Mononucleosis differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

Acute mononucleosis, acute cytomegalovirus infection and toxoplasma gondii infection have similar clinical presentations. In addition, since their management is much the same, it is not always helpful, or possible, to distinguish between infectious mononucleosis and cytomegalovirus infection. However, in pregnant women, it is imperative to differentiate mononucleosis from toxoplasmosis as toxo is associated with significant consequences in the fetus. Acute HIV infection can also mimic signs similar to those of infectious mononucleosis, and tests should be performed in pregnant women for the same reason as toxoplasmosis.

Differentiating Mononucleosis from Other Diseases

The table below summarizes the findings that differentiate Mononucleosis from other conditions that cause fever, fatigue, abdominal pain and diarrhea:

Disease	Findings
Ebola	Presents with fever, chills vomiting, diarrhea, generalized pain or malaise, and sometimes internal and external bleeding, that follow an incubation period of 2-21 days.
Typhoid fever	Presents with fever, headache, rash, gastrointestinal symptoms, with lymphadenopathy, relative bradycardia, cough and leucopenia and sometimes sore throat. Blood and stool culture can confirm the presence of the causative bacteria.
Malaria	Presents with acute fever, headache and sometimes diarrhea (children). A blood smears must be examined for malaria parasites. The presence of parasites does not exclude a concurrent viral infection. An antimalarial should be prescribed as an empiric therapy.
Lassa fever	Disease onset is usually gradual, with fever, sore throat, cough, pharyngitis, and facial edema in the later stages. Inflammation and exudation of the pharynx and conjunctiva are common.
Yellow fever and other Flaviviridae	Present with hemorrhagic complications. Epidemiological investigation may reveal a pattern of disease transmission by an insect vector. Virus isolation and serological investigation serves to distinguish these viruses. Confirmed history of previous yellow fever vaccination will rule out yellow fever.
Shigellosis & other bacterial enteric infections	Presents with diarrhea, possibly bloody, accompanied by fever, nausea, and sometimes toxemia, vomiting, cramps, and tenesmus. Stools contain blood and mucous in a typical case. A search for possible sites of bacterial infection, together with cultures and blood smears, should be made. Presence of leucocytosis distinguishes bacterial infections from viral infections.
Leukemia	Cancer of the blood or bone marrow and is characterized by an abnormal proliferation (production by multiplication) of blood cells, usually white blood cells (leukocytes). It is part of the broad group of diseases called hematological neoplasms.
Tonsillitis	Tonsillitis is characterized by signs of red, swollen tonsils which may have a purulent exudative coating of white patches (i.e. pus). In addition, there may be enlarged and tender neck cervical lymph nodes.
Pharyngitis	Typically characterized by sore throat, but commonly accompanied by fever, headache, joint pain and muscle aches, skin rashes, swollen lymph nodes in the neck, diphtheria and common cold.
Adenovirus infections	Commonly presents by a cold syndrome, pneumonia, croup and bronchitis.
Influenza	Symptoms of influenza can start quite suddenly one to two days after infection. Usually the first symptoms are chills or a chilly sensation but fever is also common early in the infection, with body temperatures as high as 39 °C (approximately 103 °F). Many people are so ill that they are confined to bed for several days, with aches and pains throughout their bodies, which are worst in their backs and legs. Common symptoms of the flu such as fever, headaches, and fatigue come from the huge amounts of proinflammatory cytokines and chemokines (such as interferon or tumor necrosis factor) produced from influenza-infected cells. In contrast to the rhinovirus that causes the common cold, influenza does cause tissue damage, so symptoms are not entirely due to the inflammatory response.
Others	Leptospirosis, rheumatic fever, typhus, and mononucleosis can produce signs and symptoms that may be confused with Ebola in the early stages of infection.

The table below summarizes the findings that differentiate the rash in Mononucleosis from other conditions, such as:

Disease	Findings
[[Insect bite]]	In an insect bite, the insect injects formic acid, which can cause an immediate skin reaction often resulting in a rash and swelling in the injured area, often with formation of vesicles.
Kawasaki disease	Commonly presents with high and persistent fever, red mucous membranes in mouth, "strawberry tongue", swollen lymph nodes and skin rash in early disease, with peeling off of the skin of the hands, feet and genital area.
Measles	Commonly presents with high fever, coryza and conjunctivitis, with observation of oral mucosal lesions (Koplik's spots), followed by widespread skin rash.
Monkeypox	Presentation is similar to smallpox, although it is often a milder form, with fever, headache, myalgia, back pain, swollen lymph nodes, a general feeling of discomfort, and exhaustion. Within 1 to 3 days (sometimes longer) after the appearance of fever, the patient develops a papular rash, often first on the face. The lesions usually develop through several stages before crusting and falling off.
Rubella	Commonly presents with a facial rash which then spreads to the trunk and limbs, fading after 3 days, low grade fever, swollen glands, joint pains, headache and conjunctivitis. The rash disappears after a few days with no staining or peeling of the skin. Forchheimer's sign occurs in 20% of cases, and is characterized by small, red papules on the area of the soft palate.
Atypical measles	Symptoms commonly begin about 7-14 days after infection and present as fever, cough, coryza and conjunctivitis. Observation of Koplik's spots is also a characteristic finding in measles.
Coxsackievirus	The most commonly caused disease is the Coxsackie A disease, presenting as hand, foot and mouth disease. It may be asymptomatic or cause mild symptoms, or it may produce fever and painful blisters in the mouth (herpangina), on the palms and fingers of the hand, or on the soles of the feet. There can also be blisters in the throat or above the tonsils. Adults can also be affected. The rash, which can appear several days after high temperature and painful sore throat, can be itchy and painful, especially on the hands/fingers and bottom of feet.
Acne	Typical of teenagers, usually appears on the face and upper neck, but the chest, back and shoulders may have acne as well. The upper arms can also have acne, but lesions found there are often keratosis pilaris, not acne. The typical acne lesions are comedones and inflammatory papules, pustules, and nodules. Some of the large nodules were previously called "cysts"
Syphilis	Commonly presents with generalized systemic symptoms such as malaise, fatigue, headache and fever. Skin eruptions may be subtle and asymptomatic. It is classically described as 1) non-pruritic bilateral symmetrical mucocutaneous rash; 2) non-tender regional lymphadenopathy; 3) condylomata lata; and 4) patchy alopecia.
Molluscum contagiosum	Lesions are commonly flesh-colored, dome-shaped, and pearly in appearance. They are often 1-5 millimeters in diameter, with a dimpled center. Generally not painful, but they may itch or become irritated. Picking or scratching the lesions may lead to further infection or scarring. In about 10% of the cases, eczema develops around the lesions. They may occasionally be complicated by secondary bacterial infections.
Mononucleosis	Common symptoms include low-grade fever without chills, sore throat, white patches on tonsils and back of the throat, muscle weakness and sometime extreme fatigue, tender lymphadenopathy, petechial hemorrhage and skin rash.
Toxic erythema	Common rash in infants, with clustered and vesicular appearance.
Rat-bite fever	Commonly presents with fever, chills, open sore at the site of the bite and rash, which may show red or purple plaques.
Parvovirus B19	The rash of fifth disease is typically described as "slapped cheeks," with erythema across the cheeks and sparing the nasolabial folds, forehead, and mouth.
Cytomegalovirus	Common symptoms include sore throat, swollen lymph nodes, fever, headache, fatigue, weakness, muscle pain and loss of appetite.
Scarlet fever	Commonly includes fever, punctate red macules on the hard and soft palate and uvula (Forchheimer's spots), bright red tongue with a "strawberry" appearance, sore throat and headache and lymphadenopathy.
Rocky Mountain spotted fever	Symptoms may include maculopapular rash, petechial rash, abdominal pain and joint pain.
Stevens-Johnson syndrome	Symptoms may include fever, sore throat and fatigue. Commonly presents ulcers and other lesions in the mucous membranes, almost always in the mouth and lips but also in the genital and anal regions. Those in the mouth are usually extremely painful and reduce the patient's ability to eat or drink. Conjunctivitis of the eyes occurs in about 30% of children. A rash of round lesions about an inch across, may arise on the face, trunk, arms and legs, and soles of the feet, but usually not on the scalp.
Varicella-zoster virus	Commonly starts as a painful rash on one side of the face or body. The rash forms blisters that typically scab over in 7-10 days and clears up within 2-4 weeks.
Chickenpox	Commonly starts with conjunctival and catarrhal symptoms and then characteristic spots appearing in two or three waves, mainly on the body and head, rather than the hands, becoming itchy raw pox (small open sores which heal mostly without scarring). Touching the fluid from a chickenpox blister can also spread the disease.
Meningococcemia	Commonly presents with rash, petechiae, headache, confusion, and stiff neck, high fever, mental status changes, nausea and vomiting.
Rickettsialpox	First symptom is commonly a bump formed by a mite-bite, eventually resulting in a black, crusty scab. Many of the symptoms are flu-like including fever, chills, weakness and muscle pain but the most distinctive symptom is the rash that breaks out, spanning the person's entire body.
Meningitis	Commonly presents with headache, nuchal rigidity, fever, petechiae and altered mental status.
Impetigo	Commonly presents with pimple-like lesions surrounded by erythematous skin. Lesions are pustules, filled with pus, which then break down over 4-6 days and form a thick crust. It's often associated with insect bites, cuts, and other forms of trauma to the skin.

Pharyngitis vs EBV

• EBV infection may cause either exudative or non-exudative pharyngitis and both of which is colonized by streptococcus pyogens present in the oropharynx

• Petechial hemorrhages present in the posterior oropharynx are characteristic of infectious mononucleosis

• Edema of the uvula is rare but if present differentiates mononucleosis from all other types of pharyngitis

Infectious mononucleosis should be differentiated from other diseases that cause runny nose, cough, and constitutional symptoms.

Disease	History	Physical examination	Laboratory or radiological findings
Acute viral nasopharyngitis	Symptoms start with sore throat, nasal congestion, and runny nose. Cough that may persist after resolution of the other symptoms. Fever is not common.	Nasal mucosa is congested and hyperemic. Pharynx is typically normal.	Diagnosis is usually clinical; lab tests are rarely needed. The virus can be cultured on human lung cells, but it takes time. PCR is rapid and accurate, but is done only when the infecting virus strain in immunocompromised patients needs to be known.
Allergic rhinitis	Characterized by repeated paroxysms of rhinorrhea, sneezing, and cough. Symptoms may be related to a specific season of the year, hence the name “seasonal allergies.”	Rhinorrhea discharge is usually clear and watery. Examination of the nose reveals a crease below the nasal bridge, formed from repeated pulling of the nose secondary to irritation. Edema in the area below the eye, if associated conjunctivitis is present.	Skin testing using intradermal skin prick tests to determine the specific allergens causing allergic rhinitis. Serum immune assays to determine IgE levels in the serum.
Acute sinusitis	Presents with symptoms similar to URTIs (sneezing, cough, and runny nose). Symptoms last for a longer time (about 10 days), with a peak between the 4th and 6th days. Usually, acute sinusitis is not associated with fever.	Inspection may show erythema and edema over the involved sinus. Palpation of sinuses shows tenderness. Transillumination of the sinuses may show opacity.	X-ray and CT may show air fluid level or bubbles in the affected sinuses. Culture of the nasal secretions is of limited use in acute sinusitis, as may be contaminated by nasal flora.
Infectious mononucleosis	Symptoms are like the symptoms of pharyngitis, which include: Sore throat and difficulty swallowing Fever Fatigue Lymphadenopathy (especially in the posterior cervical region)	Abdominal examination reveals splenomegaly. Maculopapular rash may be present.	Positive monospot test. Elevated liver enzymes.

Cytomegalovirus vs EBV

• Almost all cases of mononucleosis are caused by the EBV; however, cytomegalovirus can produce a similar symptoms but milder and with less throat pain and no rash.

• Extreme fatigue, bilateral supra-orbital edema, tender bilateral lymphadenopathy, splenomegaly, elevated liver function tests are characteristic of mononucleosis and may or may not be present in cytomegalovirus infections.

• Although, due to the presence of the atypical lymphocytes on the blood smear in both conditions, some physicians confusingly used to include both infections under the diagnosis of "mononucleosis," though EBV is by definition the infection that must be present for this illness.

• An elevated antibody (IgM) titer specific for CMV helps to differentiate it from EBV infection

Toxoplasmosis vs EBV

• In pregnant women, it is imperative to differentiate mononucleosis from toxoplasmosis as toxo is associated with significant consequences in the fetus.

• In contrast to tender bilateral lymphadenopathy observed in patients with mononucleosis, toxo causes unilateral lymphadenopathy.

• In addition, normal to moderately elevated white blood cell count, particularly the number of lymphocytes is observed with mononucleosis; while, in patients infected with toxo, the white blood cell count is typically normal.

Viral Hepatitis vs EBV

• Liver function tests may show a moderate elevation of liver enzyme levels in nearly 90% of patients infected with mononucleosis. On the contrary, there is a significant increase in enzyme levels observed in patients with viral hepatitis.

References

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