Advances in the treatment and prevention of tuberculosis
Tuberculosis has plagued humanity for thousands of years and remains a serious public health problem today. Tuberculosis kills more people worldwide than all infectious diseases combined. Multidrug-resistant TB and the emergence of super drug-resistant bacteria in recent years threaten to make TB an “incurable disease” again, and the emergence of AIDS has exacerbated the global TB epidemic. Our government attaches great importance to this issue and has made a solemn commitment to the world to control tuberculosis. Currently, we are one of the 22 countries with a high burden of tuberculosis in the world, except for India.
Back in the 1980s, developed countries in the United States, Japan, and Europe announced the elimination of TB in the 1920s and 1930s after analyzing the incidence and treatment of TB in their countries. However, the tuberculosis in these countries has not only not been eliminated, but has increased, especially with the emergence of drug-resistant tuberculosis and the increase of tuberculosis comorbidity, which has made it more difficult to control and eliminate tuberculosis.
I. What is tuberculosis and does it develop when the human body is infected with Mycobacterium tuberculosis?
Tuberculosis is a disease caused by the interaction of Mycobacterium tuberculosis with the human body after infection. Except for hair, teeth and nails, which do not suffer from tuberculosis, any other part of the body can suffer from tuberculosis. Today, more than one-third of the population is infected with the tuberculosis bacterium, but most do not develop the disease, and only 10 percent of those infected can develop tuberculosis. This is related to the following factors: the number of infected bacteria, the virulence of the bacteria, mutated bacteria, drug-resistant bacteria, the resistance of the body, immunity, whether the body is combined with other diseases and other conditions.
Tuberculosis accounts for about 70 to 80% of tuberculosis, while tuberculosis in other parts of the body is relatively rare, but very few people suffer from severe tuberculosis in multiple parts of the body.
The term “infectious or not” usually refers to whether TB is contagious or not. The spread of any infectious disease requires three conditions, namely, the source of infection, the route of transmission, and the susceptible population. Only TB patients with positive sputum smear antacid bacilli are infectious. They cough, sneeze and talk loudly to eject TB bacilli from the body through the nasal and oral cavities. According to statistics, untreated sputum-positive TB patients can infect at least 10 to 15 people with active TB each year. Thus, early detection of TB patients is particularly important. It has been proven that when a sputum-positive pulmonary patient is treated with anti-tuberculosis therapy for 7-14 days, even though he or she is still excreting bacteria, the virulence of the bacteria is reduced and the amount of bacteria decreases extremely quickly, thus making the infection much less or non-infectious. This shows that treating newly discovered patients is the best way to prevent and control tuberculosis.
Classification and typing of tuberculosis (with typical CT imaging images)
The classification and typing of tuberculosis has undergone several major improvements, so we will not go into detail here, but will only talk about the present-day national classification.
1, primary tuberculosis (type I tuberculosis).
After the tuberculosis bacterium invades the human lung for the first time, causing pathological changes with clinical manifestations, it is called primary tuberculosis. Primary tuberculosis is most common in children, and about 20% of adolescents. In recent years, the age of onset of primary tuberculosis has shifted, and there is an increasing trend of primary tuberculosis in adults. Primary TB includes primary syndrome and bronchial lymph node TB.
More than 90% of the first infected patients recover spontaneously without treatment, and it has no effect on the development and growth of children.
We have a special pediatric tuberculosis unit.
2. Blood-borne tuberculosis (type II tuberculosis)
There are three types of tuberculosis: acute disseminated pulmonary tuberculosis (acute cornified tuberculosis)
Subacute disseminated pulmonary tuberculosis (subacute cornified pulmonary tuberculosis)
Chronic disseminated tuberculosis (chronic cornified tuberculosis)
The clinical symptoms of this type of tuberculosis are more severe and can easily develop into generalized severe tuberculosis and tuberculous meningitis. For clinical diagnosis of acute disseminated pulmonary tuberculosis, lumbar puncture is routinely performed for examination, and if necessary, cranial MRI is performed to detect tuberculous meningitis without meningitis symptoms.
The hospital has a special tuberculous meningitis department.
3.Secondary tuberculosis (type III tuberculosis)
This type is the most common, accounting for 90% of pulmonary tuberculosis, and includes four specific types
Cheese type pneumonia
Tuberculosis globules
Bronchial tuberculosis
Chronic fibrous cavity type tuberculosis
The hospital has a respiratory intervention department and an intensive care tuberculosis department to treat these patients.
4.Tuberculous pleurisy(Ⅳ)
5.Extrapulmonary tuberculosis (V)
III. Diagnostic methods of tuberculosis
1, the collection of medical history.
Pay attention to past history, contact history, history of BCG vaccination and the presence of card scars and card marks, past history of anti-tuberculosis medication and medication rules, whether to interrupt, how the course of treatment, etc.
Signs and symptoms of TB are sometimes atypical, or even completely absent, and are detected during physical examinations or visits for other diseases. In one quarter of patients, a chest X-ray reveals calcified spots in the lungs, which is a result of the body being infected with a small amount of Mycobacterium tuberculosis many times, and the body’s resistance is strong and it heals itself.
2.Tuberculin skin test.
Divided old tuberculin test (OT) and pure protein derivative of Mycobacterium tuberculosis (PPD).
Value evaluation: there are false positives and false negatives, and it has diagnostic significance for strong positives in pediatric patients, but even strong positives in adults can only indicate evidence of Mycobacterium tuberculosis infection.
3, DNA loop-mediated isothermal amplification (LAMP) new technique.
The commonly used clinical methods for detecting Mycobacterium tuberculosis are sputum smear antacid staining and sputum tuberculosis culture. LAMP is a new convenient, specific, sensitive and rapid new nucleic acid gene amplification detection technology.
4. γ-interferon release assay (IGRAS).
Sensitized lymphocytes will exist in human body after the first infection with TB bacilli. When human body is exposed to TB antigen again, the sensitized lymphocytes will be rapidly activated into effector lymphocytes and produce high levels of cytokines, of which the most important cytokine is γ-interferon, so the level of γ-interferon can be used as a diagnosis Therefore, the level of γ-interferon can be used as an indicator for the diagnosis of tuberculosis and latent TB infection.
The γ-interferon release test (IGRAS) mainly includes two methods: whole blood ELISA method and enzyme-linked immunospot method (T SPOT-TB).
At present, there is a lack of PPD skin test solution in China, and this test method can be used instead, but its price is high, and there are still false negatives and false positives.
5, TB antibody and TB chip, blood sedimentation test.
6.Tuberculosis branching bacilli detection.
Sputum, pus, body fluids, necrotic tissue smear antacid staining test and culture.
7.Histopathological examination.
8.X-ray plain film examination ;
9.CT examination of chest.
10 Ultrasonography.
11.MRI examination of bones and joints, skull, etc.
12, Fiberoptic bronchoscopy.
13, Thoracoscopy, laparoscopy, mediastinoscopy, etc.
14, open chest biopsy.
Fourth, the treatment methods and treatment principles of tuberculosis.
1.Drug therapy.
2, interventional therapy.
3, surgical treatment.
4.Immunotherapy.
5, Chinese medicine treatment.
6, tuberculosis treatment to place special emphasis on the five principles
There are clinical differences between primary, re-treatment and drug-resistant tuberculosis, and between patients with and without bacteriophage excretion. Therefore, a reasonable and regular chemotherapy program must have reasonable bactericidal drugs and doses, scientific methods of medication, sufficient courses of treatment, but also regular and early medication in order to cure tuberculosis.
(11) Early: Early diagnosis and early treatment are emphasized for any disease, especially for tuberculosis must be early diagnosis, early treatment and early treatment to avoid tissue destruction and difficulties in repair. Zhu Subao, Department of Tuberculosis, Unincluded Hospital
② Combination: Combination of drugs is necessary for both primary and re-treatment patients. Combination of drugs must be combined with two or more kinds of drug treatment, which can avoid or delay the generation of drug resistance and improve the sterilization effect.
③ The right amount: drugs for any disease treatment must have an appropriate dose. This can achieve the purpose of treatment without bringing toxic side effects to the body.
④Regulation: The drug must be used regularly under the guidance of a specialist because the tubercle bacillus is a stubborn bacterium with a long division cycle and slow growth and reproduction that makes it difficult to kill.
⑤ Full course: The so-called full course of medication is the time needed to complete the chemotherapy regimen as determined by the doctor according to the patient’s condition, and the full course of treatment is one year or one and a half years. The minimum is not less than 6 months or 10 months.
V. Drug-resistant tuberculosis.
1.Single drug resistance: refers to the resistance of Mycobacterium tuberculosis to only one anti-tuberculosis drug;
2, multi-drug resistance: refers to mycobacterium tuberculosis resistant to H or R and other one or several anti-tuberculosis drug resistance;
3, multi-drug resistance: refers to Mycobacterium tuberculosis resistance to both H and R including or excluding other anti-tuberculosis drugs.
4, super drug resistance: refers to Mycobacterium tuberculosis while H, R, aminoglycans at least one, quinolones at least one drug.
VI. Anti-tuberculosis drugs.
1.Isoniazid
2.Rifampicin capsules and injections
3.Streptomycin
4.Ethylaminobutanol
5.Sodium p-aminosalicylate
6.Ethylthioisonicotinamide and propylthioisonicotinamide
7.Aminothiourea
8.Cyclosilicicic acid
9.Curly toxin
10.Kanatoxin
11.Tuberculosis actinomycin
12.Pyrazinamide
13.Fluoroquinolones
14.Rifamycin class (rifapentine, rifabutin)
15.Isoniazid para-aminosalicylic acid (tuberculosis clear)
16, anti-tuberculosis drug compound
17.Butyramine kanatoxin
18.Chlorophenothiazine
19, β class amide antibiotics and β class amidase inhibitors combined application
20.New macrolides
21.Linazolamide
22, Imipenem/cistatin.
Of course, there are still new drugs under continuous research.
Seven, anti-tuberculosis drug side effects and treatment.
(A) common adverse reactions.
1, gastrointestinal reactions
2.Electrolyte disturbance
3, liver toxicity
4, ototoxicity and vestibular dysfunction
5.Nephrotoxicity
6.Arthralgia or muscle aches
7.Hematological system damage
8.Convulsions
9.Peripheral neuritis
10.Optic neuritis
11.Psychiatric symptoms
12.Thyroid disorder
13.Allergic reaction
(B) Treatment principles.
1, seriously treat and monitor the adverse reactions caused by anti-tuberculosis drugs is the best prevention to prevent or avoid serious adverse reactions, so to achieve early detection, timely diagnosis and treatment.
2, if the adverse drug reactions are mild and do not cause abnormal liver and kidney functions, blood and urine routine, symptomatic measures can be taken to continue anti-tuberculosis treatment while closely observing and detecting adverse reactions, and if necessary, adjuvant drug therapy or appropriate adjustment of the dose or treatment plan by a specialist; but to strictly control the indications for changing anti-tuberculosis drugs or interrupting treatment due to adverse drug reactions.
Serious adverse reactions such as high fever, skin rash, yellow skin stain, change in hearing, low urine or psychiatric symptoms should be treated immediately, and all anti-tuberculosis drugs should be discontinued and hospitalized at the same time.
For infants and young children with unclear speech, ethambutol and aminoglycosides are generally not used. For those younger than 18 years old, quinolones should be used with caution or not.
VIII. Preventive measures for tuberculosis
The most infectious time of tuberculosis is before discovery and treatment, so attention should be paid to early detection and correct and timely treatment of the source of infection, which is also the most important measure to prevent and treat tuberculosis.?
1, the main preventive measures for tuberculosis are the following three?
1.1 Early detection of patients and implementation of DOTS This is currently the most important measure for TB prevention and control because it directly controls the source of TB infection. The keys to the success of this measure are.
①. People with TB symptoms go to the local TB control facility as soon as possible for early confirmation of the diagnosis;
②. The key to successful treatment is to complete the full course of treatment and not to stop the medication in the middle of the course, as this will not only lead to treatment failure but also to drug resistance, which will endanger others.
1.2 BCG vaccination BCG vaccine is a live attenuated, weakly virulent vaccine. By artificial means, it can produce a mild infection in uninfected people without the risk of disease, and it can produce resistance to tuberculosis and reduce the incidence of tuberculosis. In areas with a high incidence of tuberculosis, BCG vaccination is quite effective in preventing tuberculosis, especially serious types of tuberculosis that may endanger the lives of children, such as tuberculous meningitis and cornual tuberculosis. The main targets of BCG vaccination are newborns, infants and children. BCG vaccination is called the “first shot at birth” and should be given to newborns born in maternity homes and maternity units as soon as they are born. If they are not vaccinated in time at birth, they must go to the local tuberculosis control institution or other BCG vaccination stations within one year of age for a follow-up vaccination.
1.3 Preventive treatment for those already infected
Prevention of tuberculosis with anti-tuberculosis drugs is very effective for people who are already infected with TB bacteria. In the case of high infection rate in our country, the following special groups or key targets should be prevented with drugs, which can reduce the occurrence of tuberculosis:
①. Human immunodeficiency virus (HIV) infected people.
②. Young children and adolescents who have close contact with newly diagnosed infectious tuberculosis patients who are tuberculin-positive.
③. Children under 5 years of age who have not received BCG vaccine and have a positive tuberculin test.
④. Tuberculin-positive patients with diabetes mellitus, silicosis, long-term treatment with adrenal corticosteroids, and immunosuppressive therapy.
⑤. Those who have inactive tuberculosis lesions on X-ray chest film and have not received anti-tuberculosis treatment.
⑥. Those with strong positive tuberculin test.
IX. Issues related to bacillus-negative tuberculosis.
1. Diagnostic criteria?
(1) With typical clinical symptoms and chest X-ray manifestations of tuberculosis;
②Diagnostic anti-tuberculosis treatment is effective;
③ other non-tuberculous lung diseases can be excluded clinically;
④Strongly positive PPD (5IU) and positive serum anti-tuberculosis antibody;
⑤ Positive PCR and probe test for sputum tuberculosis;
⑥Extrapulmonary histopathology confirmed tuberculosis-like lesions;
(vii) BALF detects antacid bacilli;
(8) Histopathology of bronchus or lung confirmed tuberculosis lesion.
The diagnosis can be confirmed by having 3 of the above items from ① to ⑥ or any 1 of the above items from ⑦ to ⑧.
2. Current status of diagnosis of bacillus-negative tuberculosis in China
There are three diagnostic criteria being applied in the diagnosis of tuberculosis in China.
(1) The diagnostic criteria of pulmonary tuberculosis in Internal Medicine;
(2) “Guidelines for diagnosis and treatment of pulmonary tuberculosis” and “Chinese classification of tuberculosis” developed by the Chinese Medical Association Branch of Tuberculosis, and (3) the diagnostic criteria for pulmonary tuberculosis issued by the Ministry of Health of the People’s Republic of China on January 16, 2008 [5].
Despite these three criteria and the eight criteria for the diagnosis of bacillus-negative tuberculosis specifically developed in the guidelines for the diagnosis and treatment of tuberculosis, there are many perplexing problems with the practical application of these criteria in the diagnosis of tuberculosis – the difficulty of diagnosing bacillus-negative tuberculosis – especially in patients who have failed to obtain positive bacteriological and pathological results. In other words, the current diagnostic criteria for tuberculosis have not solved the challenge of diagnosing bacillary-negative tuberculosis.
3. Reasons for the difficulty in diagnosing “bacillary-negative” tuberculosis
In theory, it is possible to obtain bacteriological and pathological evidence for any tuberculosis patient. However, in practice, many factors influence the diagnosis.
With the improvement of socioeconomic conditions and the increase of public awareness of health protection, fewer and fewer patients are seen for typical clinical manifestations of tuberculosis. Some patients do not show cough or sputum at all, and there is no sputum to be found.
② Imaging of heterogeneous disease with the same image and heterogeneous image of the same disease is very common. Clinicians have a low awareness of TB as a common disease and ignore TB-related examinations.
③ The level of skill in obtaining clinical specimens varies greatly between hospitals of different levels and regions.
④ Not all patients or patients’ families accept or allow the use of invasive methods of obtaining specimens; even autopsy specimens are not available whenever they want to obtain them.
⑤ A positive result on further bacteriological examination may not always be TB. (Mycobacterium tuberculosis accounts for about 5% of non-tuberculous sputum specimens in Peyang)
⑥ Pathology often has atypical or difficult to define findings (e.g., reporting chronic granulomatous inflammation).
(7) Diagnostic antituberculosis treatment is effective, but a few are overdiagnosed, and the duration of “effective treatment” varies from patient to patient.
(8) Tuberculosis can coexist with other diseases, and coexisting lung infections, lung cancer, and pneumoconiosis are common. There are autopsy reports of multiple coexisting diseases in one patient.
The good diagnostic method we seek is actually a method with a high rate of correctness, not an absolute “gold standard” (including all diseases).
4. Several problems to be avoided in the diagnosis of bacillus-negative tuberculosis
① Do not treat TB as a rare disease.
② Avoid the diagnostic mindset of “diagnosis A excludes B”. There is a dialectical relationship between quantity, quality and probability in everything. It is common for multiple diseases to coexist. A diagnosis of other diseases does not necessarily exclude a diagnosis of tuberculosis. Similarly, a diagnosis of tuberculosis does not necessarily rule out other diseases.
③ Do not delay or even abandon treatment of a curable disease in order to confirm the existence of a malignant disease that is not yet certain. Pay attention to the sequence of diagnostic tests and treatment between diseases that can be cured in the short term, those that take longer to cure, those that are difficult to cure, and those that cannot be cured.
X. Judgment criteria for diagnostic anti-tuberculosis treatment
1. Diagnostic anti-tuberculosis treatment can be given in the following cases.
① Inflammatory images of the lungs + typical respiratory and systemic clinical manifestations of pulmonary tuberculosis, with no etiological or pathological basis for other diseases found in the short term.
② X-ray manifestations of typical pulmonary tuberculosis with multi-morphic lesions, multi-site distribution, appearing in the post-apical segment of both upper lobes, the dorsal segment of both lower lobes and the posterior basal segment, with no etiological or pathological basis for other diseases found in the short term.
③ Inflammatory images of the lungs + ineffective or poorly treated with anti-infective therapy.
④ Pulmonary lesion imaging + atypical chronic inflammatory pathology with no pathogenic or pathological basis for other diseases found in the short term.
⑤ Imaging of lung lesions + immunologic basis without history of antituberculosis treatment. Or history of TB treatment with fresh lesions or perifocal inflammatory changes or new cavities in the lungs. (This includes those who have found an etiological or pathological basis for other diseases. Among them, those with elevated blood count, obvious manifestations of infection toxicity or other pathogenic grounds are first treated with anti-infection therapy)
2. Suggestions on the duration of diagnostic anti-tuberculosis treatment
Most patients with tuberculosis have significant changes in symptoms within one week of treatment, and significant improvement on chest radiographs usually takes 1-2 months. However, if there is a Hirschsprung-like reaction, there may be no significant improvement for 2-3 months, and a few of these patients will not show significant improvement until after 3 months. Therefore, the duration of diagnostic antituberculosis treatment is recommended to be two months, and the duration should be extended to four months in the case of Hirschsprung’s-like reactions.
XI. Issues related to tuberculosis treatment.
1. All practitioners who provide treatment for patients with tuberculosis have an extremely important public health responsibility. To accomplish this task, practitioners must not only be able to provide appropriate treatment regimens, but also have the ability to assess and improve patient compliance with the regimen. By striving to ensure patient compliance with the protocol, the practitioner will be able to complete the treatment.
2. All untreated patients (including HIV-infected patients) should be treated with an internationally recognized regimen of first-line drugs with known high bioavailability. The initial phase should be 2 months of treatment with isoniazid, rifampin, pyrazinamide, and ethambutol. The preferred continuation regimen is a 4-month course of isoniazid and rifampicin. If this regimen affects patient compliance, 6 months of isoniazid and ethambutol during the continuation period is also an option, but this regimen has a high failure and relapse rate, especially in patients with co-infection with HIV. The use of antituberculosis drugs should be consistent with international recommendations. Two (isoniazid and rifampicin), three (isoniazid, rifampicin and pyrazinamide) and four (isoniazid, rifampicin, pyrazinamide and ethambutol) fixed combination drug formulations are strongly recommended, especially in the absence of bioavailability measurements.
3. To improve and assess adherence, a patient-centered approach to treatment management based on meeting patient needs and mutual respect between physician and patient should be extended to all patients. Supervision and support should be gender- and age-specific, and comprehensive and effective interventions and support services, including patient counseling and education, should be used. Patient-centered strategies focus on measures to assess and improve adherence to treatment and adjustments in the event of nonadherence. These measures should be tailored to each patient and accepted by both patient and physician. These measures include direct patient interviewing (direct observation of treatment DOT) by a responsible health care provider who is acceptable to the patient and the health system.
4. All patients should be monitored for treatment efficacy, with at least two sputum smear microscopies at the end of the initial phase (2 months), at the end of May, and at the end of treatment, respectively, to best evaluate the diagnosis of TB patients.
5. Written records of drug use, bacteriological feedback and adverse reactions should be kept for all patients.
6. In areas with high HIV prevalence and where TB and HIV coexist, HIV counseling and testing of all TB patients should be a routine management program.
7. All TB patients with HIV infection should be evaluated to determine the need for antiretroviral therapy in the course of TB treatment. Patients who are indicated for treatment should be managed with antiretroviral therapy as appropriate.
8. All evaluations of patient resistance based on: treatment history, exposure to drug-resistant strains, and prevalence of drug-resistant strains in the community should be obtained. Patients with treatment failure and chronic rejection cases should be evaluated for drug resistance. Drug susceptibility testing for isoniazid, rifampin and ethambutol should be performed as soon as possible for patients who are thought to have developed drug resistance.?
9. Patients with tuberculosis infected with drug-resistant strains [especially those with multidrug resistance (MDR)] should be treated with second-line anti-tuberculosis drugs.