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North American Region, IUATLD, San Antonio, 2012
Impact of effective treatment on MDRTB transmission
Preliminary Results from the Airborne Infections Research (AIR) Facility
Edward A. Nardell, MD
Brigham & Women’s Hospital
Harvard Medical School
Harvard School of Public Health
Partners In Health
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 hospitalized
100% had HIV co-infection
100% mortality – avg 16 days from TB diagnosis
Reinfection Drug Resistant TB
in 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)
NEJM 365;1:79-81, 2011
Force of Transmission Implications
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 drugresistant TB (M/XDR-TB)
2010 GLOBAL REPORT ON
SURVEILLANCE AND RESPONSE
Importance of Transmission in
Tomsk
Glemanova, et al., Bull WHO, 2007; 85:703-711.
•
Retrospective study
•
Substance abuse
•
MDR-TB occurred
– role of non-adherence and default and the acquisition of
multidrug resistance
– strong predictor of non-adherence (OR 7.3 (2.89-18.46)
– but non-adherence NOT associated with MDR-TB
– 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 MultidrugResistant Tuberculosis
Sundari Mase MD, MPH
Barbara Seaworth MD
Edward Nardell MD
Jennifer Flood MD, MPH
Julian Thomas
Discontinuation of Airborne Infection Isolation: Drug-Susceptible TB
Organization
CDC
CDC
Title
Prevention and Control of
Tuberculosis in Correctional and
Detention Facilities:
Recommendations from CDC
Guidelines for preventing the
transmission of Mycobacterium
tuberculosis in health-care
facilities, 2005
Min Days Tx Lab Results
Not
mentioned
14
Not
mentioned
Not
mentioned
Not
mentioned
14
3 neg
smears
Tuberculosis (TB): Clinical Policies
and Protocols
Not
mentioned
14
3 neg
smears
Canadian Tuberculosis Standards
6th Ed.
neg /pos
14
pos/pos
14
The Interdepartmental Working
Group on Tuberculosis: The
UK Department
prevention and control of
of Health
tuberculosis in the United Kingdom:
Department of Health – Publications
NYC Bureau of
Tuberculosis
Control
Public Health
Agency Canada
Smear
/Culture
pos /neg
Not
mentioned
3 neg
smears
3 neg
smears
none
needed
3 neg
cultures
Discontinuation of Airborne Infection Isolation: MDR-TB
Organization
Department of
Health
Title
Prevention and Control of
Tuberculosis in Correctional and
Detention Facilities:
Recommendations from CDC
Guidelines for preventing the
transmission of Mycobacterium
tuberculosis in health-care
facilities, 2005
The Interdepartmental Working
Group on Tuberculosis: The
prevention and control of
tuberculosis in the United Kingdom:
Department of Health –
Publications
Bureau of
Tuberculosis Control
Public Health
Agency Canada
Tuberculosis (TB): Clinical Policies
and Protocols
Canadian Tuberculosis Standards
6th Ed.
CDC
CDC
Smear
/Culture
Min days Tx
Lab results
Type
Suggestion
all
Not
mentioned
neg culture
comment
all
Not
mentioned
neg culture
comment
all
Not
mentioned
neg culture
case by
case
Not
mentioned
Not
mentioned
neg smear +
neg culture if possible
3 neg
cultures
guideline
all
all
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, 1956-60
Am 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 Treated
(29 GPs)
(1 GP)
100%
2%
(14 GPs)
(6 GPs)
28%
5%
– Drug-resistant TB
• 6 Untreated
• 11 Treated
*all smear positive patients, relative to the amount of time on the ward
Riley’s conclusions
ARRD 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
Ref. Loudon, et al. Am Rev Resp Dis 1969; 100:172-176.
Droplet
Drug
Concentration
Airborne
Evaporation
Droplet Nucleus
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 Facility
Witbank, Mpumalanga Provence, RSA
Collaborators:
•
MRC
–
–
–
–
–
–
–
–
–
–
•
Harvard University
Brigham & Women’s Hospital
–
–
–
•
Other collaborators
–
–
–
–
•
Paul Jensen, engineer
Charles Wells
Paul Arguin
Mpumalanga Provence Health Dept &
Specialized MDR TB Referral Center
–
–
–
–
Edward Nardell, PI
Melvin First
Ashwin Dharmadhikari
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.
Sidney Parsons*, engineer
CDC
–
–
–
•
•
CSIR
–
•
Martie van der Walt
Matsie Mphahlele
Kobus Venter
Anton Stoltz
Willem Lubbe
Thabiso Masotla
Karin Weyer
Bernard Fourie
Lourens Robberts
Daan Goosen, Veterinarian
Patients
Nurses
Administration
Doctors
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
109 patients: smear +, cavitary, coughing, recently started on therapy
# 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
* 8 different spoligotypes, but only 2 transmitted to GPs – both XDR-associated
Unsuspected, untreated TB
TB
DR
General Medical Ward
Orthopedic Ward
Obstetrics Ward
Psychiatric Ward
TB
DS
Unsuspected, untreated
MDR/XDR TB
All other patients on effective treatment
TB
TB
TB
TB
TB
DR
TB Hospital
TB
TB
TB
Potential for re-infection
TB
TB
TB
DR
TB
TB
TB
Unsuspected, untreated
XDR TB
All other patients on effective treatment
MDR
TB
MDR
TB
MDR
TB
MDR
TB
MDR
TB
MDR
TB
XDR
TB
MDR
TB
MDR
TB
MDR TB Ward
Potential for re-infection
MDR
TB
XDR
TB
MDR
TB
MDR
TB
MDR
TB
TB Triage – Rapid DR Diagnosis
Smear status may not
be critical if on
effective treatment
Individual Isolation
XDR
by
LPA
Effect of treatment
unknown
Novel interventions
Gene Xpert: TB, DS or MDR
Community based – on effective treatment – responding
Complications
Hospitalized patients on effective treatment - responding
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
F-A-S-T Core Strategy
•
•
•
•
•
•
•
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
•
•
•
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
F-A-S-T Core Strategy
•
•
•
•
•
•
•
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
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)