Management of Tuberculosis: Are the Practices Homogeneous in High-Income Countries?

Objectives: To evaluate and compare practices regarding the diagnosis, isolation measures, and treatment of tuberculosis (TB) in high-income countries and mainly in Europe. Materials and Methods: A survey was conducted from November 2018 to April 2019 within the European Society of Clinical Microbiology and Infectious Diseases Study Group for Mycobacterial Infections (ESGMYC). The practices observed were compared to the main international guidelines. Results: Among 136 ESGMYC members, 64 (17 countries) responded to the questionnaire. In their practice, two (20.7%) or three sputum samples (79.3%) were collected for the diagnosis of pulmonary TB, alternatively induced sputum (n = 37, 67.2%), bronchoscopy (34, 58.6%), and gastric aspirates (15, 25.9%). Nucleic acid amplification tests (NAATs) were performed by 41 (64%) respondents whatever the smear result and by 47 (73%) in case of smear-positive specimens. NAAT and adenosine deaminase measurement were used for extrapulmonary TB diagnosis in 83.6 and 40.4% of cases, respectively. For isolation duration, 21 respondents (42.9%) were keeping isolation until smear negativity. An initial treatment without ethambutol was offered by 14% (n = 9) of respondents. Corticosteroid therapy, cerebrospinal fluid opening pressure testing, and repeated lumbar puncture were carried out for central nervous system TB by 79.6, 51.9, and 46.3% of the respondents, respectively. For patients with human immunodeficiency virus–TB coinfection, the preferred antiretroviral therapy included dolutegravir 50 mg twice a day (56.8%). Comparing with the recommendations of the main guidelines, the practices are not totally consistent. Conclusion: This study shows heterogeneous practices, particularly for diagnosis, and isolation, although rapid molecular testing is implemented in most centers. More standardization might be needed.


INTRODUCTION
In 2017, 10 million people were diagnosed with tuberculosis (TB) in the world (1,2). Although the European region accounted for only 3% of all cases (3), TB remains a common infection. Despite a rate of latent TB estimated at 23% of the world population, there are very large disparities in incidence between continents and countries with an incidence of fewer than 10 per 10,000 inhabitants in Western Europe to more than 500 per 100,000 for countries such as South Africa, the Philippines, and Mozambique (2). The overall objective of the World Health Organization (WHO) by 2035 (The End TB strategy) is to reduce the number of deaths from TB by 95% (compared to 2015) and to reduce the incidence rate of TB by 90% to fewer than 10 per 100,000 people. In 2016, 58,994 cases of TB were reported in 30 European Union/European Economic Area (EU/EEA) countries (2). The decreasing notification rates observed in most countries are reassuring, but annual rates of decline are still insufficient to achieve the WHO target of TB elimination by 2050 in European low-incidence countries. Multidrug-resistant (MDR) TB was reported for 3.7% of 36,071 cases with drug susceptibility testing results and continues to be the highest (more than 10%) in the three Baltic countries. Extensively drug-resistant (XDR) TB was reported for 20.1% of 984 MDR TB cases tested for second-line drug susceptibility (4). Data on human immunodeficiency virus (HIV) coinfection remained widely incomplete in Europe. Of all TB cases with known HIV status, 4.5% were coinfected with the virus (5).
An evaluation of TB case management in the EU/EEA countries, with special focus on MDR and XDR-TB, was conducted in 2010, using a standardized survey tool in five European centers. Deviations from international standards of TB care were observed in the following areas: surveillance (no information available on patient outcomes); infection control (lack of respiratory isolation rooms/procedures and negativepressure ventilation rooms); clinical management of TB, MDR-TB, and HIV coinfection (inadequate bacteriological diagnosis, regimen selection, and treatment duration); laboratory support; and diagnostic/treatment algorithms (6).
A response to this need of harmonization has already been initiated through the development of European Union Standards for TB Care (ESTC) in 2012 with an update in 2017. They identified key standards for the diagnosis, management, prevention, and control of TB, MDR-TB, and XDR-TB. These standards aim to support health care workers in optimizing TB case management and thus at contributing to improved TB control in the EU/EEA (7)(8)(9)(10)(11). In fact, after the implementation of these standards, the knowledge of appropriate TB case management in high-income countries and in particular the  In a second step, in order to understand the differences in the management of TB in high-income countries, we compared the participants' responses to the main principles of TB management according to the following international recommendations: Infectious Disease Society of America/Centers for Disease Control/American Thoracic Society (IDSA/CDC/ATS) guidelines (12,13), National Institute for Health and Care Excellence (NICE) guidelines (14), ERS/ECDC (European Respiratory Society/European Centers for Disease Control) guidelines (11), WHO (15), and the recommendations of the French Hospital Hygiene Society (16). These are summarized in Tables 2-4 for comparing the proposals of each academic society.
In the case of positive culture, of 61 respondents, 38 (62%) were asking for molecular detection of rifampicin resistance mutation, 24 (39%) for an isoniazid resistance mutation, and 9 (15%) for resistance mutations to other drugs, whereas 23 (38%) were not looking for genotypic resistance.

Isolation Practices
Overall, 23% (n = 15/63) of respondents used a conventional single room to isolate pulmonary TB patients, whereas 77% (n = 50/63) reported using a negative-pressure room whatever the drug susceptibility profile of the strain. Regarding the duration of isolation for pulmonary TB with smear-positive sputum, 23/64 (36%) respondents adopted a standardized duration of 2 to 3 weeks, whereas 23/64 (36%) reported waiting for the sputum smear-negative conversion. In case of patients hospitalized with a suspicion of pulmonary TB but negative sputum smears and pending culture results, 18/64 (28%) of the respondents did not isolate the patient. Patients with a positive sputum smear were allowed to leave the hospital by 75% (n = 48/64) of respondents, in the following cases: if they agreed to wear a mask (n = 31/48, 65%), if there were no other people at home (n = 39/48, 81%), and in the absence of children (n = 29/48, 60%) or of immunocompromised individuals (n = 36/48, 75%) at home.

DISCUSSION
TB continues to be a priority public health challenge in highincome countries. While EU/EEA countries adopted the key principles of TB control and elimination through the Europespecific consensus-based documents born within the Wolfheze initiative and subsequent documents, a uniform set of guidelines summarizing essential standards to guide European clinicians and health care workers was developed only in 2012 (7,8). Both International Standards for Tuberculosis Control (ISTC) and ESTC prescribe a widely accepted level of TB care, to guide all health care providers and clinicians, both public and private, in achieving optimal standards in managing individuals who have active TB, latent TB infection, or signs and symptoms compatible with the disease. The standards are designed to complement existing national or international guidelines and are consistent with the WHO definitions and recommendations (15,17).
Our survey of TB management shows that practical attitudes currently can differ in some respects.
Regarding the diagnosis of TB, the practices are relatively consensual with the continued use of sputum examination, although the modalities may differ in number or timeframe (19). It should be noted, however, that 13.8% of participants performed only one sputum examination, whereas the guidelines always recommend performing at least two sputum smears ( Table 1). Alternative examinations when patients were unable to provide a sputum sample vary according to the centers with equally heterogeneous guidelines: IDSA/ATS/CDC recommendations favor sputum induction compared to bronchoscopy. NICE guidelines are the only ones to propose gastric lavage, whereas 25.9% of respondents use it in clinical practice (Table 1) (20,21). We observed that almost all centers use NAAT, although these tests are not yet carried out systematically for the diagnosis of TB (only 62.1% of respondents) as recommended by the guidelines (19,22,23). Despite recommendations to look for mutations conferring resistance to rifampicin and isoniazid, 16% of participants did not perform rapid molecular detection testing for rifampicin resistance in case of smear-positive patients (24,25). For extrapulmonary TB, a majority of participants (86.3%) in the survey performed several rapid molecular tests as recommended by international guidelines. In contrast, the measurement of ADA was not universally used (40%), and it was mainly confined to pleural fluid. This recommendation is not consistent across all guidelines, because the ADA is used only for the ATS/ IDSA/CDC and NICE guidelines for pleural fluid, peritoneal fluid, and CSF. The monitoring of sputum smear microscopy and sputum culture is only recommended in the ERS/ECDC and WHO guidelines at least at the end of completion of intensive phase and actually performed after 2 months of treatment by most participants (82.5%). Finally, it should be noted that almost a third and a quarter of the responders, respectively, used IGRA and TST tests for diagnosis, whereas this is not recommended in most guidelines. These tests cannot effectively differentiate active and latent TB, even though a phlyctenular TST could predict rather an active TB (26).
Concerning the prevention of the risk of transmission of TB, the ERS/ECDC and NICE guidelines clearly specify the need to isolate the patient in a negative-pressure chamber, whereas 22% of the participants did not (14,18). The isolation duration of contagious patients remains controversial, with 36% of respondents having adopted standardized isolation duration of 2-3 weeks, like the guidelines of NICE and the French Hospital Hygiene Society (14,16); 43% prefer to wait for sputum smear conversion, as recommended by WHO and ATS/IDSA/CDC guidelines (13,15). It should be noted that the conditions for patients discharged from health care facilities remains poorly studied, and this lack of evidence is reflected in the international recommendations from academic societies.
Regarding the treatment of TB, the initial treatment with four drugs is highly consensual between the respondents and the different recommendations; however, 14% still prescribed an initial treatment with only three drugs (respondents from different countries). The role of rapid molecular tests for resistance to isoniazid in guiding the withdrawal of ethambutol from the intensive phase treatment is yet unclear. The role of fluoroquinolones in first-line treatment, pyridoxine prophylaxis, CSF pressure measurement, and therapeutic drug monitoring should be better defined with additional studies. Similarly, monthly ophthalmologic monitoring of ethambutol patients is recommended only by the North American ATS/IDSA/CDC guidelines (13). On the other hand, the use of corticosteroids in the treatment of central nervous system TB is well established in the literature and among the various guidelines, whereas 20% of the participants in our survey did not routinely prescribe corticosteroids. Among HIV-positive patients, it is well established that the duration of TB treatment should be identical to that of HIV-negative patients. The importance of managing drug-drug interactions is also well emphasized in the different guidelines, although there is no clear recommendation on which antiretrovirals should be used in combination with rifampicin. Counseling is mostly developed in WHO guidelines, which target low-resource countries. The collaboration of the interpreter and the nurse in therapeutic education is still infrequent for the stakeholders of our study: 57 and 50%, respectively, whereas most European countries report increasing TB rates among newly arrived migrants (27,28).

Analysis of Differences in Practice
It is difficult to analyze the variability of practices observed between the different respondents. There may be variability between countries due to different local recommendations but also a disparity of human or economic resources. The availability of medications, funding of TB programs, laboratory practice, staff availability, and TB epidemiology can differ between countries, but this phenomenon is probably lower in high-resource European countries than on other continents. Furthermore, in our survey, 7% of respondents used only local recommendations for TB care management, whereas 78% also relied on international recommendations, which should also limit the variability between countries. It must also be emphasized that interindividual variability within the same country is possible. Although the respondents are among the TB experts for each country, their management practice cannot be fully representative of their respective countries. For instance, the practice survey conducted in France in 2013 with specialists in infectious diseases, pneumology, and internal medicine showed that different doctors often had very different habits concerning the treatment of TB or the isolation of active TB (29). Finally, the heterogeneity of practices can also be partially explained by the heterogeneity between the different national or international recommendations, as we have seen above. This lack of consistency across the different guidelines, as it is the case, for example, with regard to isolation practices, can be confusing for the clinician. The ISTC defined the essential level of care for managing patients who have or are presumed to have TB or are at increased risk of developing the disease. In a high-resource setting, such as the EU/EEA, higher standards of care can be attained with regard to TB diagnosis, prevention, and treatment. On this basis, the ESTC was published in 2012 as standards specifically tailored to the European setting. Since the publication of the ESTC, new scientific evidence has become available, and therefore, the standards were reviewed and updated in 2017. Despite these new standards tailored to the EU setting, the harmonization of practices needs to be further improved. This is conditioned by a better standardization of national and international recommendations, a wider communication with people in charge of TB, and complementary studies to increase the level of evidence on controversial aspects of TB care. If we take the example of the joint ERS and ESCMID guidelines on the management of infections due to nontuberculous mycobacteria, which are being updated, collaboration between the various European academic societies would probably be beneficial.
Our study has several limitations. First, our sample is too small to be representative. Second, the responders were selected within the ESGMYC group, with mainly microbiologists and infectious disease specialists. Therefore, this sample does not include a lot of pulmonary physicians, although they are also very involved in TB care. Third, as mentioned above, the management practice of the responders could not be fully representative of their respective countries. Nevertheless, we think that this survey gives an interesting overview of different practices in Europe and highlights a heterogeneity in the management of TB that should be confirmed by a study with larger sample. In conclusion, WHO's international recommendations for TB management are focused on countries with high incidence. Recommendations that are more adapted to the European socioeconomic and epidemiological context have also been developed under the auspices of the ERS and the ECDC. This study shows that the management of TB is probably still heterogeneous within highincome countries, in particular for the prevention of transmission and the treatment. Concerning microbiological diagnosis, the practices seem to be better standardized, as rapid molecular testing takes an important role across most European centers. With the main objective of control and eventual elimination of TB, it seems necessary to better harmonize and disseminate the recommendations for the management of TB in Europe. European scholarly societies, and in particular ESCMID, should play a prominent role.

DATA AVAILABILITY STATEMENT
The datasets analyzed in this article are not publicly available. Requests to access the datasets should be directed to frederic.mechai@aphp.fr.