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Theory of Airborne Infections
Transmission Control Interventions
Impact of Treatment
Edward A. Nardell, MD
Associate Professor
Harvard Medical School
Harvard School of Public Health
Hospitals as Causes of Human Suffering
Referring to the Hotel-Dieu in Paris which had a mortality rate of 1 in 4 patients
“A fragment of space closed on
itself, a place of internment
of men and disease, its
ceremonious but inept
architecture multiplying the
ills of its interior without
preventing their outward
diffusion, the hospital is
more of a centre of death
(foyer de mort) for the cities
where it is sited, than a
therapeutic agent for the
population as a whole”
Ref: Medicine and Magnificence – British
Hospital and Asylum Architecture, 1660
– 1815, by Christine Stevenson, Yale
University Press, 2000, page 155
Florence Nightingale 1820-1910
“Notes on Hospital Design 1859”
Airborne infections as a buildingassociated illnesses
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Hospitals, clinics, laboratories
Other indoor environments
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Prisons, jails, homeless shelters, residential
facilities
refugee camps, crowded outdoor environments
transportation safety: Airliner, shipboard
transmission
Pine Street Inn 1984 TB Outbreak
INH & SM res
Shelter
Transmission
Exogenous
Reinfection
UVGI Air
Disinfection
Air Filtration
Many other
Interventions
TB Resurgence - NYC (1985-92)
TB Case
Treatment barriers
MDR TB
Cure 50%
Transmission
Shelters, Jails, Hospitals
HIV +
HIV -
5 - 10% / year
5 - 10 % / lifetime
Tuberculosis in New York City-turning the tide
Frieden, T. R., Fujiwara, P. I., Washko, R. M., Hamburg, M. A
N Engl J Med, 1995, 333:229-33
• “Epidemiologic patterns strongly suggest that the
decrease in cases resulted from an interruption in the
ongoing spread of M. tuberculosis infection, primarily
because of better rates of completion of treatment
and expanded use of directly observed therapy.
• Another contributing factor may have been efforts to
reduce the spread of tuberculosis in institutional
settings, such as hospitals, shelters, and jails.”
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 culture
conversion
Source: Multidrug and extensively
drug-resistant TB (M/XDR-TB)
2010 GLOBAL REPORT ON
SURVEILLANCE AND RESPONSE
Transmission: Hospitals as MDR TB Factories
Tomsk, Siberia
Glemanova, et al., Bull WHO, 2007; 85:703-711.
•
Studied the role of non-adherence and default on the
acquisition of multidrug resistance
•
Substance abuse was NOT associated with MDR-TB
•
MDR-TB occurred among adherent patients who had
been hospitalized,
–
Odds Ratio: 6.34 for hospitalized vs. patients treated as
outpatients.
Patients admitted with drug susceptible TB
- Reinfected with MDR TB
Anton Chekhov, MD
Short story writer
- Disliked Tomsk and
Tomsk disliked him!
- Died of TB
TB IC Hierarchy
• Administrative controls
– Said to be most effective, least expensive
– “FAST” – Barrera and Nardell. Int J. Tuberc Lung
Dis, April, 2015
• Environmental controls*
– Require less cooperation
• Respiratory protection
– Last intervention, not against unsuspected case
TB transmission, c. 1930
Richard L. Riley & William F. Wells
Wells’ Air Centrifuge, 1931
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“On Airborne Infection, Study II.
Droplets and Droplet Nuclei”
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W. F. Wells*. Am J Hygiene, 1934:20.
611-18.
*Instructor, Sanitary Service, HSPH
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In 1931 Wells developed his air centrifuge to
sample bacteria from air
Droplet vs. Airborne spread
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Transmission within a meter
of the source
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Relatively large numbers of
organisms in inoculum (small
incoculum may be tolerated)
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Access to vulnerable site
(mucosal membranes of eye,
nose, mouth, trachea, etc.)
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Hand washing may be
effective
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Transmission beyond a
meter – shared breathing
volume
Relatively small numbers of
organisms in inoculum –
virulence required
Access to vulnerable site –
alveoli in the case of TB
Hand washing not effective.
Strobe photo of cough/sneeze
Particle size* & suspension in air
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Particle size &
deposition site
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Time to fall the
height of a room
100 
20 
10  – upper airway
1 - 5  – alveolar
deposition
*NOT organism size
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10 sec
4 min
17 min
Suspended
indefinitely by room
air currents
Fate of aerosolized TB
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10% survive aerosolization
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of those, 50% (5%) survive 6 hrs.
(Loudon)
if inhaled, only 0.25 to 50% (2.5%) lodge
in the lung
Particle deposition:
Upper and lower respiratory tract
TB is an infection of the alveolar macrophage
Airborne infection requirements
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Pathogen must be dispersed as fine
particles (1 – 5 um size)
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Remain suspended in air
Reach the alveolar level (TB)
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Respiratory tract – cough aerosol
TB wound – water pik
Resistant upper respiratory tract
Minute infectious dose (droplet nucleus)
Upper room UVGI effect on measles
in day schools, (Wells, Am J Hygiene, 35:97-121, 1942)
Wells/Riley Experimental TB
Ward
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Quantitative air sampling for TB
Riley RL, Mills C, Nyka W.
Aerial dissemination of
tuberculosis – a two year
study of contagion on a
tuberculosis ward. Am J Hyg
1959; 70:185-196.
Riley RL. What nobody
needs to know about
airborne infection. (How It
Really Happened) AJRCCM
2001; 163:7-8.
Infectivity of ward air
63 infectious particles
(120 GPs x 8 cf per day x 730 days)
= 1 infectious particle/11,000 cf
High enough to explain infection rate of nurses
Avg. 30 infectious particles added per day (1.25/hr)
but the laryngeal case generated 60/hr
Other, epidemiologic investigations have estimated 13 – 240/hr
Example: TB Hospital outbreak recovery room
Propagation of Mycobacterium tuberculosis
Environmental Factors
Room volume
Room ventilation
Temperature and humidity
Aerobiology
Environmental stresses:
oxygen
radiation
Organism
Take off
Treatment
Source
viability
drug resistance
strength
disease
Landing
number
Virulence
Host
resistance
Pathogenesis
infection
Airborne Infection - Interventions
Temperature and humidity
Aerobiology
Environmental stresses:
oxygen
radiation
Organism
Take off
Masks on
patients Source
Landing
number
Treatment
viability
Virulence
drug resistance
Host
strength
Immunization
Resp Protection
resistance
Admin.
Controls
disease
Dilution
Filtration
UVGI
Isolation
Pathogenesis
infection
Treatment of latent infection
Mechanical Ventilation –
theoretical limits of protection
Nardell EA, et. al. Am Rev Resp Dis 1991; 144:302-6
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27/67 (40%) office
workers infected over
30 days
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1st
1 secondary case
Poor ventilation
air change removes
63%,
2nd removes 63% of
what is left, etc.
Double ventilation =
reduce risk by half, and
so on….
120
100
15 cfm/person
80
p
30 cfm/person
60
40
20
0
0
2000
4000
6000
Ventilation, CFM
8000
Building Usage
Population density and distribution as a TB risk factor
Large facility:1. higher probability of infectious cases
2. more people exposed
10 Small facilities
2% risk = 98 exposed
Same 2% risk = 18 exposed,
Now 80 protected = 82% risk
reduction!!
Does the Building Matter?
Annual Risk of Infection Among Medical Students of Universidad Peruana Cayetano
Heredia in Lima, Peru, ATS, May 20, 2002, Accinelli, Alvarez and colleagues.
A
A
B
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488 students
Pos. PPD increased from
3.5% to 45.9%
over 7 years
•
6%/yr. avg.
B
How Effective are Surgical Masks on Patients?
Respirators
For patients
For health care workers
How Effective Are Surgical Masks on Patients?
Guinea
Pig
Gro
up
TST 0
TST 1
TST 2
TST 3
TST 4
Total
Intervent
ion
0
1
10
20
5
36
Control
0
4
15
39
11
69
Approx 53% Effective
Dharmadhikari AS, et. al.
Am J Respir Crit Care Med.
2012 May 15;185(10):1104-9.
NIOSH funded
Slides courtesy of Dr. Norbert Ndjeka, Director,
Drug Resistance and TB and HIV, MOH, South
32
Africa
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
2010 – Durban,
South Africa National TB Conference
33
Community Based Treatment
• Highly effective
• e.g., Peru, Lesotho,
Cambodia, KZN, and
others
• Less opportunity for
institutional
transmission
But, what about
community
transmission?
Effects of Chemotherapy on
Transmission – Early Papers
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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
•
Discordance between effect of treatment on culture and smear
– 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
• 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
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
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”.
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
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
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•
•
Sputum sample
– no evaporation
– no aerosol damage
No host defenses
Growth support optimized
Smear and culture positive
•
•
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Droplet nucleus
– evaporation with rising drug
concentration
– aerosol damage
Host defenses
Innate immunity
No guinea pig infection
How effective is treatment in stopping
MDR-TB transmission?
The AIR Facility
Witbank, Mpumalanga Provence, RSA
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
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
TB CARE Transmission Control Campaign:
“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 at all entrance points
• 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
FAST : Underlying Principles:
1. Most TB transmission is NOT due to
known or suspected patients on
effective therapy
– Much of TB IC focuses on known and
suspected cases, isolation /separation, air
disinfection, respiratory protection, and
sputum conversion.
2. Rapid identification of unsuspected TB
cases and unsuspected drug resistance
are top priorities
3. Effective treatment rapidly stops TB
transmission regardless of sputum
smear status.
Not new, but never prioritized:
Traditional TB IC
F-A-S-T Strategy
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•
•
•
•
•
•
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
USAID F-A-S-T Implementation Project
Ndola District, Zambia
Ndola Central District Hospital
Casualty
Filter ward:
Cough
Surveillance
OPD
High Cost
Clinic
NCDH Clinics:
Cough surveillance
And treatment
Lab: Xpert TB (2 hr dx TB and RMP resistance)
RX – effective treatment -> no transmission
Process indicators:
1.Time from cough onset to detection
2.Time from cough detection to sputum smear
or Xpert TB test
3. Time from sputum receipt to result
4. Time from result to effective treatment.
Twapia Clinic
AFB Smear Lab
And treatment
Early FAST Results,
National Institute of Diseases of the Chest, Dhaka, Bangladesh
Preliminary Results on the FAST Strategy at NIDCH*
Disease
Category
Total Samples
Tested
Number of
Unsuspected TB
Cases Identified (%)
Number of
Unsuspected MDR-TB
Cases Identified
(%)
Current TB disease
42
Other respiratory disease
with previous TB history
169
40 (23.66)
3 (1.77)
Other respiratory disease
850
80 (9.41)
6 (0.70)
Total
1062
120 (11.29)
12 (1.12)
*Data reflect 11 weeks of implementation, starting February 2014.
3 (7.12)
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
Continuing Communication
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Global Health Delivery On Line
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GHDonline/infection control
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