Tuberculosis 2000

 
I. Epidemiology
A. World
1. 1/3 of the world's population is infected with tuberculosis
2. there are 8 million new cases of active TB each year
3. there are 3 million deaths by TB each year
B. United States
1. roughly 2-5% of the U.S. population is infected with tuberculosis (15 million persons)
2. presently, there are Å 20,000 new cases of active tuberculosis per year
3. the top 5 high prevalence states include:
a) New York
b) California
c) Texas
d) Florida
e) Hawaii
4. roughly 5% of cases of active TB are diagnosed at autopsy suggesting that the actual incidence and prevalence of active TB is much higher then estimated
5. TB is over-represented in minority populations:
a) African American - 33% of all cases
b) Caucasian - 26% of all cases
c) Hispanic - 21% of all cases
d) Asian - 18% of all cases
e) Native American - 1% of all cases
6. after a several decade decline in incidence, the number of new cases of tuberculosis rose in the 1980s; this is felt to be because of the HIV epidemic since HIV-infected patients are much more likely to develop TB and in turn can transmit it to other persons in the community. Redirected attention to basic case finding, patient isolation, and completion of drug treatment under directly observed therapy resulted in the incidence falling in the 1990s.
7. multi-drug resistant TB is the newest TB threat
a) the greatest risk for development of drug resistant TB is inadequate or incomplete anti-TB antibiotics; however, drug resistant TB can be transmitted from person to person and in high prevalence areas (such as NY city), more than 14% of all TB is resistant to INH. Nationwide, 7.5% of TB is INH-resistant
C. Ohio
1. there were 317 reported cases of new active TB in Ohio in 1999 with 6.6% resistant to INH
a) 87 cases were in Cleveland
b) 52 cases were in Columbus
c) 20 cases were in Cincinnati
2. TB is required to be reported to the Department of Health
II. Diagnosis
A. Clinical presentation of primary TB:
1. usually asymptomatic
2. patients may have none-specific respiratory complaints or present with a mild "atypical" pneumonia
3. most patients contain the tuberculosis bacteria where it becomes dormant until a period of depressed cell mediated immunity
a) 5% of patients will later develop re-activation (post-primary) TB within the first 2 years after infection
b) 5% of patients will develop re-activation TB much later in life (often decades later)
c) 90% of patients remain asymptomatic for life and have a positive TB skin test but never develop active disease
4. rare patients develop active TB at the time of primary infection; this is known as progressive primary TB
B. Clinical presentation of re-activation (post-primary) TB:
1. fatigue
2. cough
3. fever
4. anorexia
5. hemoptysis
6. night sweats
C. When should you suspect active TB?
1. unexplained pulmonary infiltrates, especially if involving one or both upper lobes
2. unexplained systemic symptoms such as fever or weight loss
3. persistent "atypical" pneumonia
4. respiratory symptoms in patients at risk of developing active TB:
a) diabetes
b) end stage renal disease
c) HIV
d) medically underserved or lower economic group
e) immigrants from an endemic area
f) silicosis
g) patients receiving corticosteroids or other immunosuppressive medications
h) reticuloendothelial malignancies
i) intravenous drug users
5. respiratory symptoms in a person with a positive PPD skin test
D. Chest x-ray findings in TB:
1. primary TB:
a) approximately 15% of patients will present with this pattern
b) generally involves lower lobes in adults
c) initial site of inflammation is called a "Ghon" complex
2. post-primary TB:
a) approximately 85% of patients will present with this pattern
b) infiltrates generally involve the apical or posterior segments of an upper lobe
c) unusual chest x-ray findings:
(1) lymphadenopathy
(2) cavities with an air-fluid level
(3) pleural effusion
(4) isolated nodular tuberculoma
3. in HIV-infected patients, the x-ray is often atypical and will be normal in Å 20% of cases
E. Pleural tuberculosis:
1. usually unilateral
2. effusions can occur as part of primary TB or post-primary TB
3. although the pleural fluid is occasionally culture or smear positive for TB, closed needle pleural biopsy is generally required for diagnosis
F. Establishing a diagnosis:
1. initial approach:
a) chest x-ray on all patients
b) sputum AFB smear on all patients
c) sputum AFB culture on all patients
d) if patient unable to produce sputum, sputum should be induced by having the patient inhale hypertonic saline in a negative pressure chamber or room
2. secondary tests:
a) urine AFB culture
(1) if having urinary symptoms or if the urinalysis is abnormal
b) bronchoscopy
(1) if satisfactory sputum cannot be induced
c) gastric washings
(1) if satisfactory sputum cannot be induced and bronchoscopy is not available or practical
(2) there is a high incidence of atypical mycobacteria in the environment and in drinking water which can confuse the diagnosis when seen on smears of gastric washings
d) lung biopsy
(1) only rarely necessary
e) serology
(1) promising tool but at present it is no more sensitive than sputum smear
3. microbiologic diagnosis:
a) sputum AFB smear remains the most rapid means of establishing a tentative diagnosis but cannot allow distinction of M. TB from "atypical" mycobacteria
b) AFB culture on solid medium (such as L-J medium) is a long-utilized standard but requires about 4 weeks for a positive culture
c) AFB culture on Middlebrook 7H12 broth medium (eg, BACTEC system) is now the standard approach in most laboratories and requires about 2 weeks for a positive culture
d) DNA probes are very specific and can determine if a colony growing in culture is Mycobacterium TB or one of the other 3 Mycobacterium species for which there are currently available DNA probes
(1) this technique is very rapid (1 day)
(2) this is now the standard approach for species determination in most labs (in conjunction with the broth medium culture)
e) high performance liquid chromatography (HPLC) can rapidly distinguish between the various atypical mycobacteria and is used primarily in cases where M. TB has been excluded
f) polymerase chain reaction (PCR) is an investigational tool which may ultimately allow diagnosis of Mycobacterium tuberculosis from sputum smears but is not yet advanced enough to allow use in clinical practice
g) drug sensitivities should be done on ALL initial isolates of TB
III. Skin Testing
A. Technique:
1. use 5 TU PPD only (do not use 1 or 250 TU PPD)
2. use a 27 gauge needle, bevel up
3. inject 0.1 ml just under the skin and raise a bubble
4. measure the induration (not the erythema) at 48-72 hours
5. for elderly persons or other persons who may have sluggish cell mediated immune systems, repeat the PPD with a "booster" test in 1-3 weeks
B. Who should be skin tested?
1. suspected active TB
2. contacts of persons with known active TB
a) the skin test takes 6-8 weeks to convert so the PPD should be repeated 2-3 months following the last contact with the infected person if the first PPD skin test is negative
3. HIV infected persons
4. chest x-ray suggesting previous primary or post-primary TB
5. "at risk" medical conditions
a) diabetes
b) end stage renal disease
c) lymphoreticular malignancies
d) corticosteroid or immunosuppressive drug use
e) rapid weight loss
f) IV drug use
g) silicosis
h) gastrectomy or jejunoileal bypass
i) solid organ transplant
j) cancer of the head or neck
6. high risk groups
a) health care workers
b) immigrants
c) personnel and inhabitants of institutions (nursing homes, prisons, mental institutions)
d) medically underserved individuals
C. What constitutes a positive skin test?
1. 5 mm
a) HIV infected persons
b) persons with chest x-rays suggesting previous TB
c) close contacts of persons with active TB
d) patients with organ transplants or other immunosuppressed patients (ie, receiving more than 15 mg/day of prednisone for a month or more)
2. 10 mm
a) immigrants
(1) many of these patients will have recieved BCG vaccination in the past
(2) BCG can cause a false positive skin test but the reaction usually wanes with age
(3) current recommendations are to ignore BCG vaccination when interpreting the PPD skin test
b) health care workers
c) residents and employees in:
(1) prisons and jails
(2) nursing homes
(3) homeless shelters
(4) residential facilities for care of HIV-infected persons
d) low income or medically underserved persons
e) teachers
f) day care workers
g) mycobacteriology laboratory personnel
h) "at risk" medical conditions
(1) diabetes
(2) end stage renal disease
(3) lymphoreticular malignancies
(4) corticosteroid or immunosuppressive drug use
(5) rapid weight loss (more than 10%)
(6) head or neck cancer
(7) gastrectomy or jejunoileal bypass
(6) IV drug use
(7) silicosis
3. 15 mm
a) anyone with no obvious risks of acquiring TB
IV. Prophylaxis
A. Who should receive prophylaxis?
1. positive skin test and "at risk" medical conditions:
a) diabetes
b) end stage renal disease
c) lymphoreticular malignancies
d) corticosteroid or immunosuppressive drug use
e) rapid weight loss
f) IV drug use
g) silicosis
2. positive skin test and under age 4
3. close contacts of persons with active TB
a) treat with prophylactic antibiotics if the PPD is positive
b) a positive skin test will not develop for 6-8 weeks therefore it is sometimes advisable to initiate prophylaxis even if the skin test is negative and then discontinue prophylaxis if a second PPD is negative in 12 weeks
4. positive skin test and HIV infection
a) in HIV-infected persons who are anergic and have a documented exposure to someone with active TB, prophylaxis is appropriate
b) in HIV-infected persons who are anergic and live in areas where the prevalence of TB is high, prophylaxis may be appropriate even when the skin test is negative
5. persons who convert the skin test to positive within a 2 year period
a) > 10 mm increase if under 35 years of age
b) > 15 mm increase if over 35 years of age
6. persons under age 35 with a positive PPD skin test and who are:
a) immigrants
b) medically underserved
c) residents of institutions
d) health care workers or staff of chronic care institutions (because of the risk of precipitating an outbreak)
e) positive skin test in a healthy person under 35 years of age with none of the above risk factors is controversial and may be considered on an individual basis
B. Who needs sputum examinations?
1. patients with x-ray signs of previous TB (except for isolated calcified nodules) - 3 sputum samples, each on a separate day
2. HIV-infected patients with respiratory symptoms
C. Prophylaxis regimens:
1. adults:
a) INH (300 mg/day) for 9 months; treatment for 6 months is not as effective as 9 months but does provide substantial benefit may be used instead in some communities where cost containment is mandated however, all patients with HIV, children, and patients with fibrotic signs on x-ray should have 9 months
(1) directly observed therapy is an alternative: 900 mg twice weekly
b) Rifampin (600 mg/day) + pyrazinamide (2 g/day) for 2 months if patient intolerant of INH
(1) directly observed therapy is an alternative: rifampin 600 mg + pyrazinamide 4 g twice weekly
b) Rifampin (600 mg/day) for 4 months if the patient is intolerant to INH and pyrazinamide
2. children:
a) INH (10-15 mg/day) for 9 months
3. HIV infected:
a) INH (300 mg/day) for 9 months
4. silicosis or fibrotic chest x-ray patterns suggestive of previous TB:
a) INH (300 mg/day) PLUS rifampin (600 mg/day) for 4 months
b) OR INH (300 mg/day) for 12 months
5. pregnant women:
a) if HIV positive or recently infected - INH (300 mg/day) started during pregnancy
b) if HIV negative and not suspected to be recently infected, prophylaxis may be delayed until after delivery
6. suspected INH-resistance (but rifampin susceptible):
a) Rifampin (600 mg/day) + pyrazinamide (2 g/day) for 2 months
b) Rifampin (600 mg/day) for 4 months
NOTE: rifampin should not be used in patients receiving protease inhibitors or non-nucleoside reverse transciptase inhibitors; rifabutin is an alternative:
(1) 150 mg/day with indinavir, nelfinavir, or amprenavir
(2) 150 mg every other day with ritonavir
(3) 450 mg/day with efavirenz
(4) 600 mg/day with nevirapine
7. suspected multi-drug (INH + rifampin) resistance:
a) Pyrazinamide (2 g/day) + ethambutol (20-25 mg/kg/day) x 6 months (12 months if immunocompromised)
b) Pyrazinamide (2 g/day) + either levofloxacin or ofloxacin) x 6 months (12 months if immunocompromised)
D. Monitoring prophylaxis:
1. only prescribe INH in 1 month supplies
2. see patients monthly (if receiving either INH alone or rifampin alone) or at 2, 4, & 8 weeks (if receiving rifampin & pyrazinamide); inquire about symptoms suggestive of liver injury
3. obtain baseline transaminases in:
a) patients with suspected pre-existing liver disease
b) HIV-infected patients
c) pregnant patients
d) patients in the immediate (less than 3 months) post-partum period
e) patients using alcohol regularly
f) patients otherwise at risk for liver disease
4. active hepatitis and end-stage liver disease are relative contraindications for INH and pyrazinamide
5. obtain monthly transaminases in patients with baseline liver function test abnormalities and patients at risk of liver disease
a) consider discontinuing INH if transaminases rise 5 fold (in asymptomatic patients) or 3 fold (in patients with symptoms of hepatic toxicity)
6. administer pyridoxine (10-100 mg/day) to:
a) pregnant women
b) alcoholics
c) diabetics
d) malnourished patients
e) patients with end stage renal disease
f) patients with a seizure disorder
g) infants of breastfeeding women receiving INH
V. Protection of Health Care Workers:
A. early identification of infected patients
B. respiratory isolation of patients with suspected active TB
1. patients should be kept in negative pressure ventilated rooms
C. ultraviolet lights in hospitals with high numbers of cases of TB
D. masks should be used by workers exposed to persons with active TB:
1. surgical
a) generally considered inadequate to protect individuals
2. dust-mist and dust-fume-mist
a) less expensive than HEPA masks and possibly as efficient
3. HEPA (high-efficiency particulate air filter)
a) high expense ($7 - $9/mask) has precluded their widespread adoption in many hospitals since use of these masks will cost most hospitals about $500,000 per year
4. routine PPD skin testing
a) many authorities recommend a 2 stage (booster) PPD be performed as the first skin test in health care workers in order to fully establish whether the skin test is positive or negative; a single PPD can be performed on subsequent years
b) for most workers, annual PPD is sufficient
c) for pulmonologists, infectious disease specialists, etc. (who have a high likelihood of exposure to aerosolized sputum), PPD skin tests every 6 months are recommended
VI. Treatment of Active Tuberculosis:
A. Treatment of tuberculosis: general principles
1. Long course of treatment
2. Combination antibiotics mandatory
3. Use agents that are bactericidal both intra-and extracellularly
4. Drug susceptibility testing on all isolates
5. All patients with TB should be offered HIV testing
6. Isolation of patients:
a) hospitalized:
(1) place in respiratory isolation room
b) non-hospitalized:
(1) patients should be relatively isolated until non-infectious
(a) this can usually be done with the patient is his/her own home
(b) patients do not need to be isolated from household members who are already exposed
(c) patients who work outdoors are at lower risk of transmitting TB to others than those who work indoors
(d) patients who pose risk to others (ie, patients who are health care workers) may need to remain away from work longer than those who pose relatively little risk
(2) 3 negative sputum smears for TB on 3 successive days indicates extremely low risk for transmission
(3) a negative sputum culture indicates no risk for transmission
B. Treatment of tuberculosis: drug therapy
1. General principles:
a) Initial regimen should consist of 4 drugs
(1) isoniazid
(2) rifampin
(3) pyrazinamide
(4) ethambutol (or streptomycin)
b) Initial regimen of 3 drugs if the local INH resistance < 4%
(1) in some states, the incidence of INH resistance is < 4% so an initial regimen of 3 drugs is acceptable:
(a) isoniazid
(b) rifampin
(c) pyrazinamide
(2) travel history is important since many patients presenting with TB in one state will have contracted TB in other areas
(3) Ohio currently has an of INH resistance 6.6% and for most patients, a four drug initial treatment is appropriate
2. TB pharmacology:
a) Standard drugs used to treat TB:
(1) Isoniazid (INH)
(a) bactericidal
(b) complete GI absorption
(c) major toxicity is hepatitis:
i) < 20 years = 0%
ii) 20-34 years = 0.3%
iii) 35-49 years = 1.2%
iv) 50-64 years = 2.3%
(d) other toxicity = peripheral neuropathy
i) patients at risk:
(1) diabetes
(2) renal failure
(3) alcoholism
(4) malnutrition
(5) seizure disorder
(6) pregnancy
ii) prevention:
(1) pyridoxine, 10-50 mg/day
(e) drug interactions:
i) increases levels of phenytoin
(2) Rifampin (RIF)
(a) bactericidal
(b) complete GI absorption
(c) major toxicity is GI upset
(d) rare toxicities:
i) skin rash
ii) hepatitis
iii) thrombocytopenia
(e) increases clearance (ie, decreases effectveness) of:
i) coumadin
ii) methadone
iii) verapamil
iv) glucocorticosteroids
v) estrogens (including oral contraceptives)
vi) digoxin
vii) oral hypoglycemic agents
viii) quinidine
ix) theophylline
x) anticonvulsants
xi) ketoconazole
xii) cyclosporin
(f) rifampin colors tears, saliva, sweat & other body fluids orange
i) this can cause discoloration of contact lenses
(g) rifampin should NOT be used in patients receiving protease inhibitors or NNRTIs for treatment of HIV infection (rifabutin can be used as an alternative)
(3) Pyrazinamide (PZA)
(a) bactericidal
(b) active against intracellular organisms
(c) complete GI absorption
(d) major toxicity is hepatitis
(e) other toxicity is hyperuricemia
(4) Ethambutol (EMB)
(a) bacteriostatic
(b) common toxicity is retrobulbar neuritis
i) decreased visual acuity
ii) decreased red-green perception
iii) usually reversible if detected early during treatment
(5) Streptomycin (STM)
(a) bacterididal in alkaline environments
(b) given as IM injection
(c) renally excreted; dosage must be adjusted for renal insufficiency
(d) major toxicity is ototoxicity
i) vertigo most common
b) Second line drugs for TB:
(1) Para-aminosalicylic acid (PAS)
(2) Ethionamide
(3) cycloserine
(4) Capreomycin
(5) Kanamycin
(6) Thiacetazone
c) Investigational (but promising) anti-TB drugs:
(1) Amikacin
(2) Ciprofloxacin
(3) Ofloxacin
(4) Rifabutin
(5) Clofazimine
3. Treatment regimens:
a) Initial treatment of tuberculosis
(1) Option #1
(a) INH-RIF-PZA-EMB daily x 2 months
i) in areas where the incidence of INH resistance is < 4%, INH-RIF-PZA daily x 2 months is acceptible for the initial component of treatment
(b) then INH-RIF daily x 4 months
(2) Option #2
(a) INH-RIF-PZA-EMB daily x 2 weeks
(b) INH-RIF-PZA-EMB twice weekly x 6 weeks (DOT)
(c) INH-RIF twice weekly x 4 months (DOT)
(3) Option #3
(a) INH-RIF-PZA-EMB three times per week x 6 months (DOT)
b) Drug dosing in adults:
(1) Daily dosing:
(a) INH 5 mg/kg (max 300 mg)
(b) RIF 10 mg/kg (max 600 mg)
(c) PZA 15-30 mg/kg (max 2 g)
(d) EMB 15-25 mg/kg
(e) STM 15 mg/kg (max 1 g)
(2) Twice weekly dosing:
(a) INH 15 mg/kg (max 900 mg)
(b) RIF 10 mg/kg (max 600 mg)
(c) PZA 50-70 mg/kg (max 4 g)
(d) EMB 50 mg/kg
(e) STM 25-30 mg/kg (max 1.5 g)
(3) Three times per week dosing:
(a) INH 15 mg/kg (max 900 mg)
(b) RIF 10 mg/kg (max 600 mg)
(c) PZA 50-70 mg/kg (max 3 g)
(d) EMB 25-30 mg/kg
(e) STM 25-30 mg/kg (max 1.5 g)
c) DOT (directly observed therapy)
(1) this is proven to diminish the incidence of:
(a) treatment failure
(b) emergence of drug resistant strains of TB
(2) DOT should be considered for all patients with TB to improve compliance
(3) the person (s) involved in DOT should be more reliable than the patient
(4) DOT can take many forms and is limited mainly by your imagination - some examples:
(a) have school nurses administer medications to children
(b) have factory nurses administer medications to workers
(c) have community or church volunteers go to patient's homes to administer medications
(d) give patients free meals, food stamps, etc. for coming to the clinic for medications
(e) employ home nursing agencies to deliver medications
4. Baseline studies:
a) All drugs:
(1) liver enzymes
(2) CBC & platelets
(3) creatinine
b) PZA:
(1) uric acid
c) EMB:
(1) visual acuity
(2) red-green color discrimination
5. Evaluating the response to treatment
a) Patients should be clinically evaluated monthly
(1) ask about hepatitis-type symptoms
(2) if there is a question about compliance, check a urine sample - if the patient is taking rifampin, the urine should be orange
b) Monthly sputum examinations
(1) 85% of patients have negative cultures after 2 months
(2) re-evaluate patients who are still positive
c) After completion of treatment:
(1) chest x-ray
(2) sputum exam & culture
6. Causes of persistently positive sputum cultures:
a) Non-compliance (most important)
b) Drug resistance
7. Most common treatment errors:
a) Addition of a single drug to a failing regimen
b) Failure to identify drug resistance
c) Inappropriate initial drug regimen
d) Failure to recognize non-compliance
e) Inappropriate INH prophylaxis
C. Need help?
1. medications are provided FREE through local TB units of local Departments of Health
2. if your hospital or clinic cannot do TB examinations or culture, these can be done at low cost through the Ohio State Health Department Laboratory:
a) Currently using BACTEC + DNA probes
b) Free courier service
c) Cost of complete sputum evaluation = $20
(1) Smears reported next day
(2) TB culture reported 2-3 weeks
(3) Sensitivities 7-10 days after culture
VII. References:
A. Control of tuberculosis in the United States. Am Rev Resp Dis 1992; 146:1623-33
B. Treatment of tuberculosis and tuberculosis infection in adults and children. Am J Resp Crit Care Med 1994; 149:1359-74.
C. Menzies D, Fanning A, Yuan L, Fitzgerald M. Tuberculosis among health care workers. N Engl J Med 1995; 332:92-8.
D. Tuberculosis Morbidity - United States, 1997. MMWR, 1988; 47:253-6.
E. 1996 Annual Report: Ohio Tuberculosis, Ohio Department of Health.
F. Barnes PF, Barrows SA. Tuberculosis in the 1990s. Ann Intern Med 1993; 119:400-10.
G. Raviglione MC, Snider DE, Kochi A. Global epidemiology of tuberculosis. JAMA 1995; 273:220-26.
H. Schluger NW, Rom WN. Current approaches to the diagnosis of active pulmonary tuberculosis. Am J Resp Crit Care Med 1994; 149:264-7.
I. Jarvis WR, Bolyard EA, Bozzi CJ, Burwen DR, Dooley SW, Martin LS, Mullan RJ, Simone PM. Respirators, recommendations, and regulations: the controversy surrounding protection of health care workers from tuberculosis. Ann Intern Med 1995; 122:142-6.
J. The tuberculin skin test. Am Rev Resp Dis 1981; 124:356-63.
k) Targeted tuberculin testing and treatment of latent tuberculosis infection. MMWR 2000; volume 49
http://www2.cdc.gov/mmwr/mmwr_rr.html (June 9, 2000)
l) Diagnostic Standards and Classification of Tuberculosis in Adults and Children Am J Respir Crit Care Med 2000; 161:1376-95.
http://www.thoracic.org/statementframe.html
 
Last updated 9/3/00
 
 
TOP OF PAGE
 
 
Return to James Allen, MD: For Residents page
 
Return to James Allen, MD: For Referring Physicians page