Lung cancer is a major cause of cancer-related death worldwide [1]. In immunocompromised patients, infections and pneumonia are closely related to a poor prognosis [17, 18]. Therefore, it is important to recognize risk factors associated with pneumonia and prepare prevention strategies to reduce the occurrence of pneumonia in patients with lung cancer.
In our study, patients in the pneumonia group showed a shorter median OS than those in the non-pneumonia group. We explored clinical factors for pneumonia development in lung cancer patients. According to our research, the incidence of pneumonia was 28.6% in the lung cancer population and 33.6% in the subgroup of subjects who received therapy that included cytotoxic chemotherapy. Older age, advanced stage (IV), neutropenia, and smoking were independent risk factors for pneumonia development in lung cancer patients. Age, neutropenia, and smoking were independently associated with pneumonia development in lung cancer patients who received treatment that included cytotoxic chemotherapy.
There has been some research on risk factors for developing pneumonia in patients with lung cancer. Wang et al. [4] have demonstrated that being old aged (> 60 years) and having squamous cell carcinoma histopathological type might be important risk factors of postoperative pneumonia in lung cancer patients after surgery. Liu et al. [5] have reported that patients with older age, smoking, and extent of excision of more than one lobe have a higher risk for pneumonia after lung cancer surgery. Takiguchi et al. [6] have noted that the risk factors for pneumonia after bronchoscopy are old age (≥ 70 years), current smoking, and central location of the tumor. These studies were focused on pneumonia development after surgery or bronchoscopy. However, data about risk factors for pneumonia in lung cancer patients who have received active treatment such as radiation therapy and chemotherapy are limited.
Old age has been associated with pulmonary complication in many studies. Lee et al. [19] have reported that old age is associated with the development of bacterial pneumonia in patients after cytotoxic chemotherapy in advanced lung cancer patients. Age ≥ 64 years was an independent predictors for post-operative pneumonia in lung cancer patients [5]. The elderly have several risk factors of pneumonia occurrences because of their impaired physical conditions. Dysfunction of the immune system is one important cause of pneumonia. Aspirated oropharyngeal secretions into the lung can induce aspiration pneumonia due to swallowing difficulties in old patients [20].
Among risk factors for cancer treatment related pneumonia, neutropenia is one of the most well-known factors. Neutrophils are sensitive to alkylating agents and nucleoside analogs. Absolute neutrophil count decreases with increasing dose of cytotoxic chemoagents [8]. Severe neutropenia defined as a count ≤ 500/μL is associated with increased severe lung infections caused by bacterial and fungus [21]. Neutropenic pneumonia is affected by rapid onset, duration, severity, and underlying physiologic process [22-24]. Lung cancer is a solid cancer known to be associated with better prognosis in febrile neutropenic patients compared to other hematologic malignancies [25]. However, lung cancer patients might have smoking and age-related comorbidities such as chronic obstructive pulmonary disease and interstitial lung diseases in which Pseudomonas aeruginosa is frequently present. Old age is associated with high mortality in lung cancer patients with febrile neutropenia, although the risk of lung cancer is low in neutropenic patients [26].
In our study, smoking was a common risk factor for pneumonia development in total lung cancer patients and patients who received treatment that included cytotoxic chemotherapy. Smoking is known to be associated with lower-socioeconomic status, poor diet, increased alcohol consumption, and reduced physical activity. The relationship between smoking and community acquired pneumonia has been reported [27]. Smoking affects the loss of cilia, inhibits alveolar macrophage function, mucous gland hypertrophy, and increases goblet cells. This causes microbes to be present and widespread in the bronchus. Oxidative stress and cytokine release are triggered, leading to immune response. This makes the bronchial mucosal epithelium more inflammatory and susceptible to infection [28]. Nicotine can suppress natural killer (NK) cell activity. NK cells are usually activated immune response against viral infections [29-31]. Agostini et al. [16] have noted that smoking increases postoperative pulmonary complications such as increased hospital mortality, intensive care unit admission rate, and hospital length of stay. Jung et al. [32] have also shown that smoking is one of independent risk factors for the development of post-operative pneumonia in cancer patients. Smoking cessation before surgery can reduce postoperative complications [33]. The difference in pneumonia occurrence between current smokers and ex-smokers was not apparent in our study. Further studies are needed to clarify effects of smoking cessation duration before treatment in lung cancer patients.
In advanced stage cancer patients, infection occurs more easily due to bronchial permeability disorders as pressure on the bronchial walls increases caused by enlargement of tumor mass or lymph nodes [21]. In addition, cancer metastasis to the bone marrow can cause leukopenia and anemia [34]. Moreover, cough reflex impairment might be triggered by narcotics, psychotropic therapy, or metastases to the brain [35]. Cancer related treatments can cause pneumonia development in patients with advanced staged lung cancer. Most drugs used for chemotherapy suppress the function of the immune system. Alkalizing drugs, antimetabolites of purines, pyrimidines, and folic acid all have immunosuppressive effect [36]. In our study, advanced staging was associated with pneumonia development in lung cancer patients.
There was a difference in the occurrence of pneumonia according to the pathologic type. Squamous cell carcinomas are much more commonly endobronchial lesions protruding into and obstructing large central bronchus, while adenocarcinomas are much more commonly peripheral[37]. Thus, post-obstructive pneumonia occurs frequently in squamous cell carcinoma. SCLC is strongly associated with smoking. Most SCLC patients receive treatment based on cytotoxic chemotherapy and/or radiotherapy. They are vulnerable to infections due to suppressed cellular immunity [38].
This study has some limitations. First, it was a retrospective study. Nonetheless, our study included patients from multiple centers with a large sample size. Second, our study did not investigate whether pneumococcal vaccine (PSV 23 or PCV 13) was given. Chiou et al. [39] noted that the cumulative hospitalization rate for pneumonia over two years in lung cancer patients was 37.1% in the vaccinated group and 55.4% in the non-vaccinated group. Third, exclusion of radiation pneumonitis was not complete because differential diagnosis between pneumonia and radiation pneumonia was based on retrospective medical chart and radiologic findings reviews. However, we tried to exclude cases suggesting radiation pneumonitis such as those with relatively sharp demarcation consolidation or GGO with limited radiation field as much as possible.
Despite these limitations, the present study had several strengths. This study was a 7 multi-center study with a large sample size. To identify the risk factors for pneumonia development in patients with lung cancer, pneumonia patients were compared with a relatively large number of non-pneumonia patients. In addition, when the patients were newly diagnosed with lung cancer, data was collected prospectively after registration and the bias was minimized.