Uncomplicated Infectious Mononucleosis Research Articles

Cytomegalovirus and Epstein-Barr Virus Infections.

1. Swetha Pinninti, MD* 2. Catherine Hough-Telford, MD† 3. Sunil Pati, PhD† 4. Suresh Boppana, MD† 1. *Department of Pediatrics, University of Nebraska Medical Center/Children’s Hospital and Medical Center, Omaha, NE. 2. †Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL. 1. Although most infants with symptomatic congenital cytomegalovirus (cCMV) infection are at risk of developing sensorineural hearing loss, 10% to 15% of asymptomatic infants also develop hearing loss and require audiologic screening at regular intervals in the first few years after birth. 2. Unlike with other congenital infections, CMV seropositivity is not protective for fetal transmission. An estimated 75% of infants with cCMV are born in the United States following nonprimary maternal infections. 3. Most individuals with Epstein-Barr virus-associated infectious mononucleosis recover with supportive therapy; contrary to common belief, corticosteroid use is not the mainstay of treatment because airway compromise and splenic rupture can be rare complications. After completing this article, the reader should be able to: 1. Recognize routes of acquisition of cytomegalovirus (CMV) in the neonatal and postneonatal periods. 2. Recognize differences in presentations of congenital CMV infection, childhood infections, and infections in the immunocompromised individual. 3. Plan the diagnostic evaluation for congenital or acquired CMV infection in immunocompetent and immunocompromised children of various ages. 4. Understand management and long-term follow-up plans for infants with congenital CMV infection. 5. Describe the management and treatment of CMV infections in the immunocompromised host. 6. Explain the epidemiology of Epstein-Barr virus (EBV) infections and identify the clinical features associated with EBV infection in immunocompetent and immunocompromised children of various ages. 7. Recognize the potential complications of EBV infection in immunocompetent and immunocompromised children of various ages. 8. Plan management of children with uncomplicated infectious mononucleosis. Cytomegalovirus (CMV) is the most common cause of congenital infection and the leading nongenetic cause of sensorineural hearing loss (SNHL). CMV is also a significant cause of morbidity in preterm neonates who acquire infection postnatally …

Virologic Diagnosis, Viral Monitoring, and Treatment of Epstein-Barr Virus Infectious Mononucleosis.

Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is associated with severe infections in immunocompromised patients. EBV is also causally linked with several human malignancies. The heterophile antibody test and EBV-specific antibody tests remain the principal means of diagnosis of initial infection in otherwise healthy patients. Enzyme-linked immunosorbent assays have replaced the traditional immunofluorescence assays for EBV-specific antibodies. Several newer molecular diagnostic tests have become available that facilitate accurate monitoring of infection. The role of these tests for patients with uncomplicated infectious mononucleosis is limited, although these tests are being increasingly used to monitor the state and level of EBV replication for severe infections and among immunocompromised patients. Antiviral therapy has a limited, short-term effect on oropharyngeal shedding but has proven ineffective for the clinical manifestations of infectious mononucleosis. Patients with selected complications frequently benefit from short-term corticosteroid therapy.

Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome

AbstractThis study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3+, βF1+, EBER1+ T cells lacking significant cytologic atypia. Two cases were CD4+, 2 cases were CD8+, and 2 cases had admixed CD4+ and CD8+ cells without clear subset predominance. All were TIA-1+, CD56−. Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion. This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1+ T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis.

Fulminant EBV+ T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome

This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3+, βF1+, EBER1+ T cells lacking significant cytologic atypia. Two cases were CD4+, 2 cases were CD8+, and 2 cases had admixed CD4+ and CD8+ cells without clear subset predominance. All were TIA-1+, CD56−. Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion. This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1+ T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis.

INFECTIOUS MONONUCLEOSIS Complexities of a common syndrome

Infectious mononucleosis is common in adolescents and young adults. Although the syndrome is most often associated with Epstein-Barr virus, several other organisms can also cause infectious mononucleosis. Diagnosis is based on clinical findings and the presence of heterophil antibodies and atypical lymphocytes. Diagnosis may be more difficult in older adults because the presenting symptoms often differ from those seen in children. Symptoms usually resolve in 2 to 3 weeks. Treatment of uncomplicated infectious mononucleosis is supportive, but corticosteroids may be beneficial for the treatment of several complications associated with Epstein-Barr virus. Physically active patients should be counseled about the risks of splenic injury.

Common Epstein-Barr Virus (EBV) Type-1 Variant Strains in Both Malignant and Benign EBV-Associated Disorders

In the present study, Epstein-Barr virus (EBV) isolates from 18 malignant tumors (angioimmunoblastic lymphadenopathy [AILD], n = 4; Hodgkin's disease [HD], n = 3; pleomorphic T-cell non-Hodgkin's lymphoma [T-NHL], n = 1; B-cell non-Hodgkin's lymphoma [B-NHL], n = 8; gastric carcinoma, n = 2) as well as from 10 tonsils of EBV-seropositive children and from peripheral blood mononuclear cells of 12 children with uncomplicated infectious mononucleosis (IM) and of a boy with severe chronic active EBV infection were genotyped in the EBV nuclear antigen-2 (EBNA-2) gene. A total of 40 of 41 isolates harbored EBV type 1; in 1 specimen (tonsil), only EBV type 2 was found. Further molecular characterization of EBV type-1 wild-type isolates in the EBNA-2 gene and in the 40-kb distant EBV-encoded small RNAs (EBER) region showed that different groups of stable EBV type-1 variant strains exist in vivo both in benign and malignant lymphatic tissue. Group 1 is composed of EBV type-1 isolates (B-NHL, n = 3; T-NHL, n = 1; HD, n = 1; IM, n = 4) that showed a B95-8-like DNA sequence pattern in both viral genes. Group 2 isolates (HD, n = 1; AILD, n = B-NHL, n = 1; tonsils of EBV-seropositive children, n = 9; IM, n = 20 showed a nucleotide change at position 49095 in the EBNA-2 gene, leading to an amino acid substitution (Pro-->Ser), and EBV type-2 sequences in the EBER region. EBV type-1 isolates that fall into group 3 (AILD, n = 3; HD, n = 1; B-NHL, n = 4; gastric carcinoma, n = 2; IM, n = 6; severe chronic active EBV infection, n = 1) were characterized by typical nucleotide changes and a 3-bp insertion (CTC; extra Leu residue) in the EBNA-2 gene and an EBV type-2-specific sequence pattern in the EBER region. These EBV type-1 variant strains may represent the most prevalent circulating EBV type-1 strains in the exposed population and seem not to be restricted to a certain EBV-associated disease or tumor type. However, analysis of more EBV isolates from benign and malignant lesions must show whether more EBV type-1 substrains exist in vivo.

Kinetics of the Antibody Response to BamHI-K Nuclear Antigen in Uncomplicated Infectious Mononucleosis

Kinetics of the Antibody Response to BamHI-K Nuclear Antigen in Uncomplicated Infectious Mononucleosis

Complement behavior in infectious mononucleosis: possible mechanisms for the prevention of immune complex injury.

The acute-phase complement reaction was examined in patients with uncomplicated infectious mononucleosis (IM). Concentrations of both complement and complement inhibitor protein were significantly elevated during the acute phase, and turnover studies with purified 125I-labeled C3 showed this increase to result from increased C3 synthesis. Nine of 16 patients had evidence of in vivo complement activation during this period. Despite high levels of C1q-binding immune complexes in most acute-phase sera from patients with IM, the capacity of these sera to solubilize immune precipitates in vitro was normal. In contrast, four of five sera from patients with active systemic lupus erythematosus showed reduced solubilization. The level of C3b inactivator in sera from patients with IM and the percentage conversion of C3 after in vitro complement activation by aggregated IgG were inversely correlated (P less than 0.01). It is proposed that an acute-phase complement reaction limits immune complex-mediated injury to tissue by maintaining those complement functions that are required for the effective processing of circulating antigen/antibody material.

Genome of a mononucleosis epstein-barr virus contains DNA fragments previously regarded to be unique to Burkitt's lymphoma isolates

We wished to learn whether the genomes of strains of EBV isolated from patients with infectious mononucleosis are consistently distinguishable from those of strains from Burkitt's lymphoma. The genome of a new transforming strain (FF41) of EBV isolated from saliva of a patient with uncomplicated infectious mononucleosis was compared with the DNA of B95-8, the only other available virus from mononucleosis. It had been found previously that B95-8 has a deletion of about 8 Md in the region of the physical map represented by the Eco RI C, Hind III D, and Bam HI I fragments. The W91 and HR-1 isolates from Burkitt's lymphoma are not deleted in this region and it had been proposed that additional information was characteristic of EBV isolates from Burkitt's lymphoma. By means of restriction enzyme analysis, blot hybridization experiments and molecular cloning of FF41 DNA we demonstrate that the deletion found in B95-8 is not present in the new mononucleosis isolate. The FF41 genome contains an extra 8 Md of DNA, represented by Bam HI fragments B′, W′ and I′, which are located in a larger Eco RI C fragment. Thus the genome of this salivary isolate contains DNA that had previously been regarded to be unique to strains from Burkitt's lymphoma. It is therefore unlikely that major insertions or deletions in the EBV genome account for differences in disease manifestation following EBV infection.

The Lewis System and Secretor Status in Autoimmune Hemolytic Anemia Complicating Infectious Mononucleosis

Two patients with acute infectious mononucleosis and associated immune hemolysis were found to be Le(a-b-). One of them had anti-Leb antibodies during the acute phase of the disease, which disappeared during convalescence. Two other patients with previous infectious mononucleosis and hemolysis were found to be Le(a-b-) and Le(a+b-) respectively. Of the four patients, three were nonsecretors and the fourth likely to be so. The Lewis status of these four patients varies significantly from that of other patients with uncomplicated infectious mononucleosis and from the known distribution of the Lewis type in the Caucasian population. The findings suggest that the Lewis status of the patient is important in the development of hemolysis in infectious mononucleosis.

Platelet defect of infectious mononucleosis.

Platelet function has been studied in 16 patients with uncomplicated infectious mononucleosis. Some abnormality of platelet aggregation and/or release of platelet factor III or platelet factor IV was found in all patients. Six patients with platelet defects were retested after three to four months and were found to have normal platelet function and appreciably higher platelet counts. Abnormal platelet function may reflect a platelet defect which predisposes to premature platelet destruction. Recent viral illness should be excluded before attributing abnormal platelet function to other factors or to a congenital disorder.

Anti-i in infectious mononucleosis.

Anti-i appears frequently as an autoantibody in the blood of patients with infectious mononucleosis, but rarely results in autoimmune hemolytic anemia. This report deals with such a case and with the incidence of anti-i in patients without hemolytic anemia. The antibodies reacted best in the cold. In the patient with hemolytic anemia, the titer was 1:1,024 with cells of cord blood and 1:64 with normal adult blood cells, including the patient's own. About three weeks after the patient's recovery the antibodies were barely detectable by cells of cord blood, although a significant titer of heterophil agglutinins was still present. The incidence of anti-i agglutinins among 52 patients with uncomplicated infectious mononucleosis was found to be 69.2%. The serum of only one of the patients had a significant titer, whereas the vast majority had low titers and avidity for cells of cord blood. None reacted with normal adult cells at 37 C, but three reacted weakly at 4 C. Sera from 12 of the 52 patients who had recovered were retested for anti-i four to six weeks after onset of symptoms. All showed complete disappearance of the anti-i antibodies. It was concluded that anti-i shows a better correlation with the hemolytic and other complications of infectious mononucleosis than with heterophil agglutinins. No anti-i antibodies were detected in 23 sera screened for their presence.