Infectious mononucleosis (IM) is an acute proliferative infectious disease of the monocyte-macrophage system. The disease is common in pediatrics and is mainly caused by Epstein-Barr-virus (EBV), characterized by irregular fever, pharyngitis, lymph nodes and hepatosplenomegaly, a large number of abnormal lymphocytes in the blood, heterophilic agglutinins and EBV-specific antibodies in the serum.
Etiology and pathogenesis
The EBV is a double-stranded DNA virus of the herpesvirus group, which is a virus that infects humans universally and has the characteristics of latency and transformation.
After entering the oral cavity, the virus multiplies and replicates in the lymphatic tissues of the pharynx and then enters the bloodstream to produce viremia, which mainly affects the lymphatic tissues and tissues and internal organs with lymphocytes. Pharyngeal epithelial cells, B cells, T cells and NK cells all have the EBV receptor CD21 (CR-2, C3dR: complement third component receptor). However, in IM, the main infection is with B cells, which subsequently causes a strong reaction of T cells and the formation of abnormal lymphocytes that can be seen in the peripheral blood, i.e. activated suppressor T cells (CD8+ HLA-D+, CD8+ CD45RO+). The main pathological histological change of the disease is benign proliferation of lymphoid tissue, which does not septicize. The liver, spleen, myocardium, kidney, adrenal glands, lung, and central nervous system can be involved, showing abnormal lymphocytic infiltration. ebovirus does not induce cell lysis, but can produce cellular deformation and cause morphological and functional changes.
More than 90% of IM cases with similar clinical symptoms are caused by EBV, while the other 5-10% of cases called infectiousmononucleosis-likeillnesses are caused by cytomegalovirus (CMV), toxoplasma- gondii, adenovirus, and other infectious diseases. gondii), adenovirus, hepatitis virus, HIV, and herpesvirus type 6 (HHV-6).
Diagnosis
(A) Symptoms
1. The incubation period is shorter in children, about 4-15 days, mostly 10 days, and longer in young people up to 30 days.
2, the onset may be rapid or slow, half of them have prodromal signs, followed by fever and sore throat, general malaise, nausea, fatigue, sweating, shortness of breath, headache, swollen cervical lymph nodes, etc.
The younger the age, the less typical the symptoms are. For those under 2 years old, the liver, spleen, lymph node enlargement and general symptoms are not significant. Generally speaking, the typical symptoms may not appear until one week after the onset of the disease.
(1) Fever: Most of the children have fever of different degrees; the fever pattern is variable, usually fluctuating around 39’C, occasionally up to 40C or more. The fever is maintained for about 1 week, sometimes accompanied by a feeling of cold or sweating and sore throat. Although the fever is high, the symptoms of toxicity are less severe than those of bacterial pharyngitis. However, most young children do not have fever or have only low fever.
(2) Lymph node enlargement: Every case has it. Acute enlargement of lymph nodes is one of the characteristics of the disease, and the enlargement is mainly in the anterior and posterior neck (around the upper part of the sternocleidomastoid muscle) bilaterally, and the posterior neck often appears first than the anterior neck. The enlarged lymph nodes may also appear in the axilla, medial humeral epicondyle and rat chevron, with a diameter of about 1-4 cm. The enlarged lymph nodes usually shrink gradually within a few days or weeks, but in cases of slow regression, it can take up to several months.
(3) Pharyngitis: More than 80% of children have sore throat and symptoms of pharyngitis. The tonsils are congested and swollen, and white exudates can be seen in the sockets, occasionally forming pseudomembranes, which need to be differentiated from purulent tonsillitis and diphtheria. About 1/3 of the children may have papules and rashes on the anterior palate mucosa.
(4) Hepatosplenomegaly: about 20% of cases may have hepatomegaly, hepatic area pressure pain, and hepatitis-like symptoms, and about 10% may develop xanthogranuloma. The spleen may be palpable for 1-3 cm with mild tenderness about 1 week after onset. However, there are cases in which the spleen enlarges rapidly in the second week of the disease, causing swelling and tenderness in the left upper abdomen. At this time, palpation should be gentle, avoiding local impact and alerting to the risk of spleen rupture. Occasionally, cases with significant enlargement of the liver and spleen and xanthogranuloma have been reported.
(5) Rash: The incidence of rash is less than 10% and is not stereotyped; the common rash is generalized and appears mostly on day 4-10 of the course of the disease. It can be scarlet fever-like, measles-like, blister-like or urticaria-like maculopapular rash. 3-7 days to subside, no flaking and no pigmentation after subside. Skin and mucosal bleeding is only occasionally seen. Since there is no specific rash pattern, it is not very helpful for diagnosis.
In summary, the signs and symptoms of the disease are diverse and their occurrence rate varies widely.
(B) Laboratory tests
1.Blood picture The first week of the disease may show a decrease or increase in peripheral blood leukocytes. Typical blood changes are an increase in the total lymphocyte count, which is higher than 5.0×109/L, with atypical lymphocytosis reaching more than 1.0×109/L. The total leukocyte count is only moderately increased and is seen in the second week of the disease. Leukocyte classification lymphocytes can account for more than 50% and more than 10% are atypical lymphocytes (CD8+ HLA-DR+, CD8+ CD45RO+ lymphocytes). Their abnormal cell morphology can be divided into foamy (Downey type I); irregular (Downey type II) and naive (Downey type III), but they are actually difficult to distinguish in laboratory tests and of little value for diagnosis. Atypical lymphocytosis is less common in young children. The normal CD4+/CD8+ ratio of 2:1 decreases due to a decrease in CD4+ cells along with the increase in atypical lymphocytes. It should be noted that the same abnormal lymphocyte pattern as in this disease can also be seen in cytomegalovirus infection, infectious hepatitis, rubella and other diseases.
2, serum heterophilic agglutination reaction this method was first developed in 1932 by Paul and Bunnell, IM patients with blood containing antibodies that agglutinate sheep red blood cells or horse red blood cells, that is, “heterophilic agglutinin”, is a kind of IgM heterophilic antibody. It is generally considered to be positive at 1:40 or higher, and is more valuable at 1:80 or higher. It can be positive after 5 days of disease onset. However, there are cases in which a positive reaction is seen as late as 4 weeks into the disease. It usually peaks in the 2nd-3rd week of the disease and can last for 2-5 months, but also disappears in 2 weeks; however, 10% of patients are always negative. The heterophilic agglutination test can also be positive in patients with normal serum, serum sickness, leukemia, Hodgkin’s disease, and tuberculosis, so attention should be paid to differentiation.
3, EBV-specific antibody determination EBV-specific antibodies are a reliable basis for diagnosing IM, and are even more significant for those with negative serum heterophilic agglutination reactions. After infection with EBV, patients can produce a variety of antibodies. The main ones are as follows.
(1) Anti-VCAantibody: There are two types of antibodies, IgM and IgG, which appear in the acute and recovery phases of the disease respectively; IgM can be maintained for 4-8 weeks and IgG can be present for life.
(2) Anti-EAantibody: The anti-Early antigen antibody is divided into diffuse (D) and restrictive (R) by fluorescence staining; D is mostly seen in adolescents, with a positive rate of 70% and maintenance of about 3-6 months; R is mostly seen in younger children, with a lower positive rate and a peak of more than 2 weeks after the disease, generally maintaining 2 months to 3 years.
(3) Anti-EBNAantibody: appears 4-6 weeks after the onset of the disease, and the potency of the positivity is also low, but can last for a lifetime. If the antibody is found, the infection has actually been present for a long time.
Antibody determination methods are rapidly changing, such as indirect immunofluorescence, enzyme-linkedimmunosorbantas-say, and monoclonal methods. In the acute phase of IM, serum-specific antibodies, such as negative EBNA-IgG, are detected, and one or more of the following results are indicative of acute infection of the disease
(i) Positive anti-VCA-IgM antibodies that later turn negative.
(ii) A 4-fold or higher increase in the potency of VCA-IgG antibodies in both the acute and recovery phases of the double serum test.
(iii) transient increase of EA antibody.
④VCA-IgG antibody is positive in the early stage of the disease, and EBNA antibody turns positive in the later stage.
However, for children who are immunocompromised or receiving immunoglobulin therapy, it is often difficult to diagnose the disease based on EBV-specific antibodies alone.
4. EBV culture is rarely used clinically because positive results take two weeks to two months and are technically complex and expensive. Cultures are taken from saliva or lymphocytes of patients in the acute phase. However, it should be noted that 15-20% of the healthy population also carries EBV in the pharynx, and some viruses can survive for long periods of time in the lymphocytes of recovering patients. Conversely, cytomegalovirus (CMV) is rarely present in the pharynx of normal people, so it is of greater clinical significance in the differential diagnosis once the culture is positive.
5, EBV DNA detection using polymerase chain reaction (PCR) can be found in children with high concentrations of EBV DNA in the serum, suggesting the presence of viremia.
(iii) Diagnostic criteria.
1) Clinical symptoms: at least 3 or more positive
①Fever
②Pharyngitis, tonsillitis
③Enlarged lymph nodes in the neck (more than 1cm)
④hepatomegaly (under 4 years old: more than 2cm; over 4 years old: palpable)
⑤ Enlarged spleen (palpable)
2) Blood picture examination
①Lymphocytes accounted for more than 50% or total lymphocyte count higher than 5.0×109/L
② anomalous lymphocytes accounting for more than 10% or a total number higher than 1.0×109/L.
3) EBV antibody test: negative for EBNA antibody in the acute phase; positive for one of the following
①VCA-IgM antibody is positive at the beginning and turns negative later.
②Double serum VCA-IgG antibody titer more than 4 times elevated.
③Incidental increase of EA antibody.
④VCA-IgG antibodies were positive at the beginning; EBNA antibodies turned positive to negative at the later stage.
(iv) Differential diagnosis
The clinical manifestations of this disease are diverse, so it must be differentiated from similar diseases. Diagnostic difficulties can only be found in: (1) early onset; (2) mild cases and young children; (3) when there are too many or too few major symptoms and signs; (4) when there are serious complications at an early stage; (5) when there is no hematological or serological evidence. If the clinical picture is typical and the serum is negative for heterophilic agglutination, especially if the EBV-specific antibodies are also negative, the differentiation from infectious mononucleosis caused by cytomegalovirus, Toxoplasma gondii and hepatitis virus should be taken into account. In addition, about 5% of cases of infectious mononucleosis have pharyngeal cultures of group A beta-hemolytic streptococci. If the symptoms do not improve after 48-72 hours of treatment for streptococcal pharyngitis, the possibility of infectious mononucleosis should be considered. If pneumonia is present, the etiology should be clarified. Jaundice, hepatomegaly, and elevated transaminases should be differentiated from viral hepatitis. If there are neurological symptoms, it should be distinguished from other viral encephalitis and myelitis. When there are enlarged lymph nodes and liver and spleen, they should be differentiated from leukemia, tuberculosis and Hodgkin’s disease. If there is a significant increase in lymphocytes, it should be differentiated from infectious lymphocytosis, dengue fever, etc. If necessary, bone marrow examination should be done to rule out leukemia or combined hematologic comorbidities. In a few cases, lymph node biopsy is required to exclude lymphoma or Hodgkin’s disease.
Treatment
There is no special treatment for this disease, mainly symptomatic and supportive treatment.
1, general treatment in the acute stage should be bed rest, strengthen care, to avoid serious complications. In particular, avoid strenuous exercise when the spleen is enlarged to prevent rupture. Antibiotics are not effective for this disease and should only be used when accompanied by bacterial infection. Penicillin G or erythromycin may be used if group A beta streptococcus is present in the throat swab culture. Patients with this disease are hypersensitive to some antibiotics, especially aminobenzyl penicillin (ampicillin) rash occurs in up to 95%, usually after 1 week of administration, which may be related to immune abnormalities of this disease, so it is advisable to avoid it, but penicillin G is free of this complication. Saline gargle can often improve the pain and discomfort caused by pharyngitis.
2. Antiviral therapy currently uses acyclovir (acyclovir, acyclovir) and ganciclovir (5 mg/kg. times, every 12 hours intravenous drip) to treat some herpes virus infections. It is thought to have the ability to inhibit viral DNA polymerase synthesis during the virus lysis phase, thereby inhibiting viral replication and reducing viral excretion from the patient’s oral cavity, but has no significant effect on improving symptoms or shortening the duration of disease. Some reports use human leukocyte interferon, 1 million U daily, intramuscular injection, for 5 days; supplemented with vitamin B1 and C oral and symptomatic treatment, can relieve symptoms and shorten the course of treatment, such as early administration of better results.
3, symptomatic treatment can be symptomatic use of antipyretic and analgesic, sedative, cough and liver protection measures. Aspirin is often used for headache, sore throat and fever control. For severe disease such as persistent high fever, accompanied by throat obstruction or spleen swelling symptoms, short-term application of adrenocorticosteroids is appropriate, about 3-7 days, can reduce symptoms. In case of myocarditis, severe hepatitis, hemolytic anemia or thrombocytopenic purpura with bleeding, hormone application can be extended to 2 weeks. The dose is 1mg/kg/d, and the maximum daily dose does not exceed 60mg, which is gradually reduced and discontinued in the second week. However, in general cases, hormones are not necessary. Since most of the blood of adults contains specific antibodies to the disease, it has been suggested that fresh plasma transfusion of adults can be tried for children with severe disease.
4, propecia treatment: IM is a kind of EBV infection caused by immune abnormal infectious disease, IVIG treatment IM not only make the clinical performance recovery fast, and the course of the disease is significantly shortened, the efficacy is significant, is a safe and effective way to treat IM. 0.2~0.4g/(kg, d) intravenous infusion course of 3~5d.
Complications and treatment
The complications of this disease are diverse and have a great impact on the prognosis.
1. Hematological system may have Coomb’s test positive autoimmune hemolytic anemia, which appears in 1-2 weeks of the course of the disease, and most of them can stop developing within a month. In addition, granulocytopenia, eosinophilia, complete blood cytopenia or immune thrombocytopenic purpura may occur, and may even cause DIC, phagocytosis syndrome, etc.
2. Neurological system 0.37%-7.3% of children can have such comorbidities, and the symptoms vary greatly, including encephalitis, aseptic meningitis, Guillain-Barre syndrome, optic neuritis and central nervous system lymphoma, etc. Among them, transverse myelopathy is the most serious, and bilateral lower limb paralysis and urinary retention can appear suddenly. Although most of the neurological lesions can be recovered, sequelae or death may occur.
3, digestive system liver function abnormalities are generally not serious, mainly changes in liver enzymes. Jaundice may be present, due to hemolysis or hepatitis. Hepatic necrosis has been reported, and esophageal varices may also be present.
4. The respiratory system may occasionally be complicated by marked enlargement of the tonsils and hyperplasia of the lymphoid tissue in the pharynx, causing difficulty in breathing and swallowing. Pleurisy or pleural effusion, pneumonia, etc. may also be complicated.
5. The heart is uncommon, about 1-6%, with non-specific T-wave changes or mild conduction irregularities seen on the electrocardiogram. Myocarditis and pericarditis are rare.
6. The eye can be complicated by conjunctivitis, optic neuritis, retinitis, sclerositis, uveitis, diplopia, hemianopia, strabismus, ptosis, etc.
7, urinary system hematuria, proteinuria, nephritis, nephrotic syndrome and hemolytic uremic syndrome, etc.
8, other mumps, orchitis, otitis media, etc.
Prognosis]
This disease is a self-limiting disease, if there is no complication, the prognosis is mostly good, the course of the disease is about 1-2 weeks, but can be repeated. A small number of patients have a slow recovery, such as low-grade fever, swollen lymph nodes and weakness, which can last for weeks or even months. Occasionally, a period of persistent fatigue may follow IM. Some patients have a poor prognosis if they develop chronic active EBV infection.
The mortality rate is only 1-2% due to respiratory failure caused by concurrent central or peripheral nerve paralysis; a few other deaths are due to concurrent splenic rupture, meningitis, myocarditis, hepatitis, and disseminated lymphoproliferative disease.
The disease can cause rapid death in patients with congenital immunodeficiency disease. The three main features of XLP are: (1) lethal or severe infectious mononucleosis; (2) acquired hypoglobulinemia; and (3) malignant lymphoma. The causes of death are: hepatic necrosis due to massive cytotoxic T-cell infiltration of the liver, aplastic anemia, bone marrow failure, and multiple bacterial or mycobacterial infections. Hemophagocytic lymphohistiocytosis (HLH) is the characteristic manifestation. The prognosis for XLP is poor, with an average age of onset of 2.5 years and more than 70% of deaths occurring before the age of 10 years. The success rate of bone marrow transplantation is 50%, but long-term survival rates have not been reported in detail. Therefore, early diagnosis, especially in families with genetic defects, is of great importance for the prevention of death caused by XLP.
Prevention
The disease is widely distributed, mostly epidemic, and can be transmitted by close contact with oral saliva of patients. Droplet transmission is not important, and blood transfusion and feces are also a source of infection. It is mostly seen in older children and adolescents, and under 6 years of age, the infection may not be obvious. Infection in early childhood is more common in areas with poor sanitation; conversely, it is more common in adolescence in areas with better conditions. EBV can be found in the saliva of not only children, but also in the saliva of 20% of children who have recovered from the disease and 50% of those who have received immunotherapy because of positive antibodies. The pathogen can be transmitted from the incubation period to 6 months or more after the disease; even in recovering patients who are only serologically confirmed, 15% of them can still intermittently excrete the virus. Since most of the infection is transmitted by direct contact, there is no need to worry too much about droplet transmission in schools, but transmission in families is more likely. There is no practical way to prevent this disease.