Xun Sun ,Bing Dai ,Liang Lei

1Laizhou Hospital of Traditional Chinese Medicine,Laizhou 261400,China.2Shandong University of Traditional Chinese Medicine,Laizhou 261400,China.

Abstract With the wide application of immunotherapy drug PD-1/PD-L1 inhibitor in China and the continuous clinical research,a major problem that we have to face is the immune-related pneumonia caused by PD-1/PD-L1.At present,western medicine mainly treated it by hormone therapy,which may cause side effects,such as obesity,osteoporosis and osteonecrosis for hormone therapy by long-term,and increase the patients' pain.Under the guidance of the theory of syndrome differentiation,traditional Chinese medicine (TCM) advocates the methods of expelling wind and clearing away cold,resolving phlegm and relieving asthma,relieving heat from lung,and invigorating the spleen and tonifying the kidney,etc.Exact differentiation of symptoms and rational usage of drugs can play an important role in the early prevention and treatment of immune-related pneumonia,reflecting the important role of TCM in the prevention and treatment of side effects of new drugs.In order to provide an effective clinical reference for clinicians in the practice of using PD-1/PD-L1,this paper systematically reviewed the use of TCM in the treatment of immune-related pneumonia induced by PD-1/PD-L1 inhibitors.

Keywords:PD-1/PD-L1 inhibitor,Immune-related pneumonia,TCM syndrome differentiation,Prevention and treatment

Background

With the increase of people's living pressure and the change of living habits and environment,the incidence of cancer is increasing year by year in China.According to the latest statistical data in 2019,the death rate of malignant tumor accounts for 23.91% of the total death cause of residents,and the incidence and death rate of malignant tumor have been rising continuously in recent ten years.The annual medical cost caused by malignant tumor exceeds 220 billion,and the prevention and control situation is grim.With the continuous improvement of medical technology,neoadjuvant chemotherapy and immunotherapy can improve the quality of life and survival time of patients to a certain extent.However,the side effects caused by new adjuvant therapy are still a problem for the first-line clinicians.In particular,the current immunotherapy drugs PD-1/PD-L1 inhibitors are widely used,resulting to the occurrence of immune-related pneumonia,which has become a major problem that clinicians have to face.Immune-related pneumonia is a kind of new infiltrative image of the chest after the treatment of immune checkpoint inhibitor in radiological examination,accompanied by dyspnea and/or other respiratory syndromes,such as cough and shortness of breath after activity [1].In addition,the diagnose of immune-related pneumonia should be excluded the new pulmonary infection or tumor progression.Although the incidence of immune-related pneumonia is not very high,the death rate is high.In western medicine,hormone therapy is the main treatment for this disease.Traditional Chinese medicine (TCM) has unique advantage in treating immune-related pneumonia,that is,early prevention and treatment of immune-related pneumonia can be implemented under the guidance of syndrome differentiation of TCM.

The understanding of immune-related pneumonia induced by PD-1/PD-L1 inhibitors in western medicine

The pathogenesis of immune-related pneumonia in western medicine

T cell plays a significant role in anti-tumor for PD-1/PD-L1 inhibitors,which can block the signaling pathway between tumor cells and T cells [2].The antigen-presenting cells or macrophages express PD-L1 in the normal tissue or inflammatory sites of the body [3].At the sometime,PD-L1 can combine with PD-1 on the surface of the effector T cells to inhibit the function of T cells in the normal or inflammatory tissue [4],in order to avoid over activation of inflammatory reaction or cause the damage of self-organization,playing the role of immune homeostasis.

However,the mechanism of western medicine of immune-related pneumonia caused by PD-1/PD-L1 inhibitors is not clear.Some studies argued that the occurrence of immune-related pneumonia factors may be related to the patient's gender,advanced age,smoking,basic pulmonary function decline,surgical operation of lung,radiation therapy of lung,experienced of cold pathogen induced internal drink and so on [5].Some medical experts reported that infiltration of lymphocytes,plasma cells and eosinophils can be found in lung biopsies of patients with nivolumab related pneumonia [6],meanwhile,a large number of macrophages can be found in the alveolar cavity when the lung biopsy tissues were stained with PD-L1 [7].Although it proofed the immune-related pneumonia may be related to immune response,the mechanism needs further research.

Susceptible factors of immune-related pneumonia

Previous studies shows that the total incidence of immune-related pneumonia caused by PD-1/PD-L1 inhibitors is 2.7% (95% CI 1.9%-3.6%),and the incidence of immune-related pneumonia of grade 3 and above is 0.8% (95% CI 0.4%-1.2%) [8].Immune-related pneumonia caused by PD-1/PD-L1 inhibitors is related to tumor types.Compared with melanoma,patients with non small cell lung cancer were more likely to develop immune-related pneumonia (4.1% vs 1.6%,P=0.002),especially the immune-related pneumonia of grade 3 and above(1.8%vs 0.2%,P＜0.001)[9].Patients with asthma or chronic obstructive pulmonary disease (5.4% vs 3.1%)and patients who had previously received chest radiotherapy (6.0% vs 2.6%) [10] were more likely to develop immune-related pneumonia.The combination of CTLA-4 and PD-1 inhibitors is more likely to induce immune-related pneumonia (6.6%vs 1.6%,P＜0.001) and immune-related pneumonia of grade 3(1.5% vs 0.2%,P=0.001) [11].Interestingly,the occurrence of immune-related pneumonia seems to be independent with pembro dose (ORR 1.17 (95% CI 0.62-2.23,P=0.63) (2mg/kg vs 10mg/kg,q3w) [12].Therefore,it can be seen from the above data that the presence of basic lung disease and the decline of basic lung function may lead to worse tolerance,worse condition and worse prognosis of patients with immune-related pneumonia.A number of studies have suggested that the tumor type (especially lung cancer),the type of immune checkpoint inhibitor used (the incidence of PD-1 inhibitors is high,the incidence of PD-L1 inhibitors is low) may be related to immune-related pneumonia.

Diagnosis and classification of immune-related pneumonia

The most common clinical manifestations of immune-related pneumonia are shortness of breath,cough,progressive dyspnea,combined with or without fever; the manifestations of medical imageology are rapid progress of ground glass shadow and consolidation,and the change of the bilateral lung are common (Figure 1); it is no efficacious to treated by antibiotic,but the hormone therapy can take effective.It is High specificity to diagnose the immune-related pneumonia when PD-1/PD-L1 inhibitor is used again or the disease relapses after hormone withdrawal.

The most common symptoms of immune-related pneumonia are expiratory dyspnea,cough,fever and hypoxia.Compared with infectious pneumonia,fever is rare in immune-related pneumonia,but respiratory failure is more likely to occur,PD-1/PD-L1 inhibitors often appear after 3-4 cycles treatment [13].The National Cancer Institute classified immune-related pneumonia into five levels.Level 1:it is no asymptomatic,only found examination or diagnosis in clinical,without intervention cure; level 2:it has symptomatic,affecting instrumental daily activities require clinical intervention; level 3:there is some severe symptoms,limited personal self-care ability need oxygen therapy; level 4:life-threatening respiratory disorders,requiring emergency treatment(tracheotomy or intubation); level 5:death.With the grade is increasing,the disease is more serious and the mortality increases.According to diagnostic criteria,the immune-related pneumonia caused by PD-1/PD-L1 inhibitors is mainly mild to moderate pneumonia,71.1% of which was grade 1-2,while only 28.9% of them were severe pneumonia above grade 3.According to the classification of interstitial pneumonia by American Thoracic Society/European Respiratory Society,most of them are cryptogenic organic pneumonia type (60%) (Figure 2).Other types include:non-specific interstitial pneumonia type 7.1%,acute interstitial pneumonia type 4.8%,interstitial pneumonia (unclassified) type 4 cases 9.5%,in addition,some patients (14.3%) showed exogenous allergic pneumonia type[14].

The understanding of immune-related pneumonia caused by PD-1/PD-L1 inhibitors in TCM

The etiology and pathogenesis of immune-related pneumonia in TCM

There is no theory of immune-related pneumonia in TCM.According to the clinical manifestations of the patients,it is advocated to differentiate the deficiency and the excess in syndrome differentiation.Spleen and kidney are the foundation treatment,lung is the standard treatment,The ancient Chinese workHuang Di Nei Jingsaid:“all Qi stagnation belongs to the lung;all impotence,asthma and vomiting belong to the upper part”.It can be seen that although the pathogenesis of the disease is complex and there are many syndromes,the location of the disease is always the lung.

The prevention and treatment according to syndrome differentiation of immune-related pneumonia in TCM

Reducing excessiveness in the stage of progression.

Etiology of disease induced by cold,activating internal fluid or stagnated fire,combination of internal or external pathogenic factors,depressive psychosis with syndrome of phlegm-Qi stagnation and binding,which can attack in the upper and reverse airway.The cue is expelling pathogens from both interior and superficies,prescription selects Xiaoqinglong decoction or Shegan Mahuang decoction to disperse the wind cold and internal phlegm,while those who have external cold and internal heat (commonly known as cold wrapped fire) should treated by Maxing Shigan decoction or Dingchuan decoction to reduce the heat of the lung and dissipate phlegm or relieve asthma.Mahuang (Herba Ephedrae) is a good medicine of asthma with lung excess to trearment.However,it is easy for people with deficiency of body to feel flustered and fidgety after taking it.It can be supervised by Shengshigao(Gypsum Fibrosum),Baishao (Paeoniae Radix Alba),Wuweizi(Schisandra Chinensis),and sometimes it can be replaced by Suye (Folium Perillae),Zisuzi(Fructus Perillae),Huajuhong (Exocarpium Citri Grandis).Houpo (Cortex Magnoliae Officinalis) or Chenpi(Pericarpium Citri Reticulatae)can be added when the chest is pain.

The important method treatment of phlegm is to relieve asthma.The potential factor of the disease is turbid phlegm obstructing lung [15].This is called the“prolonged fluid retention” or “l(fā)atent fluid retention”,recorded in the ancient Chinese workJin Gui Yao Lue,later generations called it “interrelation of phlegm and stasis syndromes”.Prolonged fluid retention in the lung for a long time,which is caused by cold pathogen,diet overstrain or mood swings.Fighting airway is full of phlegm,there are some symptoms such as excessive phlegm and saliva,bad viscosity,full chest and diaphragm,poor constipation,greasy fur and slippery pulse,etc.On the basis of Sanzi Yangqin decoction,which can release phlegm and lower Qi in treatment,add Xingren (Amygdalus Communis Vas) to relieve asthma,Tinglizi (Semen Lepidii) to eliminating pathogens from lung for expelling fluid retentio,and the asthma will be self-healing if the Qi mechanism is unobstructed,but it should be applied in the case of no external pathogenic factors,if it belongs to wind cold,it is not appropriate to close the lung.If it also coughs should add Qianhu (Radix Peucedani),Baiqian(Rhizoma Cynanchi Stauntonii),Ziwan (Radix Asteris)and Kuandonghua (Flos Farfarae); if poor appetiteshou should add Shichangpu (Rhizoma Acori Tatarinowii) or Peilan (Herba Eupatorii); if chest pain should add Houpu (Cortex Magnoliae Officinalis) or Chenpi(Pericarpium Citri Reticulatae);if constipation should add Gualou (Fructus Trichosanthis) or Xiebai(Bulbus Allii Macrostemonis).

The way of antianaphylactin and spasmolysis treatment or promoting blood circulation for removing blood stasis treatment is a treatment based on disease differentiation[16].Pharmacological experiment found that immune-related pneumonia is related to the abnormal immune response of the patient,it can treat by empirical prescription of Allergy decoction(Yinchaihu (Radix Stellariae),Chaofangfeng (Radix Saposhnikoviae),Wumei (Fructus Mume),Wuweizi(Schisandra Chinensis),Shenggancao (Glycyrrhizae))or Desensitizing decoction(Xiangfu(Rhizoma Cyperi),Wulingzhi (Faeces Togopteri),Heibaichou (Semen Pharbitidis),Gouteng(Ramulus Uncariae Cum Uncis),Bohe (Mint),Chanyi (Periostracum Cicadae),Dilong(Allolobophora Caliginosa Trapezoides Lumbricus)),which can resist hypersensitivity and antispasmodic.A part of patients have cyanosis of the lips and nails,dim complexion,the colour of the tongue is dark purple or ecchymotic,which belongs to the period of Qi deficiency and blood stasis.The fact is that the lung governing Qi can help the heart to move blood vessels.When the lung disease lasts for a long time,the deficiency of Qi and weakness of blood circulation can cause blood stasis.Therefore,we should treat it by promoting blood circulation and removing blood stasis with the difference of syndrome,we can add herbal medicine such as Danggui (Radix Angelicae Sinensis),Chuanxiong (RhizomaLigusticiChuanxiong),Danshen (Radix Salviae Miltiorrhizae).Chuanxiong(Rhizoma Ligustici Chuanxiong) makes Qi go up and Danggui (Radix Angelicae Sinensis) makes Qi walk down.Danshen (Radix Salviae Miltiorrhizae)invigorates the circulation of blood,or with Taohong Siwu Decoction as the main treatment of promoting blood circulation and removing blood stasis,supplemented by the treatment of tonifying Qi and lung.

In addition,the syndromes type of immune-related pneumonia caused not only by turbid phlegm obstructing lung but also by reversed flow of lung and stomach Qi [17],so its treatment should except open the inhibited lung-energy and depurate the lung,it should decend of gastric Qi and disperse the depressed liver-energy to regulate Qi activity.

Strengthening body resistance in the stable stage.

The unhealthy trends frequently happened to the lung.In the early stage,as the disease progresses,it can happen to the spleen and kidney.Because the spleen being source of phlegm and the kidney being the root of Qi,benefiting the Qi of spleen and kidney can strengthen the vital Qi to weak the pathogenic Qi.For example,exogenous pathogenic factor is easier to contact the person if their surface lung Qi is insatiety,it can treated by Shengxian decoction or Shengmai decoction to reduce the solid Wei and firm the surface,supplemented Qi and Yin; the internal exuberance of phlegm-damp will get stronger if the spleen Qi become weakened,it can treated by Xiangsha Liujunzi decoction or Shenling Baizhu decoction to strengthen the spleen Qi and remove phlegm-dampness,strengthen earth to generate metal.If presented the symptoms of exhalation more than inhalation or cold and swollen limbs for kidney failing to promote inspiration,it can treated by Zhenwu decoction,Guifu Dihuang decoction or Qiwei Duqi pill to warming the kidney to help inspkation to relieve asthma and supplement of kidney-Qi.The drugs with the function of relieving asthma,such as Buguzhi (Fructus Psoraleae),Hutaorou (Walnut Meat),Nvzhenzi(Glossy Privet Fruit),Tusizi (Semen Cuscutae),Ziheche (Placenta Hominis),and Gejie (Tokay Geck),are usually used to form honey pills to enhance the therapeutic effect,due to bacuse the disease's complicated pathogenesis and syndromes.

Discussion and summary

The clinical treatment of immune-related pneumonia in western medicine is mainly hormone therapy.Patients of level 3-4 should be admitted to hospital to exclude infection and tumor progression,and can be treated by continuous administration of low flow oxygen,fluid replacement therapy or antibiotic treatment if necessary.About 86.0% patients can be completely relieved,about 16.9% of them can lead to the recurrence of pneumonia [18],and 9.0% of them were pronounced dead.Among the dead patients,part of them are died for acquired immunodeficiency syndrome,and part of them are died for concurrent infection or tumor progression.With the widespread use of PD-1/PD-L1 inhibitors,the incidence of immune-related pneumonia increases every year.The TCM theory of treatment based on syndrome differentiation advocates the treatment of expelling wind and clearing away cold,resolving phlegm and relieving asthma,relieving heat from lung invigorating the spleen and tonifying the kidney and the like.TCM plays an important role in early prevention and treatment of immune-related pneumonia with accurate dialectics and reasonable dispatch.It also enshrines the principle of TCM treatment of drug's side effects.This paper try to explore the treatment of immune-related pneumonia induced by PD-1/PD-L1 inhibitors form the aspect of TCM theory,in order to provide an effective clinical thought for the prevention and treatment of immune-related diseases.