The patient was a 72-year-old male heavy smoker (50 pack-years). During a routine examination in December 2020, a space-occupying lesion (2.9 cm x 2.6 cm) near the lung hilum (Figures 1A, F) and mild fibrotic changes of unclear origin were detected (Figures 2A, F). He underwent EBUS-TBNA pathological examination and PET-CT to confirm the final diagnosis of squamous cell lung carcinoma (SqCLC; T1N1MO, stage IIb). Genomic sequencing test showed no driver mutation for targeted therapy (ALK(-), BRAF(-), BRCA1(-), BRCA2(-), EGFR(-), ERBB2(HER2)(-), FGFR2(-), FGFR3(-), KIT(-), KRAS(-), MET(-), NRAS(-), NTRK1(-), NTRK2 (-), NTRK3(-), PDGFRA(-), RET(-), ROS1(-), and IDH2(+)); however, the patient tested positive for PD-L1 (TPS=25%, IPS<1%, tested using a Ventana SP263 assay), with tumor mutation burden of 7.26 Muts/Mb (tested using a next-generation sequencing (NGS) panel and paired with peripheral blood sample sequencing). Other genetic mutations related to immunotherapy were also tested as follows: CD274(-), PDCD1LG2(-), MLH1(-), MSH2(-), MSH6(-), PMS2(-), POLD1(-), POLE(-), TP53(+), ATM(-), ATR(-), BRIP1(-), CHEK2(-), FANCA(-), RAD50(-), PALB2(-), CHEK1(-), MRE11(-), PBRM1(-), MDM2(-), MDM4(-), DNMT3A(-), JAK1(-), JAK2(+), PTEN(-), STK11(-), CCND1(-), FGF19(-), FGF3(-), FGF4(-). The patient had no history of cardiopulmonary or connective tissue disease, and the Eastern Cooperative Oncology Group (ECOG) performance status was rated as 2 points.
Owing to the patient's age and tumor location, systemic chemotherapy combined with immunotherapy was administered: intravenous infusion of albumin-paclitaxel 160 mg (D1, D8) combined with camrelizumab 200 mg (D1). After two cycles of the above treatment, the patient developed fever after fatigue and colds on 13 February, 2021, with a maximum temperature of 39 C and shortness of breath. The patient was admitted immediately the next day. Bilateral bronchial breathing sounds and Velcro rales were detected. Laboratory examination revealed an inflammatory blood reaction (Figures 3A, B), decreased oxygen partial pressure (Figure 3C), decreased oxygen saturation (85% SaO2), and increased D-dimer levels (>=20 mug/ml) (Figure 3D). Images showed that the primary cancer foci shrank significantly and were surrounded by patchy ground-glass opacities (GGOs) and consolidation shadows (Figures 1B, G). Bilateral peribronchovascular and subpleural GGOs, reticulation, and consolidation were predominant in the middle to lower lungs (Figures 2B, G). Contrast-filling defects were also observed in the pulmonary artery branches of the upper and lower lobes of the left lung. The patient was preliminarily diagnosed with type I respiratory failure and interstitial pneumonia (CIP?), pulmonary embolism, and SqCLC (T1N1MO stage IIb, partial response [PR]). The patient was administered with mask oxygen inhalation therapy (8 L/min), systemic corticosteroid pulse therapy (methylprednisolone sodium succinate, 240 mg Q.D. for 2 days), and anticoagulation treatment (enoxaparin sodium, 4,000 U Q.D.) on February 16. Considering that infection could not be ruled out, empirical anti-inflammatory and antiviral treatments were administered, along with anti-asthmatic, gastric-protecting, calcium-supplementing, and other symptomatic support treatments. After 48 h, respiratory failure progressively aggravated, and the oxygenation index (PaO2/FiO2) was calculated as 125 mmHg. The patient was then transferred to the MICU for further treatment on February 18.
The patient was intubated for mechanical ventilation. Bedside chest radiography revealed poor lung transparency (Figure 4A). As a diagnosis of exclusion, we considered that the pulmonary symptoms and signs were caused by ICI toxicity and responded inadequately to high-dose corticosteroids. The patient had no signs of other concurrent irAEs, such as dermatitis, hepatitis, nephritis, or myopericarditis. The final diagnosis was steroid-refractory CIP grade 4 (G4), defined as a life-threatening respiratory compromise. For steroid-refractory CIP G4, infliximab (500 mg for 1 day) was administered intravenously, and the ICIs were permanently discontinued. Oral corticosteroids were slowly tempered. Two days after immunomodulatory treatment, the inflammation indicators increased again (Figures 3A, B), and plenty of sticky sputum was collected from the patient. We performed sputum culture and sputum smear and found G+ cocci, G- bacillus, Acinetobacter baumannii, and Candida albicans. We then examined the bronchoalveolar lavage fluid (BALF) using NGS and found Acinetobacter baumannii, C. albicans, and Enterocooccusum faecium infection (Table 1).
Considering severe comorbid infectious pneumonia due to compromised immune system, the patient was administered with tigecycline combined with meropenem as anti-inflammatory therapy, micafungin as antifungal therapy, and intravenous immunoglobulin pulse therapy for 3 days to enhance the self-immunological barrier. Enoxaparin sodium anticoagulant therapy was continued for pulmonary embolism. After 3 days, the temperature and laboratory indicators improved (Figure 3). Bedside chest radiography showed improved bilateral lung transmittance (Figure 4B). On March 2, endotracheal intubation was removed, and the patient was administered with nasal high-flow oxygen (45 L/min, oxygen concentration 50%).
 Figure 5 shows the management axis of CIP G4 and the critical complications in this patient. After sufficient medical care in the MICU, the patient's condition stabilized, and he was transferred to the general ward on March 9. To manage pulmonary interstitial fibrotic changes and potentially inhibit tumor growth, nintedanib 150 mg was prescribed orally twice daily during the subacute phase of CIP. With good tolerance, the dosage was increased to 200 mg orally twice daily 1 week later and has been maintained to date.
On 2 April 2021, the patient's ECOG score was rated 4 before discharge; lung CT reexamination showed no new space-occupying lesions, and the original occupation was significantly smaller than the previous one in December 2020 (Figures 1C, H). The therapeutic efficacy of SqCLC was evaluated as PR. For CIP, pulmonary injury had evolved into an organizing and fibrotic stage. Multiple GGOs, reticulation, grid lesions, and traction bronchiectasis in a cryptogenic organizing pneumonia (OP) pattern were found in the dominant lobe around the primary tumor site, with patchy lesions in the opposite lobe (Figures 1C, H). The bilateral lower lungs were predominantly fibrotic with GGOs, reticulation, consolidation, honeycomb shadows, and thickened interlobular septa (Figures 2C, H).
Owing to the patient's deteriorating physical status and COVID-19 public control policy, the patient had recuperated at home for 6 months and maintained oral nintedanib therapy (200 mg twice daily), with slow tapering of oral corticosteroid therapy. The patient visited the hospital for a review on 13 October 2021. The performance status improved, with an ECOG score of 2. The CT scan showed a lobulated mass with a size of 5.0 cm x 2.6 cm in the upper lobe of the right lung, surrounded by fine burrs and thick-walled cavities (Figures 1D, I). The interstitial changes in the bilateral lower lobes were significantly improved compared to the previous films (Figures 2D, I). There were swollen lymph nodes in the mediastinum, and the largest one was approximately 2.6 cm x 2.0 cm in size. Moreover, the levels of serum tumor markers increased (U/L): CEA, 16.6; AFP, 2.55; CA125, 102; CA153, 36.1; CYFRA, 9.43; NSE, 20.00; and SCCA, 13.6.
The therapeutic efficacy of lung cancer was evaluated as progressive disease (PD), with T2bN2M0 stage IIIa. After consultation with the patient's family, the third chemotherapeutic cycle, comprising albumin-paclitaxel, was started at 200 mg (D1, D8/q3w), and oral nintedanib treatment was continued. In addition, afatinib 30 mg orally once daily was administered as second-line cancer therapy. The patient received four to seven cycles of albumin-paclitaxel treatment on 11 and 30 November 2021, 22 December 2021, and 21 February 2022.
Lung CT examination showed that the former shadow was 4.2 cm x 4.3 cm in size (Figures 1E, J) and stable mild interstitial changes (Figures 2E, J). The largest lymph node in the mediastinum was approximately 2.4 cm x 1.8 cm in size. The remaining abdominal CT, brain MRI, and whole-body bone ECT scans showed no obvious abnormalities or metastasis. A response of stable disease was achieved. The patient showed mild adverse reactions: slightly increased levels of liver transaminase (72 U/L AST (15-40) and 69 U/L GGT (10-60). To date, the patient has maintained the current lung cancer treatment regimen. The process of antitumor therapy for the patient is shown in Figure 6.