Clinical diagnosis
Case 197
【Progress】
He was given anti-fungal medicine which induced to improve patient’s symptoms and to disappear ground opacity on chest CT.
【Discussion】
In human respiratory tract, there should be various battles between pathogen and immune system. Defense line cells are generally larger than pathogen. As pathogen, virus, mycoplasma, bacteria and fungus are listed. Their sizes are; influenza virus 0.1µm; mycoplasma 0.3µm; Tb bacillus 1µm; pneumococcus 1µm; E coli 3-5µm: pneumocystis jirovecii 7µm, tumor cells 10-30µm (1). Meanwhile, As defense line cells, their sizes are; macrophage 20µm, neutrophil 15µm, lymphocyte (killer T cell) 10µm. The first line cells engulf these pathogens. The digestive antigens are transmitted to T cell and B cell, inducing production of antibody, IgG as the third line defense, adaptative immune.
Opdivo is antibody for one of the immune check-point markers at the surface of T cell. T cell gets signals such as cytokine from other immune cells and changes how to act according to the signals which are accepted from check-point markers: activation or inactivation. T cell activates to attack organisms or tumors as second line defense and/or third line defense. However, Activated T cells are double-edged swords to give damages to self-tissues as well as enemies. Then, T cell has checkpoints for activation and inactivation. When tumor appears our body, dendrite cells recognize the tumor, get the tumor antigen, and transmit to the message to T cell. Thereafter, T cell activates and attacks tumor cells. Tumor cells look for the weak point of T cell and finds a check-point marker to inactivate T cell, called PD-1 (programmed cell death 1). Tumor produce to check point marker (Ligand) for inactivation of T cell called PD-L1. When, PD-1 of T cell is bound with PD-L1 by tumor cell, T cell falls into inactivation, inducing proliferation of tumor cells. Opdivo works to both PD-1 and PD-1L, to release the connection of this bind and leading to activation of T cell.
The continuation of T cell activation induces to injure self-tissue itself, immune-related adverse events. Opdivo-induced pneumonitis is one of the immune-related adverse events. Chest CT demonstrates radiologic patterns of HS (hypersensitivity), AIP (acute interstitial pneumonia), COP (cryptogenic organizing pneumonia) and/or NSIP (non-specific interstitial pneumonia) (2, 3). Peritumoral infiltration is specific for Opdivo-induced pneumonitis (2, 3).
Pneumocystis jirovecii pneumonia (PJP) infects human from the birth with 100%, might be called normal flora. Pneumocystis jirovecii (PJ) was once thought to be parasite (protozoa) but now identified to be one of the fungus. The size of PJ dwells dormant in respiratory tract and its size is approximately 7 µm almost the same as red blood cell. Immune system does not attack to PJ, then PJ living as dormant probably under control of lymphocytes. However, the decrease of lymphocyte count induces activation and proliferation of PJ. Steroid administration induces the decrease of lymphocyte count and block neutrophils to move to extra-vessel spaces, leading to abate inflammation. As reduce of steroid doses, neutrophils acquire the ability to penetrate vessel to respiratory tract. Associated with that lymphocytes count decreases which might imply the situation of neutrophils taking place on the role of lymphocytes, neutrophils respond PJ in the alveolar spaces and secrete proinflammatory cytokines for elimination of PJ as well as alveolar damages, inducing interstitial pneumonitis to ARDS (4). Chest CT demonstrate ground glass opacity in the early stage of PJP, gland glass opacity + consolidation in the middle stage and diffuse consolidation (alveolar damage) associated with ARDS in the final stage (5-8). This finding might reflect the degree of neutrophils involvement.
In our case, he was given Opdivo for advanced gastric cancer. Chest CT showed cloud-like (ground glass) opacity which was first considered to be due to drug induced pneumonitis. But he was also administered steroid. Laboratory test revealed decrease of lymphocyte counts and high level of D-glucan values, implying fungus infection. Then, anti-fungus treatment was conducted, leading disappearance of ground glass opacity.
【Summary】
We present a seventy seven-year-old male suffering from persistent fever 37.6 to 38.3℃. He was prescribed Opzivo and steroid therapy for metastatic lung tumors from advanced gastric cancer because chemotherapy was not effective for the metastatic tumor. Follow-up chest CT showed ground glass opacity in the bilateral lung although tumor regression was obtained. Laboratory test revealed β-D glucan 1470 pg/mL, implying fungus infection. He was administered anti-fungal medicine, leading to relieve his symptoms. It is borne in mind that Opdivo-induced pneumonitis arises by T cell activation which appears like AIP, HS COP and NISP on chest CT. Peritumoral pneumonitis is specific for Opdivo-induced pneumonitis on chest CT. Meanwhile, PJP arises from occupation of PJ in the alveolar lumen and septum which appears cloud-like appearance in the early stage, ground glass and consolidation in the middle stage and diffuse consolidation (alveolar damage) associated with ARDS in the advanced stage.
【References】
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2020.7.8