Pulmonary (interstitial) fibrosis is a worldwide intractable disease with a very poor prognosis and a lack of effective treatment methods. This paper summarizes the domestic and international research on this disease in a systematic way; focuses on the problems in clinical treatment research, and proposes clinical response strategies to deal with the “seven relationships”. In regard to the problems and gaps in the current clinical research methods of TCM, it is proposed that the focus should be on the establishment of an efficacy evaluation system with TCM characteristics while studying and referring to the advanced clinical research design methods from abroad.
1. Overview
Pulmonary (interstitial) fibrosis is a worldwide intractable disease that can occur in all races, with slightly more men than women. It has a very poor prognosis, and is said to have a “cancer-like prognosis”. However, the sample sizes of relevant studies are relatively small, and there is heterogeneity in the clarity of diagnosis and severity of the disease, so most researchers tend to believe that this conclusion needs further confirmation. The concept of interstitial lung disease (ILD) has been developed since the 1980s, when scholars at home and abroad have gradually studied different diseases with interstitial lung disease as the main site of lesion. Clinical treatment is also facing more and more confusion .
For example, it is difficult to conduct prospective, randomized controlled clinical trials because it is not a common or frequent disease; the natural and clinical course of the disease is unpredictable; there are no accurate and reliable objective indicators to identify and monitor disease progression; the prognosis is extremely poor and it is unethical to use placebo as a controlled study; during the study, patients often request to change the drug because it is ineffective, which complicates the study; it is difficult for patients to adhere to the study drug because of its side effects; and there is a lack of long-term adherence to the study drug. It is difficult for patients to adhere to the study drugs for a long time; lack of uniform evaluation criteria, etc.
2. Early diagnosis problem
The key to early diagnosis is awareness! Pulmonary function-limiting ventilation dysfunction has a certain value for early diagnosis. One of the main things is the measurement of DLco and the exercise test examination, which can show abnormal changes (down to 1/2 to 1/5 of the normal value) before there are any clinical symptoms and other examinations with abnormal manifestations (2 to 3 months).
This test also helps to determine the treatment plan and determine the efficacy. As for the question of whether and when hormones should be used, there is no single clinical indicator that can be used as a basis. The choice is mostly made on the basis of comprehensive clinical information, with pulmonary function tests taking a prominent place. If pulmonary function values are stable during the observation period, hormone therapy can be considered unnecessary; on the contrary, if pulmonary function gradually deteriorates, indicating disease progression, hormone therapy should be given promptly.
In addition, it should be noted that pulmonary function tests have certain limitations in the application of ILD. First of all, conclusions cannot be drawn from a single test alone, but should be based reliably on the dynamic changes found in a series of tests. It is not easy to distinguish normal from abnormal.
3. Clinical treatment problems
(1) Corticosteroids: The recommended treatment regimen in the relevant treatment guidelines at home and abroad is glucocorticoids or combined with cytotoxic agents (cyclophosphamide and azathioprine). Other drugs that have been reported in the literature in recent years include interferon and N-acetylcysteine (NAC). However, there is a lack of evidence-based medical evidence to support which treatment regimen improves patient quality of life or survival, and there is no universally accepted ideal dose or duration of application, which should always be adjusted according to the patient’s specific clinical response, i.e., emphasis on individualization. Survival is prolonged in patients with improved lung function and chest radiographs. The exact mechanism of treatment is not known. For the vast majority of patients, treatment with hormones, even if effective, does not stop the progression of the disease. Corticosteroids have been used extensively in the past, but such drugs are virtually ineffective in patients with clearly diagnosed IPF. Therefore, it is now believed that steroids are only effective for other types of inflammatory lung disease, and the American Thoracic Society no longer recommends their routine use in the treatment of IPF.
The current consensus is that drug therapy may be effective in those with the following clinical features: young onset; short duration of disease before treatment; pathology showing predominantly acute alveolitis; presence of immune complexes in serum, BALF and lung biopsy specimens; and a high number of lymphocytes in BALF. Since the 1990s, domestic scholars have explored the treatment of this disease in Chinese medicine, and have made promising progress from the perspective of “pulmonary impotence” and the treatment method of benefiting Qi and moistening the lung, activating blood circulation, etc. [.
(2) Non-pharmacological treatment: plasma exchange method is yet to be further clinically validated; lung transplantation: lung transplantation should be considered for those who are 60 years old, without other systemic diseases, with poor response to drug therapy and objective indicators showing deterioration of lung function.
To sum up, the treatment so far is still very difficult, and the current pharmacological treatments are aimed at controlling inflammation and delaying the development of fibrosis, making it difficult to achieve a radical cure. Moreover, these drugs have some side effects to varying degrees and need to be taken for a long time.
4, clinical response strategy thinking: deal with the “seven relationships”
(1) Standardization and individualization – and different, purpose first: Take the use of glucocorticoids as an example, although there is a “recommended treatment plan”, clinical practice should not be too confined to the so-called “standardization”. For example, in the case of glucocorticoid use, although there is a “recommended treatment plan”, clinical practice should not be too rigidly bound to the so-called “standardized” treatment plan. For example, if the disease still progresses after the application of corticosteroids, they should be rapidly withdrawn, rather than sticking to the “course of treatment”. ILD is actually a group of clinical syndromes, and although its clinical manifestations, X-ray changes and impairment of lung function have similar characteristics, it has many different etiologies, pathogenesis, natural evolution, treatment methods and prognosis. Therefore, there is no “standard” or “uniform” treatment plan. Different options must be considered for specific cases, timing and specific medications. The real optimization should be individualized, and individualization is the expression of optimization, which is the development direction of modern medicine.
(2) Etiological treatment and symptomatic treatment – complement each other and prioritize: clear and single causative factor, etiological treatment is fundamental. And the simplicity of causation is a current clinical problem. The disease is even a case of gradual accumulation of multiple and distant causes, and exorcism of the cause is difficult or even impossible. Thus, supportive and symptomatic treatment of ILD is very important. In cases where a cure is currently difficult to achieve clinically, supportive therapeutic measures can not only improve the quality of life of patients, but likewise help to control and prevent progression of the disease. When dealing with the relationship between etiological treatment and symptomatic treatment, clinical practice should follow the principle of treating the symptoms if it is urgent and treating the root cause if it is slow. For example, correct oxygen therapy, reasonable antibiotic use, etc.
(3) Chinese medicine treatment and Western medicine treatment – organic combination, timely selection: the advantage of Chinese medicine lies firstly in the issue of individualization, which is actually the embodiment of the idea of Chinese medicine discriminative treatment. The second is that for certain patients who are not sensitive to hormones and immunosuppressants, the use of Chinese medicine treatment can often achieve better clinical results; the advantage of Western medicine lies in the fact that in most patients with early detection (alveolitis), the timely use of hormones can reverse the lesions to normal. And in certain acute type cases, timely hormone shock therapy can bring about remission. There is a misconception in clinical practice that there is no cure for Western medicine and then try Chinese medicine, or that Western medicine is used in the acute phase and Chinese medicine is used in the remission phase. Chinese medicine and Western medicine have their own strengths and weaknesses, and each has its own advantages in the understanding and treatment of this disease, and they are complementary. If Chinese medicine and Western medicine are used in the process of treatment, it is of positive significance to slow down the progress of the disease and improve the symptoms.
(4) Identification treatment and disease treatment – Combination of disease and evidence, priority of identification: For example, in patients with multiple pneumonia type, clearing lung and resolving phlegm can be the main treatment. In patients with isolated pneumonia, softening and dispersing drugs can be added on the basis of clearing the lung and resolving phlegm. In diffuse interstitial pneumonia, the main treatment should be to benefit the qi and moisten the lung, etc. Identification of evidence is a holistic understanding of the functional state of the body and the differences in its environment at a certain stage of the disease, while identification of disease is based on the understanding of the pathological changes of the disease. The two are equally complementary. When there are obvious symptoms to be identified, the identification of evidence takes precedence; if there is no specificity in clinical manifestations, the identification of disease is appropriate. In other words, if there is a symptom to identify, and if there is no symptom to identify, then the identification of the disease should be combined with the identification of the disease. If the patient is found to have the basis of hypercoagulable activity in the lung, the medicine should be added or subtracted on the basis of activating blood circulation and resolving blood stasis.
(5) Psychological treatment and science education – follow good advice and seek truth from facts: clinically, it is found that when patients learn that they are suffering from this “cancer-like prognosis”, they often show two extreme intentions: one is to give up on themselves and lack good compliance in treatment; the other is to believe that there is a “miracle cure”. The first is to give up on themselves and lack good compliance in treatment; the second is to believe in “miracle cures” and to be superstitious about “prescriptions”. The patient’s condition should be adequately, commonly and aptly explained, and appropriate and specific activity guidance should be given. Clinical practice proves that psychotherapy based on popular science education is of great significance to alleviate patients’ symptoms and build up confidence to overcome the disease. However, it is important not to blindly exaggerate the efficacy of treatment in order to obtain the cooperation of patients.
(6) Efficacy and cost – taking into account the discretion and benefit of others: to obtain the best efficacy at the lowest cost is the requirement of health economics and the wish of most patients. From the perspective of clinical care, it is not easy for physicians to balance cost and efficacy in the face of difficult-to-treat diseases such as ILD! For example, the choice of lung transplantation for IPF; if the initial diagnosis can be made based on clinical manifestations and routine examinations (e.g. chest X-ray) if not needed for scientific research, whether further examinations are necessary; when one drug can basically control the disease, the efficiency of the combination is only limited, and the effectiveness and value of the combination should be carefully evaluated, etc.
(7) Quality of survival and pathological improvement – face the reality and do not give up lightly: all treatments so far are considered difficult to have a clear pathological improvement. Therefore more realistic than focusing on how to stop disease progression and prolong survival is how to improve quality of life. Quality of life is a new class of health-related multivariate indicators that has emerged with the shift in the medical paradigm. Its assessment method is to evaluate the health status of a person at a macro level and at a holistic level, which is in line with the Chinese medicine concept of the law of human life activities and health as a whole. The introduction of the concept of quality of life into the field of TCM efficacy evaluation will certainly help to make an objective evaluation standard for the efficacy of TCM that can be accepted by the medical community.
The benefit of life sciences to human beings lies not only in the breakthroughs and advances in knowledge and technology, but also in the synchronization and harmonization of rules and psychology with human ethics and cultural adaptations. The theme of the “Nobel Laureate Beijing Forum” on September 5, 2006 was life science and human health, and the main theme of life science is “the pursuit of quality of life” (as opposed to longevity). In the clinical treatment of pulmonary (interstitial) fibrosis.
The TCM efficacy evaluation system can be established by studying the TCM symptomatology and referring to the results of Western medicine research, thus establishing an efficacy evaluation system with TCM characteristics.
Since this disease is characterized by irreversible pathology, judging its efficacy by traditional physiopathological indicators lacks sufficient rationality and credibility. Therefore, we have been advocating the use of survival quality scales such as the St. George Respiratory Questionnaire (SGRQ) and the Simplified Medical Outcome Scale of 36 (SF-36) in clinical research to reflect the “people-oriented” characteristic advantages of TCM. At the same time, it is necessary to make appropriate reference to the advanced clinical study design methods in foreign countries, such as setting the treatment period for at least 3 months, which can be extended appropriately if necessary; considering that the observation indexes mostly show restrictive ventilation dysfunction and abnormal diffusion function, it is necessary to have the forceful lung volume (FVC) or lung volume (VC), one-second volume (FEV1), one-second rate (FEV1/FVC), which reflect restrictive ventilation dysfunction, and DLCO, which represents the diffusion capacity of the interstitial lung, etc.; in addition to the crude measurement of dyspnea score by the British Medical Research Council score (MRC score), the transient dyspnea index (TDI), which measures dyspnea in 3 aspects: activity intensity, effort and functional impairment, can be used to refine the assessment; the timed walking distance test is also a better method to evaluate the activity endurance of patients. All these design details can be used in TDI clinical studies as appropriate.
In addition, because chronic progressive diseases require long-term medication, the issue of monitoring possible adverse effects in treatment is also a current clinical issue that cannot be ignored.
There are not yet many clinical studies that systematically report drug safety and do not utilize objective evaluation of issues such as the safety of TCM. How long should a course of Chinese medicine be, at what point should it be withdrawn, how should the efficacy be consolidated and maintained after withdrawal, and are there any other methods of Chinese medicine other than the traditional oral drinking tablets and tonics? These time-effect studies and studies on the mechanism of efficacy are also important elements of clinical research in TCM. From the perspective of new drug research, the source of herbs should also be fixed, the quality of each herb in the prescription should be fixed, and reasonable dosage forms, such as oral liquid, granules, and injections, should be formulated according to clinical use. All these issues can be explored in depth in the future as breakthroughs in clinical research of TCM.