Infectious mononucleosis complicated by acute hepatitis and myocarditis: a response to corticosteroids
- 1Prince Philip Hospital, Respiratory Unit, Bryngwynmawr, Llanelli SA14 8QF, UK
- 2School of Medicine, University of Swansea, Swansea SA2 8PP, UK
- Robin Ghosal,
- Published 23 April 2009
Infectious mononucleosis, or glandular fever, is a viral illness which commonly affects young adults. Symptoms can vary from sore throat, enlarged lymph glands, lethargy and weight loss to more serious clinical manifestations such as myocarditis or hepatitis. Treatment is usually conservative although there has been significant debate over the role of oral corticosteroids, especially in more serious cases. Evidence based medicine suggests that there is little to no role for steroids, but there are enough published case reports where steroid therapy has been potentially life saving that the debate continues. We present a case of a fit and well man who had significant multi-organ involvement secondary to infectious mononucleosis, and our experience of oral corticosteroid treatment.
Infectious mononucleosis (IM), or glandular fever, is a systemic illness caused by viral infections. The Epstein–Barr virus (EBV) accounts for 90% of cases, but other organisms including cytomegalovirus, adenoviruses, hepatitis A, human immunodeficiency virus and Toxoplasma gondii have been reported.1–6 Differential diagnoses include leukaemia, malaria, and diphtheria.
IM occurs most often in persons aged 15–35 years with transmission through oral secretions and possibly by sexual contacts.1–6 Symptoms include sore throat, (tender) enlarged cervical glands, chills, arthralgia, weight loss, nausea, vomiting, anorexia, rash, and abdominal pain. Symptoms are often more severe in adults whereas children are often asymptomatic. Most cases are mild and self limiting with full recovery occurring over several weeks. Management is mainly supportive with bed rest, paracetamol and adequate fluid intake. More severe cases may develop systemic complications, which if untreated can result in significant long term morbidity or death.
A 20-year-old man was referred by his general practitioner to our medical assessment unit. He had felt tired for several weeks with acute worsening of severe malaise, sore throat, fever, rigors and jaundice, over the preceding 3 days associated with shortness of breath on limited exertion. He had no previous illnesses and was not prescribed medication. He smoked 20 cigarettes a day and drank alcohol socially. On examination, he looked unwell, was clinically dehydrated, pyrexial (temperature 39.1°C), jaundiced, had cervical lymphadenopathy and grossly enlarged palatine tonsils. There was no rash. Cardiovascular examination revealed a sinus tachycardia with gallop rhythm and a pan-systolic murmur over the left sternal edge. His blood pressure was 111/80 mm Hg. His chest was clear. He had mildly tender, moderate splenomegaly, but no hepatomegaly. There was no neurological deficit.
He had normal urea and electrolytes, a raised white cell count (28.3×109/l) with atypical lymphocytosis on blood film. His lymphocytes were 65% of the total leucocyte count. His alanine aminotransferase (ALT) was 418 U/L with an alkaline phosphatase (ALP) of 530 U/l and γ-glutamyl transferase (GGT) of 355 U/l (fig 1). He had a positive Monospot (based on heterophile antibody latex agglutination). An electrocardiogram confirmed a tachycardia with no other abnormalities, and a chest radiograph was normal. We made a clinical diagnosis of infectious mononucleosis and he was initially managed with supportive treatment with intravenous saline at 125 ml/h, analgesics and bed rest. An echocardiogram showed bright pericardial signals consistent with myocarditis as well as a dilated left ventricle with mildly reduced systolic function and mild mitral regurgitation, all consistent with borderline dilated cardiomyopathy. An abdominal ultrasound confirmed moderate splenomegaly (20 cm in long axis).
As the patient presented with symptoms of fever, sore throat and heart murmur, one may also consider acute rheumatic fever within the differential diagnosis. However, rheumatic fever usually occurs 2–3 weeks after a sore throat (group A streptococcal infection) and patients may have polyarthritis, subcutaneous nodules, erythema marginatum, Sydenham chorea and even fulminant heart failure.7,8
Our patient only developed a sore throat 3 days before admission and lacked these other diagnostic criteria for rheumatic fever. The presence of lymphadenopathy, splenomegaly and hepatitis as well as a positive monospot test (which is highly specific for IM), together with atypical lymphocytes on blood film, made the diagnosis of infectious mononucleosis much more likely.
OUTCOME AND FOLLOW-UP
The patient continued to be unwell over the next 4 days with persistent pyrexia, tachycardia, rising lymphocytosis (up to 20.7×109/l) and mildly worse biochemical hepatitis, so we started a 5 day reducing course of oral prednisolone (80 mg, 45 mg, 30 mg, 15 g then 5 mg). Within 24 h of starting steroids there was a notable clinical response, but biochemical improvement took another 2–3 days. He was discharged after 12 days.
Five weeks later, he was still 12 kg below his baseline weight but gaining. He was otherwise asymptomatic with no cardiac murmur and no palpable spleen. A repeat echocardiogram showed complete resolution with normal pericardial/myocardial signal and a normal size left ventricle and systolic function. His hepatitis and lymphocytosis had resolved biochemically but his spleen was still mildly enlarged at 14 cm on ultrasound. A viral screen was negative for hepatitis A–E and cytomegalovirus (CMV), indicating the IM was likely secondary to EBV.
The symptoms and signs of IM are non-specific so there is a wide differential diagnosis.
Although a mild thrombocytopenia, hepatitis and splenomegaly can occur in many viral illnesses, certain investigations can help differentiate IM from other systemic infections:
Atypical lymphocytosis—a higher percentage of atypical lymphocytes as a proportion of total leucocytes (or lymphocytes) is more strongly associated with IM. For example, >40% atypical lymphocytes is 100% specific to IM but has a sensitivity of only 25%.9 Therefore, to avoid cases being missed, Hoagland’s criteria10 recommend a diagnostic cut off of >10% atypical lymphocytes with an absolute lymphocyte count >50% which has 95% specificity and 61% sensitivity.9,10
Presence of heterophile antibodies that will react with horse erythrocytes (Monospot test). The test is 87% sensitive and 91% specific.9
Positive or rising titres of EBV antibodies.
The majority of cases are self limiting and require only supportive care. However, more severe cases may require hospital admission and may even need admission to intensive care.11
Role of oral corticosteroids
It has been suggested that steroid use should only be indicated in severe airway obstruction, neurological or haematological involvement such as aplastic anaemia, and immune thrombocytopenic purpura. A Cochrane Review looked at the randomised control trials (RCTs) performed to assess the efficacy and safety of steroid therapy for symptom control in infectious mononucleosis. Seven RCTs of varying qualities were included in the review, with the authors concluding that there was insufficient evidence to recommend steroid therapy for symptom control in IM.16
However, Fraisse et al describe a 13-month-old girl with IM and subsequent acute heart failure. An endomyocardial biopsy showed evidence of acute myocarditis and she had symptomatic improvement with corticosteroid treatment.13
In our case the patient remained unwell with rising lymphocytosis despite supportive treatment. In view of his multi-organ involvement and myocarditis, we started high dose steroids and the immediate clinical improvement suggests a beneficial effect, rather than natural disease resolution.
It is thought that EBV infects and replicates in the oropharyngeal epithelial cells and then infects B cells resulting in the spread of the virus by B cells through the lymphoreticular system. Infected B cells transform into plasmacytoid cells and secrete many immunoglobulins, including Ig G, A, and M, heterophile antibodies, antibodies to specific EBV antigens, and various autoantibodies. The infected B cells also cause massive activation and proliferation of cytotoxic T lymphocytes resulting in lymphoid hyperplasia.
Schuster et al performed a small study which showed higher concentrations of interferon γ (IFN-γ) and interleukin 6 (IL-6) in patients with acute EBV infection compared with those with chronic EBV associated disease.17 A further small prospective study showed the relationship between immune response and severity of IM. They found that patients with more severe clinical signs were found to have a more active cellular immune response, compared with mild disease.18
It is presumed that systemic glucocorticoids exert their beneficial effect by anti-inflammatory activity and reducing secondary cellular damage as well as dampening this higher cellular immune response. However, we postulate that the corticosteroids also inhibit cytokine release such as IL-6 and IFN-γ, reducing end organ damage such as myocarditis.
In terms of antiviral therapy for IM, a meta-analysis of five RCTs looking at acyclovir in the acute phase found that even though there was a trend towards the clinical effectiveness of acyclovir, it was not statistically significant.19
IM is usually a self limiting viral illness mainly caused by EBV. However, a small proportion of patients may develop serious complications. Corticosteroid treatment, especially for the cardiac complications, has been controversial but may be lifesaving. Our favourable outcome strengthens the argument for using systemic corticosteroids in selected patients with multi-organ involvement, including acute myocarditis.
Infectious mononucleosis can range from mild symptoms of lethargy and sore throat to more florid, dangerous multi-organ involvement.
Myocarditis is a rare but potentially fatal complication of infectious mononucleosis, although it predominantly occurs in children.
Although controversial, corticosteroid treatment may be potentially life-saving in the right clinical scenario such as a patient with acute myocarditis.
Competing interests: none.
Patient consent: Patient/guardian consent was obtained for publication