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• 2011 by the author

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Guidance for implementation of TB care in the EU
the ESTC
G. B. Migliori, G. Sotgiu WHO Collaborating
Centre for TB and Lung Disease, Fondazione S.
Maugeri, Care and Research Institute, Tradate,
Italy A. Sandgren, E. Huitric, D. Manissero ECDC
(European Centre for Disease prevention and
Control), Stockolm, Sweden
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Disclaimer

• The content of this presentation has been
  prepared on the basis of the evidence collected
  under ECDC supported survey on management of
  TB-/MDR-TB cases in the EU.
• The conclusions of this presentation are the sole
  responsibility of the author (representing the
  ERS Task Force) and do not represent the ECDC
  position on the matter of Standards for Diagnosis
  and Treatment.
• ECDC has responsibility on the Public Health
  Standards only

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Outline

• The key areas behind the ESTC
• The pre-final EU Standards
• The supporting enablers

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Key Areas (1)

• a) Surveillance.
• - Information on the final outcomes of the
  patients discharged should be available in the
  treating clinical centre as this represents a key
  managerial tool.

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Key areas (2)

• b) Infection control (a)
• - Sufficient respiratory isolation rooms for all
  new patients admitted (at least till the exact
  resistance pattern is identified and/or the
  patient is rendered non-infectious) and adequate
  isolation procedures needs to be available in all
  European countries.
• No evidence of secondary cases among health staff
  (1 case in one country in 10 yrs).
• - New European Standards need to look for the
  evidence and recommend this procedure if it is
  really justified.

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Key areas (2)

• b) Infection control (b)
• - Adequate administrative and personal
  protection measures (masks for patients or
  respirators for staff)
• .
• - Adequate health education practices for
  patients (e.g. cough etiquette) regular
  training of health staff are necessary
• .
• - Respirator fit testing needs to be urgently
  implemented, for all health workers wearing
  respirators, as evidence exists that inadequate
  respirator wearing renders individual respiratory
  protection useless.

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Key areas (3)

• c) Clinical management of TB and MDR-TB
• - needs to be strengthened so that complete
  information on previous treatment(s), adequate
  contact tracing procedures, adequate
  bacteriological diagnosis, prescription of at
  least 4 active drugs, correct drug choice,
  adequate dose prescription, sufficient treatment
  duration and adequate management of AE of
  treatment are urgently implemented in the EU
• d) Clinical management of HIV
• - should also be strengthened, as part of the
  development of the TB/HIV collaborative
  activities in Europe. This is particularly
  relevant in the following areas HIV-testing and
  counselling of TB cases prescription of ARVs and
  management of combined TB/HIV treatment.

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Clinical management
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Key areas (4)

• e) Laboratory support
• - including optimal laboratory practices and
  quality assurance procedures, particularly for
  second-line drugs remains a key priority in
  Europe.
• f) Diagnostic and treatment algorithms
• - need to be promoted in Europe to reduce as
  much as possible the existing differences. New
  tools (NAAT, IGRAS, rapid MDR-TB tests) should be
  promoted according to clear evidence-based
  guidelines.

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Laboratory support
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Diagnostic and treatment algorythms
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International technical assistance
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Standards for Diagnosis focus on rapid methods
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Standard 1 (Replaced ISTC 1)

• All persons presenting with signs, symptoms,
  history or risk factors compatible with
  tuberculosis should be evaluated for pulmonary
  and / or extrapulmonary tuberculosis.

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• History
• Risk factors
• As chronich cough not necessarily is the leading
  symptom

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Standard 2 (Replaced ISTC 2)

• All patients (adults, adolescents, and children
  who are capable of producing sputum) suspected of
  having pulmonary tuberculosis should have at
  least two sputum specimens submitted for
  microscopic examination, culture and drug
  susceptibility testing (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-resistance
  and when possible isoniazid-resistance, using
  validated tools in a quality-assured laboratory,
  should be done.

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• Culture DST
• Rapid test for R and H-resistance
• GeneXpert and Line Probe Assays
• Contacts and previoulsy treated cases!!!
• Quality assured laboratory
• Specialised MDR-TB management

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Gene Xpert
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Standard 3 (Replaced ISTC 3)

• For all patients (adults, adolescents, and
  children) suspected of having extrapulmonary
  tuberculosis, 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 done.

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• EP TB same laboratory approach
• Aggressive trial to get a specimen suitable for
  bacteriology
• Surgeons not in formaline only!

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Standard 4 (Replaced ISTC 4)

• All persons with chest radiographic findings
  suggestive of pulmonary tuberculosis 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 done.

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• When CXR is the entry point
• bacteriological examinations should be done (see
  Standard 2)

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Standard 5 (ISTC 5 valid, EU adapted integration
needed)

• The diagnosis of culture-negative pulmonary
  tuberculosis 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 compatible with
  tuberculosis and lack of response to a trial of
  broad spectrum antimicrobial agents. (Note
  Because the fluoroquinolones are active against
  M. tuberculosis complex and, thus, may cause
  transient improvement in persons with
  tuberculosis, they should be avoided.) In persons
  who are seriously ill or have known or suspected
  HIV infection or have any immune-compromising
  conditions, the diagnostic evaluation should be
  expedited and if clinical evidence strongly
  suggests tuberculosis, a course of
  anti-tuberculosis treatment should be initiated.

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• Culture negative cases
• Negative to direct sputum smear examinations,
  cultures and rapid molecular testing
• Using all diagnostic tools to collect the
  specimens
• New diagnostics within evidence based guidelines

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Standard 6 (ISTC 6 valid until specific EU
paediatric standards are available, EU adapted
integration needed)

• In all children, suspected of having
  intrathoracic (i.e., pulmonary, pleural, and
  mediastinal or hilar lymph node) tuberculosis,
  bacteriological confirmation should be sought
  through examination of appropriate biological
  samples (by 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
  tuberculosis should be based on the presence of
  abnormalities consistent with tuberculosis on
  chest radiography, a history of exposure to an
  infectious case, evidence of tuberculosis
  infection (positive tuberculin skin test-TST
  and/or interferon-gamma release assay- IGRA), and
  clinical findings suggestive of tuberculosis. For
  children suspected of having extrapulmonary
  tuberculosis, appropriate specimens from the
  suspected sites of involvement should be obtained
  for microscopy and for culture and
  histopathological examination.

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• Waiting for new paediatric ESTC, previous ISTC
  valid
• Same laboratory diagnostic approach than for
  adults (as per Standard 2-5)
• Try to obtain the sample!

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Standards for Treatment attention to
retreatments!
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Standard 7 (ISTC 7 maintained)

• Any practitioner treating a patient for
  tuberculosis is assuming an important public
  health responsibility to prevent ongoing
  transmission of the infection and the development
  of drug resistance. To fulfill this
  responsibility the practitioner must not only
  prescribe an appropriate regimen, but also
  utilize 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 occurs.

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• Public health jacket of the pratictioner
• Role of civil society and community emphasized

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Standard 8 (ISTC 8 valid, EU adapted integration
needed)

• 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 two months of isoniazid, rifampicin,
  pyrazinamide, and ethambutol. The continuation
  phase should consist of isoniazid and rifampicin
  given for four months (2HRZE/4HR). The doses of
  antituberculosis 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 recommended.

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• Retreatment cases should be managed according to
  the individual risk to be MDR-TB until MDR is
  excluded

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Standard 9 (ISTC 9 maintained)

• To assess and foster adherence, a
  patient-centered approach to administration of
  drug treatment, based on the patients needs and
  mutual respect between the patient and the
  provider, should be developed for all patients.
  Supervision and support should be individualized
  and should draw on the full range of recommended
  interventions and available support services,
  including patient counseling and education. A
  central element of the patient-centered 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 patients
  circumstances, based on a detailed anamnesis of
  the patients 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 or DOT) and identification and
  training of a treatment supporter (for
  tuberculosis and, if appropriate, for
  HIV-infection) who is acceptable and accountable
  to the patient and to the health system.
  Appropriate incentives and enablers, including
  financial, social and psycho-social supports, may
  also serve to enhance treatment adherence

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• Adherence
• Patient-centred approach
• DOT and treatment supporter

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Standard 10 (ISTC 10 valid, EU adapted
integration needed)

• Response to therapy in patients with pulmonary
  tuberculosis should be monitored by follow-up
  smear microscopy and culture at the time of
  completion of the initial phase of treatment (two
  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, drug
  susceptibility testing should be performed. In
  patients with extrapulmonary tuberculosis and in
  children unable to produce sputum, the response
  to treatment is assessed clinically.

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• Treatment monitoring
• Monthly SS and culture

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Standard 11(Replaced ISTC 11, see also ESTC 1, 2
and 3)

• 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 resistance or rifampicin- and/or
  isoniazid-resistance testing should be done for
  all patients suspected of resistance as defined
  in standard 2 and 8. Furthermore, patient
  counseling and education should begin immediately
  for all TB patients, in order to minimize the
  potential for transmission. Infection control
  measures appropriate to the setting should be
  applied as recommended in ESTC public health
  standard 20.

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• Rapid testing once more!
• Immediate counselling and education for infection
  control purposes
• Rapid testing does not rule out the need for DST

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Standard 12 (ISTC 12 valid, EU adapted
integration needed)

• Patients with, or highly likely to have,
  tuberculosis caused by drug-resistant (especially
  MDR/XDR) organisms should be treated with
  specialized regimens containing second-line
  anti-tuberculosis drugs. The regimen chosen may
  be standardized 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, should be used. Treatment
  should be given for at least 20 months, the
  intensive phase of treatment recommended to be 8
  months beyond culture conversion (instead of 6
  months as in previous recommendations see below
  the EU Adaptations for further detail). As the
  treatment of MDR/XDR-TB is the last chance for
  these patients to be cured and survive and,
  often, as previous defaulters belong to the
  socio-vulnerable groups, a full range of
  patient-centred measures, including counselling,
  education of patients and family members,
  observation of treatment, identification of
  patient-entrusted treatment supporter,
  psycho-social support and other incentives and
  enablers, are required to ensure adherence in
  order to avoid development of XDR-TB.

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• Specialized centres
• 4 active drugs, 20 months total, intensive phase
  8 moths beyond culture conversion
• Aggressive management of AE
• Cosillium

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Standard 13 (ISTC 13 valid, EU adapted
integration needed)

• A written record of all medications given,
  bacteriologic response, and adverse reactions
  should be maintained for all patients.

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Standards for addressing HIV Infection and
Co-morbid Conditions- universal access to
diagnosis treatment - remind other
conditions!!!- focus on LTBI
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Standard 14 (ISTC 14 maintained)

• HIV-testing and counseling should be recommended
  to all patients with, or suspected of having,
  tuberculosis. 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, in patients with symptoms
  and/or signs of HIV-related conditions. Because
  of the close relationship of tuberculosis and
  HIV-infection, integrated approaches to
  prevention and treatment of both infections are
  recommended.

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• Setting of choice cancelled
• Integrated TB/HIV management approaches to all
  cases

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Standard 15 (ISTC 15 valid, EU adapted
integration needed)

• All patients with tuberculosis and HIV-infection
  should be evaluated to determine if
  antiretroviral therapy is indicated during the
  course of treatment for tuberculosis, 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 tuberculosis should
  not be delayed.

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• General prophylactic treatment against other
  infections not relevant in the EU

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Standard 16 (ISTC 16 valid, EU adapted
integration needed)

• Persons with HIV-infection who, after careful
  evaluation, have a positive test for presumed
  latent infection with M.tuberculosis (LTBI)
  (tuberculin skin test (TST) and/or IGRAs) but do
  not have active tuberculosis should be treated
  with isoniazid for 6-9 months.

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• TLTI
• Underlined
• Not only in HIV infected, but also in all
  conditions increasing probabily of reactivation

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Standard 17(ISTC 17 valid, EU adapted integration
needed)

• All providers should conduct a thorough
  assessment of conditions that could affect
  tuberculosis 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
  individualized 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 care.

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• Treatment outcomes
• Importance underlined

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Standards for Public Health and
Preventionoutcomes and infection control!
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Standard 18 (ISTC 18 valid, EU adapted
integration needed)

• All providers of care for patients with
  tuberculosis should ensure that persons who are
  in close contact with patients who have
  infectious tuberculosis (e.g in 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 1) has undiagnosed tuberculosis 2) is
  at high risk of having been infected by the index
  case 3) is at high risk of developing
  tuberculosis if infected 4) is at risk of having
  severe tuberculosis if the disease develops.

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• Contacts
• - Risk of transmission
• - Re-modulation of priorities for contact
  tracing
• the contact 1) has undiagnosed TB 2) is at
  high risk of having been infected by the index
  case 3) is at high risk of developing TB if
  infected 4) is at risk of having severe TB if
  the disease develops

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Standard 19 (ISTC 19 valid, EU adapted
integration needed)

• Children under 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
  tuberculosis, should be treated for presumed
  latent tuberculosis infection with isoniazid.

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• Previous ISTC confirmed
• Clinicians and PH authorities should collaborate
  in contact tracing

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Standard 20 (ISTC 20 valid, EU adapted
integration needed)

• Each healthcare facility caring for patients who
  have, or are suspected of having infectious
  tuberculosis, should develop and implement an
  appropriate tuberculosis infection control plan.

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• Infection control plan
• Organisational activities, administrative
  control, personal protection interventions

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Fit test
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Respiratory Fit Testing
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Standard 21 (ISTC 21 valid, EU adapted
integration needed)

• All providers must report both new and
  re-treatment tuberculosis cases and their
  treatment outcomes to local public health
  authorities, in conformance with applicable legal
  requirements and policies.

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Supporting enablers to the ESTC

• The following supporting enablers complementing
  the ESTC are suggested to EU Countries
• Formal adoption of ESTC, ideally translated in
  the country-specific language(s) after their
  endorsement by National Medical Associations.
  Ideally thee ESTCs should be incorporated into
  training curricula of health staff.
• Development of consistent control and
  elimination strategies and policies according to
  the principles described in the New European
  Framework.
• Adoption of specific, updated, evidence-based
  tuberculosis and multidrug-resistant tuberculosis
  guidelines, together with mechanisms to update
  them on a regular basis and to monitor their
  implementation (audit- and or knowledge,
  attitudes and practices study (KAP study)-based).

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• Adoption of translated ESTC inclusion in
  training curricula
• Development of consistent elimination strategies
• Development of evidence-based guidelines and
  their up-dating

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Supporting enablers to the ESTC

• Planning and organisation of adequate laboratory
  network to ensure that a minimum, sufficient
  number, of mycobacteriology laboratories are in
  place, allowing implementation of the standards
  described in this document (adequate coverage of
  the country, adequate internal and external
  quality assurance procedures in place, sufficient
  numbers of samples per laboratory to ensure
  proficiency, availability of national
  laboratories with reference functions to support
  regional and local laboratories etc).
• Development of policies ensuring a continuous
  availability of all 1st - and 2nd -line drugs
  (e.g. through coordinated procurement with
  partner countries for the drugs not registered in
  the country or which are necessary in small
  quantities).
• Securing consistent and adequate funding for
  tuberculosis and multidrug-resistant tuberculosis
  care, prevention and control sufficient to run
  the activities mentioned above in this document,
  including psycho-social support and coordination
  of care. This applies particularly to patients
  belonging to vulnerable populations following
  the International Patients Charter for right to
  diagnosis and treatment.

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• Laboratory network less labs, more samples!
• Availability of drugs
• Adequate funding

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Conclusions 1

• The ECDC-TBNET study, based on a standardised and
  validated methodology, has provided the evidence
  necessary to development the EU-adapted
  Standards.
• Gaps in case managements are evident even in high
  resource settings and in referral centres
• Progress towards further TB control (and possibly
  elimination) in low/intermediate incidence
  settings requires adherence to the highest
  standards
• A wide consultation involving international
  agencies (e.g. ECDC, WHO) scientific societies
  (e.g. ERS, ATS), country representatives and
  other stakeholders has been carried out to draft
  preliminary EU-adapted standards

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Experts who provided input to the ESTC
Prof. Lange Christoph Dr. Leimane Vaira Prof.
Loddenkemper Robert Dr. Manissero Davide Prof.
Migliori GB Prof. Nicod Laurent Mrs. Pannetier
Carine Dr. Raviglione Mario C. Dr. Sandgrem
Andreas Prof. Sotgiu Giovanni Prof. Spanevello
Antonio Dr. Thomsen Vibeke Ostergaard Dr.van der
Werf Marieke Dr.Villar Miguel Dr. Wanlin
Maryse Prof. Wedzicha Wisia Dr. Zellweger
Jean-Pierre Dr. Zumla Alimudin

• Dr. Abubakar Ibrahim
• Dr. Aksamit Timothy
• Prof. Blasi Francesco
• Dr. Caminero Luna Jose Antonio
• Dr. Centis Rosella
• Prof. Cirillo Daniela Maria
• Dr. DAmbrosio Lia
• Dr. Danilovits Manfred
• Dr. Dara Masoud
• Dr. DeVries Gerard
• Dr. Dheda Keertan
• Prof.Dinh-XuanAnh-Tuan
• Mr. Gordon Case
• Dr. Huitric Emma
• Dr. Ibrahim Elmira
• Dr. Kliiman Kai
• Dr. Kluge Hans

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Conclusions 2
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Conclusions 2
MDR-TB management will very costly and painful
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Conclusions 3
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Conclusions 3
If will not not apply high standards!
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Thank you!