Professor Fu-Qiang Wen

Chairman of Department of Medicine, West China Hospital, West China School of Clinical Medicine, Sichuan University
Head of Department of Respiratory Medicine, West China Hospital (2005-2013)
Director of Division of Pulmonary Diseases, State Key Laboratory of Biotherapy of China
First recipient of the National Science Fund for Distinguished Young Scholars for Respirology
Committee Member and National Leader of Global Initiative for Chronic Obstructive Lung Disease
Honorary Professor, School of Medicine, University of Sydney, Australia
Co-Chair of COPD committee, Chinese Thoracic Society, and Chinese Association of Chest Physicians
Vice president of respiratory physiology committee,
Chinese Physiological Society
Associate editors of International Immunopharmacology, and
Respirology-Case Report
Authored 200 English publications in international journals
Cited more than 5000 times in international journals including NEJM, Nature, and JAMA, etc.
Received three national scientific research awards, from the Ministry of Education, and Chinese Medical Association.
Edited and published four monographs, received 5 national invention patents

The results of a large stream of data on chronic obstructive pulmonary disease in China from September 2002 to September 2004, led by Academician Zhong Nanshan and including 20,245 adults from 7 provinces and cities, were published in the American Journal of Respiratory and Critical Care Medicine in 2007. The results showed that the prevalence of chronic obstructive pulmonary disease in people over 40 years of age was as high as 8.2%. Smoking and environmental pollution have always been the greatest causes of COPD¹.

There is a large undiagnosed population of COPD patients in China, a lack of standardised treatment for diagnosed patients, and an increased frequency of acute exacerbation. In this expert interview, Professor Wen Fuqiang from the Department of Respiratory Medicine, West China Hospital, Sichuan, shares with us the new developments in anti-infective therapy strategies for AECOPD.

Q1: The number of patients with COPD in China has exceeded 100 million. The frequencies of acute exacerbations and severity are increasing.

The results of the Chinese Adult Lung Health Study (CPHS), completed between June 2012 and May 2015 and led by Academician Wang Chen, were published in The Lancet in 2018. Compared to the 2007 epidemiological survey data, the entire study included a wider geographic coverage and a larger population sample size, with about 58,000 cases. Results from the 2015 national census data showed that the number of people with COPD in China was close to 100 million².

COPD in China is not only characterised by high prevalence, but also the increasing rates of acute exacerbation and severity. These are mainly because: 1. The majority of COPD patients in China are concentrated in the rural and economically backward areas, resulting in patients not receiving standardised treatment when their conditions stabilised, because of reasons such as economic conditions and cognition, as well as the high cost of inhalers and poor accessibility; 2. The frequency of acute exacerbations and severity of the conditions increased due to exposure to factors such as smoking and environmental pollution as well as not receiving standardised treatment during the stable phase. A report in China showed that more than 80% of patients with COPD in 3 grade A hospitals were classified as GOLD group C or D, the group with the highest risk.

Q2: Infection is the most common predisposing factor of AECOPD

The pathogenesis of AECOPD is mainly related to airway inflammation. Chronic inflammation occurs locally in the airways of patients with chronic obstructive pulmonary disease. Smoke and haze toxic particles damage the clearance function of airway epithelial cell mucus and cilia, destroy the intrinsic immunity of airways, leading to airway structural disorders and alveolar damage, which aggravate airway inflammation and limit airflow. In addition, the most commonly observed precipitating factor is respiratory tract infection. 80% of AECOPD present clearly with virus or bacterial infection. The most common of which are upper respiratory viral infections, secondary airway bacterial infections, and combined viral and bacterial infections. A small percentage of infections are caused by atypical pathogens such as Chlamydia pneumoniae and Mycoplasma pneumoniae³.

Several other theories also explain the onset of AECOPD due to respiratory tract infection. For example, the Bacterial threshold theory⁴ states that factors such as respiratory microflora disorders⁵, weakened immunity function, and malnutrition⁶ also play an important role in the onset of AECOPD.

Q3: High detection rate of Pseudomonas aeruginosa and Klebsiella pneumoniae in AECOPD in China

Virus, bacteria, and atypical pathogens can all cause AECOPD. A study on antibiotic prophylaxis for COPD published The New England Journal of Medicine in 2012 mentioned that acute exacerbation of AECOPD was similar to that of respiratory viral infections, including small RNA viruses, influenza viruses and respiratory syncytial viruses. Colonisation by bacteria such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis also occurred at the same time⁷.

The pathogenic distribution of AECOPD in China is mostly similar to that of foreign countries. However, the detection rate of Pseudomonas aeruginosa and Klebsiella pneumoniae in AECOPD in China is higher. The main reason is likely due to the predominance of the elderly among AECOPD patients in China. Many of these patients have poor pulmonary function, high frequency of acute exacerbations, high degree of symptoms, and tracheal intubation. Thus, the positive isolation rate of P. aeruginosa among these patients is higher. The data from this study was published in the Chinese Medical Journal (English version)⁸ in 2013. It was also cited in the 2017 Chinese Expert Consensus on the Diagnosis and Treatment of AECOPD³.

Q4: Procalcitonin (PCT) is not recommended as a guide to the selection and assessment of AECOPD anti-infective protocols

Procalcitonin (PCT) has always been considered to be clinically significant in the selection and prognostic assessment of anti-infective protocols. However, it is now controversial.

A systematic review and Meta-analysis on the use of procalcitonin in patients hospitalised with COPD exacerbation found no significant reduction in overall antibiotic exposure⁹. Among patients with COPD exacerbation receiving treatment in the ICU, the use of procalcitonin-based algorithm to determine the initiation or discontinuation of antibiotics was associated with higher mortality compared with patients receiving standard antibiotic regime¹⁰. Based on these conflicting results, we currently do not recommend the use of procalcitonin-based algorithms to routinely guide anti-infective therapy for patients with acute exacerbation of COPD¹¹.

Q5: Anti-infection in AECOPD requires adherence to anti-infection indications and a multidimensional and comprehensive approach to anti-infection treatment strategy

According to the Global Strategy For Prevention, Diagnosis And Management Of COPD: 2022 Report (GOLD 2022) published by the Global Initiative for Chronic Obstructive Lung Disease (GOLD), antibiotics should be given to patients with COPD exacerbation who have three main symptoms: increased difficulty in breathing, increased amount of sputum, and purulent sputum (Anthonisen type I), who have two main symptoms, one of which is purulent sputum (Anthonisen type II), or who require mechanical ventilation (invasive or non-invasive)¹¹. This indication is used in China’s latest Guidelines for the diagnosis and management of chronic obstructive pulmonary disease (revised version 2021)¹² and Chinese Expert Consensus on Diagnosis and Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) (2017 updated version)³.

Anti-infective therapy must be provided to patients with anti-infective therapy indications. The anti-infective treatment strategy requires multidimensional considerations, such as the severity of pulmonary impairment, history of acute exacerbation, risk factors for specific pathogenic infections, recent hospitalisation history, history of previous antimicrobial use, comorbidities and/or complications, characteristics of the epidemiology of the pathogen, and the presence of P. aeruginosa risk factors. Broad-spectrum antimicrobial regimens, such as quinolones, can be recommended for patients with P. aeruginosa risk factors and poor prognostic risk factors. Quinolones are equally effective against atypical pathogens, such as levofloxacin.

Q6: Broad-spectrum, low-level induced drug resistance, and safety are where antimicrobial drug research for AECOPD is heading

These aspects are critical for the future of research and development of new antimicrobial drugs: 1. the rate of acute exacerbations in patients with COPD in China is very high, and the degree of acute exacerbations is very severe; 2. AECOPD treatment is not standardised, and patients have resistance to commonly used antimicrobial therapy; 3. most patients with COPD in China are elderly, and these patients may have other diseases, such as heart, kidney, liver and other diseases, and metabolic diseases such as diabetes mellitus, etc. Therefore, research and development of new antibacterial drugs should focus on drug efficiency, non-resistance, and safety. Take quinolones as an example. It would be better if new quinolones could retain the advantages of original quinolone drugs, in other words, the broad-spectrum and non-resistant properties. It would also be better if they were safer (low dosage, short treatment course).

References

1. Zhong N, Wang C, Yao W, et al. Prevalence of chronic obstructive pulmonary disease in China: a large, population-based survey[J]. Am J Respir Crit Care Med, 2007 Oct 15;176(8):753-60.
2. Wang C,  Xu J,  Yang L,  Xu Y, et al. Prevalence and risk factors of chronic obstructive pulmonary disease in China (the China Pulmonary Health [CPH] study): a national cross-sectional study[J].Lancet, 2018 Apr 28;391(10131):1706-1717.
3. Expert group on acute exacerbation of chronic obstructive pulmonary disease (AECOPD) treatment. Chinese Expert Consensus on the Diagnosis and Treatment of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) (2017 updated version) [J]: International Journal of Respiratory Medicine, 34(14):1041-1057.
4. Li ZL, Lai GX, Lin QG. Bacterial infection and acute exacerbation of chronic obstructive pulmonary disease[J]. International Journal of Respiratory Medicine, 2008, 28(17):1062-1065.
5. Hou DN, Tong L, Song YL. Advances in the study of respiratory microbiota in patients with chronic respiratory diseases[J]. Journal of Microbes and Infections, 2016, 11(5):262-267.
6. Ni N, Lin L, Xue YX, et al. The significance of malnutrition intervention and treatment during acute exacerbation of chronic obstructive pulmonary disease in the elderly[J]. Chinese Journal of Multiple Organ Diseases in the Elderly, 2017,16(6):437-441.
7. Wenzel RP, Fowler AA, Edmond MB, Antibiotic prevention of acute exacerbations of COPD[J].N Engl J Med, 2012 Jul 26;367(4):340-7.
8. Ye F, He LX,  Cai BQ, et al, Spectrum and antimicrobial resistance of common pathogenic bacteria isolated from patients with acute exacerbation of chronic obstructive pulmonary disease in mainland of China[J]. Chin Med J (Engl) 2013 Jun;126(12) :2207-2214.
9. Chen K, Pleasants KA, Pleasants RA, et al. Procalcitonin for Antibiotic Prescription in Chronic Obstructive Pulmonary Disease Exacerbations: Systematic Review, Meta-Analysis, and Clinical Perspective. Pulm Ther, 2020 Dec;6(2):201-214.
10. Daubin C, Valette X, Thiolliere F, et al. Procalcitonin algorithm to guide initial antibiotic therapy in acute exacerbations of COPD admitted to the ICU: a randomized multicenter study. Intensive Care Med 2018; 44(4): 428-37.
11. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonarydisease 2022 report[OL].(2021-11-22)[2021-12-15]. https://goldcopd.org/2022-gold-reports-2/
12. Chronic Obstructive Pulmonary Disease Study Group of the Chinese Thoracic Society, Chronic Obstructive Pulmonary Disease Working Committee of the Chinese Medical Doctor Association, Respiratory Physicians’ Branch. Guidelines for the diagnosis and treatment of chronic obstructive pulmonary disease (2021 revised edition) [J]. Chinese Journal of Tuberculosis and Respiratory Diseases, 2021,44(3):170-205.