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Diagnosis and therapy of tuberculosis
Background: Around 10 million people worldwide develop tuberculosis every year. According to the World Health Organization (WHO), it is estimated that a quarter of the world's population is latently infected with Mycobacterium tuberculosis. In Germany, the incidence fell over several decades. In 2015, however, there was an increase to 7.3 cases of tuberculosis per 100,000 inhabitants. In 2018 there were still 6.5 cases per 100,000 inhabitants (5,429 cases).
Method: The article is based on a selective literature search in PubMed and the clinical experience of the authors.
Results: Tuberculosis manifests itself pulmonarily in about three out of four patients, but it can affect any other organ. The majority of the patients come from countries with a high incidence of tuberculosis. If tuberculosis is an option for differential diagnosis, the focus is on the pathogen detection in sputum / tissue samples by culture (gold standard) as well as microscopy and nucleic acid amplification tests. Imaging methods are also used for diagnosis and follow-up. The standard therapy used is a quadruple combination of isoniazid, rifampicin, ethambutol and pyrazinamide, followed by a double combination of isoniazid and rifampicin. Hepatotoxicity is one of the most common side effects of this therapy, occurring in 2.4% of all treated patients. Multi-drug-resistant tuberculosis is relatively rare in Germany (around 100 cases per year), and treatment should be reserved for specialized centers.
Conclusions: The rapid diagnosis and initiation of targeted therapy are essential in order to prevent severe courses and further transmissions. If the symptoms are unclear, tuberculosis should always be included in the differential diagnosis. In the case of latent tuberculosis, the diagnosis and indication of therapy are made more difficult by the lack of specific biomarkers and study data.
Tuberculosis (TB) is one of the ten leading causes of death worldwide (1). In contrast, in Germany and other highly developed countries, TB is a comparatively rare disease that is almost always treatable. Since today not every doctor treats patients with TB and the symptoms can be very diverse, the diagnosis is often only made with a delay. Due to the very different possibilities of manifestation, TB is also considered a chameleon of medicine, as it can affect almost all organs. In times of increasing global migration, the importance of TB in differential diagnosis is also increasing for us, so that current principles of diagnosis and therapy should represent basic medical knowledge. The following overview describes the clinical manifestations and current management of TB. For this purpose, a selective literature search was carried out in PubMed, and the authors' scientific and clinical experience was included.
According to WHO estimates, around 1.8 billion people - around a quarter of the world's population - are infected with Mycobacterium tuberculosis (2). In 2017, around 10 million people were newly diagnosed with TB and 1.6 million people died from it (1).
In Germany, the incidence decreased from the beginning of the electronic recording of TB in 2001 to 2014 (to 5.6 per 100,000). In 2015 there was a significant increase in the number of newly diagnosed diseases (7.3 cases per 100,000) (3). There has been a slight downward trend since 2017 (6.6 cases per 100,000). With 5,429 reported cases (6.5 cases per 100,000), the number of cases in 2018 is almost unchanged compared to the previous year (4). The changed migration and the successful case finding through screening measures according to §36 Infection Protection Act (IfSG) had a decisive influence on this development. Foreign-born patients make up a large proportion of those suffering from tuberculosis. The proportion of this group has grown steadily since 2001 from around 42% (5) to 73% (6). In 2015 (21.5%) and 2016 (16.5%) in particular, a particularly large number of TB diseases were identified through screening measures in accordance with Section 36 IfSG. In 2017 (9%) this share decreased (3, 6, 7).
In 2017, almost three quarters of all tuberculosis cases in Germany affected the lungs, with four out of five being open, i.e. infectious pulmonary tuberculosis (6). In the extrapulmonary forms, lymph node tuberculosis makes up about half, the rest is distributed over a wide range of organ manifestations (6). Cases of multidrug-resistant TB (MDR-TB) still only represent a small proportion in Germany at 3% (6). The group of patients born in the countries of the former Soviet Union again showed the highest group-related proportion of MDR-TB in 2017 (19, 3%). For comparison: The proportion of MDR-TB in the group of patients born in Germany was around 1% in the same year (6).
The prognosis for people with tuberculosis in Germany is good overall, with a mortality rate of 1.9% (6).
Microbiology and pathogenesis
Mycobacterium tuberculosis, the most common TB pathogen, is an immobile, aerobically growing rod-shaped bacterium.
The transmission takes place almost exclusively through droplet infection. Whether an infection occurs essentially depends on:
- the frequency
- the duration and
- the closeness of contact with a person with open pulmonary tuberculosis, as well as with
- the amount and virulence of the pathogen released and
- the susceptibility of the exposed person (8).
After inhalation of the bacteria, extra- and intracellular bacterial growth occurs preferentially in the well-ventilated upper lung levels, especially in the alveolar macrophages. T-cell immunity develops in healthy individuals 3–4 weeks after infection, which leads to a decrease in the intracellular growth of the bacteria. However, the bacteria can survive intracellularly - initially without causing clinical symptoms. In the course of the immune defense, tuberculous granulomas develop, which typically have central cashesion (9). Clinically manifest TB disease can develop soon after infection, especially in children or immunosuppressed people, which is referred to as progressive primary TB.
In the majority of patients, however, a latent TB infection (LTBI) develops and the tuberculous granuloma becomes scarred or calcified, which does not necessarily have to be visible in the diagnostic imaging. About 5–10% of patients experience a reactivation of the LTBI due to a decrease in cellular immunity, resulting in post-primary TB (10). Reactivation is most common within two years of primary infection. HIV patients have a very high risk of reactivation (10), especially if the number of CD4 + T cells is low (e1). The risk of TB reactivation with untreated HIV infection is around 20 times higher than in HIV-negative people (11). Other impairments of the immune system, for example diabetes mellitus (e2), terminal kidney failure (e3) or therapy with tumor necrosis factor (TNF) -alpha inhibitors (12), also increase the risk of reactivation.
Clinical picture of tuberculosis
Latent tuberculosis infection (LTBI)
LTBI is infected with vital, non-replicating tuberculosis pathogens. The infected person has a positive result of an immunological test (for example IGRA, see section Diagnostics), but does not show any symptoms of the disease. In addition, there is no evidence of active TB disease even after diagnostic work-up (at least one chest x-ray). These patients are not infectious. However, if T-cell immunity is weakened, latent TB can turn into tuberculosis at any time (13). The risk of developing clinically manifest TB is around 5% in the first 18 months after infection with Mycobacterium tuberculosis and around 5% in the remaining lifetime (14).
Forms of the disease
Typical symptoms of TB include fever, night sweats, fatigue, productive cough, and hemoptysis. In adults without impairment of the immune system, the course of the disease is usually insidious, while children and immunosuppressed people can also show fulminant courses with a sudden onset of the disease. The possibility of TB should always be considered if a cough persists for more than three weeks (box).
Extrapulmonary and disseminated tuberculosis
In 2017, there were 1,375 cases in Germany with exclusively extrapulmonary manifestations of TB (26%) (6). In some industrialized countries, current data show that the number of extrapulmonary manifestations is increasing, in some regions of Spain the proportion was 37% of all detected TB cases in 2013 (15).
The clinical symptoms are varied and are determined by the respective organ involvement.
Disseminated TB (involvement of two or more organ systems) was previously observed almost exclusively in severely immunocompromised people or children, but is now increasingly occurring in adults without an obvious immune defect (16, e4). These are mostly migrants from countries with a medium or high incidence of TB. Various factors such as the language barrier and changing accommodation make it more difficult for asylum seekers, among others, to access the health system (17), which can possibly lead to a late diagnosis and thus to the progression of the disease (16, 18) (e4).
A distinction must be made here between the diagnosis of latent TB (LTBI) and clinically manifest TB disease. Indirect procedures such as interferon gamma release assays (IGRA) are now standard for diagnosing LTBI in adults. These detect the release of interferon (IFN) -γ by T lymphocytes that have been stimulated with relatively TB-specific antigens. A previous Bacille-Calmette-Guerin (BCG) vaccination usually does not lead to false positive results. IGRAs are mainly used in the examination of the environment of contact persons of an index patient with contagious pulmonary tuberculosis. Another indication is testing for LTBI prior to drug immunosuppression (see section on preventive therapy). IGRAs are not suitable for diagnosing clinically manifest TB disease, as they cannot differentiate between latent TB and TB disease.
For the diagnosis of TB disease, however, the direct detection of pathogens using microscopy, culture and nucleic acid amplification tests (NAT, usually polymerase chain reaction (PCR) -based methods) are in the foreground. If possible, the material to be examined should be obtained before the start of therapy and the examination for Mycobacterium tuberculosis should be given as a question, since in most cases it is not part of the routine program. The exclusion criterion for open pulmonary tuberculosis is still the lack of microscopic evidence of acid-fast rods from sputum samples obtained on three different days. Evidence of culture is also a sign of contagion, and this usually only takes place several weeks after the sample has been taken. Microscopy from sputum, bronchial secretions or bronchoalveolar lavage (BAL) is inexpensive and quick, as well as a marker for the patient's contagiousness. However, the sensitivity (20–80%) is very variable and dependent on the examiner (19). The specificity is also limited, since microscopic differentiation from non-tuberculous mycobacteria (NTM) is not possible. The culture needs at least several days for a positive result when fluorescence-based detection systems are used. It can take up to 8 weeks to grow visible colonies on solid culture media. However, TB culture continues to be the gold standard in TB diagnosis (20, 21) and is of central importance for resistance testing. The NAT- or PCR-based methods are characterized by speed and relatively good sensitivity as well as very high specificity (22). In addition, many PCR-based methods can be used to make a statement about resistance to the most common substances directly from sputum or other PCR-positive materials and thus detect mono-resistant or multi-resistant TB at an early stage. However, the complete resistance testing of all available substances, for example by sequencing the entire genome of the respective strain, still requires cultivation. If extrapulmonary TB is suspected, aspirates, biopsies or body fluids (urine, semen, stool, liquor) must also be examined using the methods described above. It is essential here to think of TB in terms of differential diagnosis and to send material not only for histopathological but also for microbiological diagnosis.
The chest x-ray in two planes continues to be the standard method for diagnosis and assessment of the course during therapy (Figure 1). Computed tomography (CT) achieves good results in assessing lymphadenopathy (23) and endobronchial spread (24) and is superior to chest x-rays in assessing disease activity (25, 26). A low-dose CT is recommended.
In primary TB, which occurs mainly in children and adolescents, inflammatory infiltrates are usually found - similar to lobar pneumonia - accompanied by lymphadenopathy. A pleural effusion occurs in about a quarter of patients with primary tuberculosis, whereas cavern formation is rather rare. Immunocompromised, old and very young patients have an increased risk of miliary tuberculosis, whereby multiple pulmonary nodules are particularly evident on CT (eFigure 1). In post-primary TB, caverns are often formed with necrosis and tissue destruction, preferably in the upper lobes.
In the case of extrapulmonary manifestations, various imaging methods such as CT, magnetic resonance imaging (MRI) or sonography are available for diagnosis and assessment of the course (Figure 2, eFigure 2 and eFigure 3). A diagnostic algorithm is shown in eBox 1.
The standard therapy for pulmonary tuberculosis is isoniazid (INH), rifampicin (RMP), ethambutol (EMB) and pyrazinamide (PZA) as a quadruple therapy over two months, then for a further four months as a double therapy with RMP and INH (20, 21, 27, 28 ) (Table 1). Extrapulmonary and disseminated forms sometimes require a longer duration of treatment: lymph node TB six months (20, 29), TB of the joints or bones nine months, and CNS TB twelve months (20, 21, 28). Particularly in the case of disseminated forms, the duration of the therapy should be adapted to the individual disease progression of the patient. As a rule, it is not necessary to increase the dose (deviating from Table 1). The presence of TB during pregnancy is an indication for treatment (eBox 2). In 2018, the RKI reported (6) that information on the treatment outcome was available for 84.5% (5 025 of 5 949 cases) of TB patients. With these, the treatment success was 81%. The information relates to the year 2016, because due to the long duration of treatment for TB, complete data for 2017 was not yet available at the time of the report. The successful treatment of sensitive TB was 83% below the WHO target of 90%, but significantly higher than the successful treatment of resistant TB (72%).
Resistance to standard therapeutic agents
Resistance to at least one substance (INH, EMB, RMP, PZA, streptomycin) was registered in 12–14% of cases in Germany from 2013 to 2017, with 3% being multi-resistant (MDR-TB) (6). By definition, MDR-TB is present if there is resistance to at least INH and RMP (20). In the case of monoresistance to RMP or INH, these substances can be replaced by a fluoroquinolone (moxifloxacin, levofloxacin). Therapy is then extended to a total of 6–9 months (INH resistance) or 18–20 months (RMP resistance), depending on the course (20). Patients with MDR-TB should be treated at centers with appropriate expertise.
Side effects of therapy
Serious side effects under a classic quadruple combination that lead to a change in therapy occur in 4–9% of cases (30–32). However, mild side effects such as gastrointestinal side effects (nausea, vomiting) or a rash are more common (32). These should first be treated symptomatically (20). Temporary discontinuation of therapy may be necessary in severe liver toxicity (in 2.4% of those treated) (increase in transaminases by more than three to five times the normal) (20, 21, 30, 32).Once the transaminases have normalized, the standard therapy can be restarted sequentially and the antibiotic that is toxic to the liver in the individual case can be identified and replaced in accordance with the guidelines (33, 20). Ophthalmological check-ups every four weeks are recommended for the early detection of a rare optic neuritis (< 1 %) unter="" emb="" empfohlen="" (20,="" 32).="" neurologische="" komplikationen="" wie="" periphere="" neuropathien="" oder="" psychosen="" sind="" ebenfalls="" selten=""> 1 %)>< 1 %) (32,="" 34).="" neuropathien="" entstehen="" unter="" inh-gabe="" vor="" allem="" bei="" risikopatienten="" (zum="" beispiel="" bestehender="" pyridoxinmangel,="" manifeste="" polyneuropathie,="" schwangerschaft)="" und="" können="" durch="" die="" gabe="" von="" 50 mg/d="" pyridoxin,="" verabreicht="" zusammen="" mit="" inh,="" vermieden="" werden="" (29).="" pza="" verursacht="" regelhaft="" eine="" klinisch="" meist="" irrelevante="" erhöhung="" der="" harnsäure="" im="" serum.="" eine="" dosisanpassung="" bei="" niereninsuffizienz="" muss="" im="" rahmen="" der="" standardtherapie="" lediglich="" für="" emb="" und="" pza=""> 1 %)>
The aim of preventive therapy is the elimination of "dormant" tuberculosis bacteria as part of an LTBI, so that subsequent reactivation is less likely. One indication for excluding LTBI is a newly diagnosed HIV infection (eBox 3) (20). For a complete list of test indications using IGRA and subsequent preventive therapy regimes, we refer to the relevant guidelines (11, 20). If the IGRA is positive, clinically manifest TB disease must always be ruled out before chemoprevention. This is done through a specific anamnesis, a physical examination and at least an evaluation of the chest X-ray (20). The precise implementation of preventive therapy and the advantages and disadvantages of the various regimens can be found in the guidelines (20).
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