Professor Shi Huanzhong

Capital Medical University Affiliated Beijing Chaoyang Hospital, Department of Respiratory and Critical Care Medicine – Beijing Respiratory Disease Institute

• Director of Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, selected as a “Beijing Scholar” in 2019, China’s most cited scholar for two consecutive years from 2020 to 2021.
• Began studying immunology mechanism and clinical respiratory disease in 1994, main academic contributions being: (1) introduced lymphocyte biology into immunology research on malignant pleural effusions thereby opening new frontiers for the research on the mechanism of malignant pleural effusions. (2) systematic description of the immunological characteristics of various helper T cells in the tuberculous pleurisy environment and the first to discover that pleural mesothelial cells are able to function as antigen-presenting cells. (3) proposed IL-27 as a reliable indicator for diagnosing tuberculous pleural effusion and that the diagnostic efficiency is superior to any other known soluble markers. (4) systematic exploration of whether soluble mediums such as IFN-γ, adenosine deaminase and various tumour markers, have any clinical value in differentiating benign or malignant pleural effusion so as to provide evidential and medical basis for the clinical use of these diagnostic indicators.
• Published over 100 papers as a corresponding author in academic journals such as Am J Respir Crit Care Med, Am J Respir Cell Mol Biol, Thorax, Chest, and Eur Respir J.

Clinical research are studies which are based at a medical service provider, which targets patients, and that aim to uncover the diagnosis, treatment, prognosis, etiology, and prevention of diseases. This article will discuss the significance of therapeutic research, in particular randomised controlled trials (RCTs).

What is good clinical research? Good clinical research is medical research that produce results that are able to lead scientific advancement towards new directions, change traditional mindsets towards certain medical questions, or change treatment protocols for certain diseases. Through good research, patients receive more immediate and long-term benefits that are more aligned with scientific principles. For example, the SPRINT research published in 2015 is excellent research with great significance.¹ Its results shook the entire medical industry and directly led to a change in the diagnosis standard of hypertension worldwide, lowering the original standard of 140/90 mmHg by 10 mmHg to 130/80 mmHg. Why is the SPRINT research considered good research? That is because the results of this study clearly informed us that for every four patients with a systolic pressure of ≥130 mmHg and at risk of cardiovascular disease but without diabetes, one patient may be able to avoid death by hypertension with active control of blood pressure.¹

The common consensus is that thoracentesis or chest tube insertion should be used when symptoms such as difficulty breathing occurs in patients with spontaneous pneumothorax (primary) or when the degree of pneumatosis is medium or high. Currently, this treatment philosophy is undergoing drastic change as a result of the RCT paper published in 2020 by Brown et. al.² The study indicates that, for patients with their first unilateral mid to massive spontaneous pneumothorax, in the case of evidently decreased complications, simple observation without conservative treatment such as extraction of air by suction or chest tube insertion is, overall, no less effective than active intervention.² Note that this refers to mid to massive, not small spontaneous pneumothorax. This RCT result provides adequate evidence to show that even for mid or massive spontaneous pneumothorax, we should be even more prudent and adopt a conservative attitude, avoiding suction where possible. During observation, should the patient’s pneumothorax not regain breathing function, and breathing difficulty persists or worse, exacerbates with other conditions, it would not be too late to drain the air then.

In past perspectives, it was once thought that excessive drainage of malignant pleural effusion (MPE) would cause excessive loss of protein in the body, exacerbating of the exhaustion of the body and shortening the survival period. Subsequent clinical studies have since debunked that perspective and ceased debate. The effusion should be drained out of all MPE patients as soon as possible,^3,4 followed by injecting talc powder into the chest cavity so as to encourage pleural fixation to improve the patient’s quality of life.

It is not realistic and impossible to require all RCT studies to have adequate major significance. The study will be valuable as long a certain clinical problems have no conclusive answers from past knowledge and the clinical physician is keen to find out. The results of the STOPPE study that was published on May 1 this year in Am J Respir Crit Care Med were enlightening.⁵ Several renowned physicians from numerous hospitals in Australia and the United Kingdom randomly split 80 patients with parapneumonic effusion into two groups in a 2:1 ratio. One group would receive intravenous injection of dexamethasone (twice daily, 4 mg a dose, administered over two days), and the other group would receive a placebo. The study indicates that systemic use of hormones does not bring about benefits for the patient. Before this study, everyone may consider these clinical questions unimportant and would normally not consider using hormones to treat parapneumonic effusion, and believe that hormones are not helpful to the condition. The researchers embarked on this study precisely because they were curious about whether hormonal therapy would be beneficial to treating parapneumonic effusion. What are some of the benefits, if there are any? And how big of a benefit? Data are required to answer these questions. Otherwise, it would simply be personal experience and opinion. This is the beauty of science and the original intention of scientific research.

Another research published by Eur Respir J this year was also quite interesting. I have seen many patients with recurring and persistent pleural effusion from pleuroperitoneal communication. The moment they’re hospitalised, physicians will promptly insert a chest tube to help to relieve breathing difficulties. Many patients are pushed into the respiratory ward with a drainage tube attached to their chest. This is not in violation of medical principals, but is this really the best solution? Now, we know otherwise. Repeated thoracentesis, performed only when shortness of breath is unbearable, is simpler, has fewer complications, and is more desirable. This conclusion has definitive evidential support.⁶

To date, large multicentre RCTs on malignant pleural effusion (MPE) have all focused on the aim of avoiding or reducing the formation of anterior pleural effusions. In other words, facilitating pleura fixation based on the treatment of primary tumours is the main goal in the clinical management of MPE, since breathing difficulty can only be eased once the pleura is fixed. Regarding how to evaluate whether pleural fixation has occurred and to what degree, in the past, depended on the physician, and each one had a different method. The well known IPC–Plus study uses two criteria to determine that pleural fixation has occurred: (1) less than 50 ml of liquid drained in three consecutive drainages through indwelling pleural catheter, and (2) after draining, a chest X-ray indicates “pleural fluid” less than 25% of one side of the chest cavity.⁷ These evaluative indications are undoubtably subjective and not entirely precise. To overcome this issue, the SIMPLE study introduced a new way of ultrasound application to determine pleural fixation:⁸ split one side of the chest cavity into three equal parts along the midclavicular line, midaxillary line, and scapular line, to form nine segments on the external chest wall. During the ultrasound, award one point if pleural sliding is observed, two points if it is suspected, and three points if there is no sliding. The lowest score, indicating that the pleura is not fixed, is 9, and the highest score, indicating that the pleura is fixed, is 27. This is the objective indicator to quantify if pleural fixation has formed or not.

It can be understood that the value of the SIMPLE study is not as significant as that of SPRINT, but it is still an excellent clinical study because the researchers have employed processes that comply to the norms to complete the research process and have obtained reliable data to answer an important clinical question, as well as provided a whole new evaluation method.

I would like to briefly mention “real world research”. In summary, regardless of how significant real world research results are, they cannot compare to RCTs. In fact, real world research is owing to lack of alternatives; we only obtain these research results because we were unable to perform the study under RCT. For example, we cannot conduct RCTs for rare diseases or sudden infectious diseases. Without a doubt, we cannot deny the importance of real-world research, however we must emphasise that these results cannot be high-level evidence for the development of guidelines or expert consensus.

The world has long since entered the epoch of evidence-based medicine. Strict guidelines have never denied the importance of a physician’s personal experience, but work to recommend or overthrow certain treatment regimes and to provide the best evidence. Not having evidence does not mean that a treatment method does not have efficacy, and what we need to do is to find effective and optimum evidence.

References

1. SPRINT Research Group, Wright JT Jr, Williamson JD, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med, 2015, 373(22): 2103-2116. doi: 10.1056/NEJMoa1511939. PMID: 26551272.
2. Brown SGA, Ball EL, Perrin K, et al. Conservative versus interventional treatment for spontaneous pneumothorax. N Engl J Med, 2020, 382(5): 405-415. doi: 10.1056/NEJMoa1910775. PMID: 31995686.
3. Wahidi MM, Reddy C, Yarmus L, et al. Randomized trial of pleural fluid drainage frequency in patients with malignant pleural effusions. The ASAP trial. Am J Respir Crit Care Med, 2017, 195(8): 1050-1057. doi: 10.1164/rccm.201607-1404OC. PMID: 27898215.
4. Muruganandan S, Azzopardi M, Fitzgerald DB, et al. Aggressive versus symptom-guided drainage of malignant pleural effusion via indwelling pleural catheters (AMPLE-2): an open-label randomised trial. Lancet Respir Med, 2018, 6(9): 671-680. doi: 10.1016/S2213-2600(18)30288-1. PMID: 30037711.
5. Fitzgerald DB, Waterer GW, Budgeon C, et al. Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): A pilot randomized clinical trial. Am J Respir Crit Care Med, 2022, 205(9):1093-1101. doi: 10.1164/rccm.202107-1600OC. PMID: 35081010.
6. Walker SP, Bintcliffe O, Keenan E, et al. Randomised trial of indwelling pleural catheters for refractory transudative pleural effusions. Eur Respir J, 2022, 59(2): 2101362. doi: 10.1183/13993003.01362-2021. PMID: 34413152.
7. Bhatnagar R, Keenan EK, Morley AJ, et al. Outpatient talc administration by indwelling pleural catheter for malignant effusion. N Engl J Med, 2018, 378(14): 1313-1322. doi: 10.1056/NEJMoa1716883. PMID: 29617585.
8. Psallidas I, Hassan M, Yousuf A, et al. Role of thoracic ultrasonography in pleurodesis pathways for malignant pleural effusions (SIMPLE): an open-label, randomised controlled trial. Lancet Respir Med, 2022, 10(2): 139-148. doi: 10.1016/S2213-2600(21)00353-2. PMID: 34634246.