Invasive Pulmonary Aspergillosis Complicated by Carbapenem-Resistant Pseudomonas aeruginosa Infection During Pembrolizumab Immunotherapy for Metastatic Lung Adenocarcinoma: Case Report and Review of the Literature

Abstract

The widespread use of T lymphocyte-associated antigen-4 (CTLA-4) and programmed death (PD)-1 and PD ligand-1 (PDL1)-targeted agents in cancer patients as immunotherapy has raised some issues on their safety profile. Regarding infectious complications, it has emerged that these compounds do not intrinsically increase susceptibility to opportunistic infections, which mainly correlate with the co-administration of systemic immunosuppressive therapy (high-dose corticosteroids and anti-tumor necrosis factors inhibitors) to cure immune-related adverse events (colitis, hepatitis, pneumonitis and pancreatitis), well-known complications of these targeted drugs. These observations lead experts' opinion to suggest primary anti-Pneumocystis prophylaxis in patients undergoing CTLA-4 and PD-1/PDL1 agents who will receive prednisone 20 mg daily for ≥ 4 weeks. Few data on invasive fungal infections in this context are available. We report here a case of probable invasive pulmonary aspergillosis (p-IPA) complicating first-line immunotherapy with pembrolizumab for metastatic lung cancer that was further aggravated by multidrug-resistant Pseudomonas aeruginosa superinfection of fungal cavities; the patient received concurrent systemic corticosteroid therapy as anti-edema treatment for cerebral metastases. Reviewing literature about Aspergillus diseases in subjects receiving CTLA-4 and PD-1 and PDL1-targeted agents, we found three cases of invasive aspergillosis and one case of exacerbation of chronic progressive pulmonary aspergillosis after nivolumab treatment; to the best of our knowledge, this is the first report of p-IPA complicating pembrolizumab immunotherapy. Briefly, in this new setting of biological/targeted drugs, waiting for growing clinical experience, we recommend a high level of alertness in diagnosing any infectious complications.

Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

“…Since different lymphocyte phenotypes are also correlated with different lymphocyte function, we first established an immune scoring model based on combination of the number, function and phenotype of lymphocytes to comprehensively assess host immunity. The imbalance of immunity leads to many immune-related diseases, such as autoimmune disease (hyperimmune status) [30] and opportunistic infection (hypoimmune status) [31][32][33][34][35][36]. The validation data from patients with different immune status showed that the model had high sensitivities in the determination of both hyperimmune and hypoimmune status.…”

Invasive Pulmonary Aspergillosis

“…Cases of IA have also been reported in pediatric patients with solid tumor with a very low incidence or prevalence. 73,74 Rare cases of IA have been reported in patients with solid tumor treated with targeted anticancer therapies: gefitinib (epidermal growth factor receptor tyrosine kinase inhibitor), 75 bevacizumab (antivascular endothelial growth factor monoclonal antibody), 76,77 pembrolizumab and nivolumab (anti-PD-1 receptor monoclonal antibody), 78,79 temsirolimus (inhibitor of m-TOR). 80 An acute progression of a chronic pulmonary aspergillosis has been observed in a patient receiving nivolumab.…”

Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment

“…As shown in Table 2, pembrolizumab-induced pneumonitis developed with variable intervals after treatment, ranging from 1 week to 2 years. [9–18] Pneumonitis occurred after diverse dose (median, 4 doses) of PD1 inhibitor treatment, ranging from 1 to 38 doses. [8] Regarding the risk factors for pembrolizumab-induced pneumonitis, little is known, but smoking, prior treatment, lung cancer, prior thoracic radiotherapy, and prior lung disease were suggested to promote pneumonitis development.…”

“…In the previous case reports, almost all cases were treated with steroid and more than 60% received antibiotics (Table 2). [9–18] However, descriptions of the accompanying infections were lacking (Table 2). According to the multicenter study, 60% (3 of 5) of the fatal cases had accompanying infections.…”