“The uncertainty of certainty”

There is one thing certain in the microbiology laboratory, that the results will be uncertain. This has nothing to do of course with laboratory systems or the competency of staff members. Just an acceptance that there is no such thing as a certain result…

The other thing to note is that the degree of certainty of results will vary between different tests, not only for separate tests but even for multiple tests contained in the one assay, e.g. any multiplex PCR.

Take for example a multiplex respiratory PCR, containing 24 or so different targets. (Most labs will “demand manage” such expensive assays, allowing them only for immunocompromised patients or the seriously ill. Nevertheless, such assays are becoming increasingly popular.)

In a multiplex respiratory assay, a positive result for rhinovirus is almost certainly going to have a greater chance of being “the genuine article” than a positive result for bocavirus.

This is because each individual target pathogen has a different positive predictive value (PPV), based on both its specificity and its relative prevalence in the tested population. As a result, positive predictive values for individual pathogens within a multiplex can, and do, vary greatly.

But how do we relate such information to the clinicians? Quoting the calculated PPV for each target in a multiplex would make for a long and complex laboratory report. I would not go there… It is probably best to use an appropriate comment for certain results. I.e. “Bocavirus is uncommonly seen in population x, therefore the positive predictive value of this result may be sub-optimal. Close clinical correlation is required.”

Of course, clinicians can increase the degree of certainty by clarifying the “pre-test probability”. I.e. A positive bocavirus result in a 6 month old during the winter season is much more likely to represent a true result than a positive bocavirus result in an adult during the summer season.

With multiplex PCRs, sometimes you are “forced” to perform a test, when it would be better not to know…

Clinicians, in general,  tend to believe that all laboratory results are certain, until we produce one that is very clearly wrong! After that, they will believe all results are uncertain until that trust is rebuilt over time.

To understand certainty of testing, you first of all need to understand the laws of probability. All a laboratory result ever does is convert pre-test probability of disease X into post-test probability. 

It neither confirms nor excludes…



“The Great Imitator”

There are many causes of a lymphocytic CSF, both microbiological and non-microbiological. Here is a quick and non-exhaustive summary:

  • Enteroviruses- probably the most common cause, in most parts of the world.
  • Herpes Simplex Virus (HSV)- one of the most important to diagnose/exclude as HSV encephalitis is associated with a high mortality rate.
  • “Lots of other viruses…”- There are many viruses which can cause a lymphocytic CSF, too many to list really. How many you test for depends on how much money your lab has, and how sick the patient is.
  • TB- Look for the classical risk factors and a more sub-acute presentation.
  • Cryptococcus- Usually in immunocompromised, particularly HIV. Remember cryptococcal antigen has essentially replaced Indian Ink stain as a diagnostic test.
  • Leptospirosis- Other systems (i.e. renal, respiratory) usually involved.
  • Non-infectious- Autoimmune, malignancies, drugs can all be causes of a lymphocytic CSF.

and the list goes on…

But one cause of a lymphocytic CSF that I have not mentioned is one that is often forgotten about.


Syphilis is sometimes called “The Great Imitator” because of the diversity of clinical syndromes it can cause. In the words of William Osler “Those who know syphilis, know medicine.”

William Osler

And with the massive increase in syphilis over the past few years in New Zealand (and many other parts of the world), that syndrome diversity is starting to reveal itself…

In the past two years, I have personally seen 5 cases of lymphocytic CSF due to neurosyphilis. Sometimes it has been anticipated, in others it has been completely unexpected.

So all cases of unexplained lymphocytic CSFs should really be getting treponemal serology performed on serum. A lymphocytic CSF and positive syphilis serology is neurosyphilis until proven otherwise. On those with positive syphilis serology, neurosyphilis can be confirmed by looking for VDRL and FTA in the CSF.

Neurosyphilis does not just present with an acute/subacute meningitis picture. Tertiary neurosyphilis can present with psychiatric or dementia symptoms (I have seen one case of neurosyphilis presenting as dementia). Again these cohorts of patients should all be screened for syphilis. 

Syphilis can affect the neurovasculature and present as a CVA (stroke). In the same manner as above, all patients who present clinically with stroke should get syphilis serology.

Yes, syphilis is indeed the great imitator.

We do about 25000 syphilis serology tests a year at my lab. When I started at my current position 12 years ago, we would maybe see 1 case of syphilis every month. Now we see 5 or 6 cases a week…

Syphilis is a fascinating disease, one of my favourites. But because it imitates so many other conditions, it is important to always think about it, so it isn’t missed. Missing cases of syphilis can have catastrophic consequences down the line…



“Flu in Kathmandu”

When I was offered the chance to go to a WHO influenza meeting in Kathmandu, I grabbed it with both hands. Such opportunities certainly don’t come by every day…

However the trip to Nepal did not get off to the best of starts.

On the flight to Kathmandu, I started to get toothache. By the time we landed I was in agony. The pain was compounded by the fact that my suitcase didn’t make the connection at Singapore. Ouch!

Things could only get better…

However my initial impressions of Kathmandu did little to lift my spirits. There were three power cuts in the first 24 hours, apparently a hangover from the 2015 earthquake. I had to pass on coffee in my hotel room as the tapwater had a distinct greeny brown tinge to it. I then attempted to do some initial exploration of the city on foot, but crossing roads in this city is not for the faint-hearted! Eventually fatigue and my nerves got the better of me and I retreated to the safer confines of my hotel room, wondering just what I had got myself into…

But things did eventually improve (as they almost always do!). The conference started the next day and it was good to focus for a change on just one microbiological subject (influenza) for two and a half days, as this allowed the acquisition of some in-depth knowledge. It was also good to speak to representatives from countries that I have very little knowledge of and have certainly never met anybody from before , i.e.  Timor Leste, Mongolia, Bhutan. The Nepalese people themselves were very friendly and as most of them knew a little bit of English, it was easy to strike up a conversation.

And my suitcase eventually turned up, albeit the day before I was due to leave (carry-on bag next time!). As for my toothache, the hotel concierge kept me going with a steady supply of paracetamol, which took the edge off the pain and allowed me to function. I fear a visit to the dentist will be required though on return to NZ.

The highlight of the whole trip was the final day visit of local hospitals, public health laboratories, and the Nepal National Influenza Centre. This was a fantastic opportunity to meet local laboratory professionals, and to discuss what particular challenges they faced in a sometimes challenging environment. I was extremely impressed at the systems they had in place.

“Lab and hospital tour in Kathmandu”

So despite the challenges the trip turned out to be hugely educational, both in an academic and cultural sense. I learnt a good deal about Influenza, and even more about Nepal. It is very different to New Zealand! I look forward to going back there one day,  hopefully to do some trekking in the Himalayas.

And I have made a new resolution:- to attend at least one microbiology conference a year in a place I have never been to before, even if I have to pay for it myself.