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Infectious Mononucleosis

  1. MA Epstein1,
  2. AB Rickinson2

Published Online: 15 FEB 2010

DOI: 10.1002/9780470015902.a0002318.pub2

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How to Cite

Epstein, M. and Rickinson, A. 2010. Infectious Mononucleosis. eLS.

Author Information

  1. 1

    University of Oxford, Oxford, UK

  2. 2

    University of Birmingham, Birmingham, UK

Publication History

  1. Published Online: 15 FEB 2010

Introduction

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading

Infectious mononucleosis (IM) was first defined by Sprunt and Evans in 1920. Although no infectious agent could be incriminated at the time, it was given its name because the clinical features suggested an infectious process and because of curious haematological changes with large numbers of atypical mononuclear cells, later to be identified as activated T lymphocytes, in the blood. It seems likely that some aspects of the condition had been touched on in several publications over the preceding 30 years, but grouped together with a number of disparate diseases under such names as Drüsenfieber, fièvre ganglionnaire or glandular fever. Even after the recognition of IM as a distinct entity, confusion over this nomenclature persisted for some time.

Apart from the lack of a known bacterial or viral cause during these early years, the enigma of IM was increased by the steady absence of evidence for epidemics or even case-to-case infection. Nevertheless, in 1955 epidemiological findings suggested that transmission seemed to be associated with buccal contact among young people. Hence the term ‘kissing disease’ came to be applied to IM, despite ignorance as to how kissing might aid transmission, since cases did not lead from one to another. It was a chance observation in a research laboratory in 1968 that pointed the way to an explanation.

Epstein–Barr virus (EBV), one of eight human herpesviruses now identified, had been discovered in London in 1964 during a sustained investigation into the causation of a then newly described and unusual cancer of children in Africa, Burkitt lymphoma. Samples of the virus had been made available for study to a number of laboratories and in one of these, the Henles’ laboratory in Philadelphia, sera from many different sources were being screened for antibodies to EBV in a search for further disease associations. There, a young female technician (E.H.) was using samples of her own serum as a negative control in the tests. During these studies she developed IM and, when she returned to work a few weeks later, her serum was found to have developed antibodies to EBV. This hint was rapidly followed up by the Henles, who drew on the resources of a serum bank collected over many years from students with IM at Yale University. It did not take long for the causal link between EBV and IM to be confirmed, and for the virus’ mode of spread, its peculiar epidemiology and the identity of its main target cell, the B lymphocyte, to be determined. See also Epstein–Barr Virus, Human Pathogenic Viruses, and Oncogenic Viruses

Pathophysiology

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading

General epidemiology of Epstein–Barr virus

EBV is a very ancient parasite of humans that has been in the human evolutionary tree for at least 40 million years, and as such has established a delicately balanced relationship with its host. Infection with the virus is extremely common in all human populations worldwide, with natural infection usually taking place in early childhood. In developing countries 99.9% of children are infected at 2–4 years of age, depending on geographical region (Figure 1). In contrast, in developed countries with high standards of living and good hygiene, a considerable number of individuals do not become infected as young children, with the percentage in each age cohort remaining free of infection as teenagers or young adults depending on socioeconomic status: the greater the affluence, the greater the percentage. Among the very rich as many as 50% may reach young adulthood without having been infected (Figure 1).

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Figure 1. Comparison of the ages at which individuals in different populations become infected with Epstein–Barr virus (EBV). In developing countries almost all children have acquired the virus by 2–4 years of age, depending on geographical region. In developed countries with high standards of living and hygiene, the time of infection is delayed for many individuals, more markedly among the affluent than the less well off. Among the very rich, as many as 50% may reach adolescence or young adulthood without having encountered the virus and will undergo delayed primary infection with a high risk that this will be accompanied by the symptoms of infectious mononucleosis.

When primary infection occurs in young children, it is very rarely accompanied by symptoms but always leads to the establishment of a lifelong, clinically silent, virus carrier state. This harmless childhood infection followed by virus persistence is, in evolutionary terms, the natural host–parasite relationship, and it appears that disease only results where the relationship is perturbed. Under normal circumstances, EBV persists throughout life as a latent infection in a few circulating B lymphocytes and as a low grade virus-productive infection somewhere in the mouth and/or pharynx, perhaps involving the salivary glands, and possibly also in the genital tract. In parallel, antibodies to the virus-coded foreign antigens are generated, together with virus-specific cytotoxic T lymphocytes which are able to destroy infected cells expressing such antigens. These immunological responses are maintained continuously to keep the lifelong EBV infection in check at a manageable level. See also Coevolution: Host–Parasite, and T Lymphocytes: Cytotoxic

The virus-productive component of the EBV carrier state leads to the shedding of infectious virus particles into the saliva in the mouth. Typically this occurs at low levels but may vary over time since, at any one time, some 10–20% of the virus carriers are found to be shedding in higher amounts. The identity of the productively infected cells remains uncertain, but they are likely to include latently infected B cells that have been activated into virus production while moving through the oropharynx, as well as certain epithelial cells within the oropharyngeal mucosa which become infected from such B cells. Though productively infected cells may themselves be shed into the throat, it is infectious virus particles released into the saliva which are the main means of passing on the infection.

Epstein–Barr virus as the cause of infectious mononucleosis

As described earlier, one perturbation of the natural host–parasite relationship comes about as a result of improved living standards. Thus the high levels of hygiene in developed countries cause a significant number of individuals to reach young adult life without having had a primary EBV infection; most of these will acquire the virus in the following 10–15 years (Figure 1). Although the majority of such delayed primary infections are symptom-free and in all other respects similar to infections in childhood, approximately 25–50% will be accompanied by symptoms that, in many but probably not all cases, are sufficiently severe to have them attend GP surgeries and be recognized as IM. Indeed the most severe cases of IM may present as acute admissions to hospital. This association between delayed primary infection and disease symptoms explains why IM is a disease of upper socioeconomic groups, why it is increasing in developed countries as prosperity spreads through society, and why it is still exceptionally rare in developing countries.

Similarly, the connection of IM with kissing among young people and the absence of epidemics or case-to-case transmission can also be understood. For, although IM patients continue to shed high levels of virus into the throat for some time after the resolution of disease symptoms, there are many healthy carriers who, at any one time, may also be high shedders and therefore just as capable of transmitting the infection to an as yet uninfected partner through kissing. This classic scenario appears to be exactly what happened to the technician E.H., who was originally uninfected with EBV (serum antibody-negative, ‘seronegative’) but acquired the virus, and hence antibodies to EBV, and suffered an attack of IM.

It is still not clear why children do not develop symptoms on primary EBV infection, whereas adolescents and young adults frequently become ill with IM when they meet the virus for the first time. One obvious possibility is that the dose of virus is likely to be different in the two situations. Children coming into contact with a virus-shedder's saliva do so via a small amount in airborne droplets or casually via some sucked object, and will therefore receive a markedly smaller dose than a young adult energetically kissing a shedder. Another possibility is that physiological differences in immunological responsiveness in the two age groups plays a role, with the more mature immune system of the young adult being more likely to mount the exuberant cellular responses that are associated with, and probably underpin, the disease process.

Pathological basis of infectious mononucleosis

There is increasing evidence that IM is an immunopathological disease; that is, the symptoms are caused not by the virus infection per se, but by the host's exaggerated immune response to that infection. EBV principally infects B lymphocytes and, during primary infection, drives these cells into proliferation by expressing a restricted set of viral genes, called the latent growth-transforming genes. Such latently infected growth transformed B cells spread around the body through lymphoid tissues, alerting the host immune system to the presence of the invading virus they carry. This can lead to an equally vigorous expansion of immune T cells, principally cytotoxic CD8+ T lymphocytes that are specific for EBV antigens and that are capable of killing virus-infected cells. It is this outpouring of both virus-infected B cells and virus-reactive T cells that accounts for the abnormal blood picture and for many of the other symptoms of IM. These include the swelling of tonsils and other lymphoid tissue of the mouth and pharynx, leading to a sore throat, and the frequent enlargement of the lymph glands, spleen and liver. In addition, the highly expanded virus-reactive T cells are a rich source of cytokines (immunological messenger molecules) that are shed locally and then generalize through blood circulation. At high levels, these are able to recruit more inflammatory cells and give rise to such general effects as fever and marked malaise. The resolution of clinical symptoms is associated with a normalization of the blood picture, reflecting the fact that the CD8+ T-cell response subsides as the expansion of infected B cells is brought under control. This leads to the life-long virus carrier state where a small number of latently infected B cells, in which virus gene expression is now largely switched off, and small numbers of virus-reactive CD8+ T cells, maintained as resting memory cells, remain detectable both in blood and lymphoid tissues. See also Antigen Recognition by T Lymphocytes

It is interesting that this whole sequence of events may also be set in motion when the infection is transmitted by latently infected B cells in blood rather than in the usual way by orally acquired infectious virus. Thus there are cases where blood transfusion or organ grafting from an infected (seropositive) donor to a previously uninfected (seronegative) recipient can lead to classical IM.

Frequency and Clinical Importance

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading

Accurate figures for the frequency of IM are difficult to arrive at because of the wide differences that occur between populations (developed versus developing countries) and within populations (depending on age and socioeconomic status). Nevertheless, in developed countries an annual incidence of approximately 5 per 10 000 population would appear to be a realistic estimate. But this modest rate greatly minimizes the importance of the condition for, if one considers just the characteristic age group of 15–25 years affected by IM, then rates 3 or 4 times higher are the norm, and within this age cohort itself the figures are even greater among the most socially privileged adolescents and young adults. Examples of this phenomenon have been provided by studies in the most expensive US universities, where half of all freshmen arrive without previous EBV infection and acquire delayed primary infection as students, with one in two of the latter group suffering an attack of IM. Although most cases of IM do indeed occur in the 15–25 age range, it should also be noted that the disease may develop rarely in children and the middle-aged, and very rarely even in the elderly.

The disease phase of IM is not usually long lasting (see later discussion). Nevertheless, convalescence tends to be slow and the condition is therefore a frequent cause of disruption for young people, often at a critical stage in their studies or training, with consequences that may significantly affect careers far into the future.

Major Clinical Features and Complications

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading

Symptoms

The onset of classical IM is usually preceded by several days of vague indisposition but may also appear abruptly. The first symptoms are sore throat, raised temperature with sweating, loss of appetite, headache and fatigue, accompanied by malaise quite out of proportion to these other complaints (Figure 2). The malaise is often described as a feeling of exhaustion or even prostration. A pink skin rash affects a small number of patients, but occurs as a drug reaction in the majority of those who have been given ampicillin as a bacterial antibiotic for the sore throat before the real diagnosis has been made. Swelling in the eye sockets may be noticed for a short time, and there may also be brief difficulty in swallowing (Figure 2). Very rarely the tonsils and back of the throat may become seriously swollen, with actual obstruction giving difficulty in breathing and inability to swallow food or fluids.

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Figure 2. Percentage of patients with infectious mononucleosis (IM) showing various clinical features during the course of the disease, and the timing and average duration of each.

Signs

The temperature is usually approximately 40°C during the day, but high levels and marked swings are uncommon. On examination, the fauces, back of the throat, soft palate and uvula are red and swollen and, in about half the patients, covered by a greyish exudate. General lymph gland enlargement is a typical feature 2–3 days after the onset of symptoms (Figure 2), and is most marked in the neck. The enlarged glands are bilaterally symmetrical, moveable under the skin and slightly tender. In most cases, an enlarged spleen can be felt (Figure 2) and in 15% the liver is also found to be larger than normal. The pulse rate is usually moderately decreased. Besides the pink skin rash, crops of small red spots are present on the palate in a third of cases, and slight jaundice can be detected in approximately 8% of cases (Figure 2). In older patients (>40 years) lymph gland swelling may only be moderate but liver enlargement tends to be more frequent.

Clinical course

A mild IM attack may resolve in days, but it is more usual for the disease to last for 2–3 weeks, followed by a period of lethargy before complete recovery. The duration of this phase of convalescence is influenced by psychological factors for, if patients are encouraged to resume normal activity as soon as sensible after symptoms subside, prompt recovery often ensues.

Minor complications may result from the usual symptoms of IM but readily subside as the disease resolves. However, rare, truly IM-related complications may be serious in nature and call for specific intervention (see later discussion). Secondary bacterial throat infections, traumatic rupture of the enlarged spleen, asphyxia from swelling in the throat, massive liver destruction, polyneuritis and autoimmune manifestations such as blood clotting disorders from destruction of platelets or anaemia from red blood cell destruction, have all been recorded. See also Platelets

Approximately 1 in 2000 patients may continue in a truly chronic state for months or even years, or suffer recurrent episodes of severe disease; also there are rare familial cases where IM can be rapidly fatal. But both situations arise only in very special circumstances (see the section on Very rare but serious complications). Such very rare patients are not to be confused with a growing number of individuals with ill-defined weariness often wrongly diagnosed as having ‘chronic IM’. In all probability these are manifestations of so-called chronic fatigue syndrome, myalgic encephalomyelopathy (ME) or yuppie disease. Whether these are true virus-associated entities rather than psychological disorders is controversial, but credible connections with EBV or with classical IM have not been established. See also Chronic Fatigue Syndrome

Very rare but serious complications

There are genuine cases of ‘chronic active EBV infection’ which develop very rarely following classical IM in young adults but the best documented follow primary EBV infection in children, particularly in South East Asia. The condition presents as persistent or recurrent acute IM-like symptoms, often progressing to a severe virus-associated haemophagocytic (destruction of blood cells) syndrome. Many of these cases are now known to arise from a very unusual circumstance, namely spread of the virus infection from its usual B lymphocyte reservoir into T lymphocytes or natural killer (NK) cells. These virus-infected T- or NK cells begin to proliferate and release cytokines, producing a highly exaggerated ‘cytokine storm’ that, among other things, activates macrophages and leads to haemophagocytosis.

Although the above ‘chronic active EBV infection’ syndrome is nonfamilial, a second severe consequence of primary EBV infection is seen in boys with an extremely rare, X-chromosome-linked immunodeficiency called the X-linked lymphoproliferative syndrome (XLP) or, originally, Duncan syndrome after an early family in which it was recognized. In XLP families, primary EBV infection of affected young males leads to an extremely severe IM characterized by excess lymphoproliferation, acute hepatitis and haemophagocytic syndrome. This often culminates in death within a few weeks from multisystem failure. The immune defect underlying XLP is complex but stems from a specific inability of both immune T- and NK cells to recognize and communicate with B cells. This explains why patients are unable to control EBV, a virus that predominantly infects B cells, yet are able to cope with other viruses that infect other cell types. Interestingly, when boys with the XLP trait first acquire EBV, they do make T- and NK-cell responses. However, these immune cells are unable to control the B-cell infection and are also unable to control their own numbers, therefore adding to the overall lymphoproliferation and exaggerating its consequences.

The fact that EBV infection is normally under T cell control means that the virus may also cause disease in individuals where this balance is perturbed by impaired T-cell function, for example organ graft recipients who receive immunosuppressive therapy designed to reduce the chance of graft rejection, and in patients with acquired immune deficiency syndrome (AIDS). In these circumstances, the initial widespread infection and proliferation of B lymphocytes at the start of IM may not be properly controlled, so that latently infected growth-transformed B lymphocytes are able to continue expansion. This can lead to a particular type of B lymphoproliferative lesion, often referred to as ‘posttransplantation lymphoproliferative disease’ which is fatal if not treated. See also Acquired Immune Deficiency Syndrome (AIDS), and Immunosuppression: Use in Transplantation

In the longer term, an attack of IM has been found to predispose a person to a 4-fold increased risk of developing another type of B lymphocyte-derived tumour with which EBV is implicated, Hodgkin lymphoma. In a large follow-up study of IM patients, most cases of this tumour arose within 5 years of acute IM and the majority of these tumours were EBV-positive, with the virus genome present in every tumour cell; for comparison, approximately 30–40% of Hodgkin lymphomas arising in the general population are likewise EBV genome-positive. Collectively, these findings suggest that the virus plays a role, together with as yet unidentified cofactors, in causing a significant proportion of Hodgkin lymphomas and that this role is facilitated when primary infection is symptomatic and presents as IM. The connection between the two diseases has been reinforced recently by the discovery that certain polymorphisms in the histocompatability antigen (HLA) locus that predispose to EBV-positive Hodgkin lymphoma likewise increase the chances of a delayed primary infection manifesting as IM. See also Hodgkin Disease

Differential diagnosis

Classical IM, especially in the characteristic 15–25-year-old age group, presents few diagnostic difficulties, and even slightly atypical cases at younger and older ages are not likely to be missed if the clinical picture is considered carefully. The occurrence together of fever, sore throat, headache, general lymph gland and spleen enlargement, along with marked fatigue, is enough to point clearly to the specific nature of the disease. If this is taken in conjunction with serological and haematological laboratory investigations (see later discussion), few doubts will remain. However, it should be remembered that an IM-like illness can be caused by primary infection with cytomegalovirus (another member of the Herpesviridae family) and by toxoplasma, but in both these conditions the sore throat is much less, and with the former the lymph gland enlargement is minimal or even absent. Similarly, at the time antiviral antibodies develop after recent infection with human inmmunodeficiency virus (HIV) a so-called seroconversion illness may present with fever, sore throat and enlarged lymph glands. See also Cytomegalovirus Infections in Humans, Herpesviruses (Human), and Toxoplasmosis

Management

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading

Laboratory diagnosis

During acute IM, antibodies to a large number of EBV-determined antigens are produced and appear in the serum in sequence as the disease progresses; however, after resolution of the disease, the spectrum of detectable antibodies gradually comes to resemble that which persists in virus carriers after silent primary infection of childhood. In the early stages of the disease, the presence of certain of these antibodies can be used to confirm the clinical findings. The key test detects antibodies of immunoglobulin M (IgM) class directed against the outer coat (capsid) of EBV particles: this type of antibody is the first to be elaborated and remains at least until the long-lasting IgG class antibodies are elicited a week or two later. Thus, the presence of IgM antibody to EBV capsid antigen indicates a very recent primary infection coinciding with the onset of disease, and provides a definitive diagnosis of IM. However, this immunofluorescent staining-based test is time-consuming and not widely available, so that other serological investigations are used routinely, such as commercial enzyme-linked immunoabsorbent assays (ELISAs) which are suitable for large-scale screening but lack sensitivity. See also Antibody Classes, Enzyme-linked Immunosorbent Assay, and Viral Capsids and Envelopes: Structure and Function

An altogether different type of serological test looks for the presence of unusual antibodies that are not specific for EBV antigens but are generated as part of the general immunological disturbance underlying IM. Such antibodies (called heterophil antibodies) cross-react with antigens found in mammals other than humans and are detected by the reliable commercial monospot test, which shows the ability of positive sera to clump sheep red blood cells in vitro. Although nonspecific, the heterophil antibody test is positive with approximately 85% of IM sera, but has the disadvantage that most monospot-negative cases are from outside the 15–25 age group and these atypical cases tend to pose most diagnostic difficulty. The test may also be positive in autoimmune diseases and pregnancy, irrespective of EBV infection. Where doubt exists, the test for IgM antibodies to EBV capsid antigen will resolve uncertainty.

An equally important diagnostic feature during IM is provided by the number and appearance of blood cells under light microscopy. At the start, there is a modest increase in the total white cell count (10–20×109 L−1, where normal at age 25 is approximately 7×109 L−1) owing to increased numbers of mononuclear cells, including many abnormal large forms (Figure 3) which may amount to more than 40% of the total. These changes increase in the second and third week, when the mononuclear cell count can rise well above 5×109 L−1.

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Figure 3. Photomicrographs of peripheral blood films stained by the Giemsa method (×40; insets ×100): (a) from a normal individual, showing four neutrophils (detail in upper inset) and one lymphocyte (arrow and lower inset) among a mass of red cells; (b) from a patient with infectious mononucleosis, showing numerous large atypical mononuclear cells (arrows and insets) in addition to the normal cells; though not illustrated here, when stained for differentiation markers these cells have the phenotype of activated CD8+ cytotoxic T cells. This figure was kindly provided by the late Professor DY Mason, Department of Haematology, John Radcliffe Hospital, Oxford, UK, to whom the authors are most grateful.

It is also sometimes useful to carry out liver function tests especially where the liver is enlarged and in older patients.

Treatment

Bed rest and analgesics such as aspirin or paracetamol for headache and sore throat are the only treatments required in uncomplicated IM. As soon as the fever resolves, patients should be encouraged to get up and resume some activities as fast as is practicable. Undue emphasis on rest has been shown to prolong convalescence and may lead to invalidism; however, violent exercise must be avoided for three weeks after an enlarged spleen ceases to be apparent.

Only complications call for active therapy: rupture of the spleen must be treated by immediate surgery; appropriate antibiotics should be given for bacterial infections; airway obstruction must be relieved by surgical opening of the trachea and corticosteroids should be administered for life-threatening swelling of the pharynx and for certain neurological and haematological disorders.

End Notes
  1. Based in part on the previous version of this Encyclopedia of Life Sciences (ELS) article, Infectious Mononucleosis by MA Epstein.

Glossary
Antigen

A substance capable of inducing a specific immune response.

Cytokines

Soluble mediators of immune responses released by activated lymphocytes.

Cytotoxic

Able to cause specific destruction of certain cells.

Fauces

The passage from the mouth to the pharynx.

Lymphatic system

The lymphatic vessels and lymphoid tissues.

Lymphoma

Cancer of lymphoid tissue.

Toxoplasma

A protozoan parasite causing a disease of animals and humans, transmitted from cats (the primary host).

Further Reading

  1. Top of page
  2. Introduction
  3. Pathophysiology
  4. Frequency and Clinical Importance
  5. Major Clinical Features and Complications
  6. Management
  7. Further Reading
  • Carter RL and Penman HG (eds) (1969) Infectious Mononucleosis. Oxford: Blackwell Scientific.
  • Diepstra A, Niens M, Vallenga E et al. (2005) Association with HLA class I in Epstein–Barr-virus-positive and with HLA class III in Epstein–Barr-virus-negative Hodgkin's Lymphoma. Lancet 365: 22162224.
  • Epstein MA and Achong BG (eds) (1979) The Epstein–Barr Virus. Berlin: Springer.
  • Hislop AD, Taylor GS, Sauce D and Rickinson AB (2007) Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annual Review of Immunology 25: 587617.
  • Hjalgrim H, Askling J, Rostgaard K et al. (2003) Characteristics of Hodgkin's Lymphoma after infectious mononucleosis. New England Journal of Medicine 349: 13241332.
  • Hoagland RJ (1955) The transmission of infectious mononucleosis. American Journal of Medical Science 229: 262272.
  • McAulay KA, Higgins CD, Macsween KF et al. (2007) HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. Journal of Clinical Investigation 117: 30423048.
  • Rickinson AB and Kieff E (2007) Epstein–Barr virus. In: Knipe DM and Howley PM (eds) Fields Virology, 5th edn, vol. 2, pp. 26802700. Philadelphia: Lippincott Williams and Wilkins.
  • Schlossberg D (ed.) (1989) Infectious Mononucleosis, 2nd edn. Berlin: Springer.
  • Sprunt TP and Evans FA (1920) Mononuclear leucocytosis in reaction to acute infections (‘infectious mononucleosis’). Bulletin of the Johns Hopkins Hospital 31: 410417.