One-third of the world’s population is infected with the Mycobacterium tuberculosis bacillus (“Mtb”, pronounced letter-by-letter). I’ll wager over 9/10 of the world’s clinicians don’t quite appreciate all the subtleties & pitfalls involved in a basic understanding of this fascinating infection.
For example, the following truisms are all erroneous:
- “Let’s R/O TB — do a PPD”
- “The PPD was positive because of BCG”
- “Active TB unlikely — no fever, sweats, hemoptysis or weight loss”
- “The positive PPD means you were exposed to TB”
Radiology report reads: “Upper Lobe scars from old granulomatous disease; no active TB.” A non sequitur — Absolutely Wrong!!!
Today’s post is an overview of the different “stages” of TB, & their diagnostic criteria. Next week we’ll address more specifics. Our focus will mostly be pulmonary (85% of TB in the US).
Let’s start by describing what happens with TB, from infection until, well, whatever. The jargon, terminology & abbreviations are standard among TB specialists.
NATURAL HISTORY OF TUBERCULOSIS
1. The bacterium Mtb is acquired by inhalation. Someone with active pulmonary (or the rare laryngeal) TB coughs & you breathe it in.
- Portal of entry for M. bovis, usually indistinguishable from Mtb, is via unpasteurized dairy products
2. When Mtb hits the lungs, a non-specific response from our innate immunity (WBCs & macrophages) attacks & contains it (as if we’d aspirated a piece of carrot).
3. These phagocytes transport Mtb to hilar nodes.
4. Over the next 2-10 weeks, Mtb spreads hematogenously throughout the body. Winds up deposited in virtually any organ, but survives mostly in areas of high oxygen tension [lung apices, kidneys, vertebrae, meninges, etc.].
4. During these same 2-10 weeks, an adaptive specific cell-mediated immunity (CMI) may destroy the invader. Delayed-type hypersensitivity (DTH) also develops (responsible for PPD reaction), creating granulomas which wall off the bacilli. This is Latent TB Infection (LTBI).
5. LTBI is inactive. It’s 100% asymptomatic & non-contagious. BUT…
- There’s a 5% – 10% lifetime risk the bacteria will escape the granulomas & multiply, causing Active TB Disease, which is pathologic & infectious.
- About 50% of Active TB occurs within the first 2 years of initial infection
6. Active TB Disease — Its Natural History (i.e. untreated):
- 50% of patients die within 5 years
- 30% are cured by their own immune systems
- 20% heal the first reactivation, but suffer ongoing remissions and relapses (and probably eventually die of TB >5 yrs. from infection, unless something else gets them first)
Summary thus far:
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Latent TB
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Active TB
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LATENT TB INFECTION
Diagnosed by Tuberculin Testing. There are 2 kinds of tests:
- Skin Test: purified protein derivative (PPD)
- Blood Test: interferon gamma release assay (IGRA). Brand names include QuantiFERON® and TB-Spot®.
The antigen in PPD evokes a DTH response in persons whose CMI has been stimulated by Mtb. The IGRA incubates Mtb antigen with whole blood; if T-lymphocytes are able to recognize it (due to CMI from infection), they release γ-interferon which is detectable. Older tests like the Tine and Heaf are too inaccurate to use.
“Tuberculin Testing” technically refers to the PPD, i.e. “Tuberculin Skin Test” (TST). There’s no term for the IGRA, since it’s new. I’ll use the term “tuberculin testing” to mean either, since they serve the same purpose.
We’ll discuss use of these tests in depth next posting. But the main thing to comprehend is that they identify who has Mtb residing dormant inside them, with potential to reactivate. i.e. They diagnose Infection. i.e. Latent TB Infection. It’s NOT “exposure.”
You get a note from school: your child was “exposed” to lice. Do they have lice? Probably not. Do they need treatment? Not if they ain’t got any.
But a positive PPD or IGRA means they’re infected with Mtb. The germ is inside them!!! Many such persons need treatment, with isoniazid (INH), to prevent future reactivation. But if you teach patients, “You don’t have TB, you were just exposed,” you’ve shot yourself in the foot in terms of adherence. Who wants to take 6-9 months of medicine if they were just “exposed”?
- It’s true they do not have active TB disease; they’re not ill or contagious
- But they do have Latent TB Infection. Tell them it’s dormant (or “sleeping”), but needs a cure before it reactivates (“awakens”).
So, please, never say “exposed.” Tell people they’re “infected” (but not sick).
ACTIVE TB
Cardinal symptom of active pulmonary TB is cough. It’s usually minimal, maybe slightly productive (maybe dry). The key is that it persists, doesn’t go away. You can read about patients who bounce from jail to jail, hospital to hospital, homeless shelter to shelter, office to clinic, infecting people with a lousy little hack that nobody bothered to X-ray.
- Order a chest x-ray (CXR) on any patient with cough ≥3 wks duration that hasn’t begun to improve at all, unless you make an alternative Dx (e.g. asthma)
- Order it sooner for associated hemoptysis, fever, night sweats (drenching), or weight loss. These symptoms are more specific for serious illness, but aren’t at all sensitive (i.e. not usually present with Active TB)
Up to 20% of patients with Active TB test PPD negative!!!!! This is because either:
- The illness itself is immunocompromising, so they can’t mount an immune response. But their PPD will turn positive after treatment.
- All their T-cells are too busy fighting active Mtb to respond to the PPD.
It’s OK to order a PPD or IGRA, but we case-find Active TB by chest x-ray. Apical & upper lobe infiltrates & cavities are most suspicious. A negative PPD or IGRA does not rule-out Active TB.
The gold standard for diagnosis of Active TB is a positive culture. Order “Sputum for Acid-Fast Bacilli (AFB)” — lab will do a smear (by direct microscopy) & culture. Mtb can’t be seen by Gram stain.
- For pulmonary TB, obtain 3 sputum specimens (separate days)
- Urine for renal TB, CSF for TB meningitis, tissue for other sites
Smear results return within 24 hrs., but are only 50% sensitive for pulmonary TB (much less so for extrapulmonary). The sputum culture, 98% sensitive, takes 1-2 weeks, or even more. A nucleic acid amplification test (PCR) is 80% sensitive, but expensive; order it when you have a high index of suspicion (e.g. cough with fever, hemoptysis, night sweats).
Extrapulmonary TB is harder to diagnose, because cultures are much less sensitive. If a pathology report ever mentions “caseating granulomas,” it’s TB for all practical purposes. Granulomas in sarcoid, fungal disease, etc. are “non-caseating.” “Caseating,” means “cheese-like” (that’s what the material looks like grossly) — try telling your patient their result was “cheesy.”
We’ll discuss Active TB in depth in another posting.
HEALED TB (“OLD SCAR”)
Sometimes you find small incidental “scars” on CXRs ordered for other purposes, or for work-up of asymptomatic positive screening tuberculin test. This might be one of the 30% to 50% of people whose TB either cured or remitted on its own.
Caveat — It’s impossible to distinguish inactive “old scar” from “active TB” (multiplying bacilli) radiographically with a single film! You can only say “scar” if it’s stable over time. Some radiologists don’t seem to appreciate this — NEVER accept a reading of “old” or “prior” unless there’s a direct comparison mentioned in the report.
Work-Up —
- Order daily sputum exams for 3 days, even if there’s no cough. Patients force a cough & spit whatever into the cup. A rare bacillus may be expectorated; Mtb is always a pathogen, never a contaminant or colonizer.
- Wait the 2 months it takes for sputum cultures to grow on conventional media (don’t worry about contagion; patient is asymptomatic, no cough).
- Repeat the CXR at 2 months.
If the 3 sputums are negative, & the CXR hasn’t changed at all (“stable”), then you can say “old scar” from prior, healed TB that’s now inactive.
“EXPOSURE”
Actually, Public Health does use the word “exposure” during contact tracing of active TB patients. Someone who lives in the same house was exposed, needs tuberculin testing [if negative, they weren’t infected]. Someone who went to the same ballgame as the index patient wasn’t exposed, doesn’t need (shouldn’t get) a test. More on the “shouldn’t” next posting.
Contact investigators first test the closest contacts, e.g. same home. If they’re all negative, no need to look elsewhere. But if there are positives, investigators branch out to the next closest, e.g. office cubicle. No positives there, stop; positives, try more in the office. Etc. It’s referred to as “concentric circles,” index case in the center.
SUMMARY
The following Public Health paradigm describes “classes” of TB.
TB-0 — No Exposure- Don’t perform tuberculin testing
- Case- contact. Maybe got infected with Mtb
- Perform tuberculin test to determine
- Temporary classification pending tuberculin testing results
- Tuberculin test positive
- Asymptomatic. Not contagious.
- 5%- 10% lifetime chance of developing active TB
- Many patients candidates for INH Tx (to prevent reactivation)
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Main Sx: Cough >3wks w/o improvement, no other Dx likely
- Maybe fever, sweats, hemoptysis, weight loss (but usually not)
- Suspect: Abnl. CXR (cavities, apical infiltrates)
- Sputum for AFB: smear 50% sensitive, PCR 80%, Culture 98%
- In other organs: urine / CSF / tissue biopsy, for AFB
- Pathologic. Needs Tx. Contagious
- Asymptomatic pt. w/ abnormal CXR
- Obtain 3 sputums, await final cultures on conventional media (60 days)
- When cultures no growth at 60 days, repeat CXR
- If no change in CXR (= “stability”), can Dx “Old Scar”
- High risk of reactivation; needs INH Tx. Not contagious.
- If high clinical suspicion, start 4-drug Tx pending results
- If low suspicion, await sputum results
- Temporary classification pending results
Next 2 Postings: Lots of specifics about the PPD, IGRA, CXR, & sputum analyses.
DiagnosisDude 