Tuberculosis Following PD-1 Inhibitor in A Patient with Non-Small Cell Lung Cancer; A Case Report & Literature Review

Immune checkpoint inhibitors (ICIs) – anti-programmed death-1 (PD-1) and their ligands (PD-L1 and PD-L2) have become widely used in the treatment of several malignancies. Many immune-related adverse events have been linked to these agents. However, tuberculosis (TB) reactivation during their use is increasingly reported. Herein, we present a 58-year-old lady with advanced non-small cell lung cancer (NSCLC) ALK-negative, EGFR wild, and PD-L1 Immune histochemistry (IHC) strongly positive in 95% of tumor cells. The patient presented with high-grade fever and a history of productive cough for a 1-week duration. A few days later, she was diagnosed with pulmonary tuberculosis following the 6th cycle of Pembrolizumab, an anti-PD-1 monoclonal antibody. AFB smear and TB PCR from BAL were positive (rifampin resistance not detected), and she was accordingly started on Anti-TB medications. Immunotherapy was held. Of note, the patient had a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status is negative. Her sputum AFB smear continued to be positive after four weeks of anti-TB medications. Later, the patient was discharged after her sputum was cleared from AFB (negative x 2 sets). We assumed that our patient developed reactivation of pulmonary tuberculosis secondary to an immune checkpoint inhibitor (Pembrolizumab). She was not re-challenged with Pembrolizumab following TB diagnosis.


Background
Immune checkpoint inhibitors (ICIs) are a type of cancer immunotherapy that has provided a tremendous breakthrough in the field of oncology 1 . They block specific proteins made by immune system cells, particularly T cells and some cancer cells, which in turn boost the immune system to kill cancer cells better 2 . Currently approved checkpoint inhibitors target the molecules cytotoxic Tlymphocyte-associated protein 4 (CTLA4), Programmed death receptor -1 (PD-1), and Programmed death-ligand 1(PD-L1).
Recognition of cancer cells by the toxic T lymphocytes plays an essential role in the malignant cell killing. Cancer cells may scape this process by expressing programmed death-ligand 1 (PD-L1), which binds to the programmed death receptor-1 (PD-1) on T cells surface 3 . This interaction (PD-L1/PD-1) leads to inhibition of cytokines and T cells proliferation, and eventually, cancer cells will escape the killing process. So, blocking (PD-L1/PD-1) pathway by immunotherapy becomes imminent in cancer treatment 4 . Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 13 May 2020 doi:10.20944/preprints202005.0220.v1 The role of ICIs has been studied in infectious diseases as well 5 .Various human studies & animal models suggest that immune system activated by PD-1/PD-L1 blockade is effective in targeting certain viral, bacterial and fungal pathogens by limiting T cells dysfunction 5 .
Nonetheless, in sharp contrast with other pathogens that cause chronic infection, accumulating reports demonstrate the occurrence of Mycobacterium Tuberculosis (MTB) infection during immunotherapy with ICIs even without prior immunosuppression 6 .
Herein, we present a patient with advanced non-small cell lung cancer (NSCLC) who developed pulmonary tuberculosis following treatment with Pembrolizumab, an anti-PD-1 monoclonal antibody.

Case presentation:
A 58-year-old female patient, with 20 pack-year smoking history, and type 2 Diabetes Mellitus for two years. In 2015, an incidental right apical lung mass suggestive of Pancoast tumor was seen in chest CT ( Figure 1 a & b) following abnormal chest X-ray. The patient refused further investigations at the time. In August 2018, she was admitted to Hamad General Hospital (HGH) with sepsis secondary to acute cholecystitis.  Immunohistochemistry (IHC) report was strongly positive for PD-L1 in 95% of the tumor cells ( Figure  3A &B), negative ALK gene rearrangement , and no EGFR mutation was detected.   She was treated with antibiotics as community-acquired pneumonia; however, she continued to spike fever. The initial microbiological workup was negative. Bronchoscopy and bronchoalveolar lavage (BAL) on 5th August 2019 showed positive AFB smear and TB PCR (rifampin resistance not detected). On 6th August 2019, she was started on anti TB medications (RIFA four. Further history revealed that she had sick contact with active TB patient ten years ago, but there was no documentation of latent TB or previous TB infection. Her HIV status was negative. Sputum AFB smear found positive and cleared six weeks following anti TB medications. On 23rd August 2019, chest X-ray showed new bilateral reticular, and nodular pulmonary infiltrates (figure 7).  PET CT on 22nd December 2019 (following four cycles) showed Good therapeutic response with near-complete remission of lung, liver, spleen, and lymph nodal involvements (Figure 9).
The patient remains on chemotherapy and anti TB medications for a proposed 9-month duration.

Discussion:
TB reactivation is an established adverse effect in many cancers' biological agents, especially with TNF-α inhibitors 7,8 . The incidence of TB reactivation in cancer patients is higher in hematological malignancies compared to solid tumors; among solid tumors, the highest incidence was showed in lung cancer followed by gastric cancer, breast cancer, liver cancer, and colon cancer respectively 9 .
With the expanding use of immune checkpoint inhibitors for the management of cancer, infectious complications of immune checkpoint inhibitors became an emerging adverse effect of these agents, including TB reactivation 10 .
The majority of patients infected with tuberculosis will develop a latency state where no signs of disease, up to ten percent of those patients may develop active tuberculosis infection 11 . Containments of the infection is mediated by cytokines and the interaction between macrophages and T lymphocytes (CD4 and CD8) 12 . Immunocompromised status is one of the most critical risk factors for reactivation including, HIV, organ transplanted patients, and patients receiving immunosuppressive therapy 13 .
The exact mechanism of TB reactivation following treatment with these agents remains not clearly understood. However, few preclinical studies in MTB infected PD-1-deficient mice & PD-1 blocked humans describe an increase in the IFN-α production by CD4 T cells which promote more bacterial replication and tissue destruction 6,14,15 .
Furthermore, the role of (PD-L1/PD-1) pathway has been studied also to demonstrate its effect on M. tuberculosis infection; In mice model, PD-1 deficiency showed significant sensitivity to M. tuberculosis infection and high bacillary load after exposure to aerosol infection with M. tuberculosis. PD-1 deficient mice also showed dramatic survival reduction and lung tissue was found to be severely necrotic and inflamed in comparison to the control mice 16 . On the other hand, the data about (PD-L1/PD-1) pathway role in the cytolytic activity of T lymphocytes in the human being is more contradictory 17 . However, multiple reports highlighted the reactivation of pulmonary tuberculosis infection after the use of PD-1 inhibitors 10,15,18-26 .
ICIs associated MTB infection was extensively searched by expediting all the reported cases through PubMed up to September 2019, with no language restriction applied. In general, 14 reported cases were identified retrieved from 11 articles 10,15,[18][19][20][21][22][23][24][25][26] ,in addition to our case ( In all patients, no latent TB testing (LTBT) before immunotherapy was done, and it was not clear whether TB infection is primary or secondary to latent TB reactivation. TB was microbiologically confirmed in all cases and followed by anti-TB drugs initiation. ICIs were maintained in three cases and discontinued or temporarily suspended in the remaining patients.
The time to diagnosis of TB in the current case occurred after six cycles of Pembrolizumab. TB was confirmed microbiologically by PCR and AFB. Our case gave a history of sick contact with a patient with active TB infection ten years ago, but there was no documentation of latent TB or previous TB infection.
To our knowledge, this is the first reported case from the Arab and the Middle East; it reinforces the previous observations of the association between ICIs administration and the development of MTB. Nevertheless, further studies in the clinical setting are necessary to establish the exact mechanism involved in this association. Oncologists' awareness & prompt recognition of this potential hazardous consequence are essential. Since there is no clear evidence whether LTBT prior PD-1/PD targeted immunotherapy is required, targeted LTBT before starting ICIs immunotherapy with TB chemoprophylaxis; yet to be explored, particularly in the regions where the MTB prevalence is high.

Ethics approval and consent to participate
The case report was approved the Medical Research Centre at Hamad Medical Corporation and the Hamad Institutional Review Board (IRB) under number MRC-04-20-095.

Consent for publication
This case report does not contain any personal identifier of the patient [such as name, photograph … etc.]. It only includes radiological and pathological imaging, which does not contain any identifications. A written patient informed consent of patient information, images and publication was signed by the patient.

Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.