TB Clinical CorrelationCarol Dukes Hamilton, M.D.

March 5, 1999

The handout closely approximates my lecture from March 5,1999. There are few extra slides about things that we did notdiscuss in detail, that I hope will be helpful.

CC: Juan Rodruigez is a 39 year old Mexican maletransferred to Duke Medical Center from Durham RegionalUrgent Care after a finding of bright red blood per rectumassociated with anemia in the setting of painful externalhemorrhoids.

HPI: The patient has a past history significant for recurrent“gastritis” for which he takes an unknown medication, butotherwise he has been well. About 2-3 months ago he notedworsening of his mid-epigastric pain and developed significantanorexia (decreased appetite) resulting in loss of weight – hedoes not know how much, but he had to punch a new hole inhis belt to keep up his pants. He noticed rectal burningrecently, though no diarrhea or constipation. About 4 monthsprior to admission he developed a cough that has worsenedover time, though he only rarely produces sputum. He deniesdyspnea on exertion though in general he feels weaker thanusual and more fatigued.

Other questions to ask re: history?

His epigastric pain improves if he eats, but his appetite is sopoor he has not often tried this. He has not vomited blood, norcoughed up blood. He often sweats at night, but they have noair conditioning in their Durham house and it is now themonth of August. They do not have a thermometer at home.His chest often hurts when he coughs.

Socioeconomic History:

The patient moved to North Carolina from Mexico about sixmonths ago and lives with his son in Durham. He speaks verylittle English and the interview is conducted with the help ofhis son. His wife currently resides in Mexico. He is abricklayer by trade but has been working as a painter mostrecently. He smokes about 1 pack of cigarettes per week anddoes not drink alcohol nor does he use illicit drugs. He deniesever having sex with men or sex with women other than hiswife. He says he thinks he knew people in Mexico with lungproblems, but was not sure what they were. No one is ill in thehouse where he lives, including his son, his wife and their 4-month-old infant.

Physical Examination: Vital signs in the E.D.: Supine: BP117/69, pulse 68; standing: 113/74, pulse 73. Temp is 37.9 andhis weight is 135 lbs; he is approximately 5’8”. He ischronically ill appearing but not in any acute distress.HEENT: anicteric sclera, EOMs intact, PERRL; he has nothrush or oral lesions. Neck exam normal without JVD oradenopathy. Chest exam reveals coarse breath sounds in theright mid-lung field and otherwise unremarkable. Abdomen issoft, nontender, non-distended, with normal bowel sounds andno organomegaly. Rectal exam revealed multiple externalhemorrhoid and streaks of bright red blood on exam and thiswas confirmed as blood by the stool hemoccult test.

In the Duke E.D. the patient underwent a number ofinvestigations results of which revealed that he was anemicwith a hemoglobin of 10 and hematocrit of 29 and a low MCVof 72, all consistent with chronic blood loss. His white bloodcell count was within normal limits, at 7.0 with a normaldifferential. His liver enzymes were normal.

FLAT AND DECUBITUS VIEWS OF THE ABDOMEN wasnormal.

{CHEST X-RAY finding and review of clinical manifestationsand epidemiology}

Diagnostic Tests

• Chest x-ray– Patchy or nodular infiltrate– Apical or sub-apical posterior aspects of UPPER

LOBES (or superior segment of lower lobes)– Cavity

• usually without an air-fluid level

– pneumonic lesion with enlarged hilar nodes • consider primary TB

Clinical Manifestations

• Pulmonary – Non-HIV: 85%– HIV+:

• 38% pulmonary only

• 30% extrapulmonary only

• 32% pulmonary and extrapulmonary

• X-ray findings

Clinical Manifestations: Pulmonary TB

• Coughing > sneezing, speaking– correlates with infectiousness– “The principal risk for acquiring infection with

M.Tb. is breathing” Bloom and Murray, 1992

• Fever (about 80%),

• Weight loss, malaise – Probably cytokine mediated

Infectiousness of Source Case

Transmission highly likely Less efficient transmission

Cavitary disease: billions of bacilliSputum AFB smear +++Coughing (& sneezing & talking)Household contact

Non-cavitary diseaseSputum AFB smear negativeNot coughingCasual contact

Outdoor contact very unlikely

Epidemiology: Who Gets TB?

• Who gets TB infection?

• Who gets TB disease?

• Definitions:– TB infection: TB exposure that leads to local

induration in response to intradermal injection of purified protein derivative (PPD)

– TB disease = tuberculosis = active TB

Who Gets TB infection?

• In the world - ubiquitous– ~ 1/3 of the world’s population infected– 80% in developing countries

• Immigrants from these other countries to U.S.– major source of recent increase in U.S. TB

Who Gets TB infection in the U.S.? Exposure

• medically underserved– urban (& in NC, rural) poor

• minority populations**– Southeast Asian, African-American,

Hispanic

Annual Case Rates by Race/Ethnicity

1990 Annual New-case Rate per 100,000 in U.S.

42.6 in Asian/Pacific Islanders 33.0 in blacks21.4 in Hispanics18.9 in Native Americans4.2 in U.S.-born whites

2/3 of cases occur in racial or ethnic minorities

Hospital Course:

Based on the findings of the chest x-ray, the patient was placedin respiratory isolation in the E.D. (by putting a portableHEPA-filter in his E.D. room) and the patient was eventuallyadmitted to a respiratory isolation room in the hospital. {Whatis respiratory isolation}? He was able to produce sputum thatwas sent to microbiology for routine and AFB staining andculture. Two samples were found to have “numerous” acid-fast bacilli on smear. A PPD skin test was placed.

{Slide of AFB + and + auromine}

Laboratory

• Processing: mucolysis, homogenization, bacterial contamination and concentration

• Smear staining: – Ziehl-Neelsen acid-fast stain– auramine 0 fluorescence

Laboratory

• Reading the slide:– Examined an equivalent of 300 oil immersion

fields = negative– Quantitated: 1-4+ or # bacilli/field– A positive smear = 5000-10,000 acid-fast

bacilli/ml sputum– TB or non-TB mycobacterium???

Making the Definitive Diagnosis

• Smear: Auramine-rhodamine– Increased sensitivity

• Confirmed by Ziehl-Neelson

• AFB + does not = TB – at Duke, AFB+ smear is MOTT 2x >TB– at CMC, Charlotte, AFB+ smear is TB 5x >

MOTT

Making the Definitive Diagnosis

• Cultures: Broth-based growth systems– average time to detection:

• 10-18 days, e.g. BACTEC

• 18-28 days, conventional

– Susceptibilities: additional ~ 7 days• if not at Duke, always order on first specimen

Hospital course:The patient was started on isoniazid (INH) 300 mg q day,

rifampin (RIF) 600 mg q day, pyrazinamide (PZA) 2 gms qday and vitamin B6. His PPD was read as being positive with12 mm induration. His appetite remained poor and he haddaily fevers as high as 38.9 for the first 4 days of therapy. Hewas again carefully asked regarding risk factors for HIVinfection and the patient denied any, so an HIV test was notdone.

Based on recommendations by the Infectious Diseasesservice, who quoted a North Carolina rate of INH resistance of4%, ethambutol (EMB) at 1600 mg q day was added to hisregimen to prevent the emergence of resistance while awaitingfinal culture and susceptibility testing. In addition, the I.D.team pointed out the 100-fold increase in risk of TB in HIV-infected patients and thus the significant co-existence of thesediseases. They also pointed out that the language barriermight hinder the team’s ability to get a candid assessment ofrisk from the patient, especially since his son is serving as theinterpreter. Therefore, an HIV test was done. The patientbegan to improve by the end of the first week, with a return ofappetite and gradually declining fever curve. By the end oftwo weeks, his AFB smears were reported only having “rare”AFB organisms seen and the patient was requesting to gohome.

{Review of treatment history and strategies}.

Expectations of TB Therapy: Pre-chemotherapy Era

Therapy:• Improve nutrition

• Bed rest and isolation, high altitude preferred

• Surgical intervention in some

Mortality rate at 5 years: 40-50%

History of TB Therapy

• 1940’s - Streptomycin [SM]

• 1952: Isoniazid [INH] & p-aminosalacylic acid [PAS] – determined combination prevented rapid

emergence of INH resistance

• 1960’s: Rifampin [RIF], Pyrazinamide [PZA] & Ethambutol [EMB]

History of TB Therapy

• 1970-80’s: large clinical trials world-wide – 1977: 9 mos vs 18 mos INH, RIF, Streptomycin

[SM]• Cure rates 95% in 9 mos

– 1982: 6 mos total - 2 mos INH, RIF, PZA, SM, then drop PZA for last 4 mos

– 1990: 6 mos INH, RIF, PZA (1st 2 mos) better than 9 mos INH & RIF [Cure rates 95%]

Recommended Treatment Regimens: Rationale

• INH during entire duration of Rx

• < 6 months: unacceptably high failure rate

• < 12 month regimens: must use INH and RIF, 2 mos at least

• Initial PZA makes < 9 mos possible

• Intermittent dosing (2-3 x/week) and daily dosing - equal efficacy

TreatmentOption 1 Option 2 Option 3

DailyINH, RIF, EMB or SM& PZAfor 8 weeks, then

INH & RIFfor 16 weeks more(daily or 3x/wk DOT)

(total 24 weeks)

DailyINH, RIF, EMB or SM& PZA for 2 weeks, then

Same drugs 2x/week for 6 weeks (DOT), thenINH & RIF 2x/weekfor 16 weeks more

(total 24 weeks)

DOT 3x/weekINH, RIF, EMB or SM& PZA

(total 24 weeks)

Start with Four Drug Therapy/DOT; TOTAL RX 6 months

Expectations of TB Therapy: Post-chemotherapy Era

Therapy:• Specific, potent anti-tuberculous drugs in

combination

• Improve nutrition

• Brief period of isolation

Success rate at 5 years: 95%

The hospital infection control team, who had been followingthe patient since admission, reminded the team that the patientlived in a home with a 4 month old infant and thus encouragedthem to keep him in hospital until his smears were negative.By the end of the next week the patient had 3 sputums thatwere negative for AFB. The team declared him no longerinfectious and prepared to send him home Friday afternoon ofLabor Day weekend. Prescriptions for all the drugs werewritten and handed to the patient who stated “Pero, no tengodinero!” (But, I have no money!).

{Review of public health implications of TB and North Carolina’sresources.}

Anti-TB Drugs: ResistanceAnti-TB Drugs: Resistance

Naturally occurring mutations result in drug resistance at predictable rate:

RIF: 1 in 108 organismsINH,PZA,EMB,SM: 1 in 106 organisms

TB cavitary lesionhas ~ 1 x 108 orgs

IF INH alone, 100 orgs resistant on day 1

MDR-TB: Contributing Factors

MDR TUBERCULOSIS

1. Patient non-compliance

2. Patient non-compliance

3. Patient non-compliance

Anti-tuberculous drugs available without prescription/management

Immunedeficiency(e.g., AIDS)

Antidote:Directly Observed Therapy

Other Management Issues

• respiratory isolation while waiting

• ID or pulmonary consultation

• if sending home on TB meds: – contact county health department – before 4:45 Friday afternoon– request DOT

• Services available at North Carolina County Health Depts (vary state to state)– NC will provide all TB meds free to all people with

TB, – plus DOT, – plus monitoring for symptoms, – plus contact tracing and testing, – plus nutritional support, housing and other support

during therapy

Other Management Issues

The Infectious Diseases consult team was again called. Theyreassured the team that any patient with TB is eligible toreceive all their TB medications, plus directly observedtherapy, plus any follow-up labs, for free from their countyhealth department. They also reminded the team that theywere legally obligated to report a suspected case of TB to thepatient’s county, but that at Duke the Infection Control teamdoes that for them. They encouraged the team to call thecounty where he lives and tell them he is ready to go home andarrange for them to follow the patient. The team was alsochastened to realize that notifying the agency late on a Fridaybefore a holiday weekend made their job harder.

Unfortunately, just prior to the patient’s discharge, his HIVtest returned positive. A hospital-based Spanish-speakinginterpreter was arranged for. When told the diagnosis headmitted that when he was away from home for extendedperiods seeking work, he often sought the solace of “mujeresdel noche” (“women of the night”). He also wondered if thiswas related to the recent weight loss and fevers that hadafflicted his wife in Mexico. He had been worried about herbut had not mentioned this to his son who had his own worries.

{Review risk of TB in HIV-infected people}

Relationship of HIV and TB

Risk for M.TB-infected person (e.g., + PPD)to develop active TB

HIV-seronegative:

10-15% LIFETIMErisk

HIV-seropositive:

7-10% ANNUALANNUALrisk

HIV-infected - 113 fold increaseAIDS - 170 fold increaseOther IC* - 3.6-16 fold increase

Relative Risks

The patient was re-assured that for now he would be on thesame medicines for TB and that he would be finished with hisanti-TB treatment in 6 months if he continued to improveclinically and if his cultures all became negative within threemonths. He was scheduled to see one of the doctors in theDuke ID/HIV clinic.

Meanwhile, his hemorrhoids were treated with Anusol HC andhis rectal bleeding stopped.

+PPD skin test: when to give preventive therapy?

Age in Years

35 yrs

Risk ofINH

hepatitis

2.3%

1.3%

.1

Risk ofactive

TB

HIV positive

steroid therapy/other IC

recent conversion to +PPD

healthy, nl CXR, +PPD unk time

Unlikely*

High risk*

*Risk categorized in Figure 1