A case of pulmonary tuberculosis that developed during nivolumab and ipilimumab treatment for pulmonary adenocarcinoma that recurred two months after completion of anti-tuberculous treatment

Introduction

Immune checkpoint inhibitors (ICIs) have become key agents in the treatment of non-small cell lung cancer worldwide. However, immune-related adverse events (irAEs) must be addressed to maximize the efficacy of ICIs (1). Mycobacterium tuberculosis (Mtb) infection is considered as a type of irAE associated with ICIs, but the underlying mechanism is not completely understood (2). Here, we present a case of pulmonary tuberculosis (TB) that developed during administration of nivolumab and ipilimumab for pulmonary adenocarcinoma that recurred just 2 months after completion of anti-TB treatment. We present this case in accordance with the CARE reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-23-153/rc).

Case presentation

A 67-year-old Asian man was referred to our hospital for chemotherapy. He was a former smoker and had been diagnosed with stage IVA (cT4N1M1a) lung adenocarcinoma. A Quantiferon-TB Gold Test (Qiagen, Venlo, the Netherlands) as an interferon-gamma release assay (IGRA) showed positivity at the start of initial treatment, which comprised six cycles of carboplatin and nab-paclitaxel. Bronchoscopy was performed to identify any driver mutations in the carcinoma upon recurrence of pulmonary adenocarcinoma. The sputum sample obtained during bronchoscopy showed no signs of Mtb growth. Second-line treatment with four cycles of carboplatin and pemetrexed was then administered until disease progression.

The patient then commenced third-line therapy with nivolumab and ipilimumab (Figure 1A). A month later, he developed productive cough and chest X-ray showed a cavitary lesion near the primary tumor (Figure 1B). Three weeks later, Mtb complex was cultured from sputum samples. No resistance to anti-TB drugs was detected. Treatment for TB comprised 2 months of isoniazid, rifampicin, pyrazinamide, and ethambutol, followed by 7 months of isoniazid, rifampicin (2HREZ + 7HR) with a 2-month interruption of nivolumab and ipilimumab. Three months into the anti-TB treatment, sputum cultures turned negative and remained negative for at least 1 month before completing the anti-TB regimen (Figure 2).

Figure 1 Imaging findings. Chest X-ray just before immunotherapy with ipilimumab and nivolumab (A). A residual tumor shadow is observed in the right upper lobe. Chest X-ray at first onset of pulmonary tuberculosis (B). A cavitary lesion is observed near the tumor.

Figure 2 Clinical course. NIVO, nivolumab; IPI, ipilimumab; S-1, tegafur/gimeracil/oteracil; INH, isoniazid; RFP, rifampicin; EB, ethambutol; PZA, pyrazinamide; SM, streptomycin; LVFX, levofloxacin; mPSL, methylprednisolone; PSL, prednisolone.

Five months after starting nivolumab and ipilimumab treatment, an infiltrative shadow became apparent in the left lung without any TB growth detected in sputum. Steroid pulse therapy was initiated with methylprednisolone at 500 mg/day for 3 days, followed by a maintenance dose of 20 mg/day of prednisolone for immune-related pneumonia induced by nivolumab and ipilimumab. Infiltrative shadows in the lung vanished shortly after starting steroid treatment. After ending 10 months of nivolumab and ipilimumab treatment due to an increase in the size of pulmonary metastasis, representing disease progression, he received one dose of docetaxel as a fourth-line therapy, followed by fifth-line therapy with S-1 at 100 mg/day for 14 days every 28 days.

Two months after completing anti-TB treatment during fifth-line therapy with S-1, the patient was hospitalized due to loss of appetite and disturbance of consciousness. Imaging revealed diffuse infiltration in the lingular segment and lower lobe of the left lung, along with the known cavitary lesion in the upper lobe of the right lung (Figure 3). He received empirical treatment with ceftriaxone sodium, followed by piperacillin-tazobactam. On admission, a sputum smear showed positive results for acid-fast bacilli with positive results from polymerase chain reaction for Mtb. The patient was subsequently transferred to another hospital for TB treatment. Two weeks later, sputum culture again showed positivity for Mtb, without any drug resistance. Using the variable number of tandem repeats (VNTR) test, the series of strains were confirmed to be identical.

Figure 3 Imaging findings. X-ray (A) and computed tomography (B) of the chest at the second onset of pulmonary tuberculosis. Diffuse infiltration is observed in the left lung. No marked changes to the cavitary lesion are demonstrated.

Treatments for recurrent pulmonary TB included isoniazid, rifampicin, levofloxacin, and streptomycin. However, even though the sputum culture turned negative after 2 months of anti-TB treatment, the patient died 8 months after recurrence of TB due to respiratory failure caused by lung cancer and the sequelae of pulmonary TB.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

With the increased use of ICIs, the number of case reports concerning Mtb infection or reactivation associated with ICI treatment has been escalating. However, whether the incidence of TB is increased with the use of ICIs remains contentious. Liu et al. demonstrated a significantly heightened risk of TB reactivation with the clinical use of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors, representing a risk 35 times higher than that in the general population (2). In addition, a high mortality rate has been attributed to active TB disease in patients undergoing PD-1/PD-L1 blockade therapy (2). On the other hand, Kim et al. reported that additional treatment with ICI did not increase the risk of TB in patients with advanced non-small cell lung cancer who underwent cytotoxic chemotherapy (3).

Mtb infection is considered one kind of irAE caused by ICIs. Both acute and reactivated TB have been reported in patients during treatment with ICI (4,5). However, the mechanisms underlying TB reactivation with ICI use are not completely understood. A hypersensitivity response similar to immune reconstitution inflammatory syndrome has been considered responsible. Significantly higher production of T-cell-derived cytokines was observed in PD-1-deficient animals. This might be suggested as one of the mechanisms contributing to higher Mtb bacterial growth and disease progression in PD-1-deficient animals (6). Moreover, Kauffman et al. found that PD-1 blockade drove higher levels of inflammation and increased bacterial loads from pulmonary granulomas in rhesus macaques (7). Elkington et al. showed that PD-L1 is highly expressed in normal TB granulomas, while PD-1 colocalizes with CD8, demonstrating that immune checkpoint ligands and receptors are co-expressed. On the other hand, under anti-PD-1 therapy, expression of PD-L1 and CD8 is observed within granulomas, while PD-1 immunoreactivity appears reduced, so the immune checkpoint inhibition pathway is active within TB granulomas (8).

Elkington et al. hypothesized that a rapid, T-cell-driven immune activation could lead to greater recruitment of monocytes or neutrophils to TB granulomas, which may result in increased cytotoxicity or matrix metalloproteinase-driven destruction of the extracellular matrix, which favors Mtb growth and leads to transmission of infection (9).

Lin et al. very clearly illustrated the mechanisms involved in switching from latent TB (LTB) infection to active TB infection with ICI use. When TB granulomas are formed, the body presents LTB infection (LTBI), as increased expression of PD-1 inducing the apoptosis of T cells. Conversely, ICIs can block PD-1, restore lymphocyte function and induce excessive inflammatory cells and cytokines that destroy the extracellular matrix, creating conditions conducive to the growth of Mtb and allowing active TB infection (10). Currently, TB reactivation is thought to be one of ITI-DI (immunotherapy infections due to dysregulated immunity) (11).

No previous case reports have demonstrated the recurrence of Mtb regardless of whether immunotherapy was discontinued or continued. In contrast, 2 of 23 cases of TB infection following ICI use died of TB-related complications (10). Given these facts, whether we should resume ICI treatment for patients with TB induced by ICI may be contentious. In our patient, given the improvement in TB-related signs and symptoms following TB treatment and the observed anti-tumor effects during nivolumab and ipilimumab treatment, administration of nivolumab and ipilimumab was resumed. However, our patient showed recurrence of TB only 2 months after completion of anti-tuberculous treatment. The genotypes of Mtb obtained from the second incidence were demonstrated to be consistent with the first one using VNTR analysis, although he had been receiving anti-TB therapy for a sufficient duration. Considering the clinical course of our patient, immunotherapy may need to be discontinued for patients with TB induced by ICI treatment, especially when ipilimumab or nivolumab is used.

Our patient was in an immunosuppressed state due to lung cancer and steroid use, but the use of anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and anti-PD-1 antibody may have also played important roles in TB recurrence. As for anti-CTLA-4 antibody, the incidence of pulmonary TB is rarely reported. Lin et al. reported that ICIs leading to TB involved a PD-1 inhibitor in all cases, with no cases of TB disease found during treatment with anti-CTLA-4 inhibitors (10). However, anti-CTLA-4 inhibitor could activate more T-cell clones with various epitopes against Mtb antigen in the priming phase of the immune cycle. A stronger response against Mtb followed by anti-CTLA-4 and anti-PD-1 antibody administration seems quite natural if the patient has LTB. One possible reason for the small number of patients showing TB following administration of anti-CTLA4 antibody could be that opportunities for anti-CTLA-4 antibody use are limited in non-TB-epidemic areas, or the frequency of anti-CTLA-4 antibody use itself is much lower than those of anti-PD-L1 or anti-PD-1 antibodies.

Screening for latent Mtb is not routinely performed before the use of ICIs, although a risk of Mtb has been reported (12). Recently, serial IGRA testing has been reported as a useful tool to assess the risk of developing active TB during ICI therapy (13). Patients with LTBI who are at an increased risk of TB recurrence should be treated for LTBI, but use of ICIs could cause a higher frequency of irAEs, or drug-induced organ damage. Moreover, the optimal duration of anti-TB treatment for LTB during ICI treatment has not yet been established. A pharmacodynamic study of nivolumab has indicated sustained occupancy of PD-1 molecules on circulating T cells for 2–3 months following infusion (14). TB recurrence could therefore be easily induced even after completing treatment for TB, as long as the influence of ICIs continues. Given this, 6 months of anti-TB therapy may not have been sufficient for patients administered ICIs.

The limitation of this report is that this situation was derived only from one patient. Further reports of similar cases might provide more robust evidence.

Conclusions

This represents the first report of pulmonary TB that developed during nivolumab and ipilimumab treatment, and recurred 2 months after completing anti-TB treatment. Physicians should always be mindful of the potential development and recurrence of TB following the use of ICI, especially in patients showing positive results from an IGRA.

Acknowledgments

We are deeply grateful to the Chiba Prefectural Institute of Public Health for providing results from VNTR. We also would like to express our deep gratitude to Dr. Hidenori Masuyama and Dr. Koji Kiyofuji from the International University of Health and Welfare Ichikawa Hospital for their invaluable contributions to the treatment of our patients.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-23-153/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-23-153/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-23-153/coif). The 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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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