The biomedical scientist came to find the duty Microbiologist. The Microbiologist could tell they were frustrated.
 
“Look at this“, the BMS exclaimed thrusting a request form at the Microbiologist. “How the heck do they expect us to do all of these tests on such a small sample, not to mention that most can’t even be done on an EDTA sample?”
 
Sure enough the request form was covered in a tiny scrawl of hand writing requesting about 20 different tests for the small blood sample that had been sent with the request.
 
The clinical details just said “cardiomyopathy”.
 
“Don’t worry, I’ll sort it out. It’s just that someone has probably done their exams and now knows a list of all the possible causes of cardiomyopathy and has therefore written them down” said the Microbiologist.
 
The BMS made a “harrumphing” noise and stomped off back to the lab. They were of course right, this was a ridiculous request, but cardiomyopathy is a condition where looking for the cause can be very difficult so it requires considered thought.

What is cardiomyopathy?
Cardiomyopathy is a disorder of the structure and function of heart muscle which is not caused by coronary artery disease. The last bit is important because coronary artery disease is a common condition where the blood supply to heart muscle is compromised requiring specific treatment such as angioplasty, stents and lifestyle changes. Whereas, when cardiomyopathy is not caused by coronary artery disease, the problem is with the actual muscle of the heart not its blood supply.
 
In these cardiomyopathies the heart muscle doesn’t contract properly and therefore the heart becomes less able to pump blood around the body. As this becomes worse and worse the heart eventually fails and fluid backs up into the lungs and other parts of the circulation, perfusion of the body is inadequate and without treatment the patient dies.
 
There are a number of different causes of cardiomyopathy including:

• No cause found (idiopathic) – 50%
• Myocarditis (infection) – 9%
• Previously undiagnosed ischemic heart disease – 7%
• Drugs – 4%
• Pregnancy – 4%
• Human immunodeficiency virus (HIV) infection – 4%
• Hypertension – 4%
• Connective tissue disease – 3%
• Other – 15%

 
Recent studies have shown that up to 67% of “idiopathic” cardiomyopathy is in fact caused by viruses, in which case nearly half of all cardiomyopathy is actually caused by viruses. Within infection there are a number of different microorganisms which can cause cardiomyopathy, including:

• Parvovirus B19 – 50%
• Human Herpes Virus 6 – 22%
• Coxsackieviruses – 9%
• Influenza virus (A and B) - % unknown, seasonal
• Human Immunodeficiency Virus – 4%
• Adenovirus- <2% (up to 25% in studies from the 1980s)
• Echoviruses- <2%
• Cytomegalovirus - <2%
• Epstein-Barr virus - <2%
• Lyme disease (Borrelia burgdorferi) – very rare, usually mild and self-limited
• Chagas disease (Trypanosoma cruzi) – very rare, travel history to Central and South America is essential
• Vaccinia virus inoculation (to protect from smallpox) – 1-6 per 10,000 vaccinations

 
Another recent study from Japan has also suggested 6-10% of Japanese patients with cardiomyopathy have Hepatitis C Virus, although how this then causes cardiomyopathy and whether this is also true in other countries is unknown.
 
How do viruses cause myocarditis?
Viruses can damage the heart either by causing direct injury or by triggering intracellular events that cause damage, but the details are often unclear. Coxsackievirus can cause direct damage to heart muscle cells (myocytes) without causing a cellular response but it is unclear how this occurs. There is also a coxsackie-adenovirus receptor (CAR) on the myocyte cell surface which is essential for allowing these viruses into the cell; if the CARs are absent, the virus cannot get in and this is probably a protective mechanism against myocyte damage. However if the virus gets inside the myocyte the virus genome is translated into various proteases that affect viral proteins and also myocyte proteins essential for normal cardiac function. This might all sound very complicated but it tends to suggest that the damage to the heart is more accidental than deliberate, after all what evolutionary benefit is there to the virus in killing the host before the virus can reproduce!?
 
So why is it important to have a structured approach to investigation?
It is always important to have a structured approach when looking for the underlying cause of a syndrome. Some doctors fall into the trap of sending a blanket screen of every test for every possible cause they can think of, or which they read about, without first considering how likely that cause actually is. As a result they can end up with false positive tests for diseases, if they decide to treat the “result” it not only results in unnecessary treatment but more worryingly also stops them looking for the true cause.
 
As you might have guessed, this is a real bug bear of mine. The trick is to look for the most likely causes first before considering whether to repeat the original tests or working through increasingly less likely causes if the original tests come back negative. For example if a patient has all of the symptoms and signs of “x” but the original test for “x” is negative you should look at the rate of false negative tests for “x” and decide whether to repeat the test to help improve detection; it might be that a single negative test has a false negative rate of 10% but 2 tests have a false negative rate of only 3%. A word of warning, don’t just keep repeating the test until you get a positive in this case because as the false negative rate reduces the false positive rate increases and eventually you will have a higher likelihood of a false positive than a false negative and that has its own problems. It’s like tossing a coin, essentially you have a 50:50 probability of heads or tails, but if you keep tossing until you get the answer you “want” (say tails, as heads means heading to the gym!) then your intervention has skewed the result.
 
In contrast to looking for common causes where false negatives are a problem, looking for rare causes can lead to problems with false positives. For example, if a patient has no risk factors for “y” and has no symptoms or signs of “y” then a positive test for “y” is very likely to be a false positive. That is why doctors only look for “y” if there are risk factors or clinical clues that suggest it is a likely diagnosis, whereas diagnosis via Dr Google will give you every possibility not just the likely one!

So how should an infectious cause of cardiomyopathy be investigated?
The first stage of investigation is the clinical history; are there any clues that might make a particular cause more likely than others.

• Parvovirus B19 – contact with young children, especially those with Fifth Disease
• Human Herpes Virus 6 – contact with young children, especially those with roseola infantum
• Coxsackieviruses – contact with children with rash illnesses, also prodromal coryzal or diarrhoeal illness
• Influenza virus (A and B) – winter onset, flu-like illness
• Human Immunodeficiency Virus – risk factors for blood borne or sexually acquired infection
• Adenovirus - contact with children with rash illnesses, also prodromal coryzal or diarrhoeal illness
• Echoviruses - contact with children with rash illnesses, also prodromal coryzal or diarrhoeal illness
• Cytomegalovirus - glandular fever or infectious mononucleosis like illness
• Epstein-Barr virus – glandular fever or infectious mononucleosis like illness
• Lyme disease (Borrelia burgdorferi) – tick bites, likely exposure through recreation
• Chagas disease (Trypanosoma cruzi) – travel to Central and South America, contact with reduviid bugs
• Vaccinia virus inoculation (to protect from smallpox) – history of vaccination

 
The history may suggest a good starting point but otherwise look for common things first. Parvovirus B19, Human Herpes Virus, and Coxsackieviruses make up 81% of infections.
 
First line tests:
 
History of contact with children:

1. Whole blood (EDTA sample) for Parvovirus B19, HHV6 and Adenovirus PCR
2. Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG
3. Viral Throat swab for enteroviral (Coxsackievirus and Echovirus) and Adenovirus PCR
4. Stool for enteroviral (Coxsackievirus and Echovirus) PCR

 
History of prodromal coryzal or respiratory illness:

1. Viral Throat swab for enteroviral (Coxsackievirus and Echovirus), Influenza A and B and Adenovirus PCR
2. Stool for enteroviral (Coxsackievirus and Echovirus) PCR

 
No history of exposure:

1. Whole blood (EDTA sample) for Parvovirus B19 and HHV6 PCR
2. Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG and HIV
3. Viral Throat swab for enteroviral (Coxsackievirus and Echovirus) PCR
4. Stool for enteroviral (Coxsackievirus and Echovirus) PCR

 
2nd line testing if first line negative and infectious cause still suspected:

1. Whole blood (EDTA sample) for Parvovirus B19, HHV6 and Adenovirus PCR if not already done
2. Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG if not already done
3. Serum for HIV if not already done

 
3rd line testing if first and second line negative and infectious cause still suspected:

1. Whole blood for Cytomegalovirus and Epstein-Barr Virus PCR
2. Serum for Cytomegalovirus, Epstein-Barr Virus IgM and IgG and Lyme serology

 
It is important to remember that it is difficult to be certain that a virus detected by PCR or antibody test is definitely causing the cardiomyopathy; it is possible that it might be an innocent bystander. For example, in the middle of winter when there is a lot of influenza around a patient with cardiomyopathy could have influenza AND cardiomyopathy instead of influenza causing cardiomyopathy.
 
Can viral cardiomyopathy be treated?
There is no evidence to support any specific treatments for viral cardiomyopathy although I would treat Influenza A or B with Oseltamivir or Zanamivir if I detected it. Recent studies have suggested that Interferon beta might improve cardiac function compared to placebo but this is still in the very early experimental stages and so is not currently recommended. The mainstay of treatment is therefore supportive care in the hope that the heart function will improve on its own or with medication to try and improve function e.g. beta-blockers, diuretics and digoxin. Ultimately the treatment of severe life-threatening cardiomyopathy is heart transplant.

So the Microbiologist rang the doctor who had helpfully put their number on the request form. After a discussion about the patient and what risk factors for infections they might have, the list of required tests was rationalised and further samples for different tests were arranged. The Microbiologist wandered back into the lab with the redacted form and gave the BMS the “good news”; the BMS was only slightly mollified, it had been a bad day….

So having been thinking about a case of fusarium keratitis last week I started to wonder whether the new antifungal Isavuconazole might have a role to play. I then got to thinking that it would be good to write a summary of Isavuconazole for a blog… so here it is…. :-)

Whilst authorising the results the Microbiologist saw a corneal scrape sample appear on the list, shuddering and saying “oooh” out loud, as he really doesn’t like ophthalmology it makes him squeamish! The culture result said “Fusarium species isolated” and the clinical details said “keratitis, contact lens wearer”. This was a bit out of the ordinary compared to the hundreds of urine results that he normally authorises so he picked up the phone to call the Ophthalmologist.
 
It turned out that the patient was in her mid-thirties and a contact lens wearer who had presented to the eye casualty unit with a painful red eye which had been diagnosed clinically as keratitis. The Ophthalmologist had taken a sample and started treatment for bacterial keratitis, the most common cause, as an outpatient with topical Levofloxacin 0.5% eye drops. The Ophthalmologist admitted that they weren’t confident that the patient was that careful with the sterility of their contact lens solutions.
 
The Microbiologist told the Ophthalmologist that a Fusarium species had been isolated confirming the diagnosis of fusarium keratitis so the patient was recalled for alternative treatment targeted at the fungal cause rather than the previously suspected bacterial one.
 
What is keratitis?
Keratitis is inflammation of the cornea of the eye. It can be caused by bacteria, viruses, fungi and parasites. It typically presents with a painful red eye, increased sensitivity to light, and excessive production of tears. As the infection progresses a hypopyon may develop (pus in the anterior chamber of the eye; gravity causes the pus to form a level line). Eventually the cornea may perforate, become scarred and cloudy, and the patient may become blind in that eye.

The patient came into the room looking embarrassed and a bit sheepish. He started to tell the tale of a drunken night out with his friends a couple of days ago. It turns out that he and his friends had been to the pub to celebrate a birthday, had a few too many beers and then on the way home starting daring each other to do increasingly daft things. “We’ve all been there!” When it came to the patients turn one of his friends picked up a big juicy slug from the floor and dared him to eat it… which in his inebriated state he promptly did.
 
The next morning, whilst nursing a hangover, the patient thought back to what he had done and started to wonder if this was such as sensible idea after all. A quick search on “Dr Google” and he was in a panic.
 
“You see Doc, I think I’ve got lung worm!” he exclaimed.
 
After recovering from the mental picture of the Harry Potter film where Ron Weasley’s curse “Slugulus Eructo” backfires and he starts coughing up giant slugs, the GP thought I know nothing about this. He tapped “lung worm” into his own computer and everything that came up was either to do with dogs… or Ron’s slug curse, apparently Ron’s plastic slugs were in chocolate sauce to make them more palatable! Anyway, not very helpful, time to call a Microbiologist he thought….

​“I think my patient has plague!” exclaimed the over excited junior doctor.
 
Knowing that plague had not been seen in the UK for 100 years this year the Microbiologist sighed, “Why do you think your patient has plague?” he asked.
 
“Because they have a rash and have been bitten by a rat” explained the junior doctor.
 
“Have they got a fever, headache and any swollen joints? Is the rash maculopapular?” asked the Microbiologist starting to take more of an interest, but not because they thought this might be plague.
 
“Yes!” said the junior doctor getting even more excited.
 
“This sounds like rat bite fever” said the Microbiologist “let’s get a joint fluid sample and then we can discuss treatment.”
 
“Oh, so you don’t think it’s plague then….” muttered the junior doctor.

The patient was in a right state! It took a while for the GP to calm them down enough to find out what was worrying them. Finally they were able to discover that the patient had returned a week ago from a trip snowboarding in Shiga Kogen in Japan (snow season is December – April), where he’d also visited Jigokudani or Snow Monkey Park. The patient reported he’d developed a headache earlier that evening and rushed to the out of hours GPs for help. He remembered not having a particular vaccine before he went because it was too expensive and then having since been on the internet and read 1/3 of patients with Japanese Encephalitis die, he was now convinced he had it and was going to die all because they had not had the vaccine.

I have been told many times recently by GPs and other Microbiologists that there is no point doing a throat swab from patients with pharyngitis because there is now the Centor score that allows you to identify the Group A beta-haemolytic streptococcus, Streptococcus pyogenes, without having to send any tests to the microbiology laboratory. But is this true or is Centor like the half-man half-horse Centaur - a myth?

“I have a patient with possible infective endocarditis, what antibiotics should I start” exclaimed the excited junior doctor.
 
“What makes you think they have infective endocarditis?” replied the much calmer Microbiologist.
 
“They have a high temperature and a prosthetic heart valve and splinter haemorrhages” responded the junior doctor, “so what antibiotics should I start?”
 
“Okay” said the Microbiologist, “but that's not enough to prove infective endocarditis on their own, let’s talk about Duke’s criteria…”
 
“But the splinter haemorrhages...surely they have infective endocarditis!?” pleaded the junior doctor.
 
But the Microbiologist went on and explained further…
 
So what is infective endocarditis (IE)?
Infective endocarditis is an infection of the endocardium of the heart, either on native heart tissue or prosthetic heart valves. IE usually implies infection of the heart valves; however infection can also be related to transmural thrombosis and congenital heart defects such as atrioseptal defects and ventriculoseptal defects. Microbiologists also often include other intra-cardiac device related infections in the diagnosis of IE e.g. pacemakers and implantable cardioverter defibrillators.
 
In IE an infected mass, called a vegetation, builds up on the heart tissue or valve. The vegetation is made of bacteria, fibrin and platelets and without treatment it will continue to grow until bits break off (emboli) and fly around the body or the valve itself is so badly damaged that the heart cannot function properly anymore and fails.

I was walking down the corridor when one of the Medical Registrars walked passed looking perplexed, we said hello and passed on by, then he called after me “oh can I ask your opinion on…” A standard start to many a query for a Microbiologist! But this question was different, he was reading around the subject of endocarditis and was frustrated by the “guidelines” put out there by the expert bodies… he went on “their advice is sometimes different and even contradictory! How do you know what to follow?”
 
I agreed, which didn’t seem to satisfy him at all. So let me explain further in this blog, as it will take longer than a passing corridor conversation, unless you have the old Victorian corridors still, I may be able to explain it in the time it takes to walk one of those, ah the days when we all got more exercise at work.

More than 90% (possibly as high as 99%) of cervical cancer is related to previous infection with human papillomavirus (HPV), also known as the wart viruses. HPV is a double-stranded DNA virus. Viral replication causes changes within cells which can sometimes lead to the cell becoming cancerous. Different types of HPV affect different tissues; some cause warts on hands, some cause warts on feet (verrucas) and some cause anogenital warts (with the slightly over the top medical term, condyloma acuminatum). There are more than 200 different types of HPV, many of which can cause cancer, including oropharyngeal, laryngeal cancer, and sometimes even skin cancers, however perhaps the best known link is to cervical cancer.