The Mantoux tuberculin skin test - interesting facts

The Mantoux test or the Tuberculin Skin Test (TST) is one of those tests that most doctors will do when faced with a patient who is suspected of having tuberculosis. The test involves the intradermal injection of 0.1ml of a protein called tuberculin purified protein derivative. The test is interpreted as positive or negative according to the size of induration on the skin (not erythema), measured perpendicular to the long axis of injection, between 48 and 72 hours after the injection.

The TST is not a very sensitive test. In those who are not suffering from any kind of disease that compromises their immunity, the test has a sensitivity of about 95 percent. This means that this test may miss one out of every twenty previously healthy people who develop tuberculosis. The sensitivity of the TST drops to 80 percent when an immunocompromised person develops tuberculosis. This means that for people with HIV, the TST is not reliable in excluding tuberculosis because it can be negative in 1 in 5 people with HIV infection who develop tuberculosis.

The size of induration required for a positive TST depends on who is being tested. An induration of 5mm is adequate if the person is immunocompromised in any way through disease or from medication. Otherwise an induration of 10mm is required for the test to be regarded as positive.

We would regard a person as being newly infected with tuberculosis when the tuberculin skin test was negative earlier but is positive now. If such a person has no signs of active tuberculosis (after being investigated), the person will be labelled as having latent tuberculosis.

There are situations where a positive TST is not due to latent tuberculosis or to active tuberculosis. BCG vaccination in childhood can result in a positive test for 3 to 5 years after the vaccination. The test can also remain positive for many years after a person has been successfully treated for tuberculosis in the past.

There is a peculiar phenomenon known as the booster phenomenon where a person may develop a positive test simply because of a tuberculin skin test done earlier within the past one year. This phenomenon is because the TST boosts cell mediated immunity that had previously waned. It occurs in people who had tuberculosis earlier. The danger in not being aware of this phenomenon is that we may label such patients as having latent tuberculosis because of the recent conversion in the TST.

To overcome the problem of misinterpreting the TST in people (like health care workers) who may undergo annual tuberculin skin testing, we can do the two-step tuberculin skin test. The details of how this test is done is given in the reference below.

References:
1. The two-step tuberculin skin test
2. Tuberculin skin testing

The 2013 Nobel Prize in Physiology or Medicine

 Some genetic diseases are caused by defects in the transport of proteins within cells.  An understanding of the mechanisms involving transport of proteins via vesicles was the research work that led to the 2013 Nobel Prize in Medicine / Physiology. (Read about it).  

Genetic diseases can be caused by single gene abnormalities, chromosomal abnormalities or by a combination of genetic and environmental factors. Abnormalities in genes cause diseases in various ways:

1. Excess production of proteins. An example is the fragile X syndrome which shows itself as learning disability or mental retardation and autistic behaviour. This is caused by excess production of a protein that is used in synapses of the brain.

2. Insufficient production of proteins. An example is the group of diseases called glycogen storage disorders which can present with hypoglycaemia, hepatomegaly and/or muscle weakness.

3. Production of an abnormal protein. An example is phenylketonuria which is due to production of an inactive form of the enzyme that hydrolyses the amino acid phenylalanine. This leads to delayed milestones in childhood, seizures, learning disabilities and mental retardation as well as reduced or absent pigmentation of skin, hair and eyes. 

4. Defective transport of proteins. Genetic diseases involving abnormalities in protein transport can manifest in patients as hypopigmentation of skin, defects in cell mediated immunity and/or neurological defects. Bardet-Biedl syndrome where the affected person has mental retardation, retinopathy and is of small stature with poorly developed external genitalia, Charcot Marie Tooth disease and Spinocerebellar ataxias where those affected have ataxic gait along with other neurological abnormalities, Hereditary Spastic paraplegia which causes a pure motor paraplegia, are examples of neurological conditions where the genetic defect affects protein transport within cells. Alzheimer’s disease and Type 2 diabetes mellitus may also have defects in the transport of proteins. The transport of amyloid precursor protein by vesicles has been noted to be defective in the early stages of Alzheimer’s disease.  

Reference: Insights into vesicular transport in inherited diseases

Managing patients with shock

A beautiful review about circulatory shock in the NewEngland Journal of Medicine gives us practical advice for dealing with patients in shock. I summarise here three important learning points from that article. 

1. Diagnosing circulatory shock

Do not define shock only by the presence of arterial hypotension even though a blood pressure lower than 90mm Hg systolic and a mean blood pressure less than 70mm Hg are often present. This is because in those with chronic hypertension, the fall in blood pressure may not reflect the degree of shock. Also, the blood pressure alone may be misleading as it can be low in people who have chronic hypotension or have just suffered a transient episode of vasovagal syncope. The diagnosis of shock needs signs of poor perfusion to tissues and organs. The article tells us to consider the diagnosis of shock when there is tachycardia and signs of poor tissue perfusion as seen through three windows in the body:

                a. The skin: Cold and clammy

                b. The brain: Confusion, disorientation or other signs of altered mental status

                c. The kidney: A urine output of less than 0.5ml per kg per hour.

2. The VIP rule for resuscitation

This is the Ventilate, Infuse and Pump rule.  Ventilate (when needed) to ensure adequate oxygen intake. In this context we must remember that pulse oximetry is unreliable as a measure of adequate oxygen in the blood when there is peripheral vasoconstriction. So blood gases must be measured for this purpose. 

Fluids must always be infused in patients with shock since even those with cardiogenic shock can benefit from fluid resuscitation. However infusion of fluids must be carefully monitored. A fluid challenge refers to the infusion of 300 to 500ml of fluids (usually crystalloids) over a period of 20 to 30 minutes in order to see whether there is any improvement in one or more of the parameters of circulatory shock. The results of such a fluid challenge can then guide decisions for further infusion of fluids. 

Inotropic agents need to be used when the hypotension is severe or when the response to fluid resuscitation is slow or insufficient.

3. Using inotropic agents in circulatory shock

The authors consider norepinephrine to be the agent of first choice in those with shock whose cardiac output is not decreased. This will be seen in conditions like the early stages of septic shock (distributive shock). In the dose range of 0.5 to 2ug per kg per minute, norepinephrine elevates mean blood pressure without increasing the heart rate. Dobutamine is considered the agent of first choice in those with shock who need an increase in cardiac output. Both dobutamine and norepinephrine can be used together when needed. The authors do not recommend either dopamine or epinephrine as agents of first choice. Dopamine increases the risk of arrhythmias and increases mortality in the acute stage when given to patients with cardiogenic shock. Epinephrine increases the risk of arrhythmias and reduces splanchnic blood flow. These agents can be used as second line agents if necessary. Low dose vasopressin is an agent that can be added to norepinephrine for those with septic shock who have an adequate cardiac output.