A case of hemorrhagic infectious mononucleosis.
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By the indirect immunofluorescence technique, IgM antibodies to the cell surface of an Epstein-Barr virus (EBV) producer cell line, P3HR-1, were detected in sera from infectious mononucleosis (IM) patients but not in sera from patients with Burkitt lymphoma or nasopharyngeal carcinoma nor in sera from healthy adult donors having antibodies to EBV-specific viral capsid antigen (VCA). Titers of the IgM antibodies were higher in the earlier stages of IM, a pattern similar to that for IgM antibodies to VCA. The IgM antibodies to the cell surface were identified as being those against the EBV-specific membrane antigen (MA) by the following criteria: (1) The antibodies were reactive to MA-positive cell preparations but to MA-negative cell preparations. (2) Titers of the IgM antibodies were not significantly affected after absorption of sera with sheep red blood cells which could completely eliminate heterophil antibodies in the same sera. Detection of the IgM antibodies to MA may have a particular diagnostic value for providing evidence of a recent EBV infection.
The efficiency of two types of antigen slides was compared by using the indirect fluorescent-antibody technique. Fifty sera from infectious mononucleosis patients were tested concurrently on the two sets of slides for antibody to Epstein-Barr virus. The indirect fluorescent-antibody serum titer readings from the epoxy slides were either equal to or twofold higher than those from the cover slip slides.
Metronidazole (600-1 200 mg daily) and phenoxymethyl penicillin (1.6 g daily) were administered to 21 patients with anginose type of infectious mononucleosis. A control group with 19 other patients received only phenoxymethyl penicillin in the same dosage. The patients were randomly allocated to metronidazole treatment and were stratified into 2 further groups according to the duration of tonsillitis (less than or equal to 5 and > days, respectively) before instituted therapy. Changes in the state of the tonsillitis, body temperature reaction and acute phase reactants (alfa1-antitrypsin, antichymotrypsin, C-reactive protein, haptoglobin and orosomucoid) were parameters for evaluation of the effect. Metronidazole treatment resulted in a more rapid regression of tonsillitis note on the 4th day in both treated groups and a faster defervescence noted on the 3rd day compared to controls. The effect was most pronounced in patients with a duration of tonsillitis for > 5 days at admission. At 2 weeks after start of treatment a more rapid normalization of acute phase reactants was seen in the metronidazole groups. Especially in patients with tonsillitis for > 5 days before treatment the decrease of the C-reactive protein level was rapid during the 1st week.
Epstein-Barr virus (EBV) is the aetiological agent of infectious mononucleosis (IM) which is a common sequel to primary EBV infection. Thereafter, the virus is maintained as a lifetime latent infection. Although the proteins expressed during the latent EBV infection provide a rich source of immunogenic epitopes, very little is known about cytotoxic T lymphocyte (CTL) control of primary EBV infection. The present report is based on an analysis of CTL clones derived from a patient suffering from acute IM. An intriguing feature of six CTL clones that displayed an HLA-restricted pattern of cell lysis was their initial coexpression of the T cell markers CD3, CD4, and CD8. Detailed analysis of one of these clones, which was restricted through the class II MHC antigen DR2, revealed reactivity with an epitope within the EBV lytic cycle early antigen, BHRF-1, which corresponds to the C-terminal region of the protein (AGLTLSLLVICSYLFISRG) (residues 171-189). There have been no previously published reports describing a CTL response during acute IM directed against an EBV lytic antigen. Interestingly, the coexpression of CD4 and CD8 by these CTLs during acute IM suggests that CD3+CD4+CD8+ cortical thymocytic precursor cells are recruited in order to overcome the EBV infection.
A search for antibody rises to viral antigens other than to Epstein-Barr virus, the causative agent, has been carried out in serial serum samples from 82 patients with infectious mononucleosis (IM). Fourfold or greater rises in titer rarely occurred and did did not cluster in time. No rises occurred to cytomegalovirus, only 1.2 percent to herpes simplex virus, and 8.5 percent to varicella zoster virus. Rises to measles antibody were found in 7.5 percent of patients and to rubella in 10.4 percent; these may represent natural infections or immunizations. A few patients also showed rises to respiratory viruses but there was no apparent connection to IM.
Patients with Epstein-Barr virus (EBV)-associated dissorders usually demonstrate evidence of immunosupression during active disease. Sera of some patients with EBV-induced infectious mononucleosis (IM), contain an IgG-blocking factor (IM-IgG) which inhibits in vitro cell-mediated immune responses and which we postulate plays an important role in viral immunosuppression. We had shown earlier that Isoprinosine (an immunostimulator) has a counterinhibitory effect on this IM-IgG activity. Here we describe evidence showing for the first time that the immunosuppressive activity of IM-IgG is aimed at inhibition of interleukin-2 (IL-2) synthesis and does not affect IL-2 receptors.
Bovine sera for tissue culture use were shown to contain heterophil antigen of the Paul-Bunnell-Davidsohn type by immune adherence hemagglutination tests with sera from patients with infectious mononucleosis. The antibody titers observed were comparable to those determined by two other methods; i.e., the immune adherence hemagglutination test was found to be as specific as the differential absorption test with horse erythrocytes or the ox cell hemolysis assay,but it appeared to be the most sensitive of the three procedures. All 16 individual or pooled bovine serum samples showed Paul-Bunnell-Davidsohn antigen at concentrations varying over a fourfold range. The potential usefulness of the immune adherence hemagglutination test for various Paul-Bunnell-Davidsohn antigen-related problems and implications of the observations are discussed.
Acute infection is known to perturb psycho-neuroendocrine-immune (PNI) gene expression. Oligonucleotide microarrays were used to examine PNI gene expression in the peripheral blood of 13 subjects with infectious mononucleosis (IM). Novel peripheral blood gene expression activity was correlated with central-nervous-system-mediated symptoms including fatigue and sleep disturbance. Of note, expression of the MADS box transcription enhancer factor 2 polypeptide C (MEF2C) gene, previously implicated in skeletal muscle myogenesis, correlated with symptoms of musculo-skeletal pain and fatigue. Expression of the hypocretin/orexin receptor HCRTR2, which has been implicated in narcolepsy, correlated with sleep disturbance. And, VACHT, the vesicular acetylcholine transporter, was highly correlated with neurocognitive disturbance. The expression of both HCRTR2 and MEF2C in the peripheral blood was validated by reverse transcription PCR. Thus, investigation of the PNI response in peripheral blood may provide novel insights into the complex pathophysiology of centrally mediated disease states.
We present an autopsy case of 20-month-old boy who had a fulminant course of infectious mononucleosis, with severe hepatic failure. Autopsy revealed marked infiltration of immunoblasts in the lymph nodes, liver, spleen, thymus and kidneys. We identified a large number of Epstein-Barr virus (EBV) genomes in the immunoblasts of the lymph nodes, liver and spleen by in situ hybridization. EBV genomes were also detected in the liver and spleen by Southern blot hybridization. Histology of the liver revealed diffuse feathery degeneration of the hepatocytes. However, EBV genomes were not detected in the hepatocytes by in situ hybridization and monoclonal antibody studies. Immunostaining of the autopsy liver specimen revealed a large number of suppressor/cytotoxic T cells (Leu2a positive) in the portal areas and of natural killer (NK) cells (Leu7 positive) in the portal areas and sinusoids of the liver. We therefore suggest that the hepatocellular damage was not caused by the viral replication in the hepatocytes but was mainly caused by the abnormal killer cell activity of the suppressor/cytotoxic T cells and NK cells.
By indirect immunofluorescence (IF) technique humoral antibodies to Epstein-Barr virus capsid antigen (EB-VCA) and to cytomegalovirus (CMV) were detected in 47% and 9% of persons with infectious mononucleosis (IM), respectively. In 23% of the patients examined, IgM antibodies to both viruses were detected, while in 8% of them high titres of IgG only were found in the absence of IgM class antibodies to EB-VCA or to CMV. The finding of IgM antibody to EB-VCA was in good correlation with the persisting symptoms of the disease. Discrepancy between the presence of specific IgM and the absence of heterophilic antibodies was observed in some children and in all persons with persistent or recurrent signs of IM. In the latter, specific IgM was found only during exacerbation of the disease, but during remissions IgG antibodies persisted in high levels. Antibodies to Epstein-Barr virus nuclear antigen (EBNA) were detected in all chronically ill persons and antibodies to the R-component of Epstein-Barr virus early antigen (EA) were present in the majority of them.
We have described a 10-year-old child in whom a pleural effusion complicated an otherwise typical case of IM. Although rare, pleural effusions are a possible complication of infectious mononucleosis, and IM should be considered in the differential diagnosis of pleural effusions in children.
9,249 persons were examined by Paul-Bunnell-Davidson test and in 329 heterophile antibodies were established in titre > 1/40 which enables, with corresponding clinical-laboratory parameters, diagnosis of infectious mononucleosis caused by Epstein-Barr virus. In 271 persons diagnosis could not be established by testing only one sample of serum and performing only one test. That is why Epstein-Barr virus specific tests were recommended and their diagnostic possibilities in certain stages of Epstein-Barr virus infection have been theoretically considered.
Serum total IgG, IgA, IgM, IgD, and IgE concentrations, heterophil antibody titer, Epstein-Barr virus (EBV)-specific antibodies titer, and hematologic changes were studied longitudinally in 19 patients with EBV-induced infectious mononucleosis who were followed up for 1.5-34 months. In 9 patients, the changes in these variables were compared with baseline data on a pre-illness serum sample. All 5 immunoglobulins (Ig) showed a significant rise during the acute illness followed by a drop during convalescence, and a gradual 'normalization' within several months to a year. On the average, IgE peaked to 276% during the first week, IgM to 176% at about 10 days, IgA to 154% at 15-20 days, IgG to 135% at 10-15 days, and IgD to 141% during the first 2 months after onset. IgE and IgM levels were significantly suppressed during convalescence by an average of about 40 and 25% of pre-illness level, respectively. A relationship was noted between Ig rise and the increase in circulating atypical lymphocytes. The data clearly demonstrate the polyclonal nature of Ig production during the acute phase of EBV-induced mononucleosis, with a striking and early reactivity of IgE.
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A 17-yr-old girl in end-stage renal failure was due to undergo living-related pre-emptive renal transplantation when she developed acute infectious mononucleosis (AIM) from Epstein-Barr virus (EBV). In view of the risk of post-transplant lymphoproliferative disorder (PTLD) we were unsure as to the optimal delay between AIM and renal transplantation. This report describes the process used to determine maturation of the immune response to EBV using a combination of serology, immunophenotyping and molecular viral load estimation. These tests showed that EBV had not been cleared and dialysis was instituted rather than proceed directly to transplantation. After EBV viral load became undetectable in the blood, living-related donor was successfully performed 13 months after AIM. With 42-month post-transplant follow up there has been no evidence of PTLD.
Tests for antibodies to Epstein-Barr viral capsid antigen or Epstein-Barr nuclear antigen are the most sensitive, are highly specific, and are also the most expensive for diagnosing infectious mononucleosis (strength of recommendation [SOR]: C, based on validating cohort study). Heterophile antibody tests have similar specificity and are cheaper, but are less sensitive in children or in adults during the early days of the illness (SOR: C, based on validating cohort study). The polymerase chain reaction assay for Epstein-Barr virus DNA is more sensitive than the heterophile antibody test in children, is highly specific, but is also expensive (SOR: C, based on validating cohort study). The percentages of atypical lymphocytes and total lymphocytes on a complete blood count provide another specific and moderately sensitive, yet inexpensive, test (SOR: C, based on validating cohort study).