Background and Rationale for TB Infection Control

Background and Rationale for TB Infection Control Henry M. Blumberg, M.D. Professor of Medicine and Epidemiology Program Director, Div. of Infectious Diseases Emory University School of Medicine and Hospital Epidemiologist Grady Memorial Hospital Atlanta, Georgia USA henry.m.blumberg@emory.edu

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9/4/91 40 yo HIV+ male admitted to Grady Hospital (7B) with fever (39.2 C), chills, cough CXR: RML infiltrate; CD4=6 Begun on cefuroxime for community-acquired pneumonia 9/8/91 Trimethoprim-sulfamethoxazole and erythromycin added because patient remained febrile 9/8/91 ENT consult for epistaxis: secondary to cough 9/13/91 Discharged

9/17/91 Admitted to 10B with fever (38.8 C), productive cough Admittting diagnosis community-acquired pneumonia ; gram stain of sputum showed WBCs and gram + diploccoci Begun on cefuroxime 9/19/91 Sputum for AFB smear and culture obtained 9/20/91 4+ AFB smear reported by lab Patient move to 7B respiratory isolation room Started on TB meds AFB culture subsequently positive for drug susceptible M. tuberculosis

10-B B TST Conversions PPD Negative 5 4 3 2 1 PPD Positive 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 12 1 2 3 4 5 6 7 8 9 10 11 12 1 2 3 4 5 1990 1991 1992 HCW Begins Work Exposure Period

Nosocomial Transmission of TB at Grady Hospital-- --Wards 10B/7B, 1991-1992 1992 HIV+ TB Patient Patients HCWs + Patients HIV+ HCW Other HCWs CD4=8 (10 B) Other Patients (10B/7B) JID 1995;172:1542 8 Cases of Active TB among HCWs HCW TST Conversion Rates: Ward 10 B: 48% Ward 7B: 30% General Medicine Wards: 13% Delays in Diagnosis and Rx 9 cases (patients)

Atlanta Journal Constitution April 1992

Patients with nosocomially-acquired acquired TB: Risk factors Case Incubation period (mo.) Immunocompromising Condition Exposure days 54 yo BM 2.0 HIV (CD4=2) 7 59 yo BF 2.5 steroids 2 37 yo WM 2.75 HIV (CD4=38) 4 32 yo BM 18.0 alcoholic 3 61 yo BM 26.5 HIV (CD4=347) 9 38 yo BM 29.0 HIV (CD4=600), alcoholic 3 31 yo BM 39.0 diabetes 3 27 yo WM 44.0 none 4 47 yo BM 46.25 diabetes 5

U.S. Nosocomial MDR-TB Outbreaks Investigated by CDC

Nosocomial MDR-TB Outbreaks in Countries Outside the U.S. Country Patients % HIV % Mortality Spain (1991) 48 100 98 Italy (1991-95) 116 99 95 Argentina (1994-1995) South Africa (1997) Russia (1998-99) 101 100 93 5 100 100 6 0?

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Nosocomial Transmission Amplifying and Fueling XDR-TB Outbreak Mean Age = 35 years; 51% Male 49% Female XDR-TB patients (n=53) Characteristic Prior TB Treatment: n (%) No prior TB treatment 26/47 (55%) Cure or Completed prior TB treatment Default or TB Treatment Failure 14 (30%) 7 (15%) Prior Hospitalization: 28/42 (67%) Lancet 2006; 368:1575-80 80

HIV Characteristics: XDR-TB (n=53) KwaZulu Natal, South Africa HIV Characteristics XDR TB Patients Previously Tested: n (%) 44 (86%) HIV positive (if tested): n (%) 44 (100%) Recent CD4 count: mean median (range) 73 63 (9-283) On ARV Therapy: n (%) 15 (34%) 52 of 53 (98%) of XDR patients have died Median survival = 16 days (2-210) Gandhi N. Lancet 2006; 368:1575-80 80

1.1 1.0.9 Survival among XDR TB cases Gandhi N. Lancet 2006; 368:1575-80 52 of 53 (98%) of XDR patients have died Median survival = 16 days (2-210).8 Proportion Surviving.7.6.5.4.3.2.1 0.0 -.1 0 30 60 90 120 150 180 210 240 Days since Sputum Collected

Molecular Typing Studies (Spoligotyping and IS6110-RFLP ) Supports Nosocomial Transmission 39 (85%( 85%) ) of 46 of XDR-TB isolates found to be the KZN clone XDR-TB outbreak includes HCWs (22 confirmed, 4 suspected; all died) Gandhi N. Lancet 2006; 368:1575-80 80

NG2 Acquired Resistance or Nosocomial Transmission? Acquired or amplified or resistance may explain original genesis of first XDR TB strains Current magnitude of XDR TB epidemic difficult to explain by acquired resistance alone January 2005 to March 2007 in Tugela Ferry alone: 433 TB cases resistant to at least isoniazid and rifampicin 239 (55%) XDR TB cases 194 (45%) MDR TB cases (non-xdr TB) 126 Cases of MDR TB in US in 2004 49 cases of XDR TB in US from 1993-2006 Gandhi N. IDSA 2007

Slide 28 NG2? Make HIV part of this slide it's own slide to emphasize how HIV plays a role with primary progression to active TB Neel Gandhi, 2007-05-20

XDR-TB Outbreak Continues Tugela Ferry From January 2005 to March 2007: 433 TB cases resistant to at least INH and RIF 239 (55%) XDR TB cases 199 (84%) confirmed dead 194 (45%) MDR TB cases (not XDR TB) 119 (65%) confirmed dead >90% of MDR- and XDR-TB patients are HIV-infected Source: Gandhi N. IDSA 2007

Tugela Ferry: Tugela Church Ferry of Hospital Scotland Hospital KwaZulu Natal, South Africa Gandhi N IDSA 2007

Factors Facilitating Nosocomial Outbreaks of Tuberculosis Delays in Diagnosis Failure to recognize and isolate patients with TB Comingling of patients with TB and HIV Inadequate respiratory isolation facilities Other Factors Poorly ventilated wards; lack of engineering controls Laboratory capacity-- culture and DST Lack of surveillance ; no TB/HIV screening of HCWs Lack of use of masks or respirators (PPE)?? Lack of political commitment to support TB infection control

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Turning the Tide Improved Hospital Infection Control Improved infection control is likely to have substantially decreased the number of cases citywide Enhanced Public Health Efforts Increased Federal Funding for TB Rebuilding of the Public Health Infrastructure ($1 Billion in NYC) Directly Observed Therapy Improved Laboratory Turn-around Time and Capabilities

Clinical Features of TB in HIV-infected Patients Diagnosis delayed; frequently atypical manifestations Disseminated/extrapulmonary disease common; often coexists with pulmonary disease Chest x-ray x findings frequently atypical - Lower lobe and interstitial infiltrates - Adenopathy Treatment: good response if drug- susceptible isolate and patient adherent to therapy

Hierarchy of TB Infection Control Measures 1. Administrative Controls-- --most important Careful screening of patients, isolation, early diagnosis and treatment 2. Engineering Controls e.g., negative pressure airborne infection isolation rooms; enhanced ventilation 3. Personal Respiratory Protection Equipment respirator masks

TB Infection Control Measures Implemented at Grady Memorial Hospital-1992 March 1 Expanded respiratory isolation policy key Admin. Control Increased surveillance to ensure that patients for whom AFB smears ordered were in isolation. Increased physician and nurse education Window fans added to 90 rooms to create negative pressure rooms PPD Blitz continues June 1--Submicron 1 mask introduced July 1 PPD testing frequency increased to every 6 months and expanded to include ALL HCWs (including non TB nurse epidemiologist hired (including non-employees)

Summary of Grady Expanded TB Isolation Policy CRITERIA FOR ISOLATION LENGTH OF ISOLATION 1. Active Pulmonary TB Duration of hospitalization unless >4 weeks and then must have 3 negative AFB smears 2. R/O TB or sputum AFBs Until 3 sputum AFB smears ordered (expanded surveillance) are negative 3. HIV+ patient admitted Until 3 sputum AFB smears with abnormal CXR negative NOTE: D/C isolation if patient has 3 negative AFB smears

8 TB Exposure Episodes per Month Grady Memorial Hospital (Ann Intern Med 1995; 122:658) No. of Exposure Episodes 7 6 5 4 3 2 1 0 Jul-91 Sep-91 Nov-91 Jan-92 Mar-92 May-92 Jul-92 Sep-92 Nov-92 Jan-93 Mar-93 May-93 Jul-93 Sep-93 Nov-93 Jan-94 Mar-94 May-94 OLD RI POLICY NEW RI POLICY p-value 4.4 exposures/mo 0.6 exposures/mo <0.001 35.4 exposure days/mo 3.3 exposure days/mo <0.001

3.50% Six Month PPD Conversion Rates for Grady HCWs 118/3579 118/3579 3.00% 2.50% Conversion Rate 2.00% 1.50% 1.00% 51/2975 67/4715 30/4776 23/5129 17/4894 0.50% 0.00% (Ann Intern Med 1995; 122:658) 1/92-6/92 7/92-12/92 1/93-6/93 7/93-12/93 1/94-6/94 7/94-12/94

Six Month HCW TST Conversion Rates Grady Memorial Hospital TST Conversion Rate 4% 3% 2% 1% 0% 1/92-6/92 TST Conversions 2006: 9/4600 (0.2%) 1/93-6/93 1/94-6/94 1/95-6/95 1/96-6/96 1/97-6/97 1/98-6/98 1/99-6/99

Emory House Staff PPD Conversion Rates Rate per 100 person-years 14% 13% 12% 11% 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Jan- 93 Jul- 93 Jan- 94 Jul- 94 Jan- 95 Jul- 95 Jan- 96 Jul- 96 Jan- 97 Jul- 97 Jan- 98 Jul- 98 Jan- 99 Jul- 99 Jan- 00 DEPARTMENT OF MEDICINE OTHER DEPARTMENTS TOTAL CONVERSION RATE 1998-2003: 7 PPD conversions Rate: <0.2/100 person-years Adapted from Blumberg et al Clin Infect Dis 1998; 27:826.

Hierarchy of TB Infection Control Measures 1. Administrative Controls-- --most important Careful screening of patients, isolation, early diagnosis and treatment Comprehensive Tuberculin Skin Testing Program 2. Engineering Controls negative pressure isolation rooms Increase ventilation (e.g., open the windows!) 3. Personal Respiratory Protection Equipment respirator masks

Grady Memorial Hospital--1992 < 6 ACH/hour

Engineering Controls at Grady With renovation of hospital (completed in 1995), new respiratory isolation rooms created >12 air changes per hour 50 rooms plus retrofitting of 20 other rooms (12 in ER) New 26 bed respiratory isolation (RI) ward (12B) opened in May 1999 Dedicated nursing staff Increased efficiency in evaluating patients admitted to respiratory isolation

Grady Memorial Hospital Atlanta, GA USA 1000 bed public inner-city teaching hospital Over 35,000 inpatient and 850,000 outpatient visits/year

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2007 ACH per hour with Open Doors and Windows Median IQR All Natural Ventilation 28 18-46 Natural ventilation (pre-1950) 40 26-52 Natural ventilation (1970-90) 90) 17 12-23 23 Mechanical ventilation 12 --

100 CO 2 concentration (ppm) 6000 5000 4000 3000 2000 1000 0 CO 2 release Windows opened 0 5 10 15 20 25 30 35 Time (minutes) 80 60 40 20 0 Natural ventilation built pre -1950 pre -1950 Natural ventilation built post --1970 -- 1970 Mechanical ventilation built 2000 Slow CO 2 concentration decay with windows closed 0.5 ACH Air Absolute Calculated changes ventilation TB risk hour -1 (m 3 /h/100) (%) Rapid decay with windows open 12 ACH

IOM Report on TB Infection Control

Number of Patients Impact of a Respiratory Isolation (RI) Policy, 1997 200 180 160 140 120 100 80 60 40 20 0 Blumberg HM et al. 4th Decennial International Conference on Nosocomial and Healthcare-Associated Infections. 2000 [abstract]. JAN FEB MAR APRIL MAY JUNE JULY AUG SEPT OCT NOV DEC Respiratory Isolation = 1,543: 5.4% of Adult Admissions (n=28,542) 12.8% of Med/Surg Admissions (n=12,008) RI Admit +TB # HIV+ 162/169 (96%) appropriately placed in RI on admission

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N-95

Effect of Design & Fit- Testing on Respirator Performance Coffey CC et al. J Occup Environ Hyg 2004; 1: 262 271

Percentage of Subjects Achieving SWPFs < SWPF Indicated 100 Effect of Design & Fit-Testing on 80 60 40 20 0 Respirator Performance Worst designed 3 models all subjects passing Bitrex Best Designed 3 models without fittesting 1 10 100 1,000 Simulated Workplace Protection Factor (SWPF)

Control Measures to Terminate Nosocomial Transmission of TB Hospital Jackson Mem. Miami Cabrini, NYC Admin. Extensive Extensive Control Measures Engineering Respiratory Extensive Exhaust Fans Submicron Molded Surgical Grady, Atlanta Extensive Exhaust Fans Submicron McGowan JE. Clin Infect Dis 1995; 21:489

Control measures work- US

Summary/Conclusions TB Infection Control (IC) Poor TB IC + MDR-TB (or XDR-TB) + HIV = DISASTER Urgent Need to Implement Effective TB IC measures

"Act Now or Forget it"

Global Plan to Stop TB, 2006-2015 -- 10 year perspective on the road to 2050 (TB free world) 50 million people treated for TB 800,000 MDR-TB patients to be treated 3 million patients with both TB/HIV on Antiretrovirals 14 million lives saved Global achievements in MDGs Point of care TB diagnostic test by 2010 New TB drug in 2010 (first in 40 years) Short Rx regimen by 2015 (1-2 months) 2015 new vaccine

Next Steps and How to Implement? Establish Political Will to implement TB IC Administrative Controls key measures Surveillance/Careful screening of patients for TB Geographic separation of patients with suspected TB from others (e.g., HIV+) NO COMINGLING TB patients with HIV+ Reconfigure how patients are housed in high risk hospital settings Creation of respiratory isolation rooms TB control plan

Other Administrative Measures Limit non-critical admissions, esp. HIV+ (outpt) HIV testing of HCWs (VCT)-reassign duties of HIV+ HCWs if in high risk area Move HIV clinics outside if weather/climate permits Surveillance of HCWs, Risk Assessment Improve Laboratory Capacity Smear Microscopy (immediately need capability of ruling out TB to optimize use of RI rooms) Culture and DST NEED for rapid diagnostic tests for drug resistant TB (intermediate to long term)

Engineering Controls Enhance ventilation; open windows Exhaust fans for RI rooms? Negative pressure rooms for new construction? Personal Respiratory Protection Surgical masks or respirators (e.g., N-95) N Of little benefit without effective administrative controls Operational Research Implementation of IC in LMIC

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Implications Gains in morbidity and mortality achieved by ARV and TB DOTS programs are threatened by MDR-TB and XDR-TB Improvement in infection control practices and facilities are required to prevent nosocomial transmission of TB including MDR-TB, XDR-TB Resources are needed TB control/dots, TB infection control, laboratory support (culture/susceptibility testing), 2 nd line drugs for treatment of MDR-TB cases [DOTS-Plus]

Seven Point XDR-TB Action Plan 1. Conduct rapid surveys of XDR-TB 2. Enhance laboratory capacity 3. Improve technical capacity of clinical/public health managers to respond to XDR-TB outbreaks 4. Implement infection control precautions 5. Increase research support for anti-tb drug development 6. Increase research support for rapid diagnostic test development 7. Promote universal access to ARVs under joint TB/HIV activities SAMRC, WHO, CDC