theory of airborne infections transmission control interventions impact of treatment edward a....

Theory of Airborne Infections Transmission Control

InterventionsImpact of Treatment

Edward A. Nardell, MDAssociate Professor

Harvard Medical SchoolHarvard 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 building-associated illnesses

Hospitals, clinics, laboratories Other indoor environments

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

ShelterTransmission

Exogenous Reinfection

UVGI AirDisinfection

Air Filtration

Many otherInterventions

TB Resurgence - NYC (1985-92)

TB Case Cure 50%

Shelters, Jails, Hospitals

Treatment barriers

Transmission

MDR TB

HIV + HIV -

5 - 10 % / lifetime

5 - 10% / year

Tuberculosis in New York City--turning the tide

Frieden, T. R., Fujiwara, P. I., Washko, R. M., Hamburg, M. AN 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 ONSURVEILLANCE 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, MDShort story writer- Disliked Tomsk andTomsk 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 “On Airborne Infection, Study II.

Droplets and Droplet Nuclei” W. F. Wells*. Am J Hygiene, 1934:20.

611-18. *Instructor, Sanitary Service, HSPH

In 1931 Wells developed his air centrifuge to sample bacteria from air

Droplet vs. Airborne spread Transmission within a

meter of the source

Relatively large numbers of organisms in inoculum (small incoculum may be tolerated)

Access to vulnerable site (mucosal membranes of eye, nose, mouth, trachea, etc.)

Hand washing may be effective

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

*NOT organism size

Particle size* & suspension in air Particle size &

deposition site 100 20 10 – upper

airway 1 - 5 – alveolar

deposition

Time to fall the height of a room 10 sec 4 min 17 min Suspended

indefinitely by room air currents

Fate of aerosolized TB 10% survive aerosolization

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

Pathogen must be dispersed as fine particles (1 – 5 um size) Respiratory tract – cough aerosol TB wound – water pik

Remain suspended in air Reach the alveolar level (TB)

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

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.

Quantitative air sampling for TB

Infectivity of ward air63 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 nursesAvg. 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

AerobiologyEnvironmental stresses:

Temperature and humidity

oxygen

radiation

Pathogenesis infectiondisease

Host

resistance

Source

strength

Organism

Treatment

drug resistance

number

viability Virulence

Take off Landing

Environmental FactorsRoom volumeRoom ventilation

Airborne Infection - Interventions

AerobiologyEnvironmental stresses:

Temperature and humidity

oxygen

radiation

Pathogenesisinfectiondisease

Host

resistance

Source

strength

Organism

Treatment

drug resistance

number

viability Virulence

Take off Landing

IsolationAdmin.Controls

DilutionFiltrationUVGI

ImmunizationResp Protection

Masks on patients

Treatment of latent infection

Mechanical Ventilation – theoretical limits of protection

Nardell EA, et. al. Am Rev Resp Dis 1991; 144:302-6

27/67 (40%) office workers infected over 30 days

1 secondary case Poor ventilation

1st air change removes 63%, 2nd removes 63% of what is left, etc.

Double ventilation = reduce risk by half, and so on….

0

20

40

60

80

100

120

0 2000 4000 6000 8000

Ventilation, CFM

p

15 cfm/person

30 cfm/person

Building UsagePopulation density and distribution as a TB risk factor

Large facility:1. higher probability of infectious cases

2. more people exposed

2% risk = 98 exposed

Same 2% risk = 18 exposed, Now 80 protected = 82% risk reduction!!

10 Small facilities

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.

• 488 students

• Pos. PPD increased from

3.5% to 45.9%

over 7 years

• 6%/yr. avg.

A

B

A

B

How Effective are Surgical Masks on Patients?How Effective are Surgical Masks on Patients?

For health care workersFor patients

Respirators

Guinea Pig Group

TST 0 TST 1 TST 2 TST 3 TST 4 Total

Intervention

0 1 10 20 5 36

Control 0 4 15 39 11 69

How Effective Are Surgical Masks on Patients?

Approx 53% Effective

Dharmadhikari AS, et. al.Am J Respir Crit Care Med. 2012 May 15;185(10):1104-9.

NIOSH funded

32

Slides courtesy of Dr. Norbert Ndjeka, Director, Drug Resistance and TB and HIV, MOH, South Africa

2010 – Durban, South Africa National TB Conference 33

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

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

• 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, 1956-60Am 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 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”.

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

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

How effective is treatment in stopping MDR-TB transmission?

The AIR FacilityWitbank, Mpumalanga Provence, RSA

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

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

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• 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 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

Ndola Central District Hospital

Lab: Xpert TB (2 hr dx TB and RMP resistance)

RX – effective treatment -> no transmission

Process indicators:1.Time from cough onset to detection2.Time from cough detection to sputum smear

or Xpert TB test3. Time from sputum receipt to result4. Time from result to effective treatment.

Twapia Clinic

AFB Smear Lab And treatment

Casualty

Filter ward:Cough Surveillance

OPD High Cost Clinic

USAID F-A-S-T Implementation Project

Ndola District, Zambia

NCDH Clinics:Cough surveillanceAnd treatment

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   3 (7.12)Other respiratory diseasewith 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.

Early FAST Results, National Institute of Diseases of the Chest, Dhaka, Bangladesh

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 Global Health Delivery On Line

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