Infectious Mononucleosis (the kissing disease) caused by EBV

What is Infectious Mononucleosis? What causes it?

Infectious Mononucleosis or simply ‘Infectious Mono’ is caused by the Epstein-Barr-Virus (EBV). One of the characteristic findings in the lab tests done when a patient has this infection is an increase in the number of lymphocytes, specifically monocytes, and that is where the name originates from.
The term “kissing disease” was brought about, most probably, because of the most common mode of transmission of disease, which is through contact with an infected person’s saliva (read more about this below).
The name ‘mononucleosis’ refers to the clinical syndrome that includes fever, weakness, enlargement of lymph nodes, enlargement of liver and spleen, abdominal pain, etc. Therefore, sometimes you will hear of other viruses that can cause this syndrome, such as cytomegalovirus (or CMV), and a few others.
In this chapter I will stick to discussing the classic virus – EBV.

How is EBV transmitted?

The mode of transmission from one person to the other is through contaminated saliva, and this doesn’t necessarily have to occur through kissing (it’s important not to embarrass the child or teenager when mentioning this, I always try to emphasize that the mode of transmission doesn’t necessarily entail kissing).
After a person gets EBV for the first time, they will secrete this virus in their saliva for a lengthy period of time, long after the symptoms have resolved and so the transmission of the disease is very common.
Of note, the virus often starts getting secreted in saliva before the clinical symptoms appear.
Since EBV belongs to the herpes family of viruses, we know that similarly to other members of this family, after a person is infected for their first time, the virus remains latent in the body almost forever, and sometimes it will reappear in our saliva without any clear trigger, even if we are completely asymptomatic. About 20-30% of healthy people that have had EBV in the past secrete this virus in their saliva.
And so, the transmission of this infection from one person to the other is very common and this explains why the virus spreads easily and is common all around the world.

What ages do people usually get infected with EBV and how common is the disease?

Generally speaking, one can say that the higher the socioeconomic status, the less crowded the conditions of living, and the more hygiene there is, the later in life will the transmission of the infection occur. And therefore, in Africa most children will get it at a very young age and in other places in the world the transmission will occur at a later stage in life.
In North America, as about 50% of teenagers are still unaffected in their teen years, we tend to see two peaks of infection – one in childhood and the other in college students.
Why is this information important? You’ll see below.

Is there an association between the age of transmission and the clinical manifestation of the infection?

Yes.
In childhood, the infection tends to be mild and children will often be asymptomatic.
Infection in adolescence may cause, in about half of the cases, the classic syndrome that we will be discussing below, which includes fever, a sore throat, fatigue and enlarged lymph nodes.
Again, this is just the majority of cases and sometimes you’ll get little kids with the unpleasant EBV symptoms and older teenagers with mild disease.

How long is the incubation period of EBV?

In teenagers, the length of the incubation period is 30-50 days, approximately 6 weeks. That means that if you are trying to figure out where you contracted the disease, track down the people who you interacted with 6 weeks ago, and not the person who was ill last week.
In younger children, the incubation period is shorter.

What are the signs and symptoms of Infectious Mononucleosis that is caused by EBV?

Similarly to many other diseases in pediatrics, it depends on the age of the child.
Infants and younger children are often asymptomatic. Sometimes they will have fever for a few days and a throat infection with tonsillar exudates.
In older children and adolescents – you are more likely to see the “classic” manifestations of the disease that include prolonged fever, fatigue, headache, sore throat, abdominal pain, nausea, muscle pain and pretty much everything and anything. A physical examination performed by a physician will often reveal tonsillar exudates and enlarged lymph nodes, especially in the neck area. The spleen too, which is found on the left side of the upper abdomen, will be enlarged and sometimes the liver, as well (found in the right upper part of the abdomen).
Another sign, that can be seen sometimes, is swelling of the eyelids, called Hoagland sign (read more here), but this isn’t very common.

Does EBV cause any specific rashes?

There are several different rashes that can be seen with EBV infection.
In about 15% of cases there will be a non-specific rash, as part of the infection.
Sometimes, children will develop a rash called “Gianotti-Crosti”which is characterized by symmetric red papules (small, solid, raised bumps on the skin), seen particularly on the bottom and lower limbs.
A third possible rash that could appear is one that is seen in children who have EBV and have received an antibiotic from the penicillin family.

What happens to children who have EBV and receive penicillin?

In the past, when penicillin was sold as pure penicillin, about 75% of children with EBV would get a very nasty rash. This is also the reason behind why a lot of adults think that they have an allergy to penicillin, when in reality the reason they developed a rash was because they received penicillin when they had EBV, and this reaction is not considered an allergic reaction.
Today, since Amoxicillin became the commonly prescribed antibiotics, the rates of rash seen have decreased.

How do doctors diagnose Infectious Mononucleosis?

The diagnosis is a combination of both clinical findings and laboratory tests.
Often, I see adolescents at my office who have been on antibiotics for over 48 hours and are still suffering from a sore throat full of exudates and pus. Cases like this, the clinical diagnosis is easy and clear.
Other important findings in the physical examination that help with the diagnosis are an enlarged spleen and liver. As mentioned, the lab tests may demonstrate some subtle changes that are non-specific but may point towards an EBV infection.
If you want to make a clear diagnosis, you can do so using serology testing (more about this below).

Is it possible to differentiate between a throat infection caused by EBV and one caused by streptococcus?

The truth is that it isn’t. The doctor may be able to suspect that this is EBV and not Strep throat if there are other accompanying signs and symptoms, but even the best of doctors are unable to identify the pathogen that caused the throat infection just by looking at a sore throat.
This is why a lot of children who have infectious mononucleosis are given unnecessary antibiotics.
I hope that throat swabs are being taken prior to the start of antibiotics, as I mentioned in the post about strep throat (link here), so that if the throat swab comes back negative, we realize that the cause of the throat infection is probably EBV and the antibiotic can be stopped.

What do we normally see in the lab tests of children with EBV?

Of course, not every child with EBV needs bloodwork but if they have already been done – what should we be expecting?
Again, in young children, we tend to see some non-specific findings.
On the other hand, adolescents with EBV will have lots of characteristic findings in their bloodwork, including: a white cell count with increased levels of monocytes or atypical lymphocytes. You can read more about complete blood counts (CBC) here.
Sometimes you will also see low platelet counts.
The biochemistry panel will reveal increased liver enzymes (hepatitis).

What are the antibodies that can be tested when EBV is suspected?

A clear-cut diagnosis of EBV is set with the help of a combination of the following tests.
But before we start, let me put in a reminder of the types of antibodies that are usually checked in infectious diseases and the details that you will see in the lab tests.
IgM – this is an antibody that rises quickly, as soon as the infection starts, and remains high for about 1-3 months after the onset of infection. It disappears afterwards.
IgG – an antibody that rises more slowly than IgM but remains high throughout life.

So which antibodies do we test for in EBV?
The Monospot Test – this is for advanced readers only. It is an old test that is not regularly done anymore nowadays, especially not in community labs, but it can be very helpful when used correctly in the hospital setting. This test looks for IgM antibodies that cause red blood cells, belonging to mammals, to undergo agglutination. This test is positive in 90% of the mononucleosis cases in teenagers, during their second week of illness, and in a smaller percentage of younger children.
Antibodies against the antigen found on the virus’ capsule (the Viral Capsid Antigen, or VCA). There are two types of VCA antibodies: IgM and IgG and these follow the pattern of that I mentioned above.
EBNA is another important antibody produced against the nuclear antigen. There is only one type of EBNA antibody and it is the IgG that appears about 3-4 months after a person with a competent immune system contracts the virus, and it remains high for life. So, if you are looking over serology testing and find that the EBNA is high, it can help you tell that the infection was not recent.

Now I have 3 important points I would like to mention for those of you trying to figure out their child’s EBV status by looking at their serology tests:
#Number 1 – a single test, performed at any time, can aid with confirmation of suspected infectious mononucleosis, but we are more likely to make a certain diagnosis after performing two tests, several weeks apart.
For example, take a college student who has tonsillar exudates, an enlarged spleen and a clinical picture consistent with infectious mononucleosis. If his serology tests positive for VCA IgM but negative for VCA IgG and negative for EBNA, one can assume he has contracted EBV. But only by repeating this test 4 weeks later and finding an increased VCA IgG and a decreased IgM are we able to confirm the diagnosis.

#Number 2 – sometimes, when other pathogens circulate our blood, our antibodies can get mixed up and produce a false positive result. Take the following as an example – Bob has a sore throat and his pediatrician thinks it was caused by EBV. His blood tests reveal that his IgM, IgG and EBNA are all positive. These results don’t make sense. As I mentioned, if EBNA is positive, the infection cannot be current. In practice, the reason behind false positive results is usually because a different pathogen in the blood caused a cross-reaction and the IgM antibody to rise. This happens quite often with the CMV virus.

#Number 3 – one more important point about the antibodies found in our blood following an EBV infection. Some people may develop different serological reactions to the virus. Sometimes, I see patients whose IgM was never high and other times I’ll see patients with persistently high IgM. Decoding serological tests can be a real art and it is useful to consult with an infectious disease specialist.

Are there other ways to confirm an EBV infection?

Yes, at hospitals we can use PCR tests. If a person tests positive for EBV PCR, and their serology is negative for a past infection, then a current EBV infection can be confirmed. Despite this, PCR tests are not useful in patients who are not immune-suppressed and in non-hospital settings.

What are the complications of infectious mononucleosis?

First of all, the symptoms of the disease itself, are unpleasant, especially in teenagers and elders.
Sometimes, the symptoms can last for several weeks and include fever and significant fatigue. In are cases, the primary infection can be followed by chronic fatigue.
However, I have seen hundreds of kids and adults with infectious mononucleosis due to EBV infection and I must say that only very few of them had symptoms that lasted for several months.
Therefore, even if the doctor diagnoses you or your child with infectious mononucleosis, do not lose your mind. In 99% of the cases the acute infectious will be mild and resolve quickly and the child or teenager will recover fast.
Furthermore, in very young children, it is usually a mild disease, and they are often only incidentally diagnosed or diagnosed after the child has already recovered.
But anyway, I should still mention the other complications. These include enlarged lymph nodes and tonsils to the extent that the airway may be compromised – this happens in about 5% of the cases. Another one is the ‘Alice in Wonderland’ syndrome – children that think their father’s beard is expanding or that their dog looks huge. This is odd but it happens sometimes, and it resolves too.
Several other rare complications include splenic rupture, hemolytic anemia, cardiac involvement, pneumonia and more.
In children with congenital or acquired immunodeficiencies, EBV can cause a long and complicated infection.

What about the risk of cancer?

There are certain types of cancers in which EBV seems to play a role. Despite this, they are very rare cancers, especially in developed countries (they are more common in Africa and are associated with recurrent malarial infections).

Is there an association between EBV infections and multiple sclerosis?

It seems like there may be an association between EBV infection and multiple sclerosis, but the association is not clear-cut. You can read more of this association in this link.
Most people who get EBV (about 90% of the general population), will not get multiple sclerosis, and on the other hand some people who have multiple sclerosis have never had EBV.
We really need to see what the research looking at this association reveals in the near future, in order to get a better understanding of this correlation.

Can infectious mononucleosis be treated?

The short answer is no.
The mid-length answer is – supportive treatment. This means rest, fever-reducing medications, painkillers and prevention of dehydration.
The longer answer is – there can be some medications that can be helpful. What do I mean? We can offer relief to two specific symptoms.
Sometimes adolescents with EBV develop secondary tonsillar bacterial infections called necrotizing tonsillitis. Their tonsils provide a warm hub for bacteria and this can cause secondary infections. Adolescents will present with greenish/greyish and very stinky exudates (due to the involvement of anerobic bacteria that reside in our oral cavities). In such situations, that are quite rare I must say, we offer a short course of Clindamycin antibiotics for relief. This antibiotic is not from the penicillin family and so will not cause the rash I mentioned earlier. Read more of necrotizing tonsillitis here.
Another medication is a short course of steroids in cases of enlarged tonsils that may threaten the airway. The steroids cause the tonsils to shrink rapidly and by doing so, provide the child/teenager relief.

Are there any further recommendations for children with infectious mononucleosis?

This is very important! I know that when ill most people want to rest and relax in bed. But as soon as the child shows signs of improvement, I encourage them to get out of bed and try to get back to normal activity as soon as possible. If a teenager stays in bed for more than two weeks it becomes very difficult for them to get back to their regular activities.
On the other hand, due to the risk of rare complications such as splenic rupture, it is important to avoid physical activities that entail hand-to-hand combat or high intensity athletics for a period of several weeks after resolution of symptoms, or for as long as the spleen remains enlarged.

So how shall we summarize this post? I don’t know why it took me 3 years to write a post about a subject that is so close to my heart. But better late than never.
I hope you’ve learned a little bit about EBV and the infection, how to diagnose it and some of the tricks that might help you get through this illness in an easier fashion.