As usual my delving into family history has prompted a post … I’ve been researching my Great-great-Uncle who was killed in action at Somme, France whilst serving as a WW1 ANZAC and discovered that his father, my great-great-grandfather died from (and I shall quote from the Marlborough newspaper that it was printed in) … “that dread disease consumption“.
Now you may consider TB to be a third world, old-fashioned type of disease and to a degree you would be right however TB remains the second greatest killer globally (HIV/AIDS is number one) due to a single infectious agent. In 2013, 9 million people fell ill with tuberculosis and 1.5 million died as a result – 480,000 of these cases were MDR-TB (multi drug resistant). There is an upside to all this in that 37 million lives were saved due to effective diagnosis and treatment between 2000-2013 and the number falling ill to the disease each year is declining albeit slowly. New Zealand statistics show 305 cases nationwide during 2014 and this number has been relatively stable over the past five years.
MDR-TB is defined as those strains that are resistant to at least Isoniazid and Rifampicin (the two most powerful and standard first line drugs for treatment of TB). XDR-TB are strains that are extensively drug resistant and are defined as MDR-TB with additional resistance to any fluoroquinolone and at least one of the second line agents (Amikacin, Capreomycin or Kanamycin). Of the 480,000 MDR-TB cases in 2013 about 9.0% of these were determined to be XDR-TB. Within New Zealand the rate of resistance is much lower, on average only 1-2% of isolates each year showing this level of resistance. In the past 10 years there have been 33 cases of MDR-TB in good ol’ NZ and all but two of these cases were born overseas where it has been assumed they contracted it – 29 of these 31 cases were born in an Asian country. Only one case of XDR-TB has ever been identified in New Zealand, this was in 2010. I think this is one time were our geographical isolation from a large part of the world is to our benefit.
Tuberculosis was a disease that the WHO considered dropping from their watchlist in the 1960’s/1970’s due to it’s decline however it made a huge resurgence in the 1990’s with the number of HIV/AIDS cases increasing and is certainly a disease which we cannot afford to ignore.
You can view a copy of the 2014 WHO global TB report here.
Diagnosing Central Nervous System (CNS) Tuberculosis in the laboratory is not easy. There needs to be a balance between rejecting unnecessary and inappropriate investigations for CNS TB and at the same time making sure no true cases are missed.
Here are a few tips:
Investigations for TB in CSF should always be requested only after CSF protein and cell parameters are known. (Of course these parameters can occasionally be normal in CNS TB but knowledge of them changes the positive and negative predictive value of any future testing)
Investigations for TB PCR in CSF should always be requested by a consultant clinician. (on the assumption that a consultant has the knowledge base and experience to best select the patients where testing is appropriate, not always the case however). I have seen numerous instances of junior doctors requesting TB PCR on 0.5 ml CSF on a patient with a couple of days of headache.
Investigations for TB PCR in CSF should always be approved by a clinical microbiologist. If there is no such filter, there is the risk of testing volumes running riot and inappropiate testing occurring. TB PCR is specific but only has a sensitivity of between 50 and 70% at diagnosing CNS tuberculosis. It is important to make requestors aware that a negative result is virtually meaningless. Auditing TB PCR requesting volume and indications is always a good audit project for students.
Insist on adequate CSF volume for testing. The sensitivity of both culture and PCR tests for TB in CSF increases with increasing volume submitted. Different labs have different volume requirements for these tests. For optimal testing, somewhere around 5 ml CSF are needed for these tests, which is not an insignificant volume. That is not to say that smaller volumes should always be rejected. The clinician needs to be made very aware however that doing TB culture or PCR on tiny amounts of CSF may be of extremely limited value.
Educate the requestors. With written protocols, presentations etc TB investigations in CSF is a problem that must be faced by many clinical microbiology departments throughout the world. Better to be pro-active than reactive about what is acceptable and what is not.
For more detail on the diagnosis of CNS tuberculosis see these guidelines, which are well written and still reasonably up to date. They also highlight the importance of clinical suspicion, comprehensive imaging and empirical treatment when laboratory diagnosis is proving elusive.
In the developed world, big laboratories will receive many hundreds of requests for TB culture and TB PCR in CSF, but will likely be able to count the number of probable or confirmed cases on the fingers of one hand. Close co-operation between the laboratory and the clinicians is required, as it is not a diagnosis you want to miss…