Impact of effective treatment on MDR-TB transmission

Preliminary Results from the Airborne Infections Research (AIR) Facility

Edward A. Nardell, MDBrigham & Women’s Hospital

Harvard Medical SchoolHarvard School of Public Health

Partners In Health

North American Region, IUATLD, San Antonio, 2012

53 XDR Patients in Kwazulu Natal, South Africa Gandhi, Lancet, 2006:

55% had no previous TB treatment – i.e., transmitted - most had the same “KZN” strain

67% had been hospitalized100% had HIV co-infection100% mortality – avg 16 days from TB diagnosis

Reinfection Drug Resistant TBin a Boston Homeless Shelter

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

• Proved that transmission (reinfection) was common in a 1983 outbreak of drug resistant TB in a large, crowded homeless shelter in Boston

• Conditions not dissimilar to hospital conditions in earlier times in Europe and the US, and in many poor countries today.

Don Smith Alterative Pathway to Cavitary TB Smith DW, et al. Rev Infect Dis 11: S385-S393 (1989)

Force of Transmission - Implications

NEJM 365;1:79-81, 2011

Global MDR-TB Treatment Scale Up• Estimated 500,000 new MDR-TB

cases per year– More than half result from

transmission– 2008 - 29,423 cases reported

• 7% of estimated cases• 1% treated with quality assured

drugs• Most are treated in hospitals for

first 6 months – until sputum smear or culture conversion

Source: Multidrug and extensively drug-resistant TB (M/XDR-TB)2010 GLOBAL REPORT ONSURVEILLANCE AND RESPONSE

Importance of Transmission in Tomsk

Glemanova, 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

Anton Chekhov, MD

Community Based Treatment

• Highly effective • e.g., Peru, Lesotho,

Cambodia, KZN, and others

• Less opportunity for institutional transmission

But, what about community transmission?

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

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 I solation: Drug-Susceptible TB

Organization TitleSmear

/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

Public Health Agency Canada

Canadian Tuberculosis Standards 6th Ed. all

Not mentioned

3 neg cultures guideline

Discontinuation of Airborne Infection Isolation: MDR-TB

Effects of Chemotherapy on Transmission – Early Papers

• Andrews RH. Bull WHO. 1960 (Madras, India)• Crofton J. Bull IUAT. 1962 (Edinburg, Scotland)• Brooks S. Am Rev Resp Dis. 1973 (Ohio)• Riley R. Am Rev Resp Dis. 1974 (Baltimore)• Gunnels J. Am Rev Resp Dis. 1974 (Arkansas)• Rouillon A. Tubercle. 1976 (Review):

– Smear and culture correlate with infectivity only in untreated cases– Evidence that smear and culture positive TB patients on therapy do

not infect skin test negative close contacts.

• Menzies R. Effect of treatment on contagiousness of patients with active pulmonary tuberculosis. Infect Control Hops Epidemiol 1997; 18:582-586

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.

Effects of Chemotherapy on Transmission

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

cases on domiciliary treatment (non-RIF regimen) – never hospitalized.

– A series of 6 TST results showed no transmission among 25 TST negative contacts after the start of treatment.

– Most household contacts were infected in the month or two before diagnosis and treatment .

Effects of Chemotherapy on Transmission

• 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

Effects of Chemotherapy on Transmission

• 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.

Effects of Chemotherapy on Transmission (Rouillon)

• “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

Another point of view• Menzies R. Effect of treatment on contagiousness of patients with

active pulmonary tuberculosis. Infect Control Hops Epidemiol 1997; 18:582-586.

– Assumes smear/culture pos. = infectious– But, no reported outbreaks from source case on therapy– Dismisses Madras due to high rates from the community– US studies were not randomized – Riley may have selected less infectious

patients for home treatment. – Found faults with all epi studies - uninfected household contacts less

vulnerable – Compared to early studies, most household contacts (in N. America) are

uninfected and more vulnerable. – Concluded that smear + treated patients should still be considered

infectious AFTER 2wks– But, no reported outbreaks from source case on therapy

• Fitzwater SP. Prolonged Infectiousness of tuberculosis patients in a directly observed therapy short-course program with standardized therapy. Clin Infect Dis 2010; 51:371-378.

– Drug susceptible TB took median of 37 days to convert, 10% cult pos at 60 days

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

Richard L. Riley & William F. Wells

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 and started on treatment the same day

4 months

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”.

Dramatic Increase in antibiotic concentration as respiratory droplets evaporate into droplet nuclei

Droplet

Droplet Nucleus

Evaporation

Drug Concentration

Ref. Loudon, et al. Am Rev Resp Dis 1969; 100:172-176.

Airborne

Sputum culture vs. GP Infection

• Sputum sample

– no evaporation

– no aerosol damage

• No host defenses

• Growth support optimized

Smear and culture positive

• Droplet nucleus

– evaporation with rising drug concentration

– aerosol damage

• Host defenses

• Innate immunity

No guinea pig infection

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, Stellenbosch U.

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

109 patients: smear +, cavitary, coughing, recently started on therapy

Guinea Pig Transmission: South Africa

# Patients/ Exp.

Duration

% guinea pigs infected

(# exposed)

Patients

# XDR (MGIT)

Pilot 26* / 4 mos 74%

(360)

3/11

Exp 1 24 / 3 mos 10%

(90)

5/10

Exp 2 15 / 2 mos 53%

(90)

2/11

Exp 3 27 / 3 mos 1%

(90)

0/21

0/27 (LPA)

Exp 4 17/ 3 mos 77%

(90)

2/10

109 patients: smear +, cavitary, coughing, recently started on therapy

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

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

TBDR

TBTB

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

Gene Xpert: TB, DS or MDR

XDRby LPA

Individual Isolation

Effect of treatment unknownNovel interventions

Complications

Smear status may notbe critical if on effective treatment

Conclusions• Airborne transmission may be the weak link in TB

propagation– Only about 1/3 of pulmonary TB patients infect close

contacts

• Very little effective treatment may tip the balance against transmission

• Sputum smear positivity correlates with infectiousness only in inadequately treated patients.

• Strong rationale for prompt diagnosis of drug resistance and prompt effective therapy– can be in the community

TB CARE Transmission Control Core Package:

“F-A-S-T”• Find TB cases - rapid diagnosis

• Focus on rapid molecular diagnosis – Xpert TB• Sputum smear – can also be rapid, but more limited

• Active case finding• Focus on cough surveillance

• Separate safely and reduce exposure• Building design and engineering• Cough hygiene and triage

• Treat effectively, based on rapid DST• Focus on rapid molecular DST – Xpert TB

Challenges:

Traditional TB IC• Facility assessment

• Develop a TB IC plan

• Political will and resources

• TB IC committee

• WHO TB IC Policy

– Administrative

– Environmental

– Respiratory protection

• Assessment

– Process indicators

– HCW cases

F-A-S-T Core Strategy• Risk of undiagnosed TB and

undiagnosed DR TB

• Approach: F-A-S-T

• Political will and resources

• Focus on certain administrative components

– Rapid diagnosis

– Active case finding

– Exposure reduction

– Effective treatment

• Assessment

– Process indicators

– HCW cases

Differences Traditional TB IC• Assumes that TB cases on

therapy are infectious until smear negative

• Assumes that there will be undiagnosed cases transmitting– Focus on environmental

controls – Focus on respiratory protection

• Lip service to rapid dx and rapid treatment– Someone else’s job

F-A-S-T• Assumes that TB cases on

effective therapy are non-infectious

• Assumes that all coughing patients will be screened, so no undiagnosed TB or drug resistance

• Assumes real focus of campaign is on Dx and Rx

How do we change an established paradigm?

• Objection: Isn’t diagnosis and treatment someone else’s job?– We are expert in TB IC!

• Perhaps we need a convincing demonstration (research) project to prove that HCW TB can stop through the FAST approach.

• If we change our paradigm, what are the barriers to implementation.– Barriers to HCW case monitoring

What does FAST really look like?:

Traditional TB IC• Facility assessment

• Develop a TB IC plan

• Political will and resources

• TB IC committee

• WHO TB IC Policy– Admin Education

– HCW Education

– Patient Education

• Assessment

– Process indicators

– HCW cases

F-A-S-T Core Strategy• Work through administration to:

• Designate cough officers at all facility entrance points

– HCW education re. cough surveillance

• Work with lab to assure smear and/or Xpert TB results within 1-2 days

• Triage and safe separation protocol to reduce exposure

• Rapid DST within 1-2 days in areas with drug resistance

• Remove barriers to rapid effective treatment - within 1-2 days

• Process indicators/HCW cases

The New TB IC Core Competencies

• Expertise in generating administrative support and funding for FAST approach

• Expertise in cough surveillance • Expertise in all steps in rapid molecular diagnosis (<

2d)– Consider breath VOC analysis or CXR to reduce sputum

testing

• Expertise in triage and short-term exposure reduction

• Expertise in rapid, DST-based treatment (2d)