Edward A. Nardell, MD Harvard Medical School/PIH Brigham ... · Edward A. Nardell, MD Harvard...

How Long Do TB Patients Remain Infectious?

Preliminary Data from the Airborne Infections Research (AIR) Facility

Edward A. Nardell, MDHarvard Medical School/PIHBrigham & Women’s Hospital

Outline

• Transmission (including reinfection) is a key driver of the MDR-TB epidemic

• Effectiveness of MDR-TB treatment on transmission unknown- was an ACET issue 2 years ago

• New observations suggest a rapid and profound treatment effect, similar to drug susceptible TB.

• Unsuspected, untreated patients spread TB.• Implications for hospital and ambulatory treatment,

public health law, and transmission control priorities: a focus on rapid diagnosis and effective treatment.

Developing Guidelines for Discontinuation of Isolation for Patients with Multidrug-

Resistant TuberculosisSundari Mase MD, MPHBarbara Seaworth MD

Edward Nardell MDJennifer Flood MD, MPH

Julian Thomas

• Present summary of existing guidelines• Present results of systematic review

looking at evidence for the transmission of MDR TB

• Present pros and cons for approaches to inform guidelines for discontinuing isolation for MDR TB patients

• Draft recommendations for ACET• Next Steps

Objectives

PIH introduced community-based treatment of MDR TB in Peru in 1996. Now in PIH-Lesotho, Karachi, Cambodia, and other sites

- only about 10% of patients hospitalized in LimaHighly effective, with less opportunity for institutional transmission.What about community transmission?

Treatment delivered in homes by trained, paid, community health workers

Wednesday, 26th May 2010

8/12/2010 6

8/12/2010 7

Province Registered Patients (08)

Available Beds

Variance(Beds‐Pts)

EC 797 394 ‐403

FS 265 75 ‐190

GP 601 266 ‐335

KZN 1,061 528 ‐533

LP 104 50 ‐54

MP 272 36 ‐236

NC 148 65 ‐83

NW 159 77 ‐82

WC 1,145 363 ‐782

RSA 4,552 1,824 ‐2728

Infection Control

Disease Progression (t)

HypotheticalInfectiousness

Start of therapySurrogates:CXRsmear cultureEtc.

The Charge• Advisory Committee for the Elimination of

Tuberculosis (ACET) chartered a group to review existing literature and make summary recommendations to ACET

• Develop evidence-based guidelines for discontinuation of isolation of MDR-TB patient

Public Health Importance• Transmission of MDR/XDR TB, especially

in institutional settings and to high risk individuals (threat to community)

• Morbidity and mortality for individual patients

• Emergence of more resistant, deadly strains

• Resource intensive

Existing Guidelines

Organization TitleSmear

/Culture Min Days Tx Lab Results

CDC

Prevention and Control of Tuberculosis in Correctional and Detention Facilities: Recommendations from CDC

Not mentioned

143 neg

smears

CDC

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005

Not mentioned

Not mentioned

UK Department of Health

The Interdepartmental Working Group on Tuberculosis: The prevention and control of tuberculosis in the United Kingdom: Department of Health – Publications

Not mentioned

143 neg

smears

NYC Bureau of Tuberculosis

Control

Tuberculosis (TB): Clinical Policies and Protocols

Not mentioned

143 neg

smears

Public Health Agency Canada

Canadian Tuberculosis Standards 6th Ed.

neg /pos 143 neg

smears

pos/pos 14none

needed

pos /negNot mentioned

3 neg cultures

Discontinuation of Airborne Infection Isolation: Drug-Susceptible TB


/Culture Min Days Tx Lab Results

CDC

Prevention and Control of Tuberculosis in Correctional and Detention Facilities: Recommendations from CDC

Not mentioned 14

3 neg smears

CDC

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005

Not mentioned

Not mentioned

UK Deptartment of Health

The Interdepartmental Working Group on Tuberculosis: The prevention and control of tuberculosis in the United Kingdom: Department of Health – Publications

Not mentioned 14

3 neg smears

NYC Bureau of Tuberculosis Control

Tuberculosis (TB): Clinical Policies and Protocols

Not mentioned 14

3 neg smears


Canadian Tuberculosis Standards 6th Ed. neg /pos 14

3 neg smears

pos/pos 14 none needed

pos /negNot mentioned

3 neg cultures

Discontinuation of Airborne Infection Isolation: Drug-Susceptible TB


/Culture Min days Tx Lab resultsType

Suggestion

CDC

Prevention and Control of Tuberculosis in Correctional and Detention Facilities: Recommendations from CDC all

Not mentioned neg culture comment

CDC

Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care facilities, 2005 all

Not mentioned neg culture comment

Department of Health

The Interdepartmental Working Group on Tuberculosis: The prevention and control of tuberculosis in the United Kingdom: Department of Health – Publications all

Not mentioned neg culture

case by case

Bureau of Tuberculosis Control

Tuberculosis (TB): Clinical Policies and Protocols all

Not mentioned

neg smear + neg culture if possible


Canadian Tuberculosis Standards 6th Ed. all

Not mentioned

3 neg cultures guideline

Discontinuation of Airborne Infection Isolation: MDR-TB

Questions• What evidence exists on which to base

MDR-TB isolation guidelines?• Is there evidence for a duration of time

after which isolation can be discontinued? • Is there evidence to support microbiologic

criteria for isolation discontinuation?

720 potentially relevant citations identified

470 citations selected

250 duplicate citations excluded

282 citations excluded after first screen

Flow Diagram of Study Selection

188 citations relevant to transmission of MDR TB

135 citations excluded based on relevance to review topic including:11 non-English 99 pop. & molec.

epi. studies


53 full-text articles screened;

28 articles included in review

25 articles excluded after full text screen; 8 non-report; 2 models; 1 non-English; 6 out of scope; 3 reviews


Treatment for MDR-TBMDR Therapy n %Yes 8 29

Not Reported 20 71

• Less than 1/3 reported MDR-TB regimen• No reported association between therapy

and number of transmission cases

Conclusions• Culture negativity = standard to deem case

non-infectious• Most conservative guidelines: 3 negative

cultures• Search yielded minimal evidence to inform

guidelines • Other indices of response to therapy should

be studied• Existing policy and guidelines may serve as

basis

Next Steps• ACET discussion/Engage key stakeholders from

NTCA• Review pros and cons for more stringent

guidelines for discontinuation of isolation for MDR TB

• Present different approaches to CDC, DTBE leadership

• Formulate guidelines by June, 2009

How is MDR acquired?

• 2008 WHO data:– more than 50% of MDR occurs in patients NOT

previously treated• primary, transmitted TB• not acquired through poor therapy

– Many previously treated cases are re-infected• also transmitted, but misclassified as “acquired”, as if

poor treatment was the cause

53 XDR Patients in Kwazulu Natal, South Africa55% had no previous TB treatment – i.e., transmitted

- most had the same “KZN” strain67% had been hospitalized100% had HIV co-infection100% mortality – avg 16 days from TB diagnosis

Importance of Transmission in TomskGlemanova, et al., Bull WHO, 2007; 85:703-711.

• Retrospective study– role of non-adherence and default and the acquisition of

multidrug resistance

• Substance abuse– strong predictor of non-adherence (OR 7.3 (2.89-18.46)– but non-adherence NOT associated with MDR-TB

• MDR-TB occurred – among adherent patients who had been hospitalized in the

course of therapy compared to those treated as out-patients• OR 6.34 (1.34 – 29.72) – began treatment in hospital• OR 6.26 (1.02 – 38.35) – hospitalized later during treatment

Reinfection Drug Resistant TBin a Boston Homeless Shelter

Nardell, et al. NEJM 1986; 315:1570-5

• Proved exogenous reinfection of drug resistant TB among homeless shelter residents using phage typing.

Exogenous ReinfectionProven by Genotyping

• South African (Sonnenberg et. al.)– high HIV setting– 52% reinfection

• Shanghai, China (Gao et. al.)– low HIV setting– 62% reinfection

Samara Oblast 9-yr StudyDimitrova B. Int J Tuberc Lung Dis. 2005 Jan;9(1):43-8

• TB among health workers: – TB risk: 742/100K person-years at risk

• 10X that of general population.– In-patient TB facilities

• incidence ratio of 17.7 compared general health workers

– Implications for global TB work force

The Madras Experience(Bull WHO 1966; 34:517-32)

• The first clinical trials of ambulatory TB treatment demonstrated no more household conversions after the start of treatment– Most household contacts had been exposed for

months before diagnosis and treatment– Susceptible contacts already infected– Patients no longer infectious

Effects of Chemotherapy on Transmission

• Brooks et al (ARRD 1973): – 107 TST-negative subjects living with 21 patients with positive

sputum. – After up to 23 days hospitalization, 19 smear positive patients were

sent home (they did not all become negative on culture until after 5 mos)

– No TST negative subjects in contact after the beginning of treatment converted their skin test.


• Gunnels et al (ARRD 1974): – studied contacts of 155 patients sent home after 1 month of

treatment in hospital– 69 Culture neg.– 86 Culture pos

• 52 Smear and culture positive.

• No difference in infection rate among 284 contacts of culture pos cases versus 216 contacts of culture negative contacts


• Riley and Moodie (ARRD, 1974):– studied 70 household contacts of 65 new TB cases on domiciliary

treatment (non-RIF regimen). – A series of 6 TST results showed no transmission among TST

negative contacts after the start of treatment. – Most household contacts were infected in the month or two before

diagnosis and treatment .


• Rouillon A, Perdrizet S, Parrot R. Transmission of tubercle bacilli: The effects of chemotherapy. Tubercle 1976; 57:279-299. – Sputum smear and culture positivity correlate with transmission

before but not on therapy– Discordance between effect of treatment on culture and smear– Evidence that smear and culture positive TB patients on therapy do

not infect close contacts.


• “There is an ever-increasing amount of evidence in support of the idea that abolition of the patient’s infectiousness – a different matter from ‘cure,’ which takes months and from negative results of bacteriological examinations, direct and culture, which may take weeks – is very probably obtained after less than 2 weeks of treatment”.

• “These facts seem to indicate very rapid and powerful action by the drugs on infectivity…”

CDC/ATS Policy on Treatment in general hospitals, communities, and discharge

• 1969 ATS – Guidelines for the general hospital for the admission and care of tuberculosis patients.

• 1970 ATS – Bacteriologic standards for discharge of patients• 1973 ATS – Guidelines for work for patients with tuberculosis• 1974 CDC – Recommendation for health department

supervision of tuberculosis patients

Riley Experimental TB Ward, 1956-60Am J Hyg 1959; 70:185-196.

(reprinted as “classic” Am J Epidemiol 1995; 142:3-14)

Hundreds of sentinel guinea pigs sampled the air from a 6-bed TB ward in Baltimore

TB transmission only from untreated patients - 1

• Patients selected: – strongly smear positive– cavitary TB

• 3 of 77 patients produced 35 of 48 (73%) of GP infections that were cultured– all drug resistant M.

tuberculosis on inadequate therapy

– 4 month period* of no infections when drug susceptible patients were admitted to the ward.

Riley Ward – 2nd 2-year study- included untreated patients

Relative infectivity of patients*:– Susceptible TB

• 61 Untreated (29 GPs) 100%• 29 Treated (1 GP) 2%

– Drug-resistant TB• 6 Untreated (14 GPs) 28%• 11 Treated (6 GPs) 5%

*all smear positive patients, relative to the amount of time on the ward

Riley’s conclusionsARRD 1962; 85:511-525

“The treated patients were admitted to the ward at the time treatment was initiated and were generally removed before the sputum became completely negative. Hence the decrease in infectiousness preceded the elimination of the organisms from the sputum, indicating that the effect was prompt as well as striking.”

“Drug therapy appeared to be effective in reducing the infectivity of patients with drug resistant (H, SM, PAS only) organisms, but the data do not permit detailed analysis of the problem”.

TB transmission only from untreated patients – Peru

Escombe 2008 Plos Medicine; 5:e188

– 97 HIV+ pulmonary TB patients exposed 292 guinea pigs over 505 days

• 66 cult +, 35 smear +

– 122/125 GP infections (98%) were due to 9 MDR patients

• all inadequately or delayed treatment» 108/125 infections (86%) due to 1 MDR patient

• 3 drug susceptible patients infected 1 guinea pig each» 2 had delayed treatment» 1 had treatment stopped

How effective is treatment in stopping MDR-TB transmission?

The AIR FacilityWitbank, Mpumalanga Provence, RSA

Collaborators:• MRC

– Martie van der Walt– Matsie Mphahlele– Kobus Venter– Anton Stoltz– Willem Lubbe– Thabiso Masotla– Karin Weyer– Bernard Fourie– Lourens Robberts– Daan Goosen, Veterinarian

• CSIR– Sidney Parsons, engineer

• CDC– Paul Jensen, engineer– Charles Wells– Paul Arguin

• Mpumalanga Provence Health Dept & Specialized MDR TB Referral Center

– Patients– Nurses– Administration– Doctors

• Harvard UniversityBrigham & Women’s Hospital

– Edward Nardell, PI– Melvin First– Ashwin Dharmadhikari

• Other collaborators– Dave McMurray – Texas A & M– Ian Orme – Colorado State– Randall Basaraba – Colorado State– Paul Van Helden, Rob Warren, Elizabeth

Streicher - Centre for Molecular and Cellular Biology

• Funding– USAID/CDC– MRC– Brigham & Women’s Hospital– Harvard CFAR (NIH) – two awards– NIOSH (NIH) RO1– NIH K23 (A. Dharmadhikari, PI)

AIR, Experimental Plan

A B

Odd days Even days

3 patient roomsPlus common areas

Intervention on/off on alternative days

Guinea Pig Air Sampling

Pt. TB RFLP

Guinea PigTB RFLP

UVGI orother intervention

TB transmission from unsuspected, untreated XDR patients – South Africa

53%315 / 2 mosExp 2

1%?27 / 3 mosExp 3

10%024 / 3 mosExp 1

74%2**26 / 4 mosPilot

% guinea pigs infected

# XDR Patients

# MDR*

Patients/ Exp.Duration

*92 patients: smear +, cavitary, coughing, recently started on therapy

** 11 spoligotypes, but only 2 transmitted to GPs – both XDR-associated

How much treatment on admission?

• Exp 2: 10% infection rate– 24 patients had, on average, began treatment

0.46 days after admission to the AIR facility.• Treatment duration being gathered for:

– Pilot Study– UV-2– UV-3– Mask Study (current)

Likely to be similar

Unsuspected, untreated TB

General Medical WardOrthopedic WardObstetrics WardPsychiatric Ward

TBDR

TBDS

Unsuspected, untreated MDR/XDR TB

All other patients on effective treatment

TB HospitalPotential for re-infection

TB

TBTBTB TB TBDR

TB

TBTBTB TB

DRTBTB

TB

Unsuspected, untreated XDR TB

All other patients on effective treatment

MDR TB WardPotential for re-infection

MDRTB

MDRTB

MDRTB

MDRTB

MDRTB XDR

TB

MDRTB

MDRTB

MDRTBMDR

TBXDR TB

MDRTB

MDRTB

MDRTB

TB Triage – Rapid DR Diagnosis

Community based – on effective treatment – responding

Hospitalized patients on effective treatment - responding

DS or MDR

XDR

Individual Isolation

Effect of treatment unknownNovel interventions

Complications

Smear may notbe critical if on effective treatment

Future Studies

• Better define treatment on admission

• Admit XDR patients only– Assess impact of XDR treatment

• Novel approaches to transmission control– Inhaled dry powder antibiotics

Edward A. Nardell, MD Harvard Medical School/PIH Brigham ... · Edward A. Nardell, MD Harvard...

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