A 26 year old fourth year medical student presents to the local ER with complains of productive cough with occasional blood, 13 lb weight loss over the previous 3 months, and night sweats. He denies fever, chills, nausea, vomiting, constipation, or diarrhea.

History

• Meds: Adderall for ADD since childhood

• Allergies: NKDA

• PMHx: insignificant

• PSHx: Appendectomy 2 years ago

• Social Hx: Completed MD in India, smokes cigarettes when drunk, 3-4 beers per week, occasional THC use in college

• Family Hx: Mom and dad both live in India, both are healthy. Brother and sister live here in the US while completely undergraduate studies at IU, both are healthy

Physical Exam

• GENERAL APPEARANCE:  alert, talkative, actively coughing, in no distress• VITAL SIGNS:  T - 97.5, BP 110/60, respirations 22, and HR 88 • HEENT: Head is normocephalic and atraumatic. Extraocular muscles are intact.

Pupils are equal, round, and reactive to light and accommodation. Nares appeared normal. Mucous membranes are moist. Posterior pharynx clear of any exudate or lesions.

• NECK: Supple. No carotid bruits.  No lymphadenopathy or thyromegaly.• LUNGS: mild tachypnea, decreased breath sounds and dullness to percussion in R

upper lobe, no wheeze appreciated• HEART: Regular rate and rhythm without murmur. • ABDOMEN: Soft, non-tender, and non-distended.  Normal bowel sounds.  No

hepatosplenomegaly or palpable masses were noted. • NEUROLOGIC: Cranial nerves II through XII are grossly intact, 5/5 strength in

UE and LE, DTR normal• SKIN: No bruises, ulcers, or color changes appreciated

Differential Diagnosis?

• Tuberculosis

• Pneumonia (bacterial vs viral vs fungal)

• Histoplasmosis

• Blastomycosis

• Malignancy

Evaluation

• What labs, imaging, or procedures would be appropriate?

Labs

• CBC: WBC 16,000 cells/mm3, Hgb. 13.4, PLTS 350,000/mm3

• BMP: Na 140, K 4.5, Cl 101, HCO3 23, BUN 20, Cr 1.5, Glucose 101

• ABG: pH 7.4, pCO2 31, pO2 85

• Blood cultures: pending

• Sputum stain: No organisms seen on gram stain (what other kind of stain should be ordered? - AFB stain)

• Cultures pending

Chest PA RadiographUpper lobe infiltrate with air fluid level

Acid Fast Bacilli Stain

Acid fast M. tuberculosis within macrophages

Raviglione MC, O'Brien RJ. Chapter 165. Tuberculosis. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012

Diagnosis?

Mycobacterium tuberculosis

Etiology• M. Tuberculosis is a rod shaped, non spore forming, thin aerobic bacterium• Obligate aerobe and a very slow grower (growth on solid culture takes 3-8 weeks)• Typically neutral on gram’s staining, however, once stained, the bacilli cannot be

decolorized by acid alcohol• Acid fastness is due to organism's high content of mycolic acid, long-chain cross linking

fatty acids, and other lipids• Lipoarabinomannan, cord factor, and arabinogalactan are proinflammatory, cytotoxic,

inhibit chemotaxis, and inhibit the fusion of lysosomes with phagosomes• Facultative intracellular pathogen which grows in unactivated macropages and type II

pneumocytes• Pathology is determined by the amount of antigen (number of bugs) and the extent of the

individual’s hypersensitive reaction to the antigen• Two major forms of infections occur: primary TB (pulmonary TB) and secondary (latent

reactivation) TB• Localized, progressive, and disseminated disease may occur in both forms

Epidemiology• Estimated that 1/3 of the world population is infected• Estimated that 10,000,000 in this country are infected• In the US 16,377 cases were reported in 2000, 12,904 cases were reported in 2008,

11,545 cases were reported in 2009 (119 cases in IN), and 11,182 (90 in IN) cases were reported in 2010 (provisional)

• In this country most cases occur in the those infected with HIV, the urban poor, alcoholics, iv drug users, the homeless, migrant farm workers, immigrants, and prison inmates

• Disease in the elderly usually represents reactivation of a previous infection• Disease in children often represents active transmission within the community

or family (they get it from someone else!)

CDC: Basic TB Facts, http://www.cdc.gov/TB/topic/basics/default.htm

Pathogenesis

Pathogenesis

The sequence of events in primary pulmonary tuberculosis, commencing with inhalation of virulent Mycobacterium tuberculosis organisms and culminating with the development of cell-mediated immunity to the organism. A, Events occurring in the first 3 weeks after exposure. B, Events thereafter. The development of resistance to the organism is accompanied by the appearance of a positive tuberculin test. γ-IFN, interferon-γ; iNOS, inducible nitric oxide synthase; MHC, major histocompatibility complex; MTB, M. tuberculosis; NRAMP1, natural resistance-associated macrophage protein; TNF, tumor necrosis factor.

The most common abnormality associated with primary TB on chestradiography is hilar adenopathy (white arrows). Subpleural granulomas (yellow arrow) are also common. These two findings constitute the Ghon complex. This is also shown in the gross specimento the right.Photos courtesy of Dr Glenn Merkel

Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and

cheesy debris

Microscopic Features

Granulomas with central caseation

Epithelioid granulomas with Langhans giant cells typicallyassociated with TB

Clinical Manifestations Primary TB• Most individuals (~75%) are asymptomatic or have flu-like symptoms along with fever

and chest pain • Around 3 weeks after infection, they become PPD+ (skin test, see “Diagnosis”)• For most, the lesions eventually heal with fibrosis and calcification• Dormant lesions that still contain bugs may reactivate to yield secondary TB

Progressive Primary TB• Some individuals (5-15%) don’t contain the primary infection and develop a

progressive disease that resembles a necrotizing bacterial pneumonia• This presents with fever, productive cough, and chest pain • Coughing aerosolizes secretions and distributes them throughout the lung• There are expanding areas of caseating necrosis with irregular cavity formation along

with erosion of blood vessels resulting in hemoptysis• Lesions will usually heal by fibrosis with adequate treatment

Miliary TB• This refers to the uncontrolled hematogenous dissemination of M. tuberculosis• Infection may involve any organ and the course is usually rapid when it occurs with

primary or secondary progressive disease• Multiorgan failure, septic shock, and respiratory distress, followed by death, may occur

Secondary TB• Pattern of disease that arises in a previously infected and sensitized patient• The lesions typically localize to the apex of the upper lobes• There is rapid tissue response (Th1) because of previous sensitization• Cavitary formation is very likely• Symptoms include low grade fever, night sweats, and weight loss• Without therapy, miliary TB may develop

Diagnosis• Tuberculin test (intradermal PPD)• Xray• Sputum acid fast stain• Culture • rRNA or DNA in sputum by nucleic acid amplification (results in 2-7 hours, but

does NOT replace culture)

• Tuberculin skin test– Induration measured after 48-72 hours– Induration >5mm is considered positive for recent TB contacts or immunosuppressed– Induration >10mm is positive for arrivals from high-prevalence countries, IV drug users, lab

personnel, residents and employees in high-risk settings (e.g. health care facilities, jails)– Induration >15mm is positive for persons with no risks

Treatment

• Treatment of latent TB (asymptomatic, but with radiographic evidence)

Drugs Duration Interval Minimum dosesIsoniazid 9 months Daily 270

Twice weekly* 76Isoniazid 6 months Daily 180

Twice weekly* 52Isoniazid and Rifapentine

3 months Once weekly* 12

Rifampin 4 months Daily 120

http://www.cdc.gov/tb/topic/treatment/ltbi.htm

Treatment• There are currently 10 drugs used for active TB disease• The first lines drugs are isoniazid, rifampin, ethambutol, pyrazinamide• Preferred regimen is the aforementioned drugs for 8 weeks• Afterward, maintenance therapy includes daily isoniazid and rifampin for 18 weeks

IMPORTANT STEP 1 INFORMATION ABOUT TB DRUGS!• Rifampin turns urine red, be sure to tell patient to expect it!• Isoniazid can cause peripheral neuropathy, be sure to pretreat with B6