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Clinical/translational cancer immunotherapy
Original research
Risk factors and immunomodulators use in steroid-refractory checkpoint inhibitor pneumonitis
  1. Yanlin Li1,
  2. Xiaohui Jia1,
  3. Yajuan Zhang1,
  4. Yonghao Du2,
  5. Yuzhu Chang3,
  6. Yuan Shen4,
  7. Ziyang Mao1,
  8. Mengjie Liu1,
  9. Hong Sun1 and
  10. Hui Guo1,5,6
  1. 1Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  2. 2Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  3. 3Department of Neonatology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
  4. 4Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China
  5. 5Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Xi'an, China
  6. 6Department-Bioinspired Engineering and Biomechanics Center, Xi’an Jiaotong University, Xi’an, China
  1. Correspondence to Professor Hui Guo; guohui{at}xjtufh.edu.cn; Hong Sun; sunhong2023{at}xjtu.edu.com

Abstract

Background Checkpoint inhibitor pneumonitis (CIP) that does not respond to corticosteroids is termed steroid-refractory CIP. We aimed to find risk factors of steroid-refractory CIP and evaluate the management strategies of immunomodulators (IMs).

Methods Patients with CIP were identified between August 2019 and August 2022 retrospectively. Clinical characteristics, peripheral blood biomarkers, and radiologic images were collected.

Results Among 1209 patients with solid tumor receiving programmed death (ligand)-1 antibody, 28 patients developed steroid-refractory CIP and 38 patients developed steroid-response CIP. Patients with steroid-refractory CIP had a higher proportion of previous interstitial lung disease (p=0.015) and grade 3–4 (p<0.001) at diagnosis. Otherwise, absolute neutrophil count (ANC), procalcitonin were higher and albumin was lower in steroid-refractory patients (ANC, p=0.009; procalcitonin, p=0.024; albumin, p=0.026). After multivariate analysis, grade 3–4 and higher ANC at diagnosis were confirmed to be independent risk factors for steroid-refractory CIP (grade, p=0.001; ANC, p=0.046). For grade 2 steroid-refractory CIP, additional IMs did not affect the prognosis (p=1.000). However, additional IMs reduced the risk of deterioration significantly in grade 3–4 steroid-refractory CIP (p=0.036).

Conclusions Grade 3–4 and higher peripheral blood ANC at diagnosis are associated with higher risk of steroid-refractory CIP. The use of additional IMs improves the outcome of grade 3–4 steroid-refractory CIP. These results can offer new insights to the decision-making of CIP management.

  • Immune Checkpoint Inhibitors
  • Immunotherapy
  • Blood Cell Count

Data availability statement

Data are available on reasonable request. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author had final responsibility for the decision to submit for publication.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-006982

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Steroid-refractory checkpoint inhibitor pneumonitis (CIP) was a critical and fatal adverse event of immune checkpoint inhibitors.

    WHAT THIS STUDY ADDS

    • Grades 3–4 and higher peripheral blood neutrophil at diagnosis are associated with higher risk of steroid-refractory CIP, and additional immunomodulators use improves the outcome of grades 3–4 steroid-refractory CIP.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Given these results, clinicians are able to distinct steroid-refractory CIP and make an appropriate treatment strategy before steroids fail to improve the prognosis.

    Introduction

    The widespread use of immune checkpoint inhibitors (ICIs) is leading to a rapid increasement of immune-related adverse events (irAEs), which can involve in any organ or system and limit the use of these drugs.1 Among irAEs, checkpoint inhibitor pneumonitis (CIP) is one of the most common adverse events and leads to an unexpectedly high mortality rate.2 Steroids are the dug of first choice for most irAEs recommended by current guidelines, including CIP, and are effective in most patients within 48–72 hours.3 4 Nonetheless, there are a subset of patients whose CIP do not respond well to steroids within 48–72 hours, or improve first but subsequent relapse without ICI rechallenge, which has been described as steroid-refractory CIP.5–7 The steroid-refractory CIP can be life-threatening, with the mortality rate from 34.6% to 75%.5–7 Otherwise, steroid-refractory CIP often persists and requires long-term therapy due to poor treatment response. On the one hand, persistent or recurrent pneumonitis can lead to an irreversible progression of fibrosis and a decrease of the pulmonary function, which impairs the quality of life significantly.8 9 On the other hand, long-term treatment with high-dose steroids improves the risk of steroid-related complication and makes nursing more difficult.10 11 For patients who recover from the disease, ICIs are tended to temporarily or permanently discontinued due to the remnant irreversible fibrosis and worries about relapse, which may be unfavorable to survival.

    Considering the harm of steroid-refractory CIP and the potential adverse effects of the long-term use of steroids, it is important to distinct the steroid-refractory CIP and develop an appropriate treatment strategy early, especially in those with poor performance status or that have rapidly evolving pneumonitis.12 However, the judgment is entirely based on the clinician’s personal experience due to the lack of evidence. Given that steroid-refractory CIP may have a different mechanism and clinical manifestation from steroid-response CIP, some clinical and hematological risk factors may be found before the failure of steroids treatment.13 14 Otherwise, the subsequent treatment strategy after the failure of initial corticosteroids remains controversial. Previous study has reported that escalating the steroid dose may not be a good option.10 Most guidelines recommend the addition of a second immunomodulator (IM) beyond steroids, such as tumor necrosis factor α inhibitor or intravenous Ig.3 15 But the efficacy and timing of the second IM are still unclear. Although several studies have reported some experience with second IMs use in steroid-refractory irAEs, solid evidence was not available due to limited participants and lack of comparison.5 6 Otherwise, the use of additional IM may further increase the risk of infection or other adverse events, which will make treatment more difficult.16 In general, this special type of CIP presents a diagnostic and therapeutic challenge due to a scarcity of evidence. The dilemma for oncologists and clinicians is how to assess the risk of steroids failure at the beginning of CIP treatment and to make decisions about the use and timing of additional IMs considering the efficacy and potential risks. Therefore, resolving steroid-refractory CIP will be critical if we are to achieve broad clinical benefit of ICI.

    Here, we conducted a retrospective study to determine the risk factors of the development of steroid-refractory CIP from clinical characteristic, peripheral blood tests and chest CT images. In addition, efficacy and safety of treatment strategies with steroids and additional IMs were also analyzed.

    Methods

    Study design and patient selection

    We retrospectively selected patients with solid tumor receiving anti-programmed cell death (ligand) 1 (PD-(L)1) antibodies at the First Affiliated Hospital of Xi’an Jiaotong University between August 2019 and August 2022. Patients receiving any ICIs before or the information of ICIs medication unknown were excluded. Otherwise, patients who were lost to follow-up after initial ICI treatment were also excluded because of the difficulty in CIP assessment. The time between the last patient included and the data analysis was more than 3 months. To make the prediction, the clinical characteristics, peripheral blood biomarkers and CT images were collected at the time of admission.

    Diagnosis of CIP

    The diagnosis of CIP was made by the clinical medical oncologist and supported by two independent radiologists. Moreover, the diagnosis was checked by authors during data collection. Grades of CIP were determined using the National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Two subtypes of steroid-refractory CIP were defined in our study. Initial steroid-refractory CIP was defined as a failure of improvement of pneumonitis after 72 hours of systemic steroids (methylprednisolone 1 mg/kg/day or more) referring to previous studies.6 7 Late steroid-refractory CIP was defined as CIP that was initially responded to systemic steroids (methylprednisolone 1 mg/kg/day or more) but subsequently relapsed during steroid tapering, without ICI rechallenge (also known as steroid-resistant CIP).6 Steroid-response CIP was defined as CIP that responded to systemic steroids (any dose) during the first 72 hours and did not relapse. Patients with CIP relapse who did not receive adequate steroids (less than methylprednisolone 1 mg/kg/day) initially but response to steroids at the second therapy, were also classified as steroid-response CIP. Both of the steroid-refractory and response CIP were evaluated in grade 2 or higher grade CIP since grade 1 CIP was asymptomatic and was not recommended for steroids.3 15

    Data acquisition and CT image evaluation

    Patient’s characteristics (demographic characteristics, cancer and treatment protocols, previous disease, steroids using and clinical features of CIP) and peripheral blood tests were acquired from hospital medical record system retrospectively. Previous interstitial lung disease (ILD) was defined as pulmonary interstitial changes that existed prior to ICI use, including reticular shadow, ground glass opacity, honeycombing change, etc. Concurrent infection was defined as a viral, bacterial and fungal infection supported by microbial evidence in any tissue or body fluid, or a diagnosis made by clinician considering symptoms, imaging data and changes in peripheral blood. These were previously evaluated by radiologists and clinicians during routine consultations and collected retrospectively by investigators. The chest CT images were reviewed by two radiologists blinded to clinical information. CIP was classified into four subtypes: cryptogenic organizing pneumonia, non-specific interstitial pneumonia, acute interstitial pneumonia or acute respiratory distress syndrome and others.17 18 Moreover, the lesion distribution was classified into three types: peripheral distribution, mixed or multifocal distribution and diffuse distribution. Ichikado CT score was used to describe the degree of the lesion quantitatively.19

    Definition of management, prognosis and IM-related infection

    Additional IM referred to IMs except steroids (such as tumor necrosis factor α inhibitor, intravenous Ig, mycophenolate mofetil).20 An interval of less than 72 hours between steroids use and additional IM use was defined as concurrent treatment, otherwise as sequential treatment. Prognosis of CIP was classified into two categories: improvement and deterioration. Improvement was defined as the patient steadily improving toward recovery from pneumonitis based on clinical symptoms and CT scan assessment, without relapse within 90 days. Deterioration was defined as CIP or CIP-related complications that were getting worse according to clinical symptoms or CT image. To analyze the safety of steroids and additional IMs, we evaluated the risk of IM-related infection in our patients. IM-related infection was defined as the infections diagnosed after steroids or additional IM use. Pre-existing infections and infections that were obviously due to other causes were excluded.

    Statistical analysis

    For quantitative data comparisons in two groups, unpaired t-test or Welch’s test was performed. Receiver operating characteristics curve was used to find the cut-off value at the highest Youden index. For qualitative or ordinal data, χ2 test was used. Otherwise, some blood biomarkers were log-transformed to follow a normal distribution. Univariate and multivariate analysis for risk factors of steroid-refractory CIP were conducted by binary logistic regression analysis and HR and 95% CI were estimated. Variables that were considered clinically relevant or that showed a potential relationship in univariate analyses were entered into multivariate regression model. Given the limited number of events, variables for multivariate analyses were carefully chosen. A two-sided of p<0.05 was considered statistically significant in t-test or regression analyses and a two-sided of p<0.10 was considered statistically significant in homogeneity test of variance. All the analyses were carried out with the use of SPSS V.26.0 (IBM) and Prism V.9.0.0 (GraphPad Software, La Jolla, California, USA) .

    Results

    Patients enrollment and incidence of steroid-refractory CIP

    From August 2019 to August 2022, a total of 1209 patients with solid tumor who were treated with anti-PD-(L)1 antibody were found (figure 1). After at least 3 months of follow-up, 156 (12.9%) patients developed CIP and 66 (5.5%) patients received steroids therapy. Eventually, 28 (2.3%) patients were evaluated as steroid-refractory CIP and 38 (3.1%) patients were evaluated as steroid-response CIP. Among patients with steroid-refractory CIP, 19 (67.9%) patients developed initial steroid-refractory CIP and 9 (32.1%) patients developed late steroid-refractory CIP. The proportions of addition IMs use were 42.9% in all grade steroid-refractory CIP, 30.0% in grade 2 steroid-refractory CIP and 72.2% in grades 3–4 steroid-refractory CIP. For initial and late refractory CIP, the rates of addition IMs were 68.4% and 33.3%, respectively.

    Figure 1
    Figure 1

    Flow diagram of patients enrolment. CIP, checkpoint inhibitor pneumonitis; IM, immunomodulators.

    Comparison of clinical features at diagnosis

    The clinical characteristics at the time of admission were shown in table 1. Demographic characteristic, cancer and treatment protocols, previous disease, previous steroids use and clinical characteristics of CIP were compared between steroid-refractory and response CIP. In both groups, most of the patients were male, current or former smoker, with lung cancer and receiving anti-PD-1 antibodies. However, patients with steroid-refractory CIP had a significant high proportion of previous ILD (67.9% vs 42.1%, p=0.015). The proportion of grades 3–4 CIP was also higher in patients with steroid-refractory CIP (64.3% vs 10.6%, p<0.001). Otherwise, patients with steroid-refractory CIP seemed to be more likely to have previous emphysema and concurrent infection at diagnosis (emphysema, 46.4% vs 26.3%, p=0.052; infection, 32.1% vs 13.2%, p=0.051). There was no difference between two groups in previous irAEs, previous steroids use or concurrent irAEs. In addition, we also compared clinical characteristics between initial and late steroid-refractory CIP. Patients with initial steroid-refractory CIP had a significantly higher proportion of grades 3–4 CIP at diagnosis (89.5% vs 22.2%, p=0.001). The details of previous ILD and concurrent infection were summarized in online supplemental tables 1,2.

    Supplemental material

    Supplemental material

    View this table:
    Table 1

    Clinical characteristics of enrolled patients at diagnosis

    Comparison of peripheral blood biomarkers at diagnosis

    To analyze the correlation between peripheral blood biomarkers and the development of steroid-refractory CIP, blood cells counts, some kind of proteins, lymphocyte subsets and cytokines were compared between patients with steroid-refractory and response CIP (figure 2, online supplemental figure 1, online supplemental table 3). For patients with steroid-refractory CIP, results showed that the ANC, and procalcitonin were significantly higher (ANC, mean, 8.0 vs 5.6×109/L, p=0.009; procalcitonin, mean, 1.6 vs 0.2 ng/mL, p=0.024) while albumin was significantly lower compared with patients with steroid-response CIP (mean, 32.1 vs 35.4 g/L, p=0.026). There was no significant difference in other blood cells. proteins, lymphocyte subsets and cytokines between two groups. Moreover, compared late steroid-refractory CIP, absolute lymphocyte count (ALC) was significantly lower while lactate dihydrogen (LDH) was significantly higher in initial steroid-refractory group (ALC, mean, 1.0 vs 1.7×109/L, p=0.041; LDH, mean, 368.8 vs 251.6 U/L, p=0.041) (online supplemental figure 2, online supplemental table 3). There was no significant difference in other blood indicators between two subgroups.

    Supplemental material

    Supplemental material

    Supplemental material

    Figure 2
    Figure 2

    Comparison of blood cells and proteins on admission. (A) Blood cells counts between patients with steroid-refractory and response CIP. (B) Plasma concentration of proteins between patients with steroid-refractory and response CIP. Bars indicate the mean and SEM. Unpaired t-test or Welch’s t-test. AEC, absolute eosinophil count; ALC, absolute lymphocyte count; ANC, absolute neutrophil count; CRP, C reaction protein; LDH, lactate dihydrogen; SEM, SE of mean.

    Comparison of radiologic features at diagnosis

    To analyze the association between the features of chest CT images and the risk of steroid-refractory CIP, radiologic patterns, lesion distribution types and Ichikado CT score were compared between patients with steroids-refractory and response CIP (online supplemental figure 3A-C, online supplemental table 3). For radiologic subtypes and lesion distribution types, there was no significant difference between two groups. However, the Ichikado CT score tended to be higher in patients with steroids-refractory CIP (mean, 146.7 vs 126.7, p=0.099). The features of chest CT image were also analyzed between initial and late steroid-refractory CIP (online supplemental figure 3D–F, online supplemental table 3). The major lesion distribution type was diffuse in initial steroid-refractory CIP and mixed or multifocal in late steroid-refractory CIP (p=0.063). Otherwise, the Ichikado CT score was significantly higher in initial steroid-refractory group (mean, 158.0 vs 120.0, p=0.026).

    Supplemental material

    Logistic regression of risk factors of steroid-refractory CIP

    To further confirm the risk factors of steroid-refractory CIP, the univariable and multivariable Logistic regression analysis were performed (table 2). Variables with p<0.10 and missing value <20% in previous analyses were included in univariate analysis. Quantitative data were divided into qualitive data by cut-off value (online supplemental tables 4,5). In the univariate analysis, patients with previous ILD, grades 3–4 CIP, higher ANC and lower albumin had significantly higher risk of steroid-refractory CIP (previous ILD, p=0.017; grades 3–4 CIP, p<0.001; ANC, p=0.002; albumin, p=0.005). Given the limited number of events, only the variables with p<0.05 in univariate analysis were included in multivariate analysis. In the multivariate analysis, grades 3–4 CIP and higher ANC at diagnosis were confirmed to be independent risk factors of steroid-refractory CIP (grades 3–4 CIP, OR 12.05, 95% CI 2.60 to 55.56, p=0.001; ANC, OR 4.29, 95% CI 1.03 to 17.88, p=0.046). Combined the grade and ANC level showed a higher risk in multivariate analysis (OR 21.15, 95% CI 2.20 to 203.47, p=0.008). In addition, we did not find an independent risk factor for initial or late steroid-refractory CIP in subgroup analysis (online supplemental table 6).

    Supplemental material

    Supplemental material

    Supplemental material

    View this table:
    Table 2

    Logistic regression analysis for risk factors of steroid-refractory CIP

    Management and clinical outcomes of steroid-refractory CIP

    Unsurprisingly, patients with steroid-refractory CIP had significantly worse prognosis compared with patients with steroid-response CIP (adjusted OR 10.39, 95% CI 1.79 to 60.43, p=0.009) (online supplemental figure 4A). In subgroup analysis, although the improvement proportion of initial refractory CIP was lower than late refractory CIP, there was no statistical significance after adjusting grades (adjusted OR 3.97, 95% CI 0.45 to 34.48, p=0.215) (online supplemental figure 4B). To further explore the relationship between IMs and the prognosis of steroid-refractory CIP, we compared the maximum steroid dose between patients with improvement and patients with deterioration first (online supplemental figure 5A-C), and there was no difference between two groups. Moreover, the use of additional IM was analyzed in patients with all grades, grade 2 and grades 3–4 steroid-refractory CIP, respectively (figure 3A–C). For all grade steroid-refractory CIP, patients treated with additional IM had the similar risk of deterioration compared with those treated without it (adjusted OR 0.14, 95% CI 0.01 to 1.38, p=0.092). In subgroup analyses, the effectiveness was not significant in grade 2 steroid-refractory CIP (OR 1.17, 95% CI 0.16 to 8.48, p=1.000). However, for grades 3–4 steroid-refractory CIP, the risk of deterioration was significantly low in patients treated with additional IM than those treated without additional IM (OR 0.50, 95% CI 0.27 to 0.93, p=0.036). In addition, there was no difference in prognosis between patients treated with concurrent and sequential additional IM (adjusted OR 3.20, 95% CI 0.37 to 27.86, p=0.291) (online supplemental figure 4C), though maximum steroid dose was significantly higher in patients receiving sequential IM (p<0.001)

    Supplemental material

    Supplemental material

    Figure 3
    Figure 3

    Management, prognosis and IM-related infection in patients with steroid-refractory CIP. Prognosis between patients treated with additional IM and without additional IM in all grade steroid-refractory CIP (A), grade 2 steroid-refractory CIP (B), and grades 3–4 steroid-refractory CIP (C). IM-related infection between patients treated with additional IM and without additional IM in all grade steroid-refractory CIP (D), grade 2 steroid-refractory CIP (E), and grades 3–4 steroid-refractory CIP (F). χ2 test for p value and logistic regression analysis for adjusted p value. Results in (A) and (D) were adjusted by CIP grade. CIP, checkpoint inhibitor pneumonitis; IM, immunomodulators.

    The risk of IM-related infection was also analyzed. Patients with steroid-refractory CIP had significant higher risk of IM-related infection than patients with steroid-response CIP (adjusted OR 12.40, 95% CI 1.25 to 122.66, p=0.031) (online supplemental figure 4D). In subgroup analysis, there was no significantly difference between initial and late refractory CIP (adjusted OR 3.19, 95% CI 0.27 to 38.28, p=0.361) (online supplemental figure 4E). Similarly, the maximum steroid dose had no difference between patients with improvement and patients with deterioration (online supplemental figure 5D–F). Correlation between IM-related infection and additional IM was also analyzed in patients with all grades, grade 2 and grades 3–4 steroid-refractory CIP (figure 3D–F). For steroid-refractory CIP, there was no difference between patients treated with additional IM and without additional IM (adjusted OR 3.98, 95% CI 0.59 to 26.99, p=0.157). In subgroup analyses, additional IM seemed to be related with a higher risk of IM-related infection in grade 2 CIP (OR 8.00, 95% CI 1.28 to 50.00, p=0.067). In grades 3–4 CIP, there was no difference (OR 1.20, 95% CI 0.26 to 5.54, p=1.000). Otherwise, there was also no difference between patients treated with concurrent and sequential additional IM despite of the difference in maximum steroid dose (adjusted OR 0.68, 95% CI 0.09 to 5.25, p=0.708) (online supplemental figure 4F).

    Discussion

    Given the high mortality of steroid-refractory CIP, early distinction and optimal treatment decision based on reliable evidence are very important. Therefore, we conducted this study to explore the risk factors and analyze the impact of IMs in steroid-refractory CIP. By multivariate analysis, it was found that grades 3–4 pneumonitis and higher ANC level at diagnosis were independent risk factors for steroid-refractory CIP. Combined the grade and ANC level showed a higher risk than either of them. Compared with late steroid-refractory CIP, it was observed that the initial type was presented a higher grade and higher Ichikado score at diagnosis, with a lower ALC level. For grade 2 steroid-refractory CIP, additional IM did not lead to a better prognosis, but it may increase the risk of infection. However, additional IM significantly reduced the risk of deterioration and demonstrated good safety for grades 3–4 pneumonitis. These findings will be useful for better clinical decision-making for these patients.

    As a fatal adverse event, the incidence of steroid-refractory CIP is poorly understood. Previously, it has been reported an incidence of 0.4% in patients with lung cancer treated with ICIs and 11.4% among patients with cancer requiring additional IMs for irAEs.5 6 In our study, the incidence of steroid-refractory CIP was 2.3% among patients with solid tumor and 3.7% (24/638) among patients with lung cancer, which seemed higher than previous studies. This may be due to clinicians paying more attention to irAEs during treatment and more comprehensive assessment was used in our study. Steroid-refractory CIP is not as ‘rare’ as previously thought.

    Through multivariate analyses, we demonstrated that grades 3–4 and higher ANC at diagnosis were related with the development of steroid-refractory CIP, which may serve as an indicator to help clinicians distinct this special type of CIP earlier. Steroid-refractory CIP was also reported in previous studies to be significantly associated with higher grades, with the ratio of 15/26, 10/12, and 12/14, respectively.6 7 21 Neutrophil has been observed to increase at the time of CIP development and be associated with the worse prognosis in a previous study.22 The higher the grade and peripheral ANC level suggested the more serious pulmonary inflammation in patients with CIP. The analysis of lung tissues in steroid-refractory CIP showed that diffuse alveolar injury and interstitial inflammation were the most common pathological change.6 23 In addition, a strong CD3+ cell infiltration with predominantly CD4+ cells over CD8+ and clusters of PD-L1 positive macrophage cells were also observed in the pulmonary inflammatory lesions of a steroid-refractory CIP patient.14 Previous studies have demonstrated that neutrophils can induce immune cells in the lungs, damaging alveolar structures, promoting acute lung injury and exacerbating respiratory symptoms.24 25 Higher CIP grade and peripheral blood neutrophil level may be the manifestation of these pathological changes in individual level. Therefore, a potential mechanism of steroid-refractory CIP may be that excessive inflammation and immune response lead to fibrosis of alveolar and bronchial epithelial tissues and alveolar walls, which cannot be reversed by glucocorticoids.26 Although it was considered that the incidence of infection was not significantly different between the steroid-refractory and response patients statistically, we acknowledge that the effect of infection on ANC and procalcitonin cannot be completely balanced. Therefore, this result needs to be verified in studies with larger population. Otherwise, the proportion of grades 3–4 CIP in patients with initial steroid-refractory CIP was significantly higher than that in patients with late steroid-refractory one, and there were also differences in peripheral blood biomarkers and radiological features between two groups, indicating that the two types of pneumonitis may have different clinical manifestations and need different management.

    Although most guidelines recommended the use of additional IMs as a backup after the failure of steroid therapy for steroid-refractory CIP, the supporting evidence is rare.15 In our study, we found that the efficacy and safety of additional IMs were not the same among different severity of steroid-refractory CIP. For grade 2 steroid-refractory CIP, the use of additional IMs did not significantly improve outcomes and may increase the risk of infection. For grades 3–4 steroid-refractory CIP, additional IM demonstrated an inspiring therapeutic effect and a satisfactory safety profile. Therefore, additional IMs should be considered as a better choice for patients with grades 3–4 steroid-refractory CIP, but the necessity in grade 2 needed further research considering the risks versus benefits. The administration of additional IMs is considered useful and necessary in many refractory irAEs based on the observation of clinical management and studies with small sample sizes.4 7 20 27 Since our medical center was able to provide adequate medical and nursing resources and most patients could accept IM or non-invasive oxygen therapy, the main determinant of outcomes and additional IM use was probably due to the clinician’s choice rather than other confounders related to goals of care or shift in code status. Among 16 patients with steroid refractory CIP receiving additional IM, 15 received intravenous Ig and 1 received intravenous Ig combined with mycophenolate mofetil. These IMs can regulate the function of immune cells, reduce the expression of proinflammatory cytokines and neutralize autoantibodies in inflammatory and autoimmune diseases, which are the major potential mechanisms of irAEs.12 28 Moreover, although there was a significant difference in maximum steroid doses between patients receiving concurrent and sequential additional IM, there was no difference in prognosis or IM-related infections between two groups. This may suggest that the outcomes of steroid-refractory CIP are more depended on the use of additional IMs than higher dose of steroids. Current guidelines recommended 1–2 mg/kg/day methylprednisolone equivalents.3 15 Previous study showed that, even for high-grade irAE, higher dose of methylprednisolone equivalents did not reduce the risk of deterioration. Moreover, higher-dose steroids were associated with longer courses of treatment and more steroid-related complications.10

    There were several limitations in our study. First, due to the low incidence of steroid-refractory CIP, only 66 patients were included in analysis, which inevitably leaded to some bias and made in-depth analyses out of reach. The risk factors and management strategies of steroid-refractory CIP need to be confirmed in prospective studies with lager population. Moreover, due to the difficulty in obtaining the human tissues, the mechanism could not be explored and we were not able to verify the findings at the histological level. The mechanism of steroid-refractory CIP needs to be explored to make a well-targeted treatment strategy.

    In summary, our data indicated that grades 3–4 and higher peripheral blood ANC at diagnosis were independent risk factors for the development of steroid-refractory CIP. The use of additional IMs reduced the risk of deterioration and demonstrated satisfactory safety in high grade steroid-refractory CIP.

    Supplemental material

    Data availability statement

    Data are available on reasonable request. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. The corresponding author had final responsibility for the decision to submit for publication.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study was approved by the Ethics Committee of First Affiliated Hospital of Xi’an Jiaotong University (XJTU1AF2021LSK-001).

    Acknowledgments

    We sincerely appreciate all sources of financial grants.

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    Supplementary materials

    Footnotes

    • YL and XJ contributed equally.

    • Correction notice This article has been corrected since it was first published. In the original version author Hong Sun had not been listed as a corresponding author. This has now been amended.

    • Contributors YL and XJ: data curation, formal analysis, visualization and writing-original draft. YZ: formal analysis and investigation. YD: formal analysis. YC and ZM: visualization. YS and ML: methodology and validation and supervision. HS and HG: conceptualization, funding acquisition, supervision and writing-review. HG is responsible for the overall content as the guarantor. All authors have read and approved the final version of the manuscript.

    • Funding This work was supported by Guangdong Association of Clinical Trials (GACT)/Chinese Thoracic Oncology Group (CTONG) and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (No. 2017B030314120); Clinical Key Fund of First Affiliated Hospital of Xi’an Jiaotong University (No. XJTU1AF-CRF-2019-001); and Key Industry Innovation Chain (Group) of Shaanxi Province (2022ZDLSF04-11). The funding sources were involved in the writing of the report.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.