Participant characteristics
The study included 2673 patients with lung cancer who had undergone ICI treatment. Among them, 106 lung cancer patients developed CIP after treatment. The patients were grouped based on clinical staging, contrasting grades 1 and 2 with grades 3 and 4. Details of the patient demographics, clinical characteristics, and treatments are provided in Table 1. It was found that CIP was more common in male patients, was associated with first-line treatment, frequently accompanied by chemotherapy, and observed more in squamous cell carcinoma. The two groups (grade 1–2 and grade 3–4) did not differ significantly in terms of patient age, sex, history of smoking, comorbid chronic obstructive pulmonary disease (COPD), metastatic sites, and radiotherapy. However, significant differences were seen in terms of squamous cell carcinoma (56.1% vs. 41.1%, P = 0.03) and BMI (23.00 ± 3.55 vs. 20.33 ± 3.14, P = 0.04).
Table 1
Analysis of Clinical Characteristics and Treatment of Grades 1–2 and Grades 3–4 Immune-Related Pneumonia
Various | Grade1-2 89(%) | Grade3-4 17(%) | P-value |
Gender | | | 0.90 |
Male | 83(93.2) | 16(94.1) | |
Female | 6(6.7) | 1(5.8) | |
Age | 67.69(6.75) | 68.47(5.91) | 0.66 |
Smoling | | | 0.71 |
Yes | 48(53.9) | 10(58.8) | |
No | 41(46.0) | 7(41.1) | |
COPD | | | 0.90 |
Yes | 30(33.7) | 6(35.2) | |
No | 59(66.2) | 11(64.7) | |
BMI | 23.00(3.55) | 20.33(3.14) | 0.04 |
Stage | | | |
I-II stage | 5(5.6) | 1(5.8) | 0.97 |
III stage | 32(30.2) | 4(23.5) | 0.32 |
IV stage | 52(58.4) | 12(70.5) | 0.35 |
Chemotherapy Line | | | |
First-line chemotherapy | 75(84.2) | 4(23.5) | 0.67 |
Second-line chemotherapy | 10(11.2) | 13(76.4) | 0.33 |
Second-line chemotherapy and above | 4(4.4) | 0 | 0.49 |
Combined medication | | | |
Single-agent | 5(5.6) | 3(17.6) | 0.22 |
Combined chemotherapy | 77(86.5) | 12(70.5) | 0.20 |
Combined with vascular-targeted therapy | 2(2.2) | 2(11.7) | 0.44 |
Combined chemotherapy + vascular targeted therapy | 5(5.6) | 0 | - |
Pathology | | | |
Squamous cell carcinoma | 58(56.1) | 7(41.1) | 0.03 |
Adenocarcinoma | 16(17.9) | 6(35.2) | 0.35 |
Small cell lung cancer | 11(12.3) | 3(17.6) | - |
Other neuroendocrine tumors | 1(1.1) | 1(5.8) | - |
Adenosquamous carcinoma | 3(3.3) | 0 | - |
Metastatic sites | | | |
Brain | 3(3.3) | 1(5.8) | 0.62 |
Lung | 17(19.1) | 3(17.6) | 0.89 |
Liver | 4(4.4) | 2(11.7) | 0.54 |
Bone | 13(14.6) | 5(29.4) | 0.26 |
Combined with radiotherapy | 41(46) | 4(23.5) | 0.09 |
Hormone therapy | 78(87.6) | 17(100) | |
Onset of CIP
The median interval between the start of ICI treatment and to development of CIP was 5.17 months (95% CI 4.61–5.72, Fig. 1B). There were substantial variations between individuals, ranging from 0.4 to 32.83 months. Patients with grade 4 CIP had the earliest occurrence, with a median of 2.47 months (95% CI 0-5.12) and an incidence rate of 4.7% (5/106). Most patients were classified clinically as grade 2, accounting for 58.5% (62/106), with a median onset of 4.64 months (95% CI 3.83–5.44). The incidence rate for Grade 3 was 11.3% (12/106), with a median onset of 5.17 months (95% CI 3.47–6.86). Grade 4 CIP typically occurred within six months of ICI therapy (Fig. 1).
Clinical symptoms and radiological manifestations of CIP
As depicted in Fig. 2A, over two-thirds of the patients were diagnosed with grade 1–2 pneumonia, with grade 1 pneumonia occurring in 25.4% (27/106) and grade 2 pneumonia in 58.4% (62/106). Only a relatively small number of patients developed grade 4 pneumonia (4.7%, 5/106), while 12 patients presented with grade 3 disease (11.3%, 12/106). The predominant radiological features of CIP included traction bronchiectasis (33.0%, 35/106), patchy shadows (90.6%, 96/106), ground-glass opacity (21.7%, 23/106), interlobular septal thickening (19.8%, 21/106), shadows of fibrotic streaks (40.6%, 43/106), honeycombing (9.4%, 10/106), pleural effusion (2.8%, 3/106), reticular patterns (47.2%, 50/106), and additional traction bronchiectasis (9.4%, 10/106, Fig. 2B). Approximately 28.3% (30/106) of CIP patients were diagnosed using radiological findings only, as these patients were asymptomatic at the onset of the disease. The common clinical symptoms of CIP included cough (42.5%, 45/106), shortness of breath (50.9%, 54/106), thoracodynia (5.7%, 6/106), fever (25.5%, 27/106), and fatigue (19.8%, 21/106, Fig. 2C). In the subgroup analysis, patchy shadows and shadows of fibrotic streaks were the most frequent radiological manifestations of CIP (Fig. 2B), with cough and shortness of breath as the predominant clinical presentations (Fig. 2C).
The relationship between CIP severity and patient prognosis
The results of the group analysis based on CIP severity are shown in Fig. 3. Out of 89 patients, 75 were classified as clinical stages 1–2, and 17 of these experienced disease progression during follow-up. A further 17 patients were classified as clinical stages 3–4, and 16 of these showed disease progression during follow-up. Despite a difference in the median PFS (mPFS) between the groups, the difference was not significant (mPFS 8.47 m vs. 6.50 m, HR = 3.36, log-rank P = 0.007) (Fig. 3A). Among the 32 patients classified as clinical stages 1–2, 9 died or were lost to follow-up, and a further 9 patients classified as clinical stages 3–4 died or were lost to follow-up. The median OS (mOS) rates differed significantly, with stage 3–4 patients showing shorter survival times (mOS 23.15 m vs. 11.20 m, HR = 8.97, log-rank P = 0.003) (Fig. 3B). Of 27 CIP patients classified as clinical stage 1, 23 experienced disease progression during follow-up, with 10 patients dying. The mPFS for these patients was 10.7 months (95%CI 7.87–13.53) (Fig. 3C) and the mOS was 24.4 months (95%CI 23.15‒25.65) (Fig. 3D). Of the 62 patients with stage 2 CIP, 52 showed disease progression during follow-up, with 22 dying or being lost to follow-up. The mPFS was 7.94 months (95%CI 6.58–9.22) (Fig. 3C) and mOS was 31.17 months (95%CI 14.39–47.95) (Fig. 3D). In patients with stage 3 disease, 11 of 12 showed disease progression during follow-up, of which 6 died or were lost. The mPFS was 7.95 months (95%CI 5.20–9.73) (Fig. 3C) and the mOS was 19.8 months (95%CI 6.20–33.40) (Fig. 3D). All five patients with stage 4 CIP showed disease progression during follow-up and two died. The mPFS was 3.83 months (95%CI 7.29–9.44) (Fig. 3C) and mOS was 4.03 months (95%CI 3.15–4.92) (Fig. 3D).
The risk factor analysis for CIP severity is illustrated in Table 2. Single-factor logistic regression analysis of hypothetical risk factors for CIP revealed that red blood cell count (OR = 0.32, 95% CI 0.11–0.94, P = 0.04), creatine kinase (OR = 0.98, 95% CI 0.96-1.00, P = 0.04), free thyroxine (OR = 1.36, 95% CI 1.07–1.72, P = 0.01), and ferritin (OR = 1.002, 95% CI 1.00-1.004, P = 0.02) were significant factors. Multifactorial logistic regression indicated that FVC (OR = 1.00, 95% CI 0.01–0.80, P = 0.03) was a significant independent risk factor for CIP severity (Table 2).
Table 2
Logistic regression analyses of potential risk factors for grade 3 or higher CIP
| Univariate analysis | Multivariate analysis |
Various | ORs | 95%CI | P-value | ORs | 95%CI | P -value |
Non-adenocarcinoma vs. Adenocarcinoma | 2.01 | 0.66–6.14 | 0.66 | | | |
Non-squamous cell carcinoma vs. Squamous cell carcinoma | 0.32 | 0.11–0.93 | 0.32 | | | |
Non-IV stage vs. IV stage | 1.71 | 0.55–5.26 | 0.35 | | | |
Non-1st line vs. 1st line | 0.44 | 0.17–2.13 | 0.61 | | | |
Non-monotherapy vs. Monotherapy | 3.6 | 0.77–16.78 | 0.10 | | | |
Non-combined chemotherapy vs. Chemotherapy | 0.37 | 0.11–1.25 | 0.11 | | | |
No radiotherapy vs. Radiotherapy | 0.36 | 0.11–1.19 | 0.09 | | | |
Whether coronary heart disease | 3.60 | 0.92–14.05 | 0.07 | | | |
Whether COPD | 1.07 | 0.36–3.18 | 0.90 | | | |
PDL1 low expression or 0 vs. high expression | 0.50 | 0.31–11.52 | 0.50 | | | |
Lymphocytes | 0.74 | 2.26–2.17 | 0.59 | | | |
Red blood cells | 0.32 | 0.11–0.94 | 0.04 | 0.19 | 0.01–3.21 | 0.25 |
CRP | 0.99 | 0.97–1.02 | 0.48 | | | |
Eosinophils | 5.41 | 0.96–30.58 | 0.06 | | | |
Creatine kinase | 0.98 | 0.96-1.00 | 0.04 | 0.95 | 0.90–1.01 | 0.10 |
Free thyroxine | 1.36 | 1.07–1.72 | 0.01 | 1.41 | 0.63–3.18 | 0.41 |
Ferritin | 1.002 | 1.00-1.004 | 0.02 | 1.41 | 0.99–1.01 | 0.59 |
Alanine transaminase | 0.98 | 0.93–1.04 | 0.51 | | | |
Total bilirubin | 1.04 | 0.90–1.20 | 0.60 | | | |
Albumin | 0.98 | 0.88–1.09 | 0.98 | | | |
IgE | 1.002 | 0.99–1.01 | 0.65 | | | |
FVC | 0.18 | 0.03–0.96 | 0.04 | 1.00 | 0.01–0.80 | 0.03 |
FEV1% | 0.99 | 0.93–1.04 | 0.58 | | | |
FVC% | 0.94 | 0.87–1.01 | 0.08 | | | |
FEV1/FVC | 1.08 | 0.96–1.20 | 0.19 | | | |
DlCO% | 0.95 | 0.89–1.01 | 0.11 | | | |
Absolute values of T lymphocytes (CD3) | 1.00 | 0.995–1.001 | 0.20 | | | |
Absolute values of helper/inducer T lymphocytes (CD3+, CD4) | 1.00 | 0.99–1.003 | 0.45 | | | |
Absolute values of suppressor/cytotoxic T lymphocytes (CD3+, CD8+) | 0.99 | 0.98–1.001 | 0.09 | | | |
Follow-up treatment status of patients with CIP
Of the 106 patients diagnosed with CIP, 95 (89.6%) discontinued ICI therapy. Among those who discontinued, 27 patients (35.0%) continued using inhaled corticosteroids (ICS) after treatment, while 67 patients (63.2%) did not. An additional 3 patients could not be evaluated for continued medication due to loss to follow-up or death. Among the 29 patients who continued medication, half (15/29, 51.7%) experienced CIP recurrence. Of the overall number of patients who developed CIP, 89.6% (95/106) were treated with glucocorticoids, while 10.3% (11/106) did not receive steroid treatment. Approximately one month after the start of steroid treatment, chest CT scans were performed, showing radiographic resolution in 44.2% (42/95) of patients, radiographic progression in 16.8% (16/95), radiographic stability in 25.2% (24/95), complete radiographic resolution in 1.0% (1/95), and 12.6% (12/95) were unable to undergo radiographic evaluation due to loss to follow-up or death.