Infectious mononucleosis is an acute disease with symptoms including prolonged fatigue, fever, pharyngitis, and lymphadenopathy. It occurs in most cases from the Epstein-Barr virus (EBV), depending primarily on the age and immune status of the patient. It can be caused by cytomegalovirus (CMV) particularly in sexually active young adults. In the case of CMV mononucleosis, pharyngitis and lymphadenopathy are uncommon. In both EBV and CMV mononucleosis, myalgia headaches and splenomegaly are common.

Approximately 50% of children have experienced primary infection with EBV before age 5; in most of these cases, it does not manifest clinically. In underdeveloped countries, the rate of asymptomatic infection in early childhood may be as high as 90%. In adolescents and adults, primary EBV infection is recognized as infectious mononucleosis in 30% to 70% of cases. This results in an incidence for the acute syndrome of about 45 per 100,000, whereas approximately 90% of the adult population exhibits serologic evidence of prior infection.

Infectious mononucleosis was first described in 1920; however, the Epstein-Barr virus was not recognized as the causative agent until 1968. The prevalence of the disease has increased with improved sanitation, as primary EBV infection may be postponed until an age at which it is more likely to manifest clinically.

The Epstein-Barr virus is a ubiquitous member of the family Herpesviridae. It initially replicates in the epithelial cells of the oropharynx and then infects B lymphocytes, allowing systemic spread via the bloodstream. The virus remains within the host for life and may be detected in the saliva of between 15% and 25% of healthy seropositive adults.

The most common transmission mode is exposure to infected saliva. In adolescents and adults, this often occurs via oropharyngeal contact (e.g., kissing) between an uninfected individual and an asymptomatic infected individual. Only about 5% of infectious mononucleosis patients have had recent contact with someone exhibiting the clinical syndrome. Transmission may also occur through exposure to infected blood products. The incubation period is 30 to 50 days.

• Age: The incidence of infectious mononucleosis peaks in later adolescence, ages 15 to19 (345 to 671 per 100,000). After age 35, the rate is only 2 to 4 per 100,000.
• Socioeconomic status: Early childhood EBV infection, generally asymptomatic, is nearly universal under crowded conditions. Therefore, infectious mononucleosis is more frequent among higher socioeconomic groups.
• Diminished immune function
• Blood transfusion; bone marrow transplantation
• Immunosuppression

• Fever: usually peaking late in the day; generally low grade
• Pharyngitis: often severe
• Lymphadenopathy: usually symmetric, most often in anterior and posterior cervical nodes
• Fatigue: begins a few days to a week prior to other symptoms, maximal in first 2 to 3 weeks, can last a number of months.
• Tonsillitis: with enlargement and exudates; may obstruct airway
• Splenomegaly: in about 50% of cases; maximal during second and third week; palpable just below left costal margin
• Hepatomegaly: generally mild, sometimes with hepatic percussion tenderness
• Macular erythematous rash: sometimes seen in patients misdiagnosed with streptococcal pharyngitis and treated with ampicillin
• Headache
• Abdominal pain: may be sign of splenic rupture and should be addressed with high level of suspicion ( see section entitled Complications/Sequelae for additional information)
• Nausea and vomiting

• Bacterial pharyngitis or tonsillitis, especially "strep throat"
• Heterophile negative infectious mononucleosis (e.g., cytomegalovirus)
• Toxoplasmosis
• Infectious hepatitis
• Rubella
• Influenza
• HIV infection
• Drug reaction
• Lymphoma
• Leukemia

Evaluate for cardinal symptoms: fever, pharyngitis and lymphadenopathy, especially in anterior and posterior cervical nodes. Patients over age 40 are significantly less likely to exhibit pharyngitis and lymphadenopathy, but more likely to present with prolonged fever and fatigue. Hepatomegaly and/or splenomegaly may be palpable.

Laboratory Findings

• WBC: Mild leukocytosis observed in most patients. Heterogeneous atypical lymphocytes generally account for 10% of the WBC's.
• LFTs: Serum transaminases and alkaline phosphatase levels usually elevated, serum bilirubin elevated in 40% of patients.
• Heterophile antibodies: Positive in 40 to 90% of infectious mononucleosis patients. Suspected false-negatives should be tested for EBV-specific antibodies and/or repeat heterophile tests later in the disease process when it is more likely to be positive. Usually absent in children under 5 years old and the elderly.
• CBC to check for anemia (which may be hemolytic) and thrombocytopenia

Transient immunologic abnormalities can occur

• Cryoglobulins
• Rheumatoid factors
• Cold agglutinins
• ANA (antinuclear antibody)

Infectious mononucleosis is generally self-limiting, and standard treatment is mainly supportive. Patients should rest during the acute phase and then mobilize as the symptoms abate, generally after about 2 weeks. Contact sports and heavy lifting should be avoided for 2 months due to the risk of splenic rupture, regardless of whether splenomegaly is detected.

• Acetaminophen: As analgesic and antipyretic. Avoid aspirin due to the rare association between EBV and Reye's syndrome, more common when taken with influenza or varicella viruses in children
• Corticosteroids: Use only to treat complications such as potential airway obstruction from significantly enlarged tonsils. In routine cases might reduce immune response and increase risk of bacterial superinfection. Prednisone: adult dose 40 to 60 mg/day orally bid to qid for 1 to 3 days, taper off over 1 to 2 weeks; pediatric dose 1 to 2 mg/kg orally qid, taper off over 2 weeks.

Surgery

Splenectomy indicated in the case of splenic rupture

Data from several studies find that stress and relaxation states influence human immunity. Stress-reduction measures may have specific usefulness for preventing development of viruses such as EBV.

A meta-analysis of the results of 24 studies considered changes of immune response of the serum of healthy participants as a result of a (short term) stressor. Ab-EBV titers increased significantly and interleukin-2 (IL-2) receptor expression on lymphocytes and T-cell proliferation both decreased significantly in response to phytohemagglutinin during the stress period. (Phytohemagglutinin is a lecitin isolate from red kidney beans which, under normal circumstances, stimulates T cell proliferation.) In a similar meta-analysis of ten relaxation studies, relaxation interventions consistently reduced white blood cells and increased sIgA concentration and NK cell activity. Stress-reduction measures included guided imagery, meditation, and biofeedback (Van Rood et al. 1993). While clinical relevance and translation of this analysis of in vitro trials is currently unclear, it raises interesting questions of what protective effects stress reduction through relaxation techniques may possibly confer to immune function in general and to risk of infection, including EBV, specifically.

There is some evidence that nutrition and plant-based medicines may be beneficial in reducing the long-term sequelae of EBV infection and EBV-associated complications.

The immune system requires increased folate levels during infectious processes to perform cellular multiplication and synthesize immunoglobulins. Serum folate concentration in acute infection was evaluated in 260 patients with viral and mycoplasmal infections. Serum samples from 15 patients with infectious mononucleosis revealed folate deficiency in 9 patients (<3 mcg/L). Similar findings of folate deficiency were demonstrated in the patients with other infections in the study. The authors suggest that lassitude and the need for prolonged convalescence in the case of a viral infection, a feature of EBV, may be associated with acute folate depletion. While these results are not conclusive, folate supplementation during convalescence may enhance recovery (Jacobson et al. 1987).

The value of herbal therapy in the treatment of EBV has not been explored by scientific investigation. Traditional immune-stimulating herbs are used in clinical practice. Echinacea (Echinacea spp.), wild indigo (Baptisia tinctoria), and licorice (Glycyrrhiza glabra) are used in acute conditions to stimulate immunity, enhance lymph circulation, and provide adrenal support. Astragalus (Astragalus membranaceus) and lomatium (Lomatium dissectum) are employed in established infections or chronic states for a deeper immune-enhancing action.

Although the specific application to infectious mononucleosis is not known, ursolic acid found in bearberry (Arctostaphylos uva ursi) is derived from Glechoma hederaceae L, as is oleanolic acid. Retinoic acid and glycyrrhetinic acid, derived from licorice root (Glycyrrhiza glabra), are herbs used in Chinese and Western medicine for stimulation of immune function and for antimicrobial activity.

Although lacking in scientific validation, homeopathic treatment is sometimes used to treat EBV. The following remedies are reported to be beneficial (Hunton 1986) and are best administered under the guidance of a licensed, certified homeopath who would evaluate the individual appropriately:

• Belladonna - For early acute stages of mononucleosis with sudden onset of fever; red face and lips; a dry, red throat with throbbing; swollen tonsils; and cervical lymphadenopathy. The appropriate patient is also typically not thirsty.

• Ferrum phosphorica - For the first stage of febrile illness with painful cough and sore chest. The appropriate patient feels prostrated, but is not as red and hot as described for Belladonna. There is also generally a sensation of heat in the mouth with erythematous tonsils, more pronounced on the right side, for the suitable patient whose symptoms tend to be worse at night, including accompanying night sweats.

• Kali muriaticum - Typically used for patients with follicular tonsillitis exhibiting extreme swelling, but may also be useful for treating infectious mononucleosis when administered in conjunction with Ferrum phos.

One method is to use Belladonna in the first 12 to 24 hours of treatment and then alternate Ferrum phos. and Kali mur. hourly. The author reports that patients often indicate improvement in symptoms during the second day of treatment.

Other remedies include Mercurius and Phytolacca. Mercurius is indicated for patients with fever accompanied by profuse sweating; alternating hot and cold; weakness in the limbs and painful, aching bones; a bluish-red throat with a constant desire to swallow; copious salivation and teeth marks around the edges of the tongue; and tremendous thirst. Phytolacca is indicated when pain from pharyngitis radiates to the ears upon swallowing, there is a high fever alternating with chills and prostration, and the patient is averse to hot drinks. 

Lachesis, Conium, Hepar sulphuris calcareum, and Cistus canadensis may also be relevant remedies. When mononucleosis becomes persistent and every episode of the common cold develops into tonsillitis, Baryta carbonica may be considered. Carcinosin may also be a useful remedy in prolonged or chronic EBV, particularly when there is a past history of pertussis, pneumonia, or acute fevers at an early age (Hunton 1986).

In another report, homeopathy was combined with TCM to treat eight patients with mononucleosis. Those with the EBV virus were diagnosed, in TCM terms, as having qi deficiency, kidney deficiency, qi stagnation, heat toxin, external evil, yin/blood deficiency, or blood stagnation. The most common homeopathic remedies employed were Lycopodium, Silicea, Phosphorous, Sulphur, Carboneum sulph., Mercurius, Nux vomica, Sepia, and Pulsatilla. Herbal therapeutics included Atractylodes alba, Glycyrrhiza recens, Rehmannia preparata, Bupleurum, Cortex magnolia, Phragmites, Belamcanda, Sophora subprostrata, Siler, Angelica dahurica, Paeonia alba, Dendrobium, Polygonatum officinale, and Cnidium. Each patient improved symptomatically with individualized treatment with some combination of the medicinal substances listed (Van Benschoten 1988).

Although not specifically investigated for infectious mononucleosis, acupuncture may be helpful in reducing symptoms, improving immune function, and relieving liver, spleen and lymph congestion.

This modality has not been evaluated for its use in mononucleosis specifically. However, it may prove beneficial for relieving the myalgias of chronic EBV infection and/or for stress reduction.

Most patients recover fully without recurrence of fever or other complications

• Central nervous system involvement may develop within 2 weeks: encephalitis, seizures, Guillain-Barré syndrome, peripheral neuropathy, meningitis, myelitis, cranial nerve palsies, psychosis
• Hematologic complications: Usually mild and self-limiting; e.g., hemolytic anemia in 2% of cases; Coombs' test positive; cold agglutinins; may last 1 to2 months
• Splenic rupture, requiring surgery, occurs in less than 0.5% of patients (90% male). History of trauma present in about 50% of cases of splenic rupture. Patients with splenic rupture usually present with abdominal or referred shoulder pain, a symptom that should always be treated seriously in infectious mononucleosis. The complication occasionally presents painlessly, accompanied by hypotension. More common in men.
• Airway obstruction: Potential airway obstruction from severe tonsillitis is an indication for hospitalization. If corticosteroid treatment is not effective, surgery may be necessary.
• Hepatic complications: Some abnormalities in liver function tests occur in 95% of patients. Hepatocellular enzyme levels about two to three times normal are common and resolve in 3 to 4 weeks. Fulminant cases occur rarely and if elevation is more severe, or jaundice occurs, other etiologies should be investigated.
• Rarely, autonomic nervous system dysfunction including attacks of sweating and flushing.
• Duncan's disease X-linked lymphoproliferative disorder, which may be fatal following exposure to EBV in young boys with this condition.

Most infectious mononucleosis patients recover uneventfully and can return to school or work in a few weeks. Fatigue persists for months in 1% to 2% of patients. Complications are uncommon but may be severe. Death occurs in less than 1% of patients, mostly due to complications such as encephalitis, splenic rupture, and airway obstruction.

Auwaerter PG. Infectious mononucleosis in middle age. JAMA. 1999; 281(5):454-459.

Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck & Co.; 1999:2336-2339.

Goh SH, Hew NF, Norhanom AW, Yadav M. Inhibition of tumour promotion by various palm-oil tocotrienols. Int J Cancer. 1994; 57(4):529-531.

Hunton M. The homoeopathic treatment of glandular fever. Br Homeopath J. 1986; 75(2):66-68.

Jacobson W, Wreghitt TG, Saich T, Nagington J. Serum folate in viral and mycoplasmal infections. J Infect. 1987; 14(2):103-111.

Ohigashi H, Takamura H, Koshimizu K, Tokuda H, Ito Y. Search for possible antitumor promoters by inhibition of 12-O-tetradecanoylphorbol-13-acetate-induced Epstein-Barr virus activation; ursolic acid and oleanolic acid from an anti-inflammatory Chinese medicinal plant. Glechoma hederaceae L. Cancer Lett. 1986; 30(2):143-151.

Omori M. Mononucleosis. In: Adler J, Brenner B, Dronen S, et al., eds. Emergency Medicine: An On-line Medical Reference. Accessed at www.emedicine.com/cgi-bin/foxweb.exe/showsection@d:/em/ga?book=emerg&sct=INFECTIOUS_DISEASES on January 19, 2000.

Schooley RT. Epstein-Barr virus (infectious mononucleosis). In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practices of Infectious Diseases. 4th ed. New York, NY: Churchill Livingstone Inc; 1995:1364-1377.

Van Benschoten MM. Clinical cases of Epstein Barr Virus infection treated with homeopathic and Chinese herbal therapeutics. Am J Acupunct. 1988; 16(1):19-25.

Van Rood YR, Bogaards M, Goulmy E, van Houwelingen HC. The effects of stress and relaxation on the in vitro immune response in man: a meta-analytic study. J Behav Med. 1993; 16(2):163-181.