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.
“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:
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:
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!
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.
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:
History of prodromal coryzal or respiratory illness:
No history of exposure:
2nd line testing if first line negative and infectious cause still suspected:
3rd line testing if first and second line negative and infectious cause still suspected:
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.
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:
- Whole blood (EDTA sample) for Parvovirus B19, HHV6 and Adenovirus PCR
- Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG
- Viral Throat swab for enteroviral (Coxsackievirus and Echovirus) and Adenovirus PCR
- Stool for enteroviral (Coxsackievirus and Echovirus) PCR
History of prodromal coryzal or respiratory illness:
- Viral Throat swab for enteroviral (Coxsackievirus and Echovirus), Influenza A and B and Adenovirus PCR
- Stool for enteroviral (Coxsackievirus and Echovirus) PCR
No history of exposure:
- Whole blood (EDTA sample) for Parvovirus B19 and HHV6 PCR
- Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG and HIV
- Viral Throat swab for enteroviral (Coxsackievirus and Echovirus) PCR
- Stool for enteroviral (Coxsackievirus and Echovirus) PCR
2nd line testing if first line negative and infectious cause still suspected:
- Whole blood (EDTA sample) for Parvovirus B19, HHV6 and Adenovirus PCR if not already done
- Serum (red or gold top vacutainer) for Parvovirus B19 IgM and IgG if not already done
- Serum for HIV if not already done
3rd line testing if first and second line negative and infectious cause still suspected:
- Whole blood for Cytomegalovirus and Epstein-Barr Virus PCR
- 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….
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