| disease | Pestilence Infectious Mononucleosis |
| alias | Flyer, Infectious Mononucleosis |
Infectious mononucleosis is an acute proliferative disease of the mononuclear-macrophage system, often self-limiting in its course. Clinically, it manifests as irregular fever, lymphadenopathy, sore throat, a significant increase in peripheral blood mononuclear cells, the presence of atypical lymphocytes, a positive heterophil agglutination test, and the detection of anti-Epstein-Barr virus (EBV) antibodies in the serum. Among young adults with primary EBV infection, approximately half present with infectious mononucleosis. Burkitt's lymphoma (BL) and nasopharyngeal carcinoma in African children occur only in patients previously infected with EBV. Both BL and nasopharyngeal carcinoma tumor cells contain EBV DNA and virus-determined nuclear antigens, suggesting that EBV may be a significant causative factor in BL and nasopharyngeal carcinoma.
bubble_chart Epidemiology
The disease is widely distributed, often occurring sporadically, but it can also cause epidemics. Virus carriers and patients are the sources of the pestilence. Close oral contact is the primary mode of transmission, while droplet transmission, though possible, is not significant. The incidence is higher in the age group of 15 to 30 years, with most cases in children under 6 being asymptomatic. Cases occur throughout the year, but are more common in late autumn and early winter. A single infection can confer relatively long-lasting immunity.
EB virus is the pathogen of this disease. Under electron microscopy, the morphological structure of EB virus is similar to other viruses in the herpesvirus group, but its antigenicity is different. EB virus is a DNA virus, and the complete viral particle consists of the nucleoid, membrane shell, capsomeres, and envelope. The nucleoid contains viral DNA; the membrane shell has an icosahedral symmetry shape composed of tubular protein subunits; the envelope is derived from the host cell membrane. EB virus has extremely specific growth requirements, only replicating in cultures such as African lymphoma cells, blood from infectious mononucleosis patients, leukemia cells, and healthy human brain cells, making viral isolation difficult.
EB virus has six antigenic components, such as the membrane shell antigen, membrane antigen, early antigen (which can be further divided into diffuse component D and restricted component R), complement-fixing antigen (i.e., soluble antigen S), EB virus nuclear antigen, and lymphocyte-detected membrane antigen (LYDMA). The first five can each produce their corresponding antibodies, while the corresponding antibody for LYDMA has not yet been detected.The pathogenesis has not yet been fully elucidated. The virus enters the oral cavity and initially replicates in the lymphoid tissues of the pharynx, then invades the bloodstream, causing viremia, and further affects various tissues and organs of the lymphatic system. Since B cells have receptors for the EB virus on their surface, they are the first to be affected, leading to changes in B-cell antigenicity. This subsequently triggers a strong T-cell response, which directly targets B cells infected by the EB virus. The abnormal lymphocytes in the peripheral blood are primarily T cells.
bubble_chart Pathological Changes
The pathological changes of this disease are still not well understood. Its fundamental viral characteristic is the benign hyperplasia of lymphoid tissue. Lymph nodes are enlarged but do not suppurate. Organs such as the liver, spleen, myocardium, kidneys, adrenal glands, lungs, and central nervous system can be affected, primarily due to infiltration by abnormal polymorphic lymphocytes.
bubble_chart Clinical Manifestations
The incubation period ranges from 5 to 15 days, with the majority being 10 days. The onset can be either acute or gradual, and nearly half of the cases present with prodromal symptoms. The main symptoms include:
(2) Lymphadenopathy 60% of patients exhibit superficial lymph node enlargement. Lymph nodes throughout the body may be affected, with cervical lymph nodes being the most common, followed by axillary and inguinal lymph nodes. Thoracic, mediastinal, and mesenteric lymph nodes may occasionally be involved. The enlarged lymph nodes measure 1–4 cm in diameter, are moderately firm, discrete, non-adherent, and non-tender, without suppuration, and are asymmetrical. The swelling subsides slowly, usually within 3 weeks, though it may occasionally persist longer.
(3) Pharyngitis About half of the patients experience congestion, edema, or swelling of the pharynx, uvula, and tonsils. A few may develop ulcers or pseudomembranes. Patients often report sore throat, with small petechiae visible on the palate. Gingival swelling and ulcers may also occur. Obstruction of the larynx or trachea is rare.
(4) Hepatosplenomegaly Approximately 10% of cases present with hepatomegaly, and up to two-thirds may exhibit abnormal liver function. Jaundice occurs in about 5–15% of cases. Splenomegaly is observed in almost all cases, typically extending 2–3 cm below the costal margin, though splenic rupture may rarely occur.
(5) Rash About 10% of cases develop a rash, which is polymorphic and may include maculopapules, scarlatiniform eruptions, erythema nodosum, urticaria, or occasionally hemorrhagic lesions. The rash is more common on the trunk and less likely to affect the limbs, usually appearing within 1–2 weeks of onset and resolving within 3–7 days without scarring or desquamation. A more typical presentation is a mucosal rash, characterized by multiple pinpoint petechiae at the junction of the soft and hard palate.
The course of the disease varies from a few days to 6 months, but most cases resolve within 1–3 weeks. Recurrences are occasional, with shorter and milder episodes during seasonal disease. A small number of cases may persist for months or even years, termed chronic active EB virus infection.
bubble_chart Auxiliary Examination
(1) Blood Picture At the onset of the disease, the white blood cell count may be normal. By days 10–12 of the illness, the total white blood cell count often increases, with values as high as 30,000–60,000/mm3, returning to normal by the third week. Abnormal lymphocytes (10–20% or more) may appear from days 1–21 of the illness and can be classified into three types based on cell morphology: foamy, irregular, and immature. These abnormal cells likely originate from T cells and may also be seen in other viral diseases, such as viral hepatitis, epidemic hemorrhagic fever, chickenpox, and mumps, though their percentage is generally below 10%. Platelet counts may decrease, and in rare cases, patients may exhibit agranulocytosis or lymphopenia, possibly related to abnormal immune responses in the body.
(2) Bone Marrow Picture The bone marrow findings lack diagnostic significance but can help exclude other diseases, such as hematologic disorders. Abnormal lymphocytes may appear (some suggest this may be due to dilution from peripheral blood). A left shift in neutrophil maturation and possible hyperplasia of reticular cells may also be observed.
(3) Heterophil Agglutination Test The heterophil agglutination test has a positivity rate of 80–90%. The principle is that patient serum often contains heterophil antibodies of the IgM class, which can agglutinate sheep or horse red blood cells. These antibodies persist in the body for an average of 2–5 months. Patients with delayed appearance of heterophil antibodies often recover more slowly. A small number of cases (about 10%) remain negative for the heterophil agglutination test, mostly mild cases, particularly among pediatric patients.
Normal individuals, patients with serum sickness, and a few patients with lymphoreticular cell tumors, monocytic leukemia, subcutaneous node disease, etc., may also test positive for heterophil agglutination (though antibody titers are generally low, except in serum sickness). However, these can be differentiated using guinea pig kidney and bovine red blood cell absorption tests. In normal individuals and the aforementioned patients (excluding those with serum sickness), heterophil antibodies in the blood can be completely absorbed by guinea pig kidney or partially absorbed by bovine red blood cells. In contrast, patients with this disease have heterophil antibodies that are partially absorbed by guinea pig kidney and completely absorbed by bovine red blood cells, while serum sickness patients have antibodies that are completely absorbed by both. Heterophil agglutinin titers ranging from 1:50 to 1:224 are clinically significant, with titers of 1:80 or higher generally considered diagnostic. A fourfold or greater increase in titer over successive weeks is even more significant. In recent years, the slide agglutination method, using horse red blood cells instead of sheep red blood cells, has been employed, yielding faster and more sensitive results than the tube method.
(4) EBV Antibody Testing After infection with EBV, the body produces various antibodies, including membrane capsid antibodies, anti-membrane antibodies, early antibodies, neutralizing antibodies, complement-fixing antibodies, and virus-associated nuclear antibodies. The timing and significance of these antibodies are detailed in Table 11-15.
(5) Other Tests EBV culture is rarely used clinically. Measuring serum bovine red blood cell hemolysin has diagnostic value (titers of 1:400 or higher). During the acute phase of the disease, autoantibodies such as anti-i antibodies (antigen i is only present in fetal cells) and antinuclear antibodies may also be detected. High titers of anti-i cold agglutinins can lead to autoimmune hemolytic anemia.
Table 11-15 Timing and Evaluation of Various EBV Antibodies
| Time of Appearance | Positivity Rate | Duration | Evaluation | ||
| Membrane Capsid Antibody | IgM Type | At onset of symptoms | 100 | 4–8 weeks | High sensitivity and specificity, but difficult to operate |
| IgG type | Same as above | 100 | Lifelong | High titers may persist for life, suitable for epidemiological surveys | |
| Early antibody | Anti-D | Peaks at 3–4 weeks after onset | 70 | 3–6 months | Correlates with disease severity, detectable in nasopharyngeal carcinoma patients |
| Anti-R | 2 weeks to several months after onset | Low | 2 months to >3 years | Found in Burkitt's lymphoma | |
| Virus-associated Nuclear antibody | 3–4 weeks after onset | 100 | Lifelong | Appears later, aids in diagnosis of heterophile antibody-negative sexually transmitted disease cases | |
| Complement-fixing antibody | Same as above | 100 | Lifelong | Same as above | |
| Neutralizing antibody | Same as above | 100 | Same as above | Technically challenging | |
Sporadic cases are easily overlooked, and diagnosis is primarily based on clinical symptoms, typical blood findings, and a positive heterophil agglutination test, with the latter two being particularly important. During an epidemic, epidemiological data holds significant reference value.
When serological testing is difficult to perform, diagnosis can also be made based on blood findings combined with clinical presentation. Although clinical manifestations such as high fever, pharyngitis, and cervical lymphadenopathy are relatively common, they are not always present. Serum alanine aminotransferase levels are mostly elevated during the course of the disease, even in the absence of jaundice, which warrants attention. Typical blood findings and the heterophil agglutination test may show changes or turn positive as early as the second day of the illness, but significant changes generally occur between the first and second weeks. The heterophil agglutination test may even take several months to reach a meaningful level, underscoring the importance of repeated testing. One or two negative results cannot rule out the diagnosis.
bubble_chart Treatment Measures
The treatment of this disease is symptomatic, and most cases can resolve spontaneously. During the acute phase, especially when complicated by hepatitis, bed rest is necessary. Antibiotics are ineffective against this disease and should only be considered for secondary bacterial infections of the pharynx or tonsils. Penicillin G is generally preferred, with a course of 7–10 days. If ampicillin is administered, approximately 95% of patients may develop a rash, usually occurring one week after administration or after discontinuation, which may be related to the immune abnormalities of this disease. Therefore, ampicillin should not be used for this condition. Some suggest that metronidazole and clindamycin may help with pharyngeal inflammation, indicating possible anaerobic bacterial co-infection, but clindamycin can also cause rashes. Corticosteroids are indicated for severe lesions or edema of the pharynx and larynx, as they can rapidly reduce inflammation and may even obviate the need for tracheotomy if administered promptly. Hormones may also be used for central nervous system complications, thrombocytopenic purpura, hemolytic anemia, myocarditis, pericarditis, etc.
Vigilance for possible splenic rupture should always be maintained. Prompt diagnosis, rapid volume replenishment, blood transfusion, and splenectomy can often save the patient.
Acyclovir and its derivatives have been shown to antagonize EB virus in vitro, but these drugs need not be routinely administered to general patients with infectious mononucleosis. They may be considered for AIDS patients with oral hairy leukoplakia or those with strong evidence of chronic progressive EB virus infection. The efficacy of interferon remains unclear.
The prognosis of this disease is generally good. The course of the illness typically lasts 1 to 2 weeks, but relapses may occur. Some patients may experience prolonged low-grade fever, lymphadenopathy, lack of strength, and weakness for several weeks or months. In rare cases, the disease may persist for years. The mortality rate is 1–2%, with causes of death including splenic rupture, meningitis, myocarditis, etc. In individuals with congenital immunodeficiency, the condition may rapidly deteriorate and lead to death. This disease and malignant sexually transmitted diseases of the mononuclear phagocyte system are two entirely distinct conditions. Although EB virus may also be found in lymphoma patients, this disease does not progress to lymphoma.
There is currently no effective preventive measure for this disease. Some advocate for respiratory isolation during the acute phase, with respiratory secretions disinfected using bleaching powder, chloramine, or boiling, while others believe isolating patients is unnecessary. After recovery, viremia may persist for several months, so if the patient is a blood donor, the donation period must be extended to at least six months after the onset of the illness. Immunoprophylaxis for this disease is still under exploration.
Approximately 30% of patients may develop concurrent hemolytic streptococcal infection of the pharyngeal isthmus. The incidence of acute nephritis can be as high as 13%, with clinical manifestations resembling typical nephritis. The incidence of splenic rupture is about 0.2%, usually occurring within 10 to 21 days of the disease. Around 6% of patients may develop myocarditis.
The clinical manifestations of cytomegalovirus disease closely resemble this condition. Hepatosplenomegaly in cytomegalovirus disease results from the virus's effect on target organ cells, while pestilential mononucleosis is associated with lymphocyte proliferation. Sore throat and cervical lymphadenopathy are less common in cytomegalovirus disease, and the serum lacks heterophilic agglutinins and EB virus antibodies. Diagnosis relies on virus isolation and specific antibody testing. This disease also needs to be differentiated from acute lymphocytic leukemia, for which bone marrow cytology examination has diagnostic value. In children, this disease must be distinguished from acute infectious lymphocytosis, which is more common in young children, often presents with upper respiratory symptoms, rarely involves lymphadenopathy, and does not cause splenomegaly. Total leukocyte count is elevated, primarily due to mature lymphocytes, and abnormal blood findings may persist for 4-5 weeks. Heterophilic agglutination tests are negative, and no EB virus antibodies appear in the serum. Additionally, this disease should be differentiated from type A viral hepatitis and streptococcal exudative tonsillitis.
