Utility of bronchoalveolar lavage in checkpoint inhibitor pneumonitis evaluation: a narrative review

Introduction

Background

Checkpoint inhibitor pneumonitis (CIP) is the leading cause of mortality amongst immune-related adverse events (IrAEs) in cancer patients receiving immunotherapy (1-3). CIP has rapidly emerged as an area of significant clinical and research interest due to the expanded indications of immune checkpoint inhibitors (ICIs) across various cancer types over the past decade. Due to the lack of reliable biomarkers, CIP remains a diagnosis of exclusion. Like other drug-induced interstitial lung diseases (ILDs), the presentation of CIP is highly variable, and its trajectory is often unpredictable, making diagnostic clarity based on clinical features alone challenging (4-7). Similarly, radiological features of CIP can be highly heterogenous, with multiple conditions mimicking its appearance (3,8-10). While most CIP cases are low-grade and resolve spontaneously, some patients experience rapid deterioration leading to fulminant respiratory failure (1,3). Mortality rates following diagnosis have been described as high as 22.7% to 32.7% across observational studies (1,11).

In this context, bronchoscopy and bronchoalveolar lavage (BAL) offer valuable opportunities to rule out alternative diagnoses and support clinical suspicion of CIP. Identifying potential biomarkers within the CIP microenvironment via BAL could improve diagnostic certainty and facilitate timely intervention (8,9). Although BAL is recommended as part of the diagnostic evaluation of patients with grade 2 or higher CIP, it is not strongly entrenched within the current paradigm of CIP management (6,11,12). Referral for respiratory specialist input and/or bronchoscopy is highly variable. A large retrospective analysis conducted across hospitals within the UK’s National Health Service found that only 42% of patients who developed CIP were referred to a respiratory specialist, and just 23.7% underwent bronchoscopy with BAL fluid collection to confirm diagnosis (10). Similarly, an analysis of United States insurance claims databases revealed that only 13% of patients diagnosed with CIP underwent bronchoscopy within 30 days of diagnosis (11).

Beyond resource constraints and geographical variations in clinical practice, there are likely overarching clinical features of CIP that limit and delay referrals for bronchoscopy. In low-grade CIP cases, referral to see a respiratory specialist or have a bronchoscopy may be deemed unnecessary due to the lack of severe symptoms. In contrast, for patients experiencing CIP progression to severe forms of disease, timely access to bronchoscopy can be challenging and, in some cases, unsafe due to rapid haemodynamic and respiratory deterioration. There is clearly equipoise regarding the optimal timing of bronchoscopy for evaluation of CIP. Moreover, while bronchoscopy can help exclude alternative diagnoses that mimic CIP in lung cancer patients, such as infection and cancer progression, there are currently no definitive BAL characteristics that conclusively support CIP diagnosis. Lymphocytosis is a cardinal feature of CIP and has been broadly described across CIP studies, though sample sizes of these studies remain small (13-20).

With the advent of advanced molecular and genomic sequencing approaches, along with recent developments in the lung microbiome space, BAL may provide granular and bespoke information to guide informed CIP management.

Rationale and knowledge gap

Despite current guideline recommendations for the use of BAL in the evaluation of CIP, its diagnostic value remains poorly defined. There is a critical need to clarify which BAL findings are truly reflective of CIP-related immunopathology and identify robust and clinically relevant biomarkers that can inform management.

Objective

This review examines current literature and offers a broad perspective on the role of BAL in the management of CIP, thus exploring how potential advances in research and technology may shift its role in the future. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-430/rc).

Methods

An electronic literature search was conducted using the PubMed, EMBASE, and Cochrane databases with the assistance of a medical librarian to identify relevant studies published in the 10 years preceding November 2024. The search terms included: ((“cancer”) OR (“neoplasm”) OR (“malignancy”)) AND ((“lung inflammation”) OR (“pneumonitis”)) AND ((“checkpoint inhibitor”) OR (“immunotherapy”)) (Table 1, Table S1). The search was restricted to English-language articles. Articles describing BAL findings of CIP and other ILDs were included in the review. In total, eight observational studies were identified (three retrospective and five prospective) (Table 2).

BAL technique and timing

The timing and technique of performing a BAL are critical for obtaining diagnostically useful samples that accurately reflect the cellular and acellular characteristics of the distal CIP microenvironment (22). Current American Society of Clinical Oncology (ASCO) IrAE management guidelines recommend bronchoscopy to evaluate CIP in patients with grade 2 toxicity or above (5). Grade 2 CIP is characterised by symptoms such as shortness of breath, new-onset cough, chest pain, or fever, with or without new relative hypoxia, and 25–50% parenchymal involvement on computed tomography (CT) imaging. As disease severity increases, the window of opportunity for bronchoscopic intervention narrows, underscoring the need for early assessment in patients experiencing clinical deterioration.

Bronchoscopy-derived transbronchial biopsy (TBBx), recommended in certain cases of CIP, can aid in diagnosing conditions affecting the centrilobular areas of the lung, such as organising pneumonia, lymphangitis, or other forms of tumour progression. Organising pneumonia is a histopathological finding described in patients with CIP (15,16). While complications associated with TBBx are rare, the risk of respiratory failure significantly increases in critically ill patients (23,24), and therefore, the decision to proceed in higher grades of CIP necessitates a cautious approach. Additionally, TBBx diagnostic yield is limited by smaller sample sizes, crush artefacts, and anatomical distortion (16,25,26). In contrast, BAL carries a lower risk of complications, but its scope is limited to diseases affecting alveolar structures, including infection, organising pneumonia, and diffuse alveolar haemorrhage. Given its favourable safety profile, BAL may be preferable in patients with higher-grade CIP who have adequate lung function and a favourable anaesthetic status.

Lymphocyte cell proportions within BAL

BAL lymphocytosis is a hallmark feature of CIP, recognised in several studies (13,15,16,18,19,21). It is important to recognise that a high lymphocyte count has been reported in several ILD conditions, such as sarcoidosis and hypersensitivity pneumonitis, as well as non-ILD conditions, such as fungal infections (27). In CIP, a clear lymphocytic predominance threshold is not established, but would logically lie above the normal reference range for lymphocytic proportions in BAL fluid of healthy individuals, which has been estimated at 5–15% (26).

In a recent study, Guo et al. (13) analysed the characteristics of BAL in patients with immunotherapy-treated lung cancer and found that 73.7% (n=14/19) of the study’s CIP patient cohort had a lymphocyte count ≥20%, with greater CIP severity associated with increased lymphocyte proportions in BAL. Kowalski et al. (14) compared BAL characteristics in CIP patients to healthy controls, as well as to non-cancer and cancer-associated lung disease cohorts. The median BAL lymphocyte proportion in CIP patients [45.5%; interquartile range (IQR), 32.0–64.0%; n=12] was significantly higher compared to healthy controls (7.3%; IQR 3.9–13.4%) and lung cancer patients (2.0%; IQR, 1.5–3.5%), but not significantly different from ILD comparators (24.5%; IQR, 5.6–39.4%). These findings highlight the integral role of lymphocytes in CIP pathogenesis while emphasising that lymphocytosis is not unique to CIP and can occur in other inflammatory lung diseases.

Current evidence suggests that drug-induced pneumotoxicity, including CIP, is likely associated with BAL lymphocyte proportions exceeding 26% (12,26). These findings have been corroborated in several BAL-based CIP studies (13,16), further supporting the role of BAL lymphocytosis as a potential biomarker in differentiating inflammatory ILDs.

Further exploration of the CIP immune landscape

Advances in genetic molecular analysis and flow cytometry techniques have enabled the identification of key immune cells and signalling molecules involved in CIP, as well as the mechanisms of immune crosstalk within the CIP microenvironment (Figure 1). Understanding the immune link between the tumour and CIP underscores the potential contribution of the tumour microenvironment in CIP pathogenesis. Longitudinal studies are essential to investigate the evolution of the immune system from initial exposure through to CIP onset. A detailed characterisation of the CIP microenvironment not only facilitates the identification of diagnostic and predictive biomarkers but also reveal potential therapeutic targets.

Figure 1 Current landscape of proposed cellular and molecular mechanisms driving CIP within the inflamed lung microenvironment. CIP, checkpoint inhibitor pneumonitis; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; CXCL, C-X-C motif ligand; IFN, interferon; IL, interleukin; IP-10, IFN-γ-induced protein 10; LAMP3, lysosome-associated membrane glycoprotein 3 receptor; MHC, major histocompatibility complex; PD-1, programmed cell death protein 1; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domain; TNF, tumour necrosis factor; Treg, regulatory T cell.

Intrinsic factors: genetic and primary tumour influence

The influence of the primary tumour’s immune profile on CIP development remains poorly understood but is an area of growing interest. Läubli et al. (28) demonstrated significant clonal overlap between tumour-infiltrating lymphocytes (TILs) from primary lung cancer biopsies at diagnosis and subsequent biopsies of lung tissues affected by CIP from the same patient. Additionally, lysosome-associated membrane glycoprotein 3 receptor (LAMP3)-positive migratory dendritic cells (DCs) have been found to be highly expanded in BAL samples from CIP patients, originating from the differentiation of C-X-C motif ligand (CXCL)9⁺ monocytes (29). Understanding associations between the original tumour microenvironment and subsequent CIP inflammatory milieu could expand on our current understanding of CIP pathogenesis and could inform predictive and risk stratification strategies.

CIP pathogenesis is influenced by immune cell-mediated gene expression in affected lung tissue. Both CD4⁺ and CD8⁺ T cells promote immune checkpoint genes regulating programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) (21). TIGIT, an inhibitory receptor expressed by activated T cells, regulatory T cells (Tregs), and natural killer (NK) cells, plays a critical role in attenuating B and T cell activity (21,30). CD4⁺ T cells also modulate immune cell homing by upregulating CXCL13, a chemokine that acts principally as a chemoattractant to B cells. Genes controlling interferon-γ (IFN-γ) and cytokine-driven pathways have also been implicated in CIP development (21). Furthermore, BAL-derived DCs in CIP patients exhibit increased expression of major histocompatibility class (MHC) II genes, enhancing antigen presentation (20,21), which in fundamental to immune cell activation.

T cell populations involved in CIP disease pathogenesis

Over the last few decades, flow cytometry has become a powerful tool in both clinical and research settings, particularly in understanding the role of TILs within the tumour microenvironment (31). While increased immune cell activity has been linked to increased overall and progression-free survival in various cancers, these cells have also been shown to drive CIP (32).

It is plausible that immune checkpoint blockade may lead to untargeted damage of healthy non-cancer-affected tissue within the lung. Helper T cell (Th) populations, particularly Th1 and Th17 activity, are instrumental in the initiation of cell-mediated immune responses leading to the downstream activation of inflammatory pathways. Case-control studies comparing BAL components in CIP and non-CIP patients have shown increased differentiation of CD4⁺ T helper cells into Th17 cells, a pro-inflammatory phenotype, and enrichment of CD8⁺ cytotoxic T cells with elevated cytotoxic features (20). Th17 cells play a crucial role in initiating immune responses by enhancing the trans-endothelial migration of immune cells into CIP-affected lung tissues (20).

Studies have consistently reported high levels of CD8⁺ T cells in BAL samples from patients experiencing acute CIP (13,14,17). One of the earliest BAL studies by Suresh et al. (19) suggested that CIP arises from a shift in balance between effector and inhibitory mechanisms within the tumour microenvironment, favouring a proinflammatory state. This was characterised by expansion of CD8⁺ T cell populations with increased IFN-γ and tumour necrosis factor (TNF) pathway activity, along with upregulation of central memory T cells (Tcm) and interleukin (IL)-1β^high myeloid cell populations. Similar to findings in pulmonary conditions such as chronic obstructive pulmonary disease (COPD) and immune sequelae in coronavirus disease 2019 (COVID-19) (33-35), CD8⁺ T cells have been shown to be key effectors in immune-mediated damage in CIP. Additionally, mature T cells, such as Tcm, are known to be resistant to the effects of steroid-induced apoptosis, and therefore may be play a significant role in steroid-refractory CIP (36-38).

The role of cytokines and chemokines in driving CIP inflammatory pathways

Cytokine and immunomodulatory pathways are central to CIP pathogenesis, mirroring inflammatory processes seen in cytokine release syndrome, COVID-19 pneumonitis, and acute respiratory distress syndrome. IL-6 has been implicated in the development of CIP across multiple studies (13,14,19); however, its utility as a potential biomarker due to its lack of specificity, as it represents a downstream marker of inflammation in various disease states. Si et al. (17) analysed BAL samples and found no significant differences in IL-6 levels between patients with CIP and those with infection or progressive cancer.

IFN-γ-induced protein 10 (IP-10, or CXCL-10), a chemokine produced by monocytes and endothelial cells, plays a key role in recruiting monocytes, macrophages, T cells, NK cells, and DCs, while also enhancing T cell adhesion to endothelial cells. In the Si et al. study (17), CXCL-10 levels were elevated in CIP patients compared to those with infection or progressive lung cancer disease groups. Kowalski et al. (14) further demonstrated significantly increased levels of IL-17A and IFN-γ in BAL samples from CIP patients compared to lung cancer and ILD controls. Several inflammatory pathways, including IFN-α, IFN-γ, TNF-α, and FasL, contain multiple potential junctures susceptible to dysregulation due to ICI-induced remodelling of the immune system (14,17,19,21). As such, identifying cytokines specific to CIP-driven inflammation remains a key focus of ongoing and future research.

Future directions and advancing clinical care

Identifying biomarkers specific to CIP-driven inflammation remains a challenge. However, the strategic integration of cellular and cytokine profiling with radiological and clinical assessments may pave the way for precise diagnostic and disease management strategies. High-resolution chest tomography has revolutionised ILD diagnosis, in some cases eliminating the need for tissue biopsies. However, diagnosis and management in such cases require a multidisciplinary consensus involving respiratory and radiology specialists. Similarly, a multidisciplinary approach that includes oncologists, pulmonologists, and radiologists has been heralded as a way forward to optimise patient outcomes and reduce CIP-associated morbidity and mortality (7).

Despite the challenges in diagnosing CIP, BAL analysis remains a valuable tool for both diagnosis and prognosis. While lymphocyte proportions have historically served as a broad indicator of the immune response in CIP, more detailed analyses of cellular populations, cytokines, and chemokines could facilitate more precise and informative diagnostic approaches. Improved understanding of the drivers of CIP may also facilitate targeted treatment adjustments and enhance predictive modelling of CIP disease progression.

As previously discussed, the tumour microenvironment may impact a patient’s risk of developing CIP. Bronchoscopy, commonly used in lung cancer diagnosis, provides an opportunity to collect BAL samples at baseline before initiating ICI. Longitudinal comparisons of immune profiles from baseline to acute CIP presentation could improve our understanding of CIP and aid in identifying predictive biomarkers. In this regard, early stratification of high-risk patients may allow for closer monitoring and tailored dosing regimens to prevent treatment interruption and mitigate a patient’s risk of developing CIP.

There has also been growing interest in the lung microbiome’s impact on both lung cancer and ICI effectiveness (29). BAL samples provide a valuable resource for studying the microbial landscape within lung tissue, though the relationship between the microbiome, ICI therapy, and CIP remains poorly understood (39). Yu et al. (40) analysed BAL samples from patients with CIP and IPF, identifying Proteobacteria as the dominant phylum in both groups. Additionally, Vibrio and Halomonas species strongly correlated with lymphocyte activity. The study further demonstrated that laurocylcarnitine, a metabolite associated with these species, significantly influenced IFN-γ and TNF-α production by human CD4⁺ and CD8⁺ T cells in vitro. These findings highlight the need for further research into microbiome-immune interactions and their role in CIP pathogenesis.

Conclusions

BAL fluid remains a highly valuable biospecimen in the diagnosis and management of CIP, offering a detailed understanding of the CIP microenvironment, as depicted in several studies over the last decade. However, its value in clinical practice has not been fully realised due to the lack of meaningful CIP diagnostic and predictive biomarkers. The clinical window for performing a BAL is narrow, making it challenging to establish clinical equipoise on the optimal timing for obtaining BAL samples in practice. This narrative review is subject to some limitations. Firstly, the literature search identified only a limited number of relevant studies describing BAL findings in CIP patients. Secondly, the included studies often had small sample sizes and, in some cases, lacked appropriate control cohorts, thereby limiting the strength of any conclusions that could be drawn from the findings presented. Future research aimed at identifying reliable and reproducible biomarkers for the diagnosis and management of CIP will be crucial for advancing clinical practice.

Acknowledgments

The authors acknowledge the University of Melbourne Library for their assistance in performing the literature search

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-430/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-430/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-430/coif). N.S.L.G. received conference support from Chiesi and served as Chair of Centre for Research Excellence-Pulmonary Fibrosis (CRE-PF) group. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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