Nontuberculous mycobacterial infections during cancer therapy with immune checkpoint inhibitors: a systematic review

Discussion

NTM infections occurring during immunotherapy with ICIs appear to be an acknowledged condition, with several cases identified in the literature. They are mainly due to MAC, involve primarily the lungs in patients with concomitant pulmonary neoplasia, occur on average 1 year after the start of ICIs treatment and are not associated with immunosuppressive treatment for the management of IRAEs. Apparently, this condition is more prevalent among patients from Eastern Asia, particularly Japan.

To the best of our knowledge, this is the first study depicting all the cases of NTM infection occurring during ICIs immunotherapy described in the literature. Based on the elaboration of data collected by the FAERS, the ROR for NTM infection is 5.49 among patients receiving PD-1/PD-L1 inhibitors, much higher than the ROR of 1.79 estimated for tuberculosis among the same population [7]. Therefore, the case reports we included are probably only the tip of the iceberg of NTM infections occurring during immunotherapy with ICIs, which probably are unrecognised or underreported. Overall, we did not identify any case of NTM infection among patients treated with inhibitors of CTLA-4 (ipilimumab), but only among those treated with anti-PD1 (nivolumab, pembrolizumab) or anti-PD-L1 (atezolizumab, durvalumab). Similarly to what has been reported for tuberculosis cases among patients receiving ICIs, NTM infections involved mainly the lung and were reported chiefly among patients with concomitant lung cancer, as expected considering both the therapeutic indications of ICIs and the lung as the main entry door of mycobacteria in the host [14].

The predominance of patients from Eastern Asia, and Japan, in particular, is not surprising, considering that prevalence rates of NTM-LD are among the highest worldwide in this area [15, 16]. Moreover, Japan has an economic status able to provide the global access to ICI for patients with tumours, thus allowing the occurrence in the same patient of two infrequent events: ICI immunotherapy and NTM infection. It is highly probable that reduced frequencies of NTM-LD during ICI therapy can be observed in other regions of the world characterised by a lower incidence of NTM infection. Moreover, considering the differences existing in terms of NTM species’ epidemiology, different microorganisms other than MAC can be found as predominant in other geographical settings.

The predominance of male patients is also of interest, which is unusual considering that normally females are more frequently affected by NTM-LD [17]. It should be considered how lung cancer, the reason justifying the employment of ICI, instead is much more common among male individuals in the Western-Pacific World Health Organization (WHO) Region (estimated age-standardised incidence rates in 2020 were 46.5/100 000 for males versus 21/100 000 for females), probably explaining this result [18].

It is finally worth to note that, according to the classification proposed by Morelli et al. [3], the NTM infections described in our review should be classified as immunotherapy infections due to dysregulated immunity. Indeed, none of the individuals included received a concomitant immunosuppressive treatment for an IRAE, and the clinical manifestations observed should probably be viewed as a “re-activated” immune system exerting an excessive and dysregulated immune response against the NTM encountered by the patient. This is a very relevant observation, considering that also in a case series of tuberculosis infections under ICIs only a few cases received concomitant corticosteroid administration [14]. Instead, infections with other agents were associated, even though not universally, with concomitant immunosuppressive therapy for IRAEs [1, 19].

Our study has some intrinsic limitations, being a collection of case reports with all the biases associated with this kind of study. Nonetheless, it is the first one collecting organically all the cases reported of NTM infections during ICIs immunotherapy. Considering the nature of the data collected, it is not possible to calculate the odds/risk ratio but only to describe the general clinical features of those developing the infection. Moreover, the patients identified are all from Eastern Asia, and therefore it is challenging to speculate on the transferability of these observations outside this specific geographical area.

As stated in the introduction, the possibility of having enhanced manifestations of mycobacterial infection during ICIs treatment was postulated early after the introduction of ICIs in therapy, based on the identification of mycobacteria-specific T-cells with a dysfunctional profile like that identified in neoplastic conditions. Therefore, in the cases we identified, it is possible to assume that the treatment with ICIs enhanced the immune response of NTM-specific T-lymphocytes against the mycobacteria encountered by the host during the immunochemotherapy, leading to more severe clinical manifestations and thus increasing the diagnostic rates. At least for two studies, we have the certainty of de novo infections; Baba et al. [10] described negative sputum culture before ICIs start whereas Yamaba et al. [8] did not highlight alterations compatible with NTM-LD at baseline computed tomography scan.

Acknowledging the increased risk of tuberculosis among patients receiving ICIs, evaluation of previous tuberculosis exposure, through tuberculin skin test or interferon-γ release assay, is a practice recommended by oncologic societies before treatment start to identify those subjects who may have a latent tuberculosis infection [20]. Moreover, a recent study has validated the usefulness of this test among patients receiving ICI as a tool to monitor for the development of active tuberculosis [21]. No similar tests are available for NTM, and these mycobacteria are not associated with the development of latent infection, making it hard to identify a priori those patients at higher risk of NTM infection. Therefore, particular care should be reserved for those patients developing infectious events under ICIs therapy, especially when involving the lung and when without microbiological results at commonly performed diagnostic tests or not responding to first line antimicrobial agents, because an NTM infection can be an overlooked cause of the infection. An infectious disease specialist or a pneumologist can be of support in these cases and should be involved in the clinical management of these patients.

Overall, the amount of data regarding the occurrence of NTM infection during ICIs immunotherapy is quite limited and based mainly on case reports. Further studies, such as cohort studies, are needed to understand organically the real incidence of NTM infections under ICIs, the associated risk factors and the relevance of this condition also in areas with a lower endemicity of NTM such as Western Europe or North America. This is of paramount importance considering both the increasing prevalence of NTM-LD in Western countries and the growing number of patients who are going to receive ICIs immunotherapy in the near future.