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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