The patient was in her early 20s and came to see her GP complaining of a sore throat, fever and pains in her neck. The GP examined the patient and found tender cervical lymphadenopathy and pustular tonsils. A diagnosis of tonsillitis was made and the patient was reassured that it was nothing serious whilst being given a course of Amoxicillin. Would you have given antibiotics and if so why?
The next day the patient rang the practice in a panic as she had a rapidly progressive rash. The GP was concerned about the significance of the rash and immediately arranged for the patient to be seen in the Emergency Department.
On arrival in hospital the patient did indeed have a wide spread erythematous rash and fever. Bloods were sent to the laboratory and she was started on IV Ceftriaxone as a precaution in case this was meningococcal sepsis. The blood results showed a high lymphocyte count, abnormal mononuclear cells and raised liver enzymes.
The next day the patient rang the practice in a panic as she had a rapidly progressive rash. The GP was concerned about the significance of the rash and immediately arranged for the patient to be seen in the Emergency Department.
On arrival in hospital the patient did indeed have a wide spread erythematous rash and fever. Bloods were sent to the laboratory and she was started on IV Ceftriaxone as a precaution in case this was meningococcal sepsis. The blood results showed a high lymphocyte count, abnormal mononuclear cells and raised liver enzymes.
The Emergency Department doctor rang the Microbiologist asking whether this might be Hepatitis and what antibiotics should be given? It was not the response the Emergency doctor was expecting…“hum OK, good news your patient doesn’t have hepatitis A, B or C nor septicaemia, but they almost certainly have glandular fever”. Would you have considered this? It may sound mundane but it’s actually a clever diagnosis to make and the Amoxicillin is relevant! Read on…
What is glandular fever?
Glandular fever was the term used in the late 1800s to describe the combination of fever, pharyngitis and lymphadenopathy in patients. The name changed to its proper medical name, infectious mononucleosis (IM), when microscopes allowed doctors to see the high numbers of lymphocytes and atypical mononuclear cells in peripheral blood.
What causes IM?
The main causative microorganism is the Herpes virus Epstein-Barr Virus (EBV). Apparently the link to EBV in IM was made when a laboratory worker managed to infect themselves with the EBV they were working on and developed IM! Whoops, infection control issues!
Although IM is most commonly caused by EBV, EBV infection does not always cause IM, it can be asymptomatic or just a mild febrile illness especially in early childhood. The severity of EBV infection appears to increase the later it is acquired, adults are more likely to get IM than children, probably as a result of a more intense immune response. EBV infection is often described as a “kissing contacts” disease as it is usually spread in saliva and through close contact. It is not particularly contagious but patients with EBV can continue to shed virus from the upper respiratory tract for up to 18 months and that’s a lot of time to share kisses (and EBV) especially if you are a teenager.
What is glandular fever?
Glandular fever was the term used in the late 1800s to describe the combination of fever, pharyngitis and lymphadenopathy in patients. The name changed to its proper medical name, infectious mononucleosis (IM), when microscopes allowed doctors to see the high numbers of lymphocytes and atypical mononuclear cells in peripheral blood.
What causes IM?
The main causative microorganism is the Herpes virus Epstein-Barr Virus (EBV). Apparently the link to EBV in IM was made when a laboratory worker managed to infect themselves with the EBV they were working on and developed IM! Whoops, infection control issues!
Although IM is most commonly caused by EBV, EBV infection does not always cause IM, it can be asymptomatic or just a mild febrile illness especially in early childhood. The severity of EBV infection appears to increase the later it is acquired, adults are more likely to get IM than children, probably as a result of a more intense immune response. EBV infection is often described as a “kissing contacts” disease as it is usually spread in saliva and through close contact. It is not particularly contagious but patients with EBV can continue to shed virus from the upper respiratory tract for up to 18 months and that’s a lot of time to share kisses (and EBV) especially if you are a teenager.
Once EBV has been acquired it enters the B lymphocytes which then spread it around the lymphoreticular system and are responsible for the high lymphocyte count. The incubation period is approximately 4-8 weeks. The B lymphocytes produce both viral specific antibodies and also heterophile antibodies. These heterophile antibodies can be extracted from the patient’s blood and tested for in a laboratory.
In order to fight the infection the body starts to produce specific cytotoxic T lymphocytes which appear as atypical mononuclear cells in peripheral blood usually a week or more after the onset of symptoms. These atypical mononuclear cells are what give glandular fever its name, Infectious Mononucleosis.
How does IM present?
The typical clinical features of IM are:
Most of the symptoms resolve within a month of illness but fatigue can persist for up to 6 months in over 10% of patients. There are clinical studies that show objective evidence that persistence of fatigue is more common in young female university students compared to any other group but no one knows why.
It is also quite common for patients with IM to develop a maculopapular rash and this is especially the case if the patient is inadvertently treated with a Beta-lactam antibiotic such as Ampicillin or Amoxicillin, as happened with the patient above. The cause of this harmless rash, which can last for up to 3 weeks, is unknown but has been described in up to 70-90% of IM patients given either of these two antibiotics.
Some patients with IM do not have the pharyngitis; these patients also do not have the heterophile antibodies described above. This is sometimes referred to as the “typhoidal form” of IM but the correct term is “heterophile-negative IM”. It makes the diagnosis more difficult, however the treatment and outcome is the same.
How do I diagnose IM?
The diagnosis of IM is strongly suggested by the combination of fever, pharyngitis and lymphadenopathy in a patient with a lymphocytosis and a positive heterophile antibody test.
The heterophile antibody test, e.g. the Paul-Bunnell test or the Monospot test, uses sheep or horse blood to detect the presence of heterophile antibodies in peripheral blood and when combined with the classic triad of symptoms is enough to confirm the diagnosis of IM. These tests tend to be done in haematology laboratories rather than microbiology laboratories even though the tests are detecting an infection.
Heterophile antibody tests can be falsely negative, especially early on the in the infection where the false negative rate is 25% in week 1 decreasing to 5% in week 3. In this case more specific EBV antibody tests can be done. This is also the way to diagnose EBV infection in those patients without pharyngitis who have “heterophile-negative IM”. In this situation a number of EBV antibodies are tested looking for evidence of acute or past infection; IgM and IgG against viral capsid antigen (VCA) and IgG against Epstein-Barr nuclear antigen (EBNA). VCA IgM and IgG are usually present at the onset of symptoms and IgM starts to disappear after 3 months whilst IgG persists for life. EBNA IgG starts to appear 6-12 weeks after onset of symptoms when the virus begins to become latent.
The laboratory report may look like alphabet soup, but the combination of results can be interpreted as follows:
In order to fight the infection the body starts to produce specific cytotoxic T lymphocytes which appear as atypical mononuclear cells in peripheral blood usually a week or more after the onset of symptoms. These atypical mononuclear cells are what give glandular fever its name, Infectious Mononucleosis.
How does IM present?
The typical clinical features of IM are:
- Fever
- Pharyngitis mimicking streptococcal tonsillitis
- Lymphadenopathy (especially symmetrical posterior cervical lymphadenopathy which occurs in all patients hence the name glandular fever)
- Fatigue
- Atypical lymphocytosis and mononuclear cells
Most of the symptoms resolve within a month of illness but fatigue can persist for up to 6 months in over 10% of patients. There are clinical studies that show objective evidence that persistence of fatigue is more common in young female university students compared to any other group but no one knows why.
It is also quite common for patients with IM to develop a maculopapular rash and this is especially the case if the patient is inadvertently treated with a Beta-lactam antibiotic such as Ampicillin or Amoxicillin, as happened with the patient above. The cause of this harmless rash, which can last for up to 3 weeks, is unknown but has been described in up to 70-90% of IM patients given either of these two antibiotics.
Some patients with IM do not have the pharyngitis; these patients also do not have the heterophile antibodies described above. This is sometimes referred to as the “typhoidal form” of IM but the correct term is “heterophile-negative IM”. It makes the diagnosis more difficult, however the treatment and outcome is the same.
How do I diagnose IM?
The diagnosis of IM is strongly suggested by the combination of fever, pharyngitis and lymphadenopathy in a patient with a lymphocytosis and a positive heterophile antibody test.
The heterophile antibody test, e.g. the Paul-Bunnell test or the Monospot test, uses sheep or horse blood to detect the presence of heterophile antibodies in peripheral blood and when combined with the classic triad of symptoms is enough to confirm the diagnosis of IM. These tests tend to be done in haematology laboratories rather than microbiology laboratories even though the tests are detecting an infection.
Heterophile antibody tests can be falsely negative, especially early on the in the infection where the false negative rate is 25% in week 1 decreasing to 5% in week 3. In this case more specific EBV antibody tests can be done. This is also the way to diagnose EBV infection in those patients without pharyngitis who have “heterophile-negative IM”. In this situation a number of EBV antibodies are tested looking for evidence of acute or past infection; IgM and IgG against viral capsid antigen (VCA) and IgG against Epstein-Barr nuclear antigen (EBNA). VCA IgM and IgG are usually present at the onset of symptoms and IgM starts to disappear after 3 months whilst IgG persists for life. EBNA IgG starts to appear 6-12 weeks after onset of symptoms when the virus begins to become latent.
The laboratory report may look like alphabet soup, but the combination of results can be interpreted as follows:
Click for larger image
What is the treatment of IM?
There is no specific treatment of IM but supportive care can be given with Paracetamol or Ibuprofen for fever and the patient encouraged to keep hydrated.
Complications of IM
There are a number of complications that can occur with IM, the most common of which include:
Can any other microorganisms cause IM?
A number of different microorganisms can cause a similar clinical illness to EBV including Cytomegalovirus (CMV), Human Immunodeficiency Virus (HIV) and Toxoplasma gondii. The most common of these is CMV as it tends to occur in the same “kissing contacts” as EBV.
CMV can be difficult to distinguish from EBV. The most common difference is that fever is more predominant with CMV and cervical lymphadenopathy and splenomegaly are more common with EBV. Pharyngitis is usually much milder in CMV but hepatitis more severe. CMV infection can be confirmed by the presence of IgM antibodies directed against CMV.
So the patients Amoxicillin was stopped and she was reassured that all should be fine. A Monospot test confirmed that she had infectious mononucleosis (glandular fever). She was allowed to go home but warned about the need to seek medical attention if she developed abdominal pain, and to refrain from sports for the next 4 weeks. She was also told that the reaction to Amoxicillin was not an allergic reaction but due to the combination of antibiotic and the virus which caused the rash and that she was safe to have penicillin in the future… For reference, I wouldn’t have given antibiotics at the initial consultation. I would have taken a throat swab and if that grew Group A Beta-haemolytic Streptococcus then I would have given Penicillin, to prevent any post-streptococcal complications e.g. rheumatic heart disease, as it has a narrower spectrum than Amoxicillin.
There is no specific treatment of IM but supportive care can be given with Paracetamol or Ibuprofen for fever and the patient encouraged to keep hydrated.
Complications of IM
There are a number of complications that can occur with IM, the most common of which include:
- Splenomegaly – occurs in 50-60% patients and lasts for up to 3 weeks
- Splenic rupture – occurs spontaneously in 1-2 per 1000 patients within the first 3 weeks and is life-threatening; it can also occur as a result of minor abdominal trauma during sport and therefore sports should be avoided until 4 weeks after the onset of symptoms
- Neurological symptoms e.g. Guillain-Barre syndrome, nerve palsies, meningoencephalitis, transverse myelitis, encephalomyelitis
- Hepatitis – nearly all patients have raised AST and ALT and some develop jaundice
- Reactivation – EBV as a Herpes Virus remains in the body and becomes latent; it is able to reactivate and cause further infections if the patient becomes immunosuppressed
- Hodgkin’s Lymphoma – this haematological malignancy is probably the most feared complication but it is not common and could be a blog in its own right… watch this space…
Can any other microorganisms cause IM?
A number of different microorganisms can cause a similar clinical illness to EBV including Cytomegalovirus (CMV), Human Immunodeficiency Virus (HIV) and Toxoplasma gondii. The most common of these is CMV as it tends to occur in the same “kissing contacts” as EBV.
CMV can be difficult to distinguish from EBV. The most common difference is that fever is more predominant with CMV and cervical lymphadenopathy and splenomegaly are more common with EBV. Pharyngitis is usually much milder in CMV but hepatitis more severe. CMV infection can be confirmed by the presence of IgM antibodies directed against CMV.
So the patients Amoxicillin was stopped and she was reassured that all should be fine. A Monospot test confirmed that she had infectious mononucleosis (glandular fever). She was allowed to go home but warned about the need to seek medical attention if she developed abdominal pain, and to refrain from sports for the next 4 weeks. She was also told that the reaction to Amoxicillin was not an allergic reaction but due to the combination of antibiotic and the virus which caused the rash and that she was safe to have penicillin in the future… For reference, I wouldn’t have given antibiotics at the initial consultation. I would have taken a throat swab and if that grew Group A Beta-haemolytic Streptococcus then I would have given Penicillin, to prevent any post-streptococcal complications e.g. rheumatic heart disease, as it has a narrower spectrum than Amoxicillin.
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