2014年 · 第37卷第10期

"Clinical Lung Function" edited by Professor Zhu Lei is about to be republished. When I was invited to write a preface, I couldn't help but feel a lot of emotion, so I would like to share it with readers.

As a global infectious disease, chemotherapy (chemotherapy for short) of tuberculosis has been facing severe tests. In view of the biological characteristics of MTB, the chemotherapy of tuberculosis has gradually developed from the early application of single anti-tuberculosis drug to the most basic four-drug combination therapy in the 1970s. Since the advent of standard short-course chemotherapy regimens, the basic principles of early, combined, regular, appropriate and full-course anti-tuberculosis chemotherapy have always been carried out, which is also the guarantee for the rational use of anti-tuberculosis drugs. The 2013 Global Tuberculosis Epidemic Report suggests that both the incidence, prevalence and mortality of tuberculosis show a downward trend^[1]Our country has made great contributions to this. According to the data of epidemiological sampling survey in China from 1990 to 2010, the decline of the above three rates is even more remarkable. Such brilliant achievements are closely related to the popularization and application of standard short-course chemotherapy regimens and the rational use of anti-tuberculosis drugs.

In view of the serious situation of tuberculosis epidemic in China, anti-tuberculosis treatment has a long way to go. Although the implementation of powerful chemotherapy methods has revolutionized the tuberculosis epidemic since the 1950s, after the 1980s, with the epidemic and spread of drug-resistant tuberculosis, the emergence of acquired immunodeficiency syndrome (AIDS), and many reasons such as the slow development of drugs and the slow update of knowledge about tuberculosis prevention and treatment, the tuberculosis epidemic remains high. In this situation, the patients admitted to tuberculosis specialist hospitals are also worsened by drug resistance, which makes the treatment more difficult. Clinicians are at a loss when faced with tuberculosis patients who are very difficult to treat and have no drug options, and often blindly adopt inappropriate chemotherapy regimens. The results are difficult to achieve the intended purpose, and to a certain extent, adverse reactions that are difficult to handle may occur, which again leads to intermittent irregular medication, and even causes more serious drug resistance. Therefore, there are many irrational and unscientific phenomena in tuberculosis chemotherapy at present. The author discusses some clinical phenomena here and strives to reach a consensus with fellow colleagues.

In the nearly 50 years since the advent of rifampicin, the research and development of new anti-tuberculosis drugs has not been satisfactory, which cannot meet the increasing need for drug-resistant tuberculosis treatment. The role of fluoroquinolones in the treatment of drug-resistant tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB), has made up for the shortage of new anti-tuberculosis drugs and made certain contributions to the treatment of drug-resistant tuberculosis^[1,2,3,4]。 However, with the change of drug-resistant MTB, the application of fluoroquinolones in drug-resistant tuberculosis has been greatly challenged. How to better evaluate and use fluoroquinolones rationally is a question that clinicians look forward to answering.

In the subgroup of anti-tuberculosis drugs, "anti-tuberculosis drugs for injection" refer to drugs that do not have oral dosage forms but only injectable dosage forms, including streptomycin, kanamycin, amikacin and capreomycin, excluding the injectable dosage forms of isoniazid, rifampicin, sodium p-aminosalicylate and fluoroquinolones. Streptomycin, discovered in 1944, is the second antibiotic after penicillin and the first aminoglycoside drug discovered. Together with penicillin, it has saved countless patients with infectious diseases; Streptomycin is also the first chemotherapy drug sensitive to MTB to come out, ushering in a new era of tuberculosis treatment. For 80 years, kanamycin, amikacin and capreomycin have been used in clinic successively and have played an important role in the treatment of tuberculosis.

At present, the prevalence of active pulmonary tuberculosis in the elderly is on the rise^[1]The prevalence of smear-positive pulmonary tuberculosis was higher in the 75-80-year-old group, and about 50% of pulmonary tuberculosis patients were over 60 years old. Therefore, the treatment of elderly pulmonary tuberculosis patients should be paid attention to. Due to the decline of physiological function of the elderly, the absorption of drugs is weakened, the onset of action is delayed, the metabolic capacity is decreased, and it is easy to accumulate in the body, so that the safe range of medication is narrowed. Based on years of clinical experience, the author discusses the standard short-course chemotherapy regimen for elderly patients with pulmonary tuberculosis for your reference.

Rifamycins are the last drugs to be added to the short-course chemotherapy (chemotherapy) regimen of tuberculosis, and they are also the most important class of anti-tuberculosis drugs in modern tuberculosis control strategies. Among them, the research and development of rifampicin is a milestone of anti-tuberculosis drugs in the 1960s. However, with the emergence and spread of multidrug-resistant MTB strains, which are resistant to two major bactericidal drugs: isoniazid and rifampicin, the epidemic situation of tuberculosis has worsened again, and multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) may become new incurable diseases. The study found that most of the resistance to rifampicin is acquired resistance, that is, due to the irregular application of drugs and the irregular administration of drugs by patients. Therefore, the rational use of rifamycin drugs for patients with new tuberculosis, from the source to eliminate the occurrence of secondary rifampicin resistance is a key issue in the MDR-TB era.

In the 1990s, with the increase of drug-resistant tuberculosis (MDR-TB) and related diseases, the number of tuberculosis patients in different physiological states such as diabetes, human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), immunosuppressant application, liver disease, kidney disease, and pregnant women, children and the elderly also increased accordingly. Different from the general population, this part of the population needs appropriate adjustment in drug selection, chemotherapy plan formulation and treatment course. Moreover, there are many adverse drug reactions and high treatment failure rate in the treatment process. It is an important way to control the epidemic situation of tuberculosis to actively treat these special groups of tuberculosis and improve their cure rate.

After more than 10 years of efforts, the overall epidemic situation of tuberculosis in China began to show a downward trend, and standardized anti-tuberculosis treatment played an important role in this process. However, the development momentum of the drug-resistant tuberculosis epidemic has not been diminished by this, and it is imperative in clinical practice to carry out individualized treatment on the basis of standard anti-tuberculosis chemotherapy according to the patient's drug resistance or past medication history. By understanding the relationship between standardized treatment and individualized treatment, the correct choice and formulation of reasonable anti-tuberculosis chemotherapy regimen can not only promote the continuous decline of tuberculosis epidemic situation, but also be a powerful weapon to control the epidemic of drug-resistant tuberculosis.

Since my country's Food and Drug Administration approved the tuberculosis T cell test (T-SPOT.TB) developed by Oxford Immonotec in the United Kingdom to be marketed in China in 2010, γ-interferon release test (IGRAs) has been officially used as an in vitro immunodiagnostic technology for tuberculosis in China for clinical diagnosis. In the past few years, eight kits based on IGRAs principle have been approved for marketing in China. Due to the complexity of tuberculosis diagnosis, the previous diagnostic methods such as bacteriological diagnostic methods, PPD test, anti-tuberculosis antibody and imaging are far from meeting the clinical needs. IGRAs has been rapidly popularized and applied to clinic once it was introduced. In the clinical application process, there are inadequate understanding of the technical principle caused by improper use and improper understanding of the test results. The author has presided over the clinical verification of a number of IGRAs kits. Combining the principle of IGRAs and the clinical characteristics of tuberculosis, I would like to talk about my personal experience in explaining the clinical significance of IGRAs test results.

Interferon-γ release assays (IGRAs) are used to detect gamma-interferon produced by T cells stimulated by antigen-specific antigens of Mycobacterium tuberculosis (MTB) to determine whether there is MTB infection. IGRAs can make up for the shortcomings of PPD testing. At present, many countries have used it to diagnose latent tuberculosis infection (LTBI). Some hospitals in my country have also routinely carried out this test, and many IGRAs reagents have entered or will soon enter clinical application.

At present, most patients with bronchial asthma (asthma for short) can achieve disease control after existing drug treatment, but some cases (5% ~10%) are still difficult to treat clinically, that is, the so-called severe asthma or refractory asthma (severe/refractory asthma). The best management method and the underlying pathogenesis are still unclear. In 1999 and 2000, the first expert consensus on severe/refractory asthma was published in the European Respiratory Journal and the American Journal of Respiratory and Critical Medicine, respectively^[1,2]。 At that time, the author introduced the main content of this consensus and airway inflammation in severe asthma^[3,4]。

Isoniazid p-aminosalicylic acid (PAS-INH), formerly known as dipasic, was reportedly produced by Geistlich Pharmaceutical Factory in Switzerland in 1953. At that time, it was thought to be a compound of p-aminosalicylic acid (PAS) and isoniazid^[1]。 After the introduction of the drug into China in the mid-1990s, many domestic pharmaceutical factories successively produced generic drugs of the drug, and it was proved by basic research that it is the same drug as Li Pai Lung Disease^[1]。 PAS-INH is known as tuberculosis clear, Likefenil, Likang tuberculosis tablets and pasniazid in China, and has been approved by the State Food and Drug Administration, and has been used in China until now. From a global perspective, some countries used PAS-INH in the 1950s and 1960s, and there were basically no reports on the application of this drug since then. The reason for this is difficult to verify. It is speculated that it is related to the advent of rifampicin and the successful implementation of HRZE (H: isoniazid, R: rifampicin, Z: pyrazinamide, E: ethambutol) short-course chemotherapy methods. The author discusses the problems existing in the current clinical application of PAS-INH in China.

Tuberculosis is a chronic infectious disease caused by MTB, which is mainly respiratory infection. It is also an infectious disease with the highest mortality rate caused by single pathogenic bacteria infection. It is the number one killer of infectious diseases, and the epidemic situation of tuberculosis is serious in recent years. According to the statistics of the World Health Organization (WHO), the annual incidence of tuberculosis in China in 2012 was 1.03 million, accounting for 12% of the global annual incidence rate, ranking second in the world^[1]。 Macrophages are the main host cells of MTB in vivo^[2]。 Iron metabolism is related to intracellular infection^[3]The iron metabolism of macrophages is closely related to the growth and reproduction of MTB^[4], iron is essential for the growth of MTB within macrophages. Iron can promote the growth of MTB. Liu Zhi et al^[5]It is believed that serum iron level can be used as one of the important auxiliary indexes in the diagnosis and curative effect of tuberculosis. The relationship between macrophage and MTB iron metabolism and tuberculosis is reviewed as follows.

chronic cough refers to those with cough as the only symptom or main symptom, for more than 8 weeks, and no obvious abnormalities in chest X-ray examination. The main known causes include cough variant asthma, eosinophilic bronchitis, gastroesophageal reflux cough and upper airway cough syndrome, etc.^[1]。 Epidemiological data show^[2,3,4,5]The incidence rate of chronic cough is as high as 3.3% ~18%, of which 7% ~46% of chronic cough has unknown etiology, negative auxiliary examinations (blood test, chest X-ray, sinus CT, lung function, bronchial challenge test and 24-hour pH monitoring, etc.), ineffective empirical cough treatment, and seriously affects the quality of life and psychological quality of patients, which has become an urgent problem to be solved in clinical practice. Recent studies have shown that this type of cough is associated with increased cough reflex sensitivity. Therefore, Morice^[6]The term "chronic cough hypersensitivity syndrome (CCHS)" was proposed to address the above problems. The development history, pathogenesis, clinical manifestations, evaluation methods and treatment progress of CCHS are reviewed.

chronic thromboembolic pulmonary hypertension (CTEPH) is a kind of chronic progressive disease, and its incidence is about 15/100,000~19/100,000^[1]If it cannot be diagnosed and treated in time, its mortality rate is high, according to literature reports^[2]: Patients with mean pulmonary artery pressure (mPAP)>50 mmHg (1 mmHg =0.133 kPa) have a 3-year mortality rate of 90%. With the development of pulmonary endarterectomy (PEA) and the application of targeted drugs, the prognosis of CTEPH patients has improved significantly. Most patients with CTEPH who can undergo PEA can be cured. The results of the study show that the 5-year survival rate after PEA can be as high as 90%^[3]However, some patients still have persistent pulmonary hypertension (PH) after surgery or cannot be operated due to distal pulmonary vascular disease or serious complications; A considerable proportion of CTEPH patients have hemodynamic instability before PEA, which increases the risk of surgery. For the above patients, in addition to general basic treatments including oxygen inhalation, anticoagulation, diuresis and appropriate cardiotonic therapy, clinical studies have demonstrated that targeted drug therapy can improve patients' hemodynamics and activity tolerance, and improve survival rate. The application of targeted drugs in the treatment of CTEPH is now evaluated.

hypoxia-inducible factor-1 (HIF-1) is a highly conserved transcription factor, whose expression is mainly affected by oxygen concentration in the body and regulates the expression of many genes in vivo. As a heterodimer, HIF-1 consists of two subunits, HIF-1 α and HIF-1 β. HIF-1 β is widely expressed in vivo, while HIF-1 α is poorly expressed under normoxic conditions^[1]。 Yu et al.^[2]Analyzed at 10% O₂HIF-1 α under conditions^＋/－and HIF-1 α^＋/＋Physiological response in mice, it was found that HIF-1 α^＋/－Right ventricular hypertrophy, pulmonary hypertension, and pulmonary vascular remodeling were all significantly delayed in mice compared to litter-born wild-type. As a key mediator for maintaining oxygen balance, HIF-1 is also the first transcription factor identified as induced and activated by the reduction of oxygen partial pressure. After activation, HIF-1 can upregulate the transcription level of genes adapted to hypoxic environment^[3]。 The above evidence indicates that HIF-1 plays an important role in the formation of hypoxic pulmonary hypertension and the process of pulmonary vascular remodeling. The mechanism of action of HIF-1 in hypoxic pulmonary hypertension is reviewed below.

idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with unclear pathogenesis and lack of effective drugs to prevent the development of the disease. The pathological changes are common interstitial pneumonia^[1]。 The proliferation and transformation of fibroblasts play an important role in the development of pulmonary fibrosis. It has been reported that basic fibroblast growth factor (bFGF) levels are high in BALF and lung tissues of patients with pulmonary fibrosis^[2], a large number of mast cells expressing bFGF protein and mRNA can be detected, and these cells are mainly distributed in the region of fibroblast foci where lung fibroblasts and myofibroblasts proliferate abundantly^[3,4]。 It suggests that bFGF may be involved in the proliferation and transformation of lung fibroblasts. In this study, the effects of bFGF antisense oligonucleotide on the proliferation and transformation of lung fibroblasts induced by transforming growth factor (TGF) -β 1 and the possible mechanism were observed by in vitro culture of lung fibroblasts.

A 26-year-old female was a clothing salesperson. On March 13, 2013, he went to Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine for "cough, expectoration and fever for more than 2 months". More than 2 months ago, the patient developed cough and expectoration without obvious trigger, with yellow and white phlegm color, accompanied by fever, and his body temperature was about 38 ℃. There was no obvious time characteristic. He had taken cough drugs by himself, but the symptoms did not improve significantly. One month ago, a chest CT examination in a local hospital showed multiple patches and increased gauze density in both lungs. After "amoxicillin/sulbactam" anti-infective treatment, the chest CT lesions were not absorbed after re-examination. Percutaneous pulmonary puncture pathology showed multiple fibrous nodules and Langhans giant cell reaction. Because pulmonary tuberculosis could not be ruled out, he went to Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine for further diagnosis and treatment. Physical examination after admission: body temperature 36.9℃, pulse 100 beats/min, breathing 18 beats/min, blood pressure 120/70 mmHg (1 mmHg =0.133 kPa), clear consciousness, no cyanosis of the lips, several swollen lymph nodes palpable in the neck, the size of a mung bean, medium quality, no tenderness, soft neck, no distension of the jugular vein, coarse breathing sounds in both lungs, no obvious dry and wet rales, heart rate 100 beats/min, uniform rhythm, no obvious pathological murmur in the auscultation area of the heart valves, flat and soft abdomen, no tenderness and rebound pain in the whole abdomen, no liver and spleen under the costs, negative mobile voicing, no edema in both lower limbs, and negative pathological signs. Preliminary diagnosis of admission: the nature of lung shadow is to be investigated. Routine blood test after admission: white blood cells were 10.1×10⁹/L, 0.78 for neutrophils and 57 mg/L for hypersensitive C-reactive protein. There were no obvious abnormalities in blood biochemistry and blood tumor markers, and serum MTB antibody was positive. Chest CT showed multiple irregular ground glass shadows in both lungs, surrounded by consolidation rings (Figure 1,Figure 2,Figure 3)。 Multiple sputum smears were negative for acid-fast bacilli, and the γ-interferon release test was positive (261 ng/L). Bronchoscopy showed no obvious abnormalities in each lumen of the trachea, BALF and brush smear were negative for acid-fast bacilli, and TB-DNA in BALF was 3.28×10⁷Copies/L. The pathological results of cervical lymph node puncture showed a large number of agglomerated epithelial cells, multinucleated giant cells, a large number of lymphocytes and lymphocyte granulomatous lesions.

Adenoid cystic carcinoma (ACC) is one of the most common primary malignancies of the trachea in adults (approximately 30%)^[1]。 This study summarized the manifestations of ACC diagnosed and treated in Beijing Coal General Hospital in recent years on CT imaging and under bronchoscopy for clinical reference.

Ventilator-associated pneumonia (VAP) is the most common ICU-acquired infection, with an incidence of 6% to 52%^[1]。 VAP leads to increased mortality, prolonged hospital stay and higher hospital costs. In recent years, research on VAP has made some progress, especially after the introduction of relevant clinical guidelines^[2]The global incidence rate is decreasing year by year, but the high incidence rate and mortality rate of VAP in China are still grim. The author intends to introduce the pathogenesis and treatment strategies of ventilator-associated pneumonia in combination with recent research progress as follows.

At present, the epidemic situation of tuberculosis in China is still very severe, especially the incidence of drug-resistant tuberculosis is on the rise. In the review column of this issue, Professor Xiao Heping, deputy editor-in-chief of this journal, wrote in the article "Rational use of anti-tuberculosis drugs is the cornerstone of controlling the epidemic of drug-resistant tuberculosis": As a global infectious disease, chemotherapy of tuberculosis has been facing severe tests. The chemotherapy of tuberculosis has gradually developed from the early application of single anti-tuberculosis drugs to the most basic combination of four drugs in the 1970s. The 2013 global tuberculosis epidemic report suggests that the incidence, prevalence and mortality of tuberculosis are all showing a downward trend. The epidemiological sampling survey data in China from 1990 to 2010 shows that the decline of the above three rates is even more remarkable, which is closely related to the popularization and application of standard short-course chemotherapy regimens and the rational use of anti-tuberculosis drugs. Against the background of the decline of the global tuberculosis epidemic, the incidence of multidrug-resistant tuberculosis, especially extensively drug-resistant tuberculosis, is on the rise. The results of the 2010 National Tuberculosis Epidemiological Sampling Survey showed that the incidence of multidrug-resistant tuberculosis was 2.1%, which was higher than 0.68% in 2007-2008, which was shocking. Faced with this situation, Professor Xiao put forward 9 aspects that should be paid attention to in the process of tuberculosis treatment in this article, which have important reference value for slowing down the occurrence of drug-resistant tuberculosis and are worth reading carefully.