How to break immune-related pneumonia?

*Only for medical professionals to read and refer to the 15th case sharing of "Jinling Lung Cancer Network Forum" to learn about the entire process of the MDT team's precise diagnosis and precise treatment of CIP! Immunotherapy is an anti-cancer sharp edge, but the immune-related side effects caused by it have a special mechanism, which is significantly different from other treatment methods, which arouses the attention of clinicians.

In the Jinling Lung Cancer Network Forum, the immune-related adverse event (irAE) MDT team at the General Hospital of Tianjin Medical University brought a case of stage IIIB left lung squamous cell carcinoma with metastasis to the lock area, mediastinum, and hilar lymph nodes.
This case is immune-related.
After MDT consultation, CIP has clear diagnosis and precise treatment, which guarantees the follow-up anti-tumor.

Does CIP diagnosis require pathological testing? Does the diagnosis and differential diagnosis of irAE play an active role in the formulation of treatment plans? In the forum, the case was discussed around the diagnosis of CIP.

Basic information: He was diagnosed as a stage III unresectable male, 62 years old.
He developed a cough in August 2018 and gradually worsened.

The KPS score is 90 points.

He had a history of hypertension for 2 years, sinus bradycardia in November, and a history of smoking and drinking for 40 years.

Chest CT prompts: 1.
Left upper lobe bronchial stenosis with surrounding soft tissue masses, consider central type lung cancer; 2.
Left neck deep, posterior triangle, bilateral lock area, mediastinum around the trachea, right brachial vein, cavity There are multiple nodules in the posterior vein, adjacent to the aortic arch, main lung window, subcarina, left side of the middle esophagus, and bilateral hilum.
Lymph node metastasis should be considered.

The chest CT results of the admission were detected by bronchoscopy and pathological examination, suggesting that it was squamous cell carcinoma.
The preliminary diagnosis result was cT4N3M0 stage IIIB of left lung squamous cell carcinoma (metastasis in locked area, mediastinum, and lung lymph nodes).Treatment process: Progressed after concurrent radiotherapy and chemotherapy.
From May 9, 2018 to August 2018, the patient was treated with paclitaxel 240 alcohol 240 mg d1 + carboplatin 500 mg d1 for four cycles in the first line, and the efficacy was evaluated as partial remission (PR) , There are adverse reactions such as hair loss, fatigue, anorexia, and bone marrow suppression.

In September 2018, chest radiotherapy was applied to the patient.
The dose was 2.
1Gy*28f/58.
8Gy; PTV 1.
8Gy*28f/50.
4Gy; the curative effect was evaluated as PR, and there were no serious adverse reactions.

The patient was followed up for 6 months from September 2018 to March 2019.
CT showed that the left hilar mass of the patient gradually increased, and there was a small amount of pleural effusion.
A mass of about 2 cm in length was found on the patient’s abdominal wall.
The pathology showed metastatic squamous cell carcinoma, the curative effect was evaluated as disease progression (PD), and the progression-free survival (PFS) was 10 months.

CT result comparison chart At this time, the patient progressed after concurrent radiotherapy and chemotherapy.
In order to formulate a follow-up treatment plan, the patient was genetically tested and found that the expression of PD-L1 was 50%-60%, and the tumor mutation burden (TMB) was 15.
8 muts/mb , Suggesting that the patient may be benefited from immunotherapy.

Considering the retention of the posterior treatment strategy, no combination treatment plan was selected, and the treatment plan for the patient was determined as: pembrolizumab single-agent treatment.

Gene test results report pembrolizumab single-agent treatment CT results comparison chart CT from March to October 2019 shows that the effect of patients with pembrolizumab single-agent treatment is continuous PR, but the CT in January 2020 suggests The lungs gradually showed ground-glass shadow changes, and a realistic mass appeared in the lower lobe of the left lung.

The question is here: how to differentially diagnose whether the tumor is progressing? MDT started a heated discussion 1 Director of Imaging Department Su Datong: From the analysis of imaging, ground-glass shadows and solid masses are difficult to distinguish based on imaging alone.
The role of imaging is to reduce the size as much as possible in addition to the detection of lesions.
Differentiate the scope of diagnosis to assist the clinic in better exclusive diagnosis. Specifically for this case, when the chest CT was re-examined on January 8, multiple small consolidations, ground glass density shadows, and nodules with halo signs (halo nodules) were found in both lungs.
The soft tissue mass in the left lower lung was found On the thin layer, you can see the penetrating small blood vessels.
In this case, it is generally defined as a solid lesion, which can exist in infectious lesions and tumor lesions.

Considering that the patient is currently undergoing immunotherapy, his immunity is impaired to a certain extent, and multiple halo nodules can be seen in both lungs, so infectious lesions are prioritized.

On January 8th, the patient’s chest CT showed that the lymph nodes behind the phrenic angle and adjacent to the abdominal aorta were significantly larger than before, and the tumor is considered to have metastasized.

However, it is relatively rare for metastatic lesions in the lungs to have both consolidation and ground glass density and halo nodules, so this is regarded as a secondary diagnosis.

In addition, the possibility of CIP should also be considered.

Considering that it may also be an infectious disease, routine blood tests were performed on the patient, but it was found that the patient’s white blood cells were not high, the percentage of neutrophils was slightly higher, and the C-reactive protein was high but not obvious.
Bacterial infection The evidence is normal for procalcitonin, almost all antibodies to viral and atypical pathogen infections are negative, and the test for fungal infections is also negative, so other pathological factors should be considered.

Furthermore, considering the possible progression of tumors, tumor markers were also tested.

Since the patient is a patient with lung squamous cell carcinoma, the trend analysis of the two tumor markers of SCC and Cyfer21-1 shows that the tumor markers of the patient were high at the beginning, but showed a downward trend during the treatment process, and in January 2020 , The two tumor markers showed an increasing trend, and finally the tumor was pathologically punctured.

Tumor marker trend analysis chart.
The pathological report of pathological puncture shows: (lung biopsy) the specimen is peripheral lung tissue, interstitial acute and chronic inflammatory infiltration, alveolar type II epithelial cell hyperplasia, and cellulose exudate in some alveolar cavities Accompanied by organizing, fibroblast plugs are formed. Pulmonary puncture pathology report Figure 1 Pulmonary puncture pathology report Figure 2 Pulmonary puncture pathology report Figure 32 Director Yang Jing of the Pathology Department: Judging from the biopsy results, it can be seen from Figure 1 that the patient has mainly inflammatory changes.
It is not particularly serious inflammation, but it includes interstitial pneumonia and organizing pneumonia (COP).
From the left picture of Figure 1, it can be seen that the alveolar cavity still exists, and the alveolar space is slightly wider, and some alveolar cavities can be seen To a bit of consolidation, the red part in the right picture is the exuded fibrin and cellulose components, and the left picture already shows the organization and the presence of fibroblast plugs.

In Figure 2 with a higher multiple, you can see that the alveolar space in the left figure is slightly wider, there are more lymphocytes, and some plasma cells are infiltrated, showing typical changes in interstitial pneumonia.

On the right, you can see the exudation of red-stained fibrin.
Fibroblasts have begun to organize around fibrin.
This case is mainly characterized by interstitial pneumonia with organizing pneumonia.

Follow-up treatment: first use hormones to stabilize the condition, and then start immunotherapy with miraculous effects.
Combined with the comments of the director of the pathology department and the director of the imaging department and the patient's medication history, consider the scattered ground glass shadows in the patient’s lungs and the lower left The solid lung lesions were pneumonia caused by immunotherapy, so immunotherapy was discontinued and hormone therapy (prednisone 30 mg qd) was used.

From January to March 2020, the amount of hormones decreased during the two-month treatment period.

CT showed that the ground-glass shadow of the right upper lobe and the right lower lobe gradually decreased, and the solid nodules in the left lower lobe gradually relieved.

Comparison of CT results after using hormone therapy.
After two months of CIP treatment, the patient's tumor still exists.
Considering that the patients who have previously used immunotherapy have benefited significantly, it was decided in March 2020 to re-challenge the patient for immunotherapy.

The treatment plan is: Pembrolizumab 200mg d1 treatment.

During the two cycles of treatment from March to May 2020, it can be seen that CIP continues to improve, and the tumor progression is also in a relatively stable state.

Therefore, the treatment plan lasted for two more cycles.
CT showed increased pleural effusion and ground-glass shadows on the left lung.
Consider reappearing CIP.
At the same time, it was found that multiple lymph nodes throughout the body, including the neck and groin, were unconfirmed.
Disease progression (iuPD).

The CT results of immunotherapy suggest that the patient is confirmed disease progression (icPD) through pathological analysis.

In summary, this patient belongs to stage III unresectable lung cancer.
After standard treatment with radiotherapy and chemotherapy, the disease progressed, and immunotherapy was tried.

The first immunotherapy was discontinued due to CIP.
After MDT discussion, a follow-up treatment plan was formulated, and then immunotherapy was challenged to achieve more than 2 years of survival.

The treatment was discussed by experts ▌ Professor Chen Bi (Department of Respiratory and Critical Care Medicine, Xuzhou Medical University): The diagnosis of CIP in this patient is relatively accurate.
First of all, this patient has a relatively clear history of PD-1 inhibitor application, and secondly from the clinical symptoms.
Look at the lack of typical symptoms of infection, such as fever.

From the perspective of CT, the patient is sporadic air cavity consolidation.
The left lower lung consolidation shows partial bronchial inflation.
The results of percutaneous lung biopsy show that there is cellulose exudation and fibroblast infiltration in the alveolar cavity.
From the pathological point of view, it is consistent with the pathological manifestations of cellulosic organizing pneumonia (AFOP).

At the same time, after the first occurrence of CIP, the degree of damage to the patient's lung function may have an impact on the effect of the second challenge of immunotherapy.
It is hoped that the assessment of lung function can attract attention.

▌Professor Han Zhengxiang (Department of Oncology, Xuzhou Medical University): The PFS after the application of pembrolizumab for this patient reached 26 months, and the curative effect was still very good.
After the treatment, the patient developed inguinal lymph node metastasis.
After the biopsy, it is clear that it is icPD.
For the patient's next diagnosis and treatment, a second-generation sequencing (NGS) should be performed to find some targets for treatment. ▌ Professor Shen Qin (Department of Pathology, Jinling Hospital, Nanjing University School of Medicine): How to differentiate CIP pathologically from other inflammatory reactions caused by radiotherapy or other non-infectious lung inflammation? Is there a standard? Professor Shen mentioned that it is difficult to identify these inflammations pathologically, because most of these inflammations are non-specific inflammations.
The purpose of pathological testing is mainly to exclude specific infections, such as tuberculosis, fungi, and the presence or absence of tumors.
The performance of verification is diverse, and it is difficult to identify and distinguish.

▌ Professor Song Yong (Department of Respiratory and Critical Care Medicine, Jinling Hospital Affiliated to Nanjing University School of Medicine): This case is quite perfect from the collation of data and the process of diagnosis and treatment.
We can learn from it.
First of all, the treatment model of the MDT team The system guarantees the scientific treatment of such symptoms.
Second, I suggest that if there are serious complications or immune-related clinical problems, the success rate of transfer to the ICU may be higher.

For the treatment principle of CIP, the dose should be appropriately large in the initial treatment stage.
Sometimes we are too careful with hormones.
From 40mg to 80mg to 160mg at the beginning, I think the thinking should be reversed, and relatively large should be used at the beginning The dosage of serotonin will control the condition more quickly and the course of treatment may be shortened.

At the same time, do not reduce the dose too fast, as many patients have relapsed in the early stage.