Transcript No Slide Title

TB Clinical Correlation
Carol 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 not
discuss in detail, that I hope will be helpful.
CC: Juan Rodruigez is a 39 year old Mexican male
transferred to Duke Medical Center from Durham Regional
Urgent Care after a finding of bright red blood per rectum
associated with anemia in the setting of painful external
hemorrhoids.
HPI: The patient has a past history significant for recurrent
“gastritis” for which he takes an unknown medication, but
otherwise he has been well. About 2-3 months ago he noted
worsening of his mid-epigastric pain and developed significant
anorexia (decreased appetite) resulting in loss of weight – he
does not know how much, but he had to punch a new hole in
his belt to keep up his pants. He noticed rectal burning
recently, though no diarrhea or constipation. About 4 months
prior to admission he developed a cough that has worsened
over time, though he only rarely produces sputum. He denies
dyspnea on exertion though in general he feels weaker than
usual and more fatigued.
Other questions to ask re: history?
His epigastric pain improves if he eats, but his appetite is so
poor he has not often tried this. He has not vomited blood, nor
coughed up blood. He often sweats at night, but they have no
air conditioning in their Durham house and it is now the
month 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 six
months ago and lives with his son in Durham. He speaks very
little English and the interview is conducted with the help of
his son. His wife currently resides in Mexico. He is a
bricklayer by trade but has been working as a painter most
recently. He smokes about 1 pack of cigarettes per week and
does not drink alcohol nor does he use illicit drugs. He denies
ever having sex with men or sex with women other than his
wife. He says he thinks he knew people in Mexico with lung
problems, but was not sure what they were. No one is ill in the
house where he lives, including his son, his wife and their 4month-old infant.
Physical Examination: Vital signs in the E.D.: Supine: BP
117/69, pulse 68; standing: 113/74, pulse 73. Temp is 37.9 and
his weight is 135 lbs; he is approximately 5’8”. He is
chronically ill appearing but not in any acute distress.
HEENT: anicteric sclera, EOMs intact, PERRL; he has no
thrush or oral lesions. Neck exam normal without JVD or
adenopathy. Chest exam reveals coarse breath sounds in the
right mid-lung field and otherwise unremarkable. Abdomen is
soft, nontender, non-distended, with normal bowel sounds and
no organomegaly. Rectal exam revealed multiple external
hemorrhoid and streaks of bright red blood on exam and this
was confirmed as blood by the stool hemoccult test.
In the Duke E.D. the patient underwent a number of
investigations results of which revealed that he was anemic
with a hemoglobin of 10 and hematocrit of 29 and a low MCV
of 72, all consistent with chronic blood loss. His white blood
cell count was within normal limits, at 7.0 with a normal
differential. His liver enzymes were normal.
FLAT AND DECUBITUS VIEWS OF THE ABDOMEN was
normal.
{CHEST X-RAY finding and review of clinical manifestations
and 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
Cavitary disease: billions of bacilli
Sputum AFB smear +++
Coughing (& sneezing & talking)
Household contact
Less efficient transmission
Non-cavitary disease
Sputum AFB smear negative
Not coughing
Casual 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
33.0
21.4
18.9
4.2
in Asian/Pacific Islanders
in blacks
in Hispanics
in Native Americans
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 placed
in respiratory isolation in the E.D. (by putting a portable
HEPA-filter in his E.D. room) and the patient was eventually
admitted to a respiratory isolation room in the hospital. {What
is respiratory isolation}? He was able to produce sputum that
was sent to microbiology for routine and AFB staining and
culture. Two samples were found to have “numerous” acidfast 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 q
day and vitamin B6. His PPD was read as being positive with
12 mm induration. His appetite remained poor and he had
daily fevers as high as 38.9 for the first 4 days of therapy. He
was again carefully asked regarding risk factors for HIV
infection and the patient denied any, so an HIV test was not
done.
Based on recommendations by the Infectious Diseases
service, who quoted a North Carolina rate of INH resistance of
4%, ethambutol (EMB) at 1600 mg q day was added to his
regimen to prevent the emergence of resistance while awaiting
final culture and susceptibility testing. In addition, the I.D.
team pointed out the 100-fold increase in risk of TB in HIVinfected patients and thus the significant co-existence of these
diseases. They also pointed out that the language barrier
might hinder the team’s ability to get a candid assessment of
risk from the patient, especially since his son is serving as the
interpreter. Therefore, an HIV test was done. The patient
began to improve by the end of the first week, with a return of
appetite and gradually declining fever curve. By the end of
two weeks, his AFB smears were reported only having “rare”
AFB organisms seen and the patient was requesting to go
home.
{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
Treatment
Option 1
Daily
INH, RIF, EMB or SM
& PZA
for 8 weeks, then
Option 2
Daily
INH, RIF, EMB or SM
& PZA for 2 weeks, then
INH & RIF
for 16 weeks more
(daily or 3x/wk DOT)
Same drugs 2x/week
for 6 weeks (DOT), then
INH & RIF 2x/week
for 16 weeks more
(total 24 weeks)
(total 24 weeks)
Option 3
DOT 3x/week
INH, 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 following
the patient since admission, reminded the team that the patient
lived in a home with a 4 month old infant and thus encouraged
them to keep him in hospital until his smears were negative.
By the end of the next week the patient had 3 sputums that
were negative for AFB. The team declared him no longer
infectious and prepared to send him home Friday afternoon of
Labor Day weekend. Prescriptions for all the drugs were
written and handed to the patient who stated “Pero, no tengo
dinero!” (But, I have no money!).
{Review of public health implications of TB and North Carolina’s
resources.}
Anti-TB Drugs: Resistance
Naturally occurring mutations result in
drug resistance at predictable rate:
RIF: 1 in 108 organisms
INH,PZA,EMB,SM: 1 in 106 organisms
TB cavitary
lesion
has ~ 1 x 108 orgs
IF INH alone, 100 orgs
resistant on day 1
MDR-TB: Contributing
Factors
1. Patient non-compliance
2. Patient non-compliance
3. Patient non-compliance
Antidote:
Directly Observed Therapy
MDR TUBERCULOSIS
Anti-tuberculous drugs available
without prescription/management
Immune
deficiency
(e.g., AIDS)
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
Other Management Issues
• 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
The Infectious Diseases consult team was again called. They
reassured the team that any patient with TB is eligible to
receive all their TB medications, plus directly observed
therapy, plus any follow-up labs, for free from their county
health department. They also reminded the team that they
were legally obligated to report a suspected case of TB to the
patient’s county, but that at Duke the Infection Control team
does that for them. They encouraged the team to call the
county where he lives and tell them he is ready to go home and
arrange for them to follow the patient. The team was also
chastened to realize that notifying the agency late on a Friday
before a holiday weekend made their job harder.
Unfortunately, just prior to the patient’s discharge, his HIV
test returned positive. A hospital-based Spanish-speaking
interpreter was arranged for. When told the diagnosis he
admitted that when he was away from home for extended
periods seeking work, he often sought the solace of “mujeres
del noche” (“women of the night”). He also wondered if this
was related to the recent weight loss and fevers that had
afflicted his wife in Mexico. He had been worried about her
but 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:
HIV-seropositive:
10-15% LIFETIME
risk
7-10% ANNUAL
risk
Relative Risks
HIV-infected
AIDS
Other IC*
-
113 fold increase
170 fold increase
3.6-16 fold increase
The patient was re-assured that for now he would be on the
same medicines for TB and that he would be finished with his
anti-TB treatment in 6 months if he continued to improve
clinically and if his cultures all became negative within three
months. He was scheduled to see one of the doctors in the
Duke ID/HIV clinic.
Meanwhile, his hemorrhoids were treated with Anusol HC and
his rectal bleeding stopped.
+PPD skin test: when to give preventive therapy?
HIV positive
steroid therapy/other IC
High risk*
recent conversion to +PPD
2.3%
Risk of
INH
hepatitis
healthy, nl CXR, +PPD unk time
Risk of
active
TB
1.3%
Unlikely*
.1
35 yrs
Age in Years
*Risk categorized in Figure 1