Development of Mycobacterium avium Complex Lung Disease in Patients With Lung Cancer on Immune Checkpoint Inhibitors.

Immunotherapy with immune checkpoint inhibitors (ICIs), while ameliorating lung cancer, can cause infectious diseases, including tuberculosis, in addition to immune-related noninfectious complications. In the clinical setting, the efficacy of ICIs to treat mycobacterial infection remains controversial. We report 3 cases of acute Mycobacterium avium complex lung disease during immunotherapy with ICIs.

Recent advances in immunotherapy with immune checkpoint inhibitors have improved the outcomes of patients with lung cancer [1, 2]. Although immune checkpoint inhibitors manifest drastic effects, unique adverse events, including skin rash, hepatotoxicity, and endocrine disturbances, are known to occur during treatment. These events are termed immune-related adverse events (irAEs). Among the several types of irAEs, cases of infectious diseases have been increasing steadily [3]. The threat of mycobacterial infection has been particularly alarming because of multiple reported cases [4-7].

We experienced 3 cases of acute development of Mycobacterium avium complex lung disease (MAC-LD) in patients with lung cancer on immune checkpoint inhibitors. These may emerge as thought-provoking cases.

CASE PRESENTATION AND SUMMARY

Case 1

A 66-year-old woman underwent surgical resection of right lower-lobe lung adenocarcinoma. Her adenocarcinoma recurred after 12 years. Computed tomography (CT) images acquired at that time showed no bronchiectasis or nodules in the bilateral lobes. She received 60-Gy stereotactic radiotherapy. On disease progression, she received 1 cycle of combined carboplatin and pemetrexed as initial therapy. Because of adverse events, her chemotherapy regimen was revised to gemcitabine. However, her disease progressed. She received nivolumab as the third-line therapy. After 15 cycles of nivolumab, she developed wet cough with excessive sputum. CT images showed infiltration in the upper left lung lobe and lingula. Two consecutive sputum cultures were positive for Mycobacterium intracellulare at the 17th cycle of nivolumab therapy. A diagnosis of MAC-LD was established, and specific treatment for MAC was initiated along with continued nivolumab therapy.

Case 2

An 80-year-old man was diagnosed with stage 3a right upper lobe non–small cell lung cancer by bronchoscopy. Although lung cancer was diagnosed, CT images only showed bilateral emphysema but no bronchiectasis or nodules. Sequential chemoradiotherapy was initiated. He received 1 cycle of combined carboplatin and nanoparticle albumin–bound paclitaxel (nabPTX) therapy, followed by radiotherapy (66 Gy). He attained 3 years of progression-free survival. However, the cancer recurred in the form of a single brain metastasis and multiple lower left nodules. He underwent gamma knife therapy for brain metastasis and was initiated on second-line systemic immunotherapy with atezolizumab. At the 23rd cycle of atezolizumab therapy, he developed wet cough and excessive sputum production. CT images revealed multiple reticulonodular infiltrates in the lower left lung lobe. Two consecutive sputum cultures at the 24th cycle of atezolizumab were positive for M. avium and M. intracellulare. He was diagnosed with MAC-LD; specific treatment was initiated for MAC alongside the atezolizumab therapy.

Case 3

A 66-year-old man was diagnosed with stage 4a advanced squamous cell carcinoma of the right upper lung lobe. Although lung cancer was diagnosed, CT images showed bilateral emphysemas but no bronchiectasis or nodules. He received initial therapy with 6 cycles of combined carboplatin and nabPTX. However, tumor progression was confirmed after 3 months. Second-line therapy with nivolumab was initiated. However, disease progression was confirmed after 6 cycles of nivolumab therapy. As the third-line therapy, he received 7 cycles of docetaxel and, subsequently, fourth-line therapy with atezolizumab after docetaxel failure. Concomitantly, he experienced right main bronchus stenosis because of tumor progression, and palliative radiotherapy (37.5 Gy) was administered. CT images acquired during atezolizumab therapy revealed rapidly worsening right lower lobe infiltration. Two consecutive sputum cultures at the fourth cycle of atezolizumab therapy were positive for M. intracellulare, and a diagnosis of MAC-LD was established. However, because of severe debilitation, treatment for MAC-LD was not initiated and atezolizumab immunotherapy was discontinued.

Summary of Cases

Table 1 shows the summary of all 3 cases. In this study, CT images were retrospectively reviewed to assess possible changes of MAC-LD predating ICI immunotherapy. All patients had advanced lung cancer and received cytotoxic chemotherapy before treatment with ICIs. Moreover, they received thoracic radiotherapy before the pathogenesis of MAC-LD. ICI immunotherapy was continued in 2 patients after they were diagnosed with MAC-LD. The median time to MAC-LD diagnosis from induction of initial ICI (range) was 17 (17–19) months.

Table 1.

Characteristics of the Patients who Developed Mycobacterium avium Complex Lung Disease

	Case 1	Case 2	Case 3
Age at diagnosis of MAC, y	78	80	66
Sex	Female	Male	Male
Smoking status, pack-years	Never	45	20
Cavities/bronchiectasis before ICI	None	None	None
Histopathology	Adenocarcinoma	Not otherwise specified	Squamous cell carcinoma
Staging at diagnosis	Postoperative recurrence	cT1bN2M0; stage 3a	cT4N2M1a; stage 4a
Driver oncogene alteration	Wild-type	Wild-type	NE
PD-L1 expression	NE	NE	<1%
Type of ICI	Nivolumab	Atezolizumab	Nivolumab + atezolizumab
Infected MAC strain	M. intracellulare	M. avium + M. intracellulare	M. intracellulare
Time to MAC-LD diagnosis,a mo	17	17	19b
Cycles of ICI, No.	38	24	6 (nivolumab) + 4 (atezolizumab)
Prior radiotherapy	60 Gy	60 Gy	37.5 Gy
Prior chemotherapy
1st-line	Carboplatin + pemetrexed	Carboplatin + nabPTX	Carboplatin + nabPTX
2nd-line	Gemcitabine	-	Nivolumab
3rd-line	-	-	Docetaxel
Response to MAC treatment	Good	Fair	No medication

Abbreviations: ICI, immune checkpoint inhibitor; MAC, Mycobacterium avium complex; nabPTX, nanoparticle albumin-bound paclitaxel; NE, not evaluated; PD-L1, programmed cell death–ligand 1.

aTime from initiation of immune checkpoint inhibitor therapy to diagnosis of Mycobacterium avium complex lung disease.

bDuration included that of docetaxel treatment.

Discussion

We experienced 3 acute cases of MAC-LD during ICI immunotherapy. Previous reports indicate that development of tuberculosis during ICI immunotherapy has become an emerging concern [4-7]. Multiple cases of tuberculosis were suspected reactivation of latent infection. Some authors have suggested the development of tuberculosis to be similar to immune reconstitution inflammatory syndrome [4, 7]. A similar presentation is expected of nontuberculous mycobacterial infection; however, to date, no paper has reported the development of nontuberculous mycobacterial infection. In our 3 cases, no fibro-cavitary or reticulonodular shadow was noted that could indicate nontuberculous mycobacteria (NTM) infection at the initial diagnosis of lung cancer. Therefore, it is unclear whether MAC-LD developed from reactivation of existing disease or was a de novo infection.

Although the precise mechanisms underlying MAC-LD are unknown, anti-PD-1/PD-L1 antibodies are known to have possible antimicrobial effects that are mediated by upregulation of T-cell-mediated immunity [8]. A previous report suggested a favorable effect of nivolumab for the treatment of Mycobacterium abscessus lung disease [9]. Our present cases might partly reflect this paradoxical reaction, that is, overresponse to mycobacteria. In contrast, Barber et al. reported that PD-1/PD-L1 knockout mice displayed increased susceptibility to tuberculosis through enhanced CD4 T-cell-mediated tissue destruction [10]. In patients receiving ICIs, Barber et al. also discovered similar profiles for CD4 T-cell-, CD8 T-cell-, and T-cell-mediated cytokine dynamics [11]. These data suggested that Th1 function with anti-PD-1/PD-L1 antibodies might cause the development of tuberculosis. In actual clinical settings, treatment with anti-PD-1/PD-L1 antibodies is expected to show similar responses. Therefore, the effects of ICIs with regard to mycobacterial diseases in clinical setting remain controversial.

Alternatively, ICI immunotherapy might initiate a state of autoimmunity that mimics diseases like rheumatoid arthritis, which are known to be strongly associated with NTM-LD. Well-designed population-based studies are required to investigate such causal associations. Cumulative experience will reveal the complete picture. All of our patients had advanced-stage lung cancer and had received relatively long-term treatment, including cytotoxic chemotherapy; therefore, the influence of both the cancer and the treatment in the development of MAC-LD cannot be ignored. Furthermore, cytotoxic chemotherapy can exacerbate NTM disease [12]. Previous cytotoxic chemotherapy before induction of ICIs might favor the clinical outcome moderately.

The following alternate interpretation is also important. Japan has one of the highest burdens of NTM globally [13, 14]. Moreover, ICI immunotherapy is becoming popular in Japan. Therefore, physicians in places with a high burden of NTM should pay more attention to the development of MAC-LD during immunotherapy regimens with ICIs.

Conclusions

Physicians should be cautious toward the development of MAC-LD in patients on immunotherapy with ICIs, especially in countries such as Japan, which has a high burden of NTM.