According to the WHO, there will be 9.87 million new TB cases worldwide in 2021, compared with 842 000 tb patients in mainland China. TB may seem distant, but it's all around us.
March 24, 2022 marks the 27th World TB Day, and this year's WHO campaign theme is: Invest to End TB. Save lives (life first, full commitment to ending tb), and the mainland slogan is: life first, action for all, sharing health, end tb tb.
So how to diagnose tuberculosis early? What are the differences and significance of TB-related tests?
Early detection, standardized treatment, and curing tuberculosis patients are the most important links in tuberculosis prevention and control. So how exactly is tuberculosis detected?
1. Symptomatic visit: suspicious symptoms of tuberculosis: cough, sputum cough ≥ 2 weeks, hemoptysis or blood sputum is the main local symptom of tuberculosis, with any of the above symptoms is a suspicious symptom of tuberculosis. In addition, chest tightness, chest pain, low-grade fever, night sweats, fatigue, loss of appetite and weight loss are common systemic symptoms in patients with tuberculosis.
2. Active screening: People at high risk of tuberculosis (such as close contacts of pathogen-positive tuberculosis patients, HIV-infected people and AIDS patients) can carry out active screening for tuberculosis; where conditions permit, students, supervisors, migrant workers living in concentrated areas, workers in factories and mining enterprises, and specific groups in areas with high incidence of the epidemic can be carried out according to the actual situation and local conditions.
3. Health examination: various health examination findings (mainly through chest x-ray or chest CT physical examination)
So, how to confirm the diagnosis after the suspected case of tuberculosis is found?
For people with suspicious symptoms of tuberculosis or those who require active screening or health examination, we mainly detect patients with suspected tuberculosis through chest imaging.
The new tuberculosis diagnostic criteria divide tuberculosis into: 1. 2. Primary tuberculosis;2. 3. Hematogenous disseminated tuberculosis;3. 2. Secondary tuberculosis;4. Tracheal and bronchial tuberculosis; Tuberculous pleurisy.
1. Chest imaging examination
The detection of tuberculosis first requires imaging to detect abnormalities in the lungs, and if there is no abnormality in the lungs, tuberculosis can be basically ruled out. Common chest imaging methods include chest x-ray (chest x-ray), chest CT, etc
Advantages and disadvantages of chest x-ray versus ct chest:
Chest x-ray: low cost, low radiation dose, convenient (bedside), but spatial resolution and tissue resolution are far inferior to chest CT
Chest CT: compared with the chest x-ray cost is slightly higher, the radiation dose is slightly higher (but it is a safe dose), its spatial resolution and tissue resolution are much higher than the chest x-ray, especially high-resolution CT can detect small lesions, and the morphological characteristics of the lesion, density and relationship with pulmonary tissue blood vessels are shown very clearly, making the chest CT imaging diagnosis more accurate.
Studies have shown that the overdiagnosis rate of smeared yin tuberculosis through chest x-ray is as high as 21.2% to 45%, indicating that the accuracy of chest radiograph imaging diagnosis for the diagnosis of bacterial yin tuberculosis is low, and it is subjectively affected by the diagnostic doctor.
The International Federation of Tuberculosis has organized a reading of 1100 chest X-films by 90 experts from 9 countries with extensive experience in imaging diagnostics, and 6 questions about reading (are there calcifications in the lungs?). Need treatment? Is there a hole? Is there possible nodule? Are lymph nodes abnormal? Is there an abnormality in the chest x-ray? The inconsistencies in the answers were 42%, 31%, 28%, 37%, 60%, and 34%, which was surprising.
It can be seen that chest x-ray diagnosis of tuberculosis is very subjective and relatively low specificity, and the better spatial resolution and tissue resolution of chest CT greatly improve the accuracy of diagnosis, but it is still related to the level of diagnostician reading.
1. Primary pulmonary tuberculosis: mainly manifested as primary lesions in the lungs and intrathoracic lymphadenopathy, or simple intrathoracic lymphadenopathy. Intrathoracic lymph node ring strengthening is a relatively characteristic imaging manifestation of intrathoracic lymph node tuberculosis. Ct of the chest may reveal mediastinal lymphadenopathy but needs to be differentiated from tumor lymph node metastases, lymphoma, and sarcoidosis.
*Primary pulmonary tuberculosis (intrathoracic lymph node tuberculosis): mediastinal lymphadenopathy, characterized by enhanced ring strengthening.
*Lymphoma: Mediastinal lymphadenopathy ("see stitch insert" feature)
*Pulmonary sarcoidosis: symmetrical lymphadenopathy of the mediastinum and both hilars, evenly strengthened
2. Hematologically disseminated tuberculosis: acute hematologically disseminated tuberculosis is manifested as a millet grain shadow with uniform size and density of the two lungs, and diffuse lesions of subacute or chronic hematogenous disseminated tuberculosis are mostly distributed in the upper middle of the two lungs, with different sizes and densities, and may be fused. Need to be distinguished from welders' pneumoconiosis, lung metastases and other diseases.
*Hematogenous disseminated tuberculosis: evenly distributed miliary nodules of uniform size and density
*Welder's pneumoconiosis misdiagnosed as hemodialotic tuberculosis, diffuse lung disease must be asked for occupational history, and the diagnosis of hematogenous disseminated tuberculosis without fever should be cautious
*Lung metastases of thyroid cancer: 27-year-old female, diffuse miliary opacities in both lungs, misdiagnosed as blood sowing, questioning the diagnosis due to the absence of fever, and finally diagnosed with thyroid cancer lung metastases.
3. Secondary tuberculosis: Secondary tuberculosis chest imaging is diverse. In mild cases, it is mainly manifested as patches, nodules and cords, or as tuberculosis tumors or isolated cavities, while in severe cases, it can be manifested as lobular infiltrates, caseous pneumonia, multiple cavities and bronchial dispersal to form tree bud signs;
Repeated progression may cause lung damage, damaged lung tissue volume reduction, multiple fibrous thick-walled cavities, secondary bronchiectasis, or accompanied by multiple calcifications, etc., adjacent hilar and mediastinal structural traction displacement, thoracic collapse, pleural thickening adhesion, other lung tissues out of modern compensatory emphysema and bronchial dissemination lesions of different old and new.
It is the most common form of tuberculosis and is easily confused with non-tuberculous mycobacterial infections, pneumonia, lung cancer, pulmonary fungal infections, and other lung diseases.
*Typical secondary pulmonary tuberculosis: right upper lung lesions (posterior upper apex and dorsal lower lobe are tuberculosis-prone sites), proximal ventricular cavities, visible drainage of bronchial tubes, peripheral disseminated foci (satellite foci)
* Multiple cavities dominated by double upper lungs, positive sputum acid-resistance staining, actually non-tuberculous mycobacterium lung disease (intracellular mycobacterium lung disease), misdiagnosed as tuberculosis
*Typical folio-epilodoste spreading along the bronchi, confirmed as tuberculosis (but still needs to be differentiated from other Mycoplasma pneumonia and non-Tuberculous mycobacterium lung disease)
*Left upper lung lesions, with polymorphisms and multifocality, misdiagnosed as tuberculosis, actually mycoplasma pneumonia (tree fog sign)
*Tuberculosis manifested as "anti-halo syndrome", which has been described as characteristic imaging manifestations such as machined pneumonia and vasculitis, is not uncommon in tuberculosis.
*Misdiagnosis of pneumoconiosis as tuberculosis is very common in the clinic, and the inquiry of occupational history must be emphasized for diffuse lesions
*Air crescent signs are often present as characteristic imaging of Aspergillus, but tuberculosis can also be present. In this case, patients have tuberculosis.
4. Tracheal and bronchial tuberculosis: tracheal and bronchial tuberculosis are mainly manifested as irregular thickening of the trachea or bronchial wall, narrowing or obstruction of the lumen, narrowing of the distal bronchi lung tissue may appear secondary atelectasis or consolidation, bronchiectasis and other parts of bronchial dissemination lesions.
5. Tuberculous pleurisy: chest imaging can only detect pleural effusion for tuberculous pleurisy, which is difficult to distinguish from other pleural effusions such as malignant pleural effusions alone, suggesting limited diagnostic significance. Encapsulated pleural effusion, pleural hypertrophy, and intrapulmonary tuberculosis foci suggestive diagnostic significance.
*CT chest suggests a large pleural effusion on the right side, and it is impossible to distinguish tuberculous pleural effusion from malignant pleural effusion or other causes, and requires aspiration or pleural biopsy to confirm the diagnosis.
The above few cases vividly show the typical imaging performance of tuberculosis and the objective phenomena of co-shadow and co-pathogenesis. Although imaging is not the basis for confirming the diagnosis of tuberculosis, accurate analysis of CT imaging manifestations of tuberculosis, grasp of the imaging characteristics of tuberculosis, and familiarity with the imaging manifestations of atypical tuberculosis are important means for us to improve the level of imaging diagnosis of tuberculosis.
2. Etiological examination
How do we diagnose suspected tuberculosis in the lungs by chest x-ray or chest CT? Theoretically, the detection of tuberculosis bacteria is the diagnosis of tuberculosis, which is also what we call the etiological examination.
Pathogenic testing first requires the selection of suitable test specimens, for tuberculosis, simple and easy specimens are sputum specimens, which can be coughed up for qualified sputum specimens, such as no sputum, can be used hypertonic saline atomization to induce sputum.
For infants or children, gastric juice samples are recommended in view of the inability to collect sputum samples or bronchial lavage fluids. For patients who are truly unable to retain sputum specimens, and given the relatively low positive rate of sputum specimens, invasive collection techniques such as bronchoscopy, fine needle aspiration, and lung biopsy tissue specimens for relevant etiologic testing can be obtained for patients with negative sputum specimens.
For tuberculosis other than tuberculosis, specimens of the corresponding sites can be obtained for pathogenic testing, such as pleural fluid, ascites, cerebrospinal fluid, purulent discharge, puncture fluid, urine, feces, biopsy tissue, etc.
After obtaining the specimens, the main laboratory test methods for tuberculosis pathogens are as follows:
1. Sputum smear microscopy: both dead bacteria, live bacteria, Mycobacterium tuberculosis (Mtb) and non-mycobacterium tuberculosis (NTM) can be detected. Low sensitivity, with at least 5,000 to 10,000 acid-resistant bacteria per milliliter of sputum specimens detected.
2. Mycobacterial culture: the sensitivity is higher than the smear, and 10 to 100 Mtb per milliliter sputum specimen can be detected, which is the gold standard for the diagnosis of tuberculosis, but it takes a long time and generally takes 8 weeks. After a positive culture, a species identification distinction between Mtb and NTM can be done, and a further drug susceptibility test can be used to guide clinical use.
3. Nucleic acid detection of Mycobacterium tuberculosis (molecular biology test): Taking the clinical specimen as the test object and mtb-related genes as the diagnostic markers, a series of test methods are completed to determine whether the specimen contains Mtb nucleic acid or drug resistance genes.
Commonly used detection techniques include:
1) Real-time PCR: including Gene Xpert MTB/RIF and MTB complex nucleic acid detection kit.
2) Isothermal (constant temperature) amplification technology: including ring-mediated isothermal amplification technology (LAMP), cross-primer detection technology (CPA) and real-time fluorescent nucleic acid constant temperature amplification detection technology (SAT), of which SAT detects mtb RNA, which is easily degraded in the environment, and can be regarded as the presence of live bacteria in the specimen after generally excluding pollution.
3) Probe reverse hybridization technology: including linear probe (HAIN) and gene chip, mainly used for drug resistance gene detection and strain identification of isoniazid and rifampicin.
4) Probe dissolution curve technology: it is mainly used for the detection of resistance of isoniazid, rifampicin, ethambutol and quinolones.
5) Gene sequencing technology
The detection principles of the above molecular detection methods are different, and the selected target genes are different (some of which are detected by mycobacterium tuberculosis complex), of which Gene Xpert Mtb/RIF, HAIN, and LAMP are recommended by the WHO.
In theory, positive is the detection of mycobacterium tuberculosis nucleic acid, but in practice, especially for the detection of very low or low copy number positive results, it is still necessary to combine clinical data and immunological examination to exclude specimen contamination and other factors caused by false positives.
3. Immunological examination
It is mainly used to detect whether the body has tuberculosis infection, and it is impossible to distinguish whether it is sick or not. Can be used to diagnose latent tuberculosis infection and differential diagnosis of tuberculosis.
1. Tuberculosis cell immunological examination, mainly including:
1) Tuberculin skin test (TST, the current PPD test), which is simple and inexpensive, but can be affected by BCG vaccination and non-Tuberculous mycobacterium infection, resulting in false positives.
2) Tuberculosis γ Interferon Release Test (IGRA): Commonly used internationally for QFT-G and T-SPOT kits. At present, there are more IGRA kits listed in China. IGRA sensitivity and specificity is superior to PPD, is not affected by BCG vaccination, and has cross-antigens with only 5 non-tuberculous mycobacteria, but is more expensive. Regardless of the IGRA of the kit, laboratory quality control is very important to avoid false negative results.
3) Recombinant Mycobacterium tuberculosis fusion protein (EC) skin test: ESAT-6 and CFP-10 (the same specific antigen as IGRA) were used as specific antigens for skin testing, which had high consistency with T-SPOT.
2. Humoral immunological examination of tuberculosis: tuberculosis antibodies, etc
Overall, tuberculosis immunological examination mainly determines whether the body is infected with tuberculosis through in vitro antigen antibodies and other tests, and it is impossible to distinguish whether tuberculosis is suffering from tuberculosis.
Generally speaking, positive manifestations of infection with tuberculosis, negative means no tuberculosis infection, but affected by the body's immunity and kits, laboratory quality control, etc., especially the clinical false negative false positive rate of tuberculosis antibodies is high, and the WHO does not recommend tuberculosis antibodies as tuberculosis infection and auxiliary diagnostic work.
PPD and IGRA can be used as aids in the diagnosis of tuberculosis infection and tuberculosis, it should be noted that its positive does not represent the disease, negative to exclude tuberculosis is of great value, but still need to pay attention to whether the patient's immune status and laboratory quality control affect the false negative.
4. Pathological examination
If the diagnosis is still not confirmed by the above means, a tissue sample is obtained by percutaneous lung aspiration biopsy or transbronchoscopic lung biopsy or surgical biopsy, and the diagnosis is made by pathology.
In general, for most diseases, pathological diagnosis is the gold standard, but as infectious diseases, the etiology is the gold standard for diagnosis. The pathology of tuberculosis is typical of granulomatous with caseous necrosis.
Pathology often needs to be distinguished from other granulomatous diseases, such as other infectious granulomatous non-tuberculous mycobacteria infection, fungal diseases (Cryptococcus, Aspergillus, Mucormycetes, histoplasma, etc.), parasitic diseases, leprosy, etc.; and other non-infectious granulomatous diseases such as sarcoidosis, granulomatous polyangiitis, eosinophilia polyangiitis, cloning disease, foreign granulomatous, etc.
Special staining (note that a positive antacid stain still does not distinguish between tuberculosis and non-tuberculous mycobacterium), as well as molecular pathology, can help to differentiate the diagnosis.
V. Others: Adenosine dehydrogenase (ADA)
Elevated pleural adenosine dehydrogenase (ADA) (commonly used ≥ 40U/L as the diagnostic criterion, with different literature reporting cut off points being different) has high sensitivity and specificity for the diagnosis of tuberculous pleurisy and can be used as a clinical diagnostic indicator of tuberculous pleurisy.
6. Diagnostic anti-tuberculosis therapy
Because the positive rate of tuberculosis pathogen is less than 50% (the positive rate of sputum smear is less than 30%), and the acceptance of invasive tests such as lung biopsy is not high, it is more common to give clinical diagnosis through clinical symptoms + chest imaging + tuberculosis immunology and comprehensive discussion to exclude other diseases, and to confirm the diagnosis of tuberculosis through diagnostic anti-tuberculosis therapy.
The author of this article: Wuhan Pulmonary Hospital, Deputy Chief Physician of the Department of Respiratory and Critical Care Medicine, Yang Qingqing
Typography: Super League
Image source: Courtesy of the author
Caption: Stand Cool Helo
bibliography:
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5. Expert Consensus on Molecular Diagnosis of Tuberculosis Etiology -2018
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