Table 1– Differences between the European Union Standards for Tuberculosis care (ESTC) and the third edition of the International Standards for Tuberculosis Care (ISTC)
ESTC [4]ISTC [3]Differences
1. To ensure early diagnosis, providers must be aware of individual and group risk factors for TB and perform prompt clinical evaluations and appropriate diagnostic testing for persons with symptoms and findings consistent with TBNew standard included in ISTC
Standards for TB diagnosis
1. All persons presenting with signs, symptoms, history or risk factors compatible with TB should be evaluated for pulmonary and/or extrapulmonary TB2. All patients (including children) with unexplained cough lasting ≥2 weeks or with unexplained findings suggestive of TB on chest radiographs should be evaluated for TBThe ISTC standard puts focus on the signs and symptoms of cough and unexplained findings suggestive of TB on chest radiographs, while according to the ESTC persons with any signs or symptoms compatible with TB should be evaluated. The ESTC standard specifically mentions individual risk factors for TB. This is taken into account in the new ISTC standard
2. All patients (adults, adolescents and children who are capable of producing sputum) suspected of having pulmonary TB should have at least two sputum specimens submitted for microscopic examination, culture and DST in a quality-assured laboratory. When possible, at least one early morning specimen should be obtained. In countries, settings or populations in which MDR-TB is suspected in a patient, rapid testing for the identification of rifampicin and isoniazid resistance, using validated tools in a quality-assured laboratory, should be performed3. All patients (including children) who are suspected of having pulmonary TB and who are capable of producing sputum should have at least two sputum specimens submitted for smear microscopy or a single sputum specimen for Xpert MTB/RIF testing in a quality-assured laboratory. Patients at risk for drug resistance, who have HIV risk or who are seriously ill should have Xpert MTB/RIF performed as the initial diagnostic test. Blood-based serological tests and IGRA should not be used for diagnosis of active TBWHO recommendations for Xpert MTB/RIF [10–12] are included in the ISTC standard whereas the ESTC standard mentions rapid testing for the identification of rifampicin and isoniazid resistance, using validated tools The ESTC standard recommends DST for all patients The ESTC standard puts more focus on the use of quality assured culture-based methods as these are more broadly available in the EU The 2011 WHO policy statement [13] against the use of blood-based serological tests and the 2011 WHO policy statement against the use of IGRAs [14] in low- and middle-income countries have been included in the ISTC
3. For all patients (adults, adolescents and children) suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement should be obtained for microscopy, culture, DST and histopathological examination in a quality-assured laboratory. In countries, settings or populations in which MDR-TB is suspected in a patient, rapid testing for the identification of rifampicin and isoniazid resistance in a quality-assured laboratory could be performed4. For all patients (including children) suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement should be obtained for microbiological and histopathological examination. An Xpert MTB/RIF test is recommended as the preferred initial microbiological test for suspected tuberculous meningitis because of the need for a rapid diagnosisThe ISTC standard includes a specific recommendation for using the Xpert MTB/RIF test as the preferred initial microbiological test for suspected TB meningitis because of the need for a rapid diagnosis The ESTC emphasises culture confirmation and rapid testing of MDR-TB for all extrapulmonary TB cases, but does not specify which type of rapid molecular testing to use
4. All persons with chest radiographic findings suggestive of pulmonary TB should have sputum specimens submitted for microscopic examination, culture and DST in a quality-assured laboratory. In countries, settings or populations in which MDR-TB is suspected in a patient, rapid testing for the identification of rifampicin resistance and, when possible, isoniazid resistance in a quality-assured laboratory should be performedCombined with standard 2
5. The diagnosis of culture-negative pulmonary TB should be based on the following criteria: all bacteriological tests are negative (including direct sputum smear examinations, cultures and rapid molecular testing); chest radiographic findings are compatible with TB; there is a lack of response to a trial of broad-spectrum antimicrobial agents (because fluoroquinolones are active against Mycobacterium tuberculosis complex and, thus, may cause transient improvement in persons with TB, they should be avoided). In persons who are seriously ill or have known or suspected HIV infection or have any immunocompromising conditions, the diagnostic evaluation should be expedited and, if clinical evidence strongly suggests TB, a course of anti-TB treatment should be initiated5. In patients suspected of having pulmonary TB whose sputum smears are negative, Xpert MTB/RIF and/or sputum cultures should be performed. Among smear and Xpert MTB/RIF negative persons with clinical evidence strongly suggestive of TB, anti-TB treatment should be initiated after collection of specimens for culture examinationThe main difference is that the ESTC standard uses the culture-based case definition and the ISTC standard uses the sputum smear status. The ISTC includes the use of Xpert MTB/RIF as a diagnostic test for patients with pulmonary TB and negative sputum smears. The ESTC does not specify which type of rapid molecular test should be used A trial of broad-spectrum antimicrobial agents is recommended by the ESTC A specific recommendation for expedited investigation of immunocompromised patients is included in the ESTC standard
6. In all children suspected of having intrathoracic TB (i.e. pulmonary, pleural and mediastinal or hilar lymph node), bacteriological confirmation should be sought through examination of appropriate biological samples (expectoration or induced sputum, bronchial secretions, pleural fluid or gastric washings) for smear microscopy, culture and DST in a quality-assured laboratory. In the event of negative bacteriological results, a diagnosis of TB should be based on the presence of abnormalities consistent with TB on chest radiography or other imaging, a history of exposure to an infectious case, evidence of TB infection (positive TST and/or IGRA) and clinical findings suggestive of TB. For children suspected of having extrapulmonary TB, appropriate specimens from the suspected sites of involvement should be obtained for microscopy, culture, DST and histopathological examination6. In all children suspected of having intrathoracic TB (i.e. pulmonary, pleural and mediastinal or hilar lymph node), bacteriological confirmation should be sought through examination of respiratory secretions (expectorated sputum, induced sputum or gastric lavage) for smear microscopy, Xpert MTB/RIF test and/or cultureThe ISTC standard indicates that as well as smear microscopy and culture, the Xpert MTB/RIF test can be used for bacterial confirmation of TB in children. The ESTC standard provides more details on how to diagnose TB in children
Standards for TB treatment
7. Any practitioner treating a patient for TB is assuming an important public health responsibility to prevent ongoing transmission of the infection and the development of drug resistance. To fulfil this responsibility the practitioner must not only prescribe an appropriate regimen, but also utilise local public and/or community health services, agencies and resources when necessary, to perform contact investigation, to assess the adherence of the patient and to address poor adherence when it occurs7. To fulfil their health responsibility, as well as their responsibility to the individual patient, the provider must prescribe an appropriate treatment regimen, monitor adherence to the regimen and, when necessary, address factors leading to interruption or discontinuation of treatment. Fulfilling these responsibilities will probably require coordination with local public health services and/or other local servicesThe ESTC standard specifically mentions the obligation of the practitioner treating a TB patient to collaborate with the local public and/or community health services to perform contact investigation
8. All patients (including those with HIV infection) who have not been previously treated and without any risk factors for drug resistance should receive an internationally accepted first-line treatment regimen using drugs of known bioavailability. The initial phase should consist of 2 months of isoniazid, rifampicin, pyrazinamide and ethambutol. The continuation phase should consist of isoniazid and rifampicin given for 4 months (2HRZE/4HR). The doses of anti-TB drugs used should conform to international recommendations. Fixed dose combinations of two (isoniazid and rifampicin), three (isoniazid, rifampicin and pyrazinamide) and four (isoniazid, rifampicin, pyrazinamide and ethambutol) drugs are highly recommended8. All patients who have not been treated previously and do not have other risk factors for drug resistance should receive a WHO-approved first-line treatment regimen using quality-assured drugs. The initial phase should consist of 2 months of isoniazid, rifampicin, pyrazinamide nd ethambutol. The continuation phase should consist of isoniazid and rifampicin given for 4 months. The doses of anti-TB drugs used should conform to WHO recommendations. Ethambutol may be omitted in children who are HIV negative and who have non-cavitary diseaseThe ISTC standard specifically mentions that patients should be treated with a WHO-approved first-line treatment regimen whereas the ESTC standard mentions an internationally accepted first-line treatment regimen The ESTC standard promotes the use of fixed dose combinations
9. To assess and foster adherence, a patient-centred approach to administration of drug treatment, based on the patient’s needs and mutual respect between the patient and the provider, should be developed for all patients
Supervision and support should be individualised and should draw on the full range of recommended interventions and available support services, including patient counselling and education. A central element of the patient-centred strategy is the use of measures to assess and promote adherence to the treatment regimen and to address poor adherence when it occurs. These measures should be tailored to the individual patient’s circumstances, based on a detailed anamnesis of the patient’s clinical and social history, and be mutually acceptable to the patient and the provider. Such measures may include direct observation of medication ingestion (directly observed treatment) and identification and training of a treatment supporter (for TB and, if appropriate, HIV infection) who is acceptable and accountable to the patient and to the health system. Appropriate incentives and enablers, including financial, social and psychosocial supports, may also serve to enhance treatment adherence
9. A patient-centred approach to treatment should be developed for all patients in order to promote adherence, improve quality of life and relieve suffering. This approach should be based on the patient’s needs and mutual respect between the patient and the providerThere are no relevant differences between the ESTC and the ISTC standards The ESTC standard provides more details about how and what supervision and support should be provided
10. Response to therapy in patients with pulmonary TB should be monitored by follow-up smear microscopy and culture at the time of completion of the initial phase of treatment (2 months for drug-susceptible TB). If the sputum smear and culture are positive at completion of the initial phase, sputum smears should be examined again at 3 months and, if positive, DST should be performed. In patients with extrapulmonary TB and in children unable to produce sputum, the response to treatment is assessed clinically10. Response to treatment in patients with pulmonary TB (including those with TB diagnosed by a rapid molecular test) hould be monitored by follow-up sputum microscopy at the time of completion of the initial phase of treatment (2 months). If the sputum smear is positive at completion of the initial phase, sputum microscopy should be performed again at 3 months and, if positive, rapid molecular drug sensitivity testing (Line-probe assays or Xpert MTB/RIF) or culture with DST should be performed. In patients with extrapulmonary TB and in children, the response to treatment is best assessed clinicallyThe ISTC standard specifically mentions that patients diagnosed by a rapid molecular test should be monitored The ISTC standard mentions that if sputum is still positive at 3 months a rapid molecular DST (Line-probe assays or Xpert MTB/RIF) or culture with DST should be performed. The ESTC standard does not specify the test to be used for DST
11. An assessment of the likelihood of drug resistance, based on history of prior treatment, exposure to a possible source case having drug-resistant organisms and the community prevalence of drug resistance, should be obtained for all patients. Rapid testing, including rapid rifampicin and isoniazid resistance testing should be performed for all patients suspected of resistance as defined in standards 2 and 8. Furthermore, patient counselling and education should begin immediately for all TB patients, in order to minimise the potential for transmission. Infection control measures appropriate to the setting should be applied as recommended in ESTC public health standard 2011. An assessment of the likelihood of drug resistance, based on history of prior treatment, exposure to a possible source case having drug-resistant organisms, and the ommunity prevalence of drug resistance (if known), should be obtained for all patients. DST should be performed at the start of therapy for all previously treated patients. Patients who remain sputum smear positive at completion of 3 months of treatment and patients in whom treatment has failed, have been lost to follow-up, or relapsed following one or more courses of treatment should always be assessed for drug resistance. For patients in whom drug resistance is considered to be likely, an Xpert MTB/RIF test should be the initial diagnostic test. Line-probe assay or culture and testing for susceptibility to at least isoniazid and rifampicin should be performed promptly if rifamycin resistance is detected. Patient counselling and education, as well as an empiric second-line treatment regimen, should begin immediately to minimise the potential for transmission. Infection control measures appropriate to the setting should be appliedThe ISTC standard is more restrictive in recommending DST. Instead of recommending it for all TB patients (ESTC) it recommends DST for previously treated patients, patients who remain sputum smear positive at completion of 3 months of treatment and patients in whom treatment has failed, who have been lost to follow-up, or who relapsed following one or more courses of treatment The ESTC standard recommends rapid testing, whereas the ISTC standard recommends using the Xpert MTB/RIF test for patients in whom drug resistance is considered to be likely, followed by a Line-probe assay if rifamycin resistance is detected. A note to the ESTC standard stresses that rapid molecular testing does not rule out the requirement to perform culture DST to confirm results
12. Patients with, or highly likely to have, TB caused by drug-resistant (especially MDR-/XDR-TB) organisms should be treated with specialised regimens containing second-line anti-TB drugs. The regimen chosen may be standardised or based on suspected or confirmed drug susceptibility patterns. At least four drugs to which the organisms are known or presumed to be susceptible to, including an injectable agent and pyrazinamide, should be used. Treatment should be given for at least 20 months, the recommended intensive phase of treatment being 8 months (instead of 6 months as in previous recommendations)12. Patients with, or highly likely to have, TB caused by drug-resistant (especially MDR-/XDR-TB) organisms should be treated with specialised regimens containing quality-assured second-line anti-TB drugs. The doses of anti-TB drugs should conform to WHO recommendations. The regimen chosen may be standardised or based on suspected or confirmed drug susceptibility patterns. At least pyrazinamide and four drugs to which the organisms are known or presumed to be susceptible, including an injectable agent, should be used in an 8 month intensive phase and at least three drugs to which the organisms are known or presumed to be susceptible should be used in the continuation phase. Treatment should be given for at least 18–24 months beyond ulture conversion. Patient-centred measures, including observation of treatment, are required to ensure adherence. Consultation with a specialist experienced in treatment of patients with MDR-/XDR-TB should be obtainedThe ISTC standard recommends that the doses of the anti-TB drugs should conform to WHO recommendations The ISTC standard specifies that the continuation phase needs to contain at least three drugs to which the organisms are known or presumed to be susceptible
13. A written record of all medications given, bacteriological response and adverse reactions should be maintained for all patients13. An accessible, systematically maintained record of all medications given, bacteriologic response, outcomes and adverse reactions should be maintained for all patientsThere are no relevant differences between the ESTC and the ISTC standards
Standards for addressing HIV infection and comorbidity conditions
14. HIV testing and counselling should be recommended to all patients with, or suspected of having, TB. Testing is of special importance as part of the routine management of all patients in areas with a high prevalence of HIV infection in the general population and in patients with symptoms and/or signs of HIV-related conditions. Because of the close relationship between TB and HIV infection, integrated approaches to prevention and treatment of both infections are recommended14. HIV testing and counselling should be conducted for all patients with, or suspected of having, TB unless there is a confirmed negative test within the previous 2 months. Because of the close relationship of TB and HIV infection, integrated approaches to prevention, diagnosis and treatment of both TB and HIV infection are recommended in areas with high HIV prevalence. HIV testing is of special importance as part of routine management of all patients in areas with a high prevalence of HIV infection in the general population, in patients with symptoms and/or signs of HIV-related conditions, and in patients having a history suggestive of high risk of HIV exposureThere are no relevant differences between the ESTC and the ISTC standards
15. All patients with TB and HIV infection should be evaluated to determine if ART is indicated during the course of treatment for TB, according to the severity of their immunodeficiency. Appropriate arrangements for access to antiretroviral drugs should be made for patients who meet indications for treatment. However, initiation of treatment for TB should not be delayed and the antiretroviral treatment prescribed as soon as possible based on evidence15. In persons with HIV infection and TB who have profound immunosuppression (CD4 counts <50 cells·mm−3), ART should be initiated within 2 weeks of beginning treatment for TB unless tuberculous meningitis is present. For all other patients with HIV and TB, regardless of CD4 counts, ART should be initiated within 8 weeks of beginning treatment for TB. Patients with TB and HIV infection should also receive cotrimoxazole as prophylaxis for other infectionsThe ISTC standard includes the 2013WHO recommendation that ART should be initiated within 2 weeks of beginning treatment for TB in persons with profound immunosuppression unless tuberculous meningitis is present [15]. For all other patients with HIV and TB, regardless of CD4 counts, ART should be initiated within 8 weeks of beginning treatment for TB The ESTC standard does not provide recommendations for patients with HIV infection, while the ISTC standard does, i.e. co-infected patients should receive cotrimoxazole as prophylaxis for other infections
16. Persons with HIV infection who, after careful evaluation, have a positive test for presumed LTBI with M. tuberculosis (TST and/or IGRAs) but do not have active TB should be treated with isoniazid for 6–9 months or any new regimen for which evidence becomes available16. Persons with HIV infection who, after careful evaluation, do not have active TB should be treated for presumed LTBI with isoniazid for at least 6 monthsThe ISTC standard recommends that all persons with HIV infection and without active TB, independent of having a positive test for LTBI, are treated for presumed LTBI whereas the ESTC standard only recommends preventive treatment for those with a positive LTBI test or who are highly probable to have LTBI
17. All providers should conduct a thorough assessment of conditions that could affect TB treatment response or outcome. At the time the case management plan is developed, the provider should identify additional services that would support an optimal outcome for each patient and incorporate these services into an individualised plan of care. This plan should include assessment of and referrals for treatment of other illnesses with particular attention to those known to affect treatment outcome, for instance care for diabetes mellitus, drug and alcohol treatment programmes, tobacco smoking cessation programmes and other psychosocial support services, or to such services as antenatal or well-baby care17. All providers should conduct a thorough assessment for comorbid conditions and other factors that could affect TB treatment response or outcome and identify additional services that would support an optimal outcome for each patient. These services should be incorporated into an individualised plan of care that includes assessment of and referrals for treatment of other illnesses. Particular attention should be paid to diseases or conditions known to affect treatment outcome, e.g. diabetes mellitus, drug and alcohol abuse, under nutrition and tobacco smoking. Referrals to other psychosocial support services or to such services as antenatal or well-baby care should also be providedThere are no relevant differences between the ESTC and the ISTC standards
Standards for public health and TB prevention
18. All providers of care for patients with TB should ensure that persons who are in close contact with patients who have infectious TB (e.g. in families, congregate settings like migrants shelters, schools and prisons), are evaluated and managed in line with international recommendations. The risk of TB transmission depends on the concentration of the mycobacteria in the air, the duration of the contact and the susceptibility of the contact to infection and disease. The determination of priorities for contact investigation is based on the likelihood that a contact has undiagnosed TB, is at high risk of having been infected by the index case, is at high risk of developing TB if infected, and is at risk of having severe TB if the disease develops18. All providers should ensure that persons who are in close contact with patients who have infectious TB are evaluated and managed in line with international recommendations. The highest priority contacts for evaluation are persons with symptoms suggestive of TB, children aged <5 years, contacts with known or suspected immunocompromised states (particularly HIV infection), and contacts of patients with MDR-/XDR-TBThe ESTC standard does not provide a list of priority contacts for evaluation, instead it provides the determinants of TB transmission and susceptibility of a contact that should be assessed
19. Children <5 years of age and persons of any age with HIV infection who are close contacts of an infectious index patient and who, after careful evaluation, do not have active TB should be treated for presumed LTBI with isoniazid19. Children <5 years of age and persons of any age with HIV infection who are close contacts of patient person with infectious TB and who, after careful evaluation, do not have active TB should be treated for presumed LTBI with isoniazid for at least 6 monthsThere are no relevant differences between the ESTC and the ISTC standards
20. Each healthcare facility caring for patients who have, or are suspected of having, infectious TB should develop and implement an appropriate TB infection control plan20. Each healthcare facility caring for patients who have, or are suspected of having, infectious TB should develop and implement an appropriate TB infection control plan to minimise possible transmission of M. tuberculosis to patients and healthcare workersThere are no relevant differences between the ESTC and the ISTC standards
21. All providers must report both new and retreatment TB cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policies21. All providers must report both new and re-treatment TB cases and their treatment outcomes to local public health authorities, in conformance with applicable legal requirements and policiesThere are no relevant differences between the ESTC and the ISTC standards
  • TB: tuberculosis; DST: drug susceptibility testing; MDR: multidrug resistant; IGRA: interferon-γ release assay; WHO: World Health Organization; H: isoniazid; R: rifampicin; Z: pyrazinamide; E: ethambuthol; EU: European Union; TST: tuberculin skin test; XDR: extensively-drug resistant; ART: antiretroviral therapy; LTBI: latent TB infection. Xpert MTB/RIF test is manufactured by Cepheid (Sunnyvale, CA, USA).