The Diagnosis and Treatment of Tuberculosis
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Background: Around 10 million people worldwide contract tuberculosis every year. According to the World Health Organization (WHO), approximately one-quarter of the world’s population is latently infected with Mycobacterium tuberculosis. In Germany, the incidence of tuberculosis was in decline over several decades but rose in 2015 to 7.3 new cases per 100 000 persons. In 2018, a total of 5429 new cases were documented, corresponding to 6.5 new cases per 100 000 persons.
Methods: This article is based on literature retrieved by a selective search in PubMed and on the authors’ clinical experience.
Results: Tuberculosis involves the lungs in almost 75% of patients but can generally involve any organ. In Germany, the majority of patients come from high-incidence countries. If a patient’s differential diagnosis includes tuberculosis, the main tests for the detection of the pathogen in sputum and tissue samples are culture (the gold standard), microscopy, and nucleic acid amplification tests. Imaging studies are also used for diagnosis and follow-up. The standard treatment consists of a combination of isoniazid, rifampicin, ethambutol, and pyrazinamide, followed by a combination of isoniazid and rifampicin only. Liver damage is one of the more common adverse effects of this treatment, arising in 2.4% of patients. Multidrug-resistant tuberculosis, which is rare in Germany (around 100 cases per year), should be treated in specialized centers.
Conclusion: Rapid diagnosis and targeted treatment are essential to prevent an unfavorable course of the disease as well as its transmission to other individuals. In patients presenting with unclear symptoms, tuberculosis should always be considered as a differential diagnosis. The diagnosis of latent tuberculosis and decision-making regarding its treatment are difficult because of the lack of specific biomarkers and of relevant data from clinical trials.
Tuberculosis (TB) is one of the ten leading causes of death worldwide (1). In Germany and other highly developed countries, however, TB occurs relatively seldom and can almost always be treated successfully. The rarity of TB means that not all physicians regularly encounter the disease, and the pronounced variability of the symptoms often leads to delayed diagnosis. TB is a “medical chameleon,” in that its manifestations differ widely and almost any organ may be affected. The trend towards increasing global migration is raising the profile of TB in our country, to the point where every physician should have basic familiarity with the prevailing recommendations for the diagnosis and treatment of this illness. This review article describes the clinical presentations and current management of TB, based on a selective survey of publications in PubMed backed up by the authors’ own research and clinical experience.
The World Health Organization (WHO) estimates that 1.8 billion people—around one fourth of the global population—are infected with Mycobacterium tuberculosis (2). In 2017, roughly 10 million people contracted TB and 1.6 million died of the disease (1).
In Germany, the incidence of TB decreased from the introduction of electronic documentation in 2001 up to 2014, when it occurred in 5.6 cases per 100 000 inhabitants. The number of newly diagnosed cases rose sharply to 7.3 per 100 000 in 2015 (3). A slight decrease was noted in 2017 (6.6 cases per 100 000), and the figures for 2018 are practically unaltered (5429 cases of TB registered, i.e., 6.5 per 100 000 inhabitants) (4). The trend in numbers of cases documented was determined largely by changes in migration and active case finding through screening as stipulated in §36 of the Protection Against Infection Act (Infektionsschutzgesetz; IfSG). A large proportion of the tuberculosis patients in Germany were born in other countries: 42% in 2001 (5), rising steadily to 73% in the latest statistics (6). Particularly in the years 2015 (21.5%) and 2016 (16.5%), most of the TB cases were detected by screening according to §36 IfSG. The corresponding figure in 2017 was lower, at 9% (3, 6, 7).
In 2017, almost three quarters of the cases of TB registered in Germany affected the lungs, and four fifths of these patients had infectious pulmonary TB (6). Lymph node Tb accounts for about half of all extrapulmonary cases; the rest is accounted for by various other organ manifestations (6). Multidrug-resistant tuberculosis (MDR-TB) continues to account for only a small proportion (3%) of cases in Germany (6). The subgroup of patients born in the countries of the former Soviet Union showed the highest proportion of MDR-TB cases in 2017 (19.3%). For comparison, in the same year the corresponding figure for the subgroup of patients born in Germany was around 1% (6).
The prognosis for persons with TB in Germany is good overall, with a mortality rate of 1.9% (6).
Microbiology and pathogenesis
Mycobacterium tuberculosis, the most common TB-causing pathogen, is a nonmotile, aerobic, rod-shaped bacterium.
Transmission occurs almost exclusively through droplet infection. Whether infection ensues depends essentially on:
- The frequency of contact with a person who has infectious pulmonary TB
- The duration of contact
- The closeness of contact
- The amount and virulence of pathogen transferred
- The susceptibility of the person exposed (8).
After inhalation, extracellular and intracellular bacterial growth takes place preferentially in the well-ventilated upper levels of the lungs, especially in the alveolar macrophages. At 3 to 4 weeks post infection, healthy or non-immunocomprised individuals develop T-cell immunity, leading to decreased intracellular growth of the bacteria. The bacteria can nevertheless survive intracellularly—initially without causing clinical symptoms. In the course of immune defense mechanisms tuberculous granulomas arise, typically with central caseation (9). Especially in children or immunosuppressed individuals, clinically manifest TB may develop shortly after infection. Such cases are referred to as progressive primary TB.
Most patients, however, develop a latent TB infection (LTBI) accompanied by scarring or calcification of the tuberculous granuloma, which is not always visible on diagnostic imaging. In around 5% to 10% of patients, decreasing cellular immunity leads to reactivation of the LTBI, resulting in postprimary TB (10). Reactivation most commonly occurs within 2 years of primary infection. HIV patients are at very high risk of reactivation (10), particularly if their CD4+ T-cell count is low (e1). The risk of TB reactivation is therefore around 20 times higher in the case of untreated HIV infection than for HIV-negative persons (11). However, the risk of reactivation is also increased by other immunosuppressive conditions, e.g., diabetes mellitus (e2), terminal kidney failure (e3), or treatment with inhibitors of tumor necrosis factor-alpha (TNF-α) (12).
Clinical presentation of tuberculosis
Latent tuberculosis infection (LTBI)
LTBI is infection with vital, non-replicating TB pathogens. The infected person has a positive result on immunological testing (e.g., interferon gamma release assays; see “Diagnosis” below), but shows no symptoms of disease. Furthermore, diagnostic tests (at least chest radiography) reveal no sign of active TB. These patients are not infectious. In the presence of weakened T-cell immunity, however, LTBI can turn into active disease at any time (13). The risk of developing clinically manifest TB is about 5% during the first 18 months after infection with M. tuberculosis and circa 5% over the remaining life span (14).
Forms of disease
The typical symptoms of pulmonary TB include fever, night sweats, abnormal fatigue, productive cough, and hemoptysis. In non-immunocomprised adults the disease advances only slowly, in contrast to children and immunocompromised persons, who may experience fulminant TB with abrupt onset. Persistence of cough for more than 3 weeks should always prompt consideration of TB (Box).
Extrapulmonary and disseminated tuberculosis
In 2017, 1375 (26%) of all TB cases in Germany were exclusively extrapulmonary (6). Recent data from some industrialized countries show increasing incidence of extrapulmonary manifestations: in some regions of Spain, 37% of cases of TB detected in 2013 fell into this category (15).
The clinical symptoms can take many forms and are determined by the specific organ(s) involved.
Disseminated TB (affecting two or more organ systems), previously observed almost exclusively in children or in persons with immune suppression, is now increasingly being found in adults with no apparent immune defect (16, e4). Most of these patients are immigrants from countries with moderate to high TB incidence. Various factors such as the language barrier and frequent relocation hamper access of asylum seekers and others to the healthcare system, which may delay diagnosis and thus facilitate progress of the disease (16, 18) (e4).
The detection of LTBI has to be distinguished from the diagnosis of active TB. Indirect procedures such as the interferon-gamma release assays (IGRA) are the modern standard for diagnosis of LTBI in adults. These assays detect the secretion of interferon-gamma (IFN-γ) by T lymphocytes, which are stimulated by means of relatively TB-specific antigens. Prior bacille Calmette–Guérin (BCG) vaccination usually does not lead to false-positive results. IGRA are used principally to investigate the persons who have been in contact with an index patient who has contagious pulmonary TB. Another indication is testing for LTBI in advance of administration of drugs to achieve immunosuppression (see “Preventive treatment” below). IGRA are not suitable for diagnosis of clinically manifest TB, because they do not distinguish between latent TB and active disease.
The principal techniques for diagnosis of active TB are direct microscopic demonstration of the pathogen, culture, and nucleic acid amplification tests (NAAT; generally polymerase chain reaction [PCR]–based procedures). The sample for testing should be obtained before the commencement of treatment, and investigation for M. tuberculosis should be specified on the request form, as it does not always form part of the routine program. Open pulmonary tuberculosis can be excluded if microscopy fails to detect acid-fast rods in samples of sputum collected on three separate days. Demonstration of M. tuberculosis in culture also demonstrates infectivity but TB diagnosis by culture takes several weeks to become positive. Microscopy of samples of sputum, bronchial secretion, or bronchoalveolar lavage (BAL) fluid is economical, quick, and represents a marker for the patient’s infectiousness. However, its sensitivity is very variable (20% to 80%) and differs among investigators (19). The specificity of microscopy is also limited, because it cannot distinguish M. tuberculosis from nontuberculous mycobacteria (NTM). At least several days’ culture are required for a positive result when fluorescence-based detection systems are used, while the growth of visible colonies on solid culture media can take up to 8 weeks. Culture nevertheless remains the gold standard of TB diagnosis (20, 21) and is of central importance for resistance testing. NAAT-based methods are characterized by their swiftness, relatively good sensitivity, and very high specificity (22). Moreover, many PCR-based methods permit conclusions regarding resistance to the commonly used substances to be drawn directly from sputum or other PCR-positive materials, thus enabling early detection of monoresistant or multiresistant TB. However, comprehensive testing of resistance to all available substances, e.g., via whole-genome sequencing of the strain concerned, requires culture. If extrapulmonary TB is suspected, aspirates, biopsy samples, or body fluids (urine, sperm, stool, cerebrospinal fluid) must also be investigated using the methods described above. It is essential to include TB among the differential diagnoses and send material not just for histopathology but also for microbiological examination.
Biplanar chest radiography remains the standard method for diagnosis of TB and for monitoring the effect of treatment (Figure 1). Computed tomography (CT) achieves good results in the assessment of both lymphadenopathy (23) and endobronchial extension (24) and is superior to chest radiography for evaluation of disease activity (25, 26). Low-dose CT is recommended.
In primary TB, which is found principally in children and adolescents, one finds mostly inflammatory infiltrates—similar to lobar pneumonia—accompanied by lymphadenopathy. Around one fourth of patients with primary TB have pleural effusion, whereas cavity formation tends to be rare. Immunosuppressed persons, the elderly, and the very young are at elevated risk of miliary TB. In this case, multiple pulmonary nodules are seen particularly clearly on CT (eFigure 1). In postprimary TB there is often cavity formation with necrosis and tissue destruction, preferentially in the upper lobes.
Various imaging modalities are available for diagnosis and monitoring of extrapulmonary manifestations, such as CT, magnetic resonance imaging (MRI), and sonography (Figure 2, eFigure 2, eFigure 3). An algorithm for the diagnostic imaging of TB is shown in eBox 1.
The standard treatment for pulmonary TB comprises 2 months of quadruple therapy with isoniazid (INH), rifampicin (RMP), ethambutol (EMB), and pyrazinamide (PZA) followed directly by a further 4 months’ dual administration of RMP and INH (20, 21, 27, 28) (Table 1). Extrapulmonary and disseminated forms of TB sometimes require more extended treatment: lymph-node TB, 6 months (20, 29); articular or osseous TB, 9 months; TB of the central nervous system, 12 months (20, 21, 28). Particularly in disseminated TB, the duration of treatment should be individually adjusted according to the disease course. Doses higher than those listed in Table 1 are generally not necessary. TB during pregnancy represents an indication for treatment (eBox 2). In 2018, the Robert Koch Institute reported that information on the outcome of treatment was available for 84.5% of TB patients (5025 of 5949 cases) (6). The success rate was 81%. The data related to the year 2016; owing to the extended nature of treatment for TB, results for 2017 were not yet available. At 83%, the success rate for treatment of drug-susceptible TB was below the WHO target of 90%, but much higher than the success rate for drug-resistant TB (72%).
Resistance to standard drugs
Resistance to at least one substance (INH, EMB, RMP, PZA, streptomycin) was recorded for 12% to 14% of patients with TB in Germany between 2013 and 2017; in 3% of cases, multiple resistance (MDR-TB) was documented (6). By definition, MDR-TB is present whenever resistance at least to INH and RMP is found (20). In patients with monoresistance to RMP or INH, a fluoroquinolone (moxifloxacin, levofloxacin) can be used instead. The duration of treatment is then increased to a total of 6 to 9 months (INH resistance) or 18 to 20 months (RMP resistance), depending on the individual course (20). Patients with MDR-TB should be treated at centers possessing the necessary expertise.
Adverse effects of treatment
Severe adverse effects leading to a change in treatment occur in 4% to 9% of patients who receive the classic quadruple combination of INH, EMB, RMP, and PZA (30–32). Most adverse effects, however, are milder, such as gastrointestinal effects (nausea, vomiting) or exanthema (32), and should initially be treated symptomatically (20). Severe hepatic toxicity (elevation of transaminases to more than 3 to 5 times normal) occurs in 2.4% of cases and may necessitate temporary discontinuation of treatment (20, 21, 30, 32). Once the transaminase levels have returned to normal, the four antibiotics can be reintroduced one by one, enabling identification of the drug responsible for the toxicity in the given patient. This substance can then be replaced as advised in the guidelines (20, 33). Ophthalmological examination at 4-week intervals is recommended for early detection of the rare cases of optic neuroma (<1%) that occur in patients taking EMB (20, 32). Neurological complications such as peripheral neuropathy and psychosis are equally rare (<1%) (32, 34). Neuropathy occurs particularly in high-risk patients (e.g., existing pyridoxine deficiency, manifest polyneuropathy, pregnancy) receiving INH and can be avoided by administering 50 mg/d pyridoxine together with the INH (29). PZA regularly causes a usually clinically irrelevant elevation in serum uric acid. In the context of standard treatment, dose adjustment in the presence of kidney failure is required only for EMB and PZA.
The goal of preventive treatment is elimination of “resting” tuberculosis bacteria in persons with LTBI, reducing the likelihood of later reactivation. One indication for exclusion of LTBI is newly diagnosed HIV infection (eBox 3) (20). A comprehensive list of the indications for testing (by means of IGRA) and information on the subsequent preventive measures can be found in the pertinent guidelines (11, 20). Following a positive IGRA result, clinically manifest TB must be excluded before initiation of chemoprophylaxis. This is achieved by specific history taking, physical examination, and review of at least a chest radiograph (20). The guidelines supply precise directions for preventive treatment and describe the advantages and disadvantages of the different regimens (20).
Chemoprophylaxis in patients receiving immunosuppressive drugs
Numerous immunosuppressive drugs (biologics) for the treatment of autoimmune diseases and cancer have ben developed in recent years. For many of these substances the degree of risk for reactivation of latent TB is not yet known. It has been confirmed that treatment with TNF-α antagonists is associated with elevated risk. Thus, LTBI has to be excluded before these agents are given. Testing for LTBI and administration of chemoprophylaxis should also be considered prior to planned immunosuppression in organ or bone marrow transplantation. Estimates of the risk for reactivation of TB involved in treatment with other immunomodulatory drugs can be found in Table 2 (35–38). These recommendations are based on expert opinion formed by experimental findings from animal studies and by clinical observation.
Tuberculosis is a rare disease in Germany nowadays, but for that very reason it should not be forgotten. A timely specific diagnostic work-up followed by prompt treatment can effectively prevent further spread of the disease and avoid a severe course of illness in the individual patient (39). In industrialized countries, TB occurs most frequently in immigrants and in persons with impaired immune defenses. The growing use of immunosuppressive drugs to treat various illnesses broadens the spectrum of persons at risk. IFN-γ release assays (IGRA) are increasingly being applied to detect latent TB infection (LTBI) in these groups of patients so that they can receive preventive treatment.
Conflict of interest statement
Dr. Rademacher has received lecture fees from Omniamed.
The remaining authors declare that no conflict of interest exists.
Manuscript received on 21 April 2019, revised version accepted on 1 August 2019
Translated from the original German by David Roseveare
PD Dr. med. Dr. nat. med. Jan Rybniker
Medizinische Klinik I, Universitätsklinik Köln
Kerpener Str. 62
50937 Köln, Germany
Cite this as:
Suárez I, Fünger SM, Kröger S, Rademacher J, Fätkenheuer G,
Rybniker J: The diagnosis and treatment of tuberculosis.
Dtsch Arztebl Int 2019; 116: 729–35. DOI: 10.3238/arztebl.2019.0729
For e-References please refer to:
Diagnostic and Interventional Radiology Institute, University Hospital Cologne
Diagnostic and Interventional Radiology Institute, University Hospital Cologne
*2 Joint last authors
Division of Infectious Diseases, Department of Internal Medicine I, University Hospital Cologne:
Dr. med. Isabelle Suárez, Dr. med. Sarah Maria Fünger, Prof. Dr. med. Gerd Fätkenheuer,
PD Dr. med. Dr. nat. med. Jan Rybniker
German Center for Infection Research, Cologne–Bonn, Partner Site Cologne:
Dr. med. Isabelle Suárez, Prof. Dr. med. Gerd Fätkenheuer, PD Dr. med. Dr. nat. med. Jan Rybniker
Department of Infectious Disease Epidemiology, Robert Koch Institute, Berlin:
Dr. rer. nat. Stefan Kröger
Department of Pneumonology, Hanover Medical School: Dr. med. Jessica Rademacher
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