acquisition of data, analysis and interpretation of the data, statistical analysis, and writing of the article. D.Z.: Acquisition of data and analysis and interpretation of the data. H.F.: Conception and design of the research and statistical analysis. J.J.: Analysis and interpretation of the data and critical revision of the article for intellectual content. Ca.L.: Acquisition of data and critical revision of the article for intellectual content. Ch.L.: Acquisition of data and critical revision of the article for intellectual content. L.Z.: Critical revision of the article for intellectual content. Y.H.: Conception and design of the research, analysis and interpretation of the data, and critical revision of the article for intellectual content. All authors read and approved the final draft.
Ethics Approval and Consent to Participate
This study was conducted with approval from the ethics committee of Affiliated Hospital of North China University of Science and Technology (no. 20240313021). This study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants.
Footnotes
Data Availability
The datasets used or analyzed during the current study are available from the corresponding author upon reasonable request.
Author Disclosure Statement
The authors declare that they have no conflicts of interest regarding this work.
Funding Information
This research was supported by Research on the Mechanism of Thoraco-abdominal Coupling Motion in Sleep Breathing and Unconstrained Monitoring Methods (Project Code: 6187012466); Application for the 2025 Government-funded Project for Outstanding Clinical Medical Talents (Project Code: 24120204B); Study on the Metabolic Transformation of Fibroblasts in the Tumor Microenvironment and the Expression of Cysteine Proteases and Their Interaction Mechanism with Lung Cancer Metastasis (Project Code: 8187103180); and Clinical study of bronchoalveolar lavage combined with microscopic application of acetylcysteine in the treatment of community-acquired pneumonia, Hebei Provincial Medical Science Project Program (Project Code: 20221547).