Preventing Transmission of TB: Research and Reality

Fennelly: Preven+ng Transmission of TB: Research and Reality

2/24/16-‐Advances in the Science

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Preventing Transmission of TB: Research and Reality

Kevin P. Fennelly, MD, MPH Pulmonary Clinical Medicine Section

Division of Intramural Research CV-Pulmonary Branch, NHLBI, NIH

Bethesda, MD, USA

[email protected] 24 March 2016

§  To summarize current CDC and WHO

recommendations about preventing TB transmission in health care facilities

§  To provide an update of recent research on the transmission of TB §  How it can help inform decision-making about the

infectiousness of TB patients

Objectives

§  My comments and recommendations are mine and mine alone and do not reflect endorsement by the NIH, NHLBI, or others.

Disclaimer



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§  None related to this talk (unfortunately).

§  I had submitted a patent application on a point of care device to collect cough aerosols, but it did not work as hoped.

§  The reality of research!

Potential Conflicts of Interest

Reason’s Swiss Cheese Model of System Failure

Infectious TB patients

Policies & Procedures -international guidelines -MOH -Hospital / HCF

PRP

Environmental

Administrative

Nosocomial LTBI

Nosocomial TB Disease and Death

Clinical Suspicion Rapid Diagnosis Appropriate Treatment Assessing Infectiousness

Good ventilation If not, UVGI De-crowding Isolation or separation

CDC and WHO TB Infection Control Guidelines

TB is transmitted by aerosols, NOT by sputum

- Tang JW, Settles GS. N Engl J Med 2008 Oct 9;359(15):e19.



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Life Cycle of M. tuberculosis

EC IC

EC IC

Extracellular in Environment: Transmission = Survival + Transport

Aerosolization: Infectiousness Inhalation

Deposition Innate Responses Adaptive Immunity

Active TB Susceptible Host

Progression LTBI (Intracellular)

Cough Aerosol Sampling System, v.2

Six-stage Andersen cascade impactor



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Changes in cough aerosols with treatment

Fennelly KP et al. AJRCCM 2004; 169: 604

4 of 16 (25%) of sputum smear + MDR-TB patients in Denver

0

0.5

1

1.5

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2.5

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3.5

1 2 3 4 5 6 7 8

Week of Treatment

Log 1

0 Aer

osol

CFU

0

0.5

1

1.5

2

2.5

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3.5

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4.5

Gra

de o

f Spu

tum

Sm

ear &

Cul

ture

Aerosol Culture Sputum Culture Sputum Smear

Are bacilli exposed to antibiotics more susceptible to the stresses of aerosolization? than those in sputum?

- Fennelly KP et al. Am J Resp Crit Care Med 2004; 169; 604-9

Size Distribution of Mtb in Cough Aerosols

Fennelly KP et al. AJRCCM 2012: 186:450



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Variability of Infectious Aerosols in TB

Fennelly KP et al. AJRCCM 2012: 186:450

Cough Aerosols of M. tuberculosis Predict

New Infection: A Household Contact Study

Jones-Lopez EC et al. AJRCCM 2013; 187:1007

Cough Aerosols of M. tuberculosis Predict New Infection: A Household Contact Study

Jones-Lopez EC et al. AJRCCM 2013; 187:1007



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§  124 index cases and 731 HHCs in Brazil §  High transmission associated with severity of cough

-  visual analog cough scale (VACS; p<0.001) and -  the Leicester Cough Questionnaire (LCQ)

§  and cavitation on chest radiograph.

§  SCG 3b strains more prevalent in low (27.3%) than in high (12.5%) transmission households (p = 0.11). §  SCG associated with bilateral disease on chest radiograph

(p = 0.002) §  marginally associated with LCQ sores (p = 0.058) §  group 3b patients having weaker cough.

Cough & M. tuberculosis Strains

Jones-Lopez EC et al. PLoS One 2014

§  Not yet on appropriate treatment. §  High bacillary load

§  Positively associated with grades of AFB smear or semi-quantitative culture §  Negatively associated with days to postive (DTP) in liquid culture systems

(BACTEC, MGIT, etc.) ) (Fennelly KP, 2012) §  Cycle threshold (e.g. Xpert) surprisingly not as helpful yet

§  Strong, frequent cough (Loudon; Fennelly) §  +/- Salivary appearing secretions (vs purulent) (Fennelly KP, 2012)

§  +/- Cavitary disease

§  Young adults > children or elderly (Bordorff MW, Am J Epidemiol 2001)

§  Men>women (Bordorff MW, Am J Epidemiol 2001)

§  ‘Superspreading environments’: §  crowded or poorly ventilated or long durations of exposures

§  High CFU (10+ in 10 minutes of coughing) in cough aerosols. §  (Jones-Lopez EC, 2013)

Host: who is most infectious with active TB ?

§  RNA expression signatures may help distinguish LTBI from early active disease and TB from other diseases. §  Reviewed in Yates TA et al. Lancet ID 2016; 16:227

§  Ongoing study in South Africa of over 6,000 adolescents has identified gene expression 600 days before disease diagnosed. §  Hatherill M; presented at Union TB Meeting, Cape Town, 2015

Exposed host: who is most likely to progress to TB disease after infection?



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Increased cellular activity in thoracic lymph nodes in early human LTBI

Ghesani N et al. Am J Resp Crit Care Med 2014: 189: 748-750 We now have a research tool to ascertain more accurately WHEN someone has been recently infected. Needs confirmation in a larger study.

PneumoniaCheck™ invented by Dr. David Ku, Georgia Tech U

Possible methods of sampling cough aerosols in the future?

Cough samples as a replacement to sputum Antonino Catanzaro (UCSD), Wael Elmaraachli (UCSD), Patrick Sislian (Deton), and Stephen Chapman (Deton)

Sample quality affects Dx output

Pa+ents emit infec+ous droplets

Sputum is difficult to process which leads to >10X higher limit of detec+on than theore+cally possible.

Sputum is unobtainable in ~20% of TB popula+on.

Infec+ous droplets emiUed from a pa+ent can be collected.

Pa+ents with TB infect others by coughing.

Deton’s device collects infec+ous cough droplets and delivers a ‘diagnos+c-‐ready’

sample

Proof of concept in CF

pa+ents

96% sensi)vity achieved

Collected cough droplets and processed using PCR on oprL segment of P. aeruginosa DNA

24 cough posi=ve out of 25 CF pa=ents with history of P. aeruginosa infec=on confirmed by sputum culture

Device is under development to serve as a disposable low-‐cost alterna+ve to

sputum.



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Face Mask Sampling for M tb In Aerosols

Williams CML PLoS One. 2014; 9(8): e104921.

Ventilation

Recommended Review: Li Y et al. Role of ventilation… Indoor Air 2007: 17: 2-18

TB Transmission: What is ready to use now?

RESEARCH §  FAST/masks on pts §  Ventilation-good evidence §  UVGI-lab evidence §  PRP- modeling evidence §  Cough aerosol collection §  WGS / bacillary RNA §  Exposed host RNA

expression

§  Bottom line

REALITY §  ‘Easy’ to implement now §  Now. §  Now when feasible §  Now. §  Not yet; closer. §  Not yet; close. §  Not yet; but exciting!

Perhaps guided by PET +/- cough aerosols?

§  We still need good, smart TB clinicians to help assess infectiousness



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Acknowledgements National Jewish Health Michael Iseman Leonid Heifets Pam Lindholm-Levy John Martyny James Cook (U of Illinois) UMDNJ-NJMS (Rutgers U) Edward Jones-Lopez (now Boston U) Jerrold Ellner (now Boston U) Nasrin Ghesani University of Florida Jennifer Hosford NIH Ken Olivier (NHLBI) Clif Barry (NIAID) Steve Holland (NIAID) Dan Barber (NIAID)

Makerere U/ Mulago Hospital Harriet Menyha Irene Ayakaka Christopher Muchwa Roy Mugerwa Moses Joloba Mulago Hospital nurses and patients Colorado State U-Ian Orme U of Leicester- Mike Barer

Supported by CDC Coop Agreement NIH (K23) AI01676-01 Wellcome Trust 063410/ABC/00/z UF Department of Medicine & SNTC UF Emerging Pathogens Institute NIH-NHLBI Division of Intramural Research My wife and children

§  Yates TA et al. The transmission of

Mycobacterium tuberculosis in high burden

settings. Lancet ID 2016; 16: 227-38

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Preventing Transmission of TB: Research and Reality

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