Cytotoxic lymphocytes in infectious mononucleosis.

Seven patients with a clinical diagnosis of infectious mononucleosis (IM) and detectable heterophil antibodies were found to have peripheral blood lymphocytes that were cytotoxic for lymphoid cells containing Epstein-Barr virus from a patient with Burkitt''s lymphoma. The cytotoxic lymphocytes persisted in the peripheral circulation for up to 45 days. Patients who had had IM 1 to 5 years previously lacked such cytotoxic lymphocytes. Patients who had signs and symptoms of IM but no detectable heterophil antibodies lacked cytotoxic lymphocytes. The lymphocytes of one patient with IM showed progressive diminution of cytotoxic ability after prednisone treatment.     

EBV与HCMV传染性单核细胞增多症患儿的实验室指标比较

目的观察EB病毒（EBV）与人类巨细胞病毒（HCMV）感染所致的传染性单核细胞增多症（IM）患儿超敏C-反应蛋白（hs-CRP）、白细胞（WBC）计数、嗜中性粒细胞比值（N）、异常淋巴细胞（异淋）、嗜异性抗体和血清酶的变化。方法选择70例确诊有EBV病毒感染且具备传染性单核细胞增多症临床特点的患儿（A组）进行实验室检测指标分析及总结;并与37例HCMV相关传染性单核细胞增多症患儿（B组）进行比较。结果与EB组（A组）比较,HCMV组（B组）感染患儿hs-CRP水平、肌酸激酶同功酶（CK-MB）、丙氨酸氨基转移酶（ALT）、外周血WBC计数、异型淋巴细胞增高程度较低（P〈0.05）,嗜异性抗体常为阴性,两组N值差异无统计学意义（P〉0.05）。结论 EBV与HCMV感染所致的传染性单核细胞增多症患儿的实验室指标变化不同,应重视IM患儿的实验室检查以辅助诊断。     

SPONTANEOUS SPLENIC RUPTURE IN MONONUCLEOSIS

Infectious mononucleosis is a disease entity with many and various manifestations. Suspicion of the disease is of the utmost importance. When indicated, adequate tests often repeated must be made to prove or disprove a suspicion of infectious mononucleosis. The disease is usually a benign condition; one of the more serious complications is “spontaneous” splenic rupture. Whether rupture is indeed spontaneous or is caused by relatively light trauma to a weakened organ is debatable. Splenectomy is the treatment for this complication; it does not cure the underlying disease. Once the diagnosis of infectious mononucleosis has been established, abdominal examinations should be limited and cautious.     

The association of anaerobic bacteria with infectious mononucleosis

This review summarizes the information that supports the potential importance of anaerobic bacteria in the pharyngo-tonsillitis (PT) associated with infectious mononucleosis (IM). Evidence supportive of the potential of involvement of bacteria in IM was provided by several studies that showed increased recovery of bacteria on the tonsillar surfaces in IM. Several studies demonstrated that metronidazole therapy alleviated the clinical symptoms of tonsillar hypertrophy and shortened the duration of fever in IM. Metronidazole has no antimicrobial activity against aerobic bacteria and is only effective against anaerobic bacteria. A possible mechanism of its action is the suppression of the oral anaerobic flora that might contribute to the inflammatory process induced by the Epstein-Barr virus. This explanation is supported by the increased recovery of Prevotella intermedia and Fusobacterium nucleatum from the tonsillar surfaces during the acute phases of IM and an immune response against these organisms by patients with IM. Although more studies are needed, these findings support the possible pathogenicity of Gram-negative anaerobic bacteria in the PT associated with IM.     

Spontaneous Splenic Rupture in a Vivax Malaria Case Treated with Transcatheter Coil Embolization of the Splenic Artery

An enlarged spleen is considered one of the most common signs of malaria, and splenic rupture rarely occurs as an important life-threatening complication. Splenectomy has been recommended as the treatment of choice for hemodynamically unstable patients. However, a very limited number of splenic rupture patients have been treated with transcatheter coil embolization. Here we report a 38-year-old Korean vivax malaria patient with ruptured spleen who was treated successfully by embolization of the splenic artery. The present study showed that angiographic embolization of the splenic artery may be an appropriate option to avoid perioperative harmful effects of splenectomy in malaria patients.     

The cellular basis for viral-induced immunodeficiency: analysis by monoclonal antibodies

Viral infections are often associated with immunodeficiency states. Although T lymphocytes have been thought to suppress the host's response, the precise etiology remains unclear. Therefore, we characterized T lymphocytes from six patients during both acute and convalescent phases of infectious mononucleosis (IM) with monoclonal antibodies (titer, 10(-5) to 10(-7) to antigens restricted to the TH2- helper (T4) and TH2 suppressor (T5) T cell subsets as well as to a common T cell antigen (T3) and HLA-D related Ia antigens. It was found that during acute infectious mononucleosis, there is both activation and increase of suppressor T cells (T5+, Ia+ phenotype). Fuctionally, the acute IM lymphocytes suppress autologous T cell proliferation to antigens as well as pokeweed mitogen driven B cell immunoglobulin production. In contrast, convalescence is associated with a return to normal of T cell subsets and immune function. These results demonstrate that viral infections can preferentially activate a specific T cell subset and suppress the overall human immune response.     

Studies on Infectious Mononucleosis: II: Attempts at Experimental Transmission to Monkeys

Heparinized blood specimens obtained from two patients in the acute phase of infectious mononucleosis and from a healthy technician were injected intravenously into rhesus monkeys (Macaca mulatta) and the animals were observed for three weeks to one month for clinical, hematological and serological signs of infectious mononucleosis.Splenomegaly was the only definite clinical finding after 12 and 16 days, respectively. There were no definite hematological changes.At autopsy, hyperplasia of the germinal centres of lymphoid follicles, occasional foci of lymphocytic infiltration in the red pulp, and abnormal lymphoid cells in venules or arteries of the spleen were noted.The lesions in the spleen suggest that asymptomatic, presumably viral, infections occur in rhesus monkeys after inoculation with material from patients with infectious mononucleosis.     

Splenic hematoma as a first manifestation of cytomegalovirus infection

Splenic rupture is rare but life threatening complication of mononucleosis syndrome. It has been suggested that subcapsular splenic hematoma formation precedes rupture. The case of 44-year-old, previously healthy, male with splenic hematoma occurring after rising of heavy cargo is reported. Mononucleosis syndrome was suggested based on routine laboratory tests (elevated white blood cell count with predominance of lymphocytes and raised serum transaminases) and CMV infection was confirmed by serological test. Nonoperative management was used since the patient was hemodynamically stable with no further signs of splenic rupture. The same approach has been used in growing number of cases of patients with spontaneous splenic rupture in mononucleosis syndrome. Importance of considering splenic hematoma and/or rupture if abdominal pain occurs in the course of mononucleosis syndrome is outlined as well as importance of routine laboratory tests in suspecting mononucleosis syndrome in otherwise clinically silent patient.     

An Updated Meta-Analysis of Risk of Multiple Sclerosis following Infectious Mononucleosis

Background

Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published.

Methods/Principal Findings

We performed a Medline search to identify articles published since the original meta-analysis investigating MS risk following IM. A total of 18 articles were included in this study, including 19390 MS patients and 16007 controls. We calculated the relative risk of MS following IM using a generic inverse variance with random effects model. This showed that the risk of MS was strongly associated with IM (relative risk (RR) 2.17; 95% confidence interval 1.97–2.39; p<10⁻⁵⁴).

Discussion

Our results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis. Future work should focus on the mechanism of this association and interaction with other risk factors.     

Impaired Epstein-Barr Virus-Specific Neutralizing Antibody Response during Acute Infectious Mononucleosis Is Coincident with Global B-Cell Dysfunction

Here we present evidence for previously unappreciated B-cell immune dysregulation during acute Epstein-Barr virus (EBV)-associated infectious mononucleosis (IM). Longitudinal analyses revealed that patients with acute IM have undetectable EBV-specific neutralizing antibodies and gp350-specific B-cell responses, which were associated with a significant reduction in memory B cells and no evidence of circulating antibody-secreting cells. These observations correlate with dysregulation of tumor necrosis factor family members BAFF and APRIL and increased expression of FAS on circulating B cells.     

Epstein-Barr virus serology

Because of the ubiquitous nature of EBV, most people are infected with this virus by the time they are adults. People acquire the virus at an early age, earlier in developing countries and in socioeconomically deprived areas of the United States, where about 80% of 5-year-old children are seropositive. In economically privileged areas, only about 40–50% of children are seropositive by age 5. Infections during childhood are usually asymptomatic. In contrast, 50% of adolescents who become infected with EBV develop the fatigue, fever, pharyngitis, and atypical lymphocytosis characteristic of acute infectious mononucleosis (IM). Heterophil antibodies, which are the basis for screening tests for IM, usually appear in the serum of these patients. However, approximately 10% of patients (more commonly children) with EBV induced IM do not develop heterophil antibodies. For this reason, tests for specific antibody-mediated immune responses to EBV may be necessary for diagnosis.     

Immunity to Epstein-Barr virus in Hodgkin's disease preceded by infectious mononucleosis

A patient who developed Hodgkin''s disease four years after infectious mononucleosis had elevated serum antibody titres to Epstein-Barr virus and delayed hypersensitivity reactions to membrane antigens prepared from fresh autologous spleen, from spleen cells of another Hodgkin''s patient, and from cell lines known to carry the Epstein-Barr virus genome. Additional studies in more lymphoma patients will be needed to determine the significance of the reactivity against tumour and virus-associated antigens which has been documented in this patient.     

Epidemiologic studies assessing the role of the Epstein-Barr virus in Hodgkin's disease.

The hypothesis that an infection plays a role in the etiology of Hodgkin''s disease (HD) is suggested by both its clinical and histologic features. Its bimodal age-incidence pattern also suggests an infectious process among younger persons. In economically advantaged populations, the first peak occurs among young adults, while in disadvantaged populations, it occurs among children at a much lower frequency. It appears that the age distribution of HD shadows that of susceptibility to common childhood infections, such as the Epstein-Barr virus (EBV); furthermore, that risk of HD is increased among those susceptible to a relatively late infection, in parallel with infectious mononucleosis (IM), and it has been found that people who have had IM have about three times the expected rate of HD. Serologically, there is a consistent association between EBV and HD. As a group, patients have an altered antibody pattern against EBV which suggests chronic reactivation, both following and preceding diagnosis. This altered pattern is common to all age groups. Severity of infection may alter host control among younger people, while diminished cellular immunity with aging may allow similar reactivation among older persons. Whether the EBV plays a direct role or simply reflects the action of a more primary factor is unknown.     

EB病毒抗体和DNA联合检测可提高儿童传染性单核细胞增多症的诊断灵敏度

目的评估EB病毒抗体VCA-IgM、VCA-IgG、EA-IgG、EBNA-1-IgG及EBV-DNA载量检测在儿童传染性单核细胞增多症(传单)中的诊断意义。方法用ELISA方法检测70例传单患儿和25例健康儿童血清中EBV四种抗体及PCR荧光定量法检测外周血单个核细胞EBV-DNA载量。结果传单患儿组EBV-DNA的阳性率为87.14%(61/70),对照组阳性率为8.00%(2/25),传单组与对照组EBV-DNA的阳性率比较差异有统计学意义(P<0.01)。EBV抗体检测中,传单组的VCA-IgM阳性率最高,达91.43%(64/70),对照组VCA-IgM全部阴性。传单组EB病毒VCA-IgM和EBV-DNA联合检测的阳性率97.1%。结论 EBV抗体和EBV-DNA载量检测对儿童传单的诊断有极高的价值,尤其是VCA-IgM抗体和EBV-DNA联合检测,可提高儿童传单的临床诊断的敏感性。     

Severe Neutropenia in Infectious Mononucleosis

Mild neutropenia is a well-known concomitant of infectious mononucleosis caused by the Epstein-Barr virus (EBV) occurring in the first weeks of illness. However, severe neutropenia (less than 200 polymorphonuclear leukocytes per μl) is not generally regarded as a complication of infectious mononucleosis. Three patients were seen with severe neutropenia and EBV infection, and an additional eight cases were found in the literature. In two of the latter cases the neutropenia was fatal.In the 11 cases the severe neutropenia began 14 to 40 days after illness and usually lasted for three to seven days. At the time of severe neutropenia, studies of marrow specimens showed increased proportions of promyelocytes and myelocytes. Our data suggest that EBV infection is the proximate cause of the severe neutropenia in some patients with infectious mononucleosis and that in such cases close observation and early treatment of suspected superinfections is necessary.     

Infectious Mononucleosis and Mononucleosis Syndromes: Clinical,Virological and Immunological Features

Infectious mononucleosis (IM) and cytomegalovirus (CMV) mononucleosis are caused by a primary infection with related viruses, Epstein-Barr virus (EBV) and CMV. Despite the similarity of clinical manifestations, basic differences exist: (1) The heterophil antibody (HA) response is absent in CMV mononucleosis, whereas it is present in IM. (2) In IM atypical lymphocytosis reflects proliferation of B cells early and of T cells later in the disease course; in CMV mononucleosis the situation appears complex. (3) In blood, EBV is restricted to B lymphocytes, whereas CMV is found in polymorphonuclear and mononuclear leukocytes. (4) Complications of CMV mononucleosis such as hepatitis and pneumonitis may be due to virus cytopathic effect in target organs. Prominent tonsillopharyngitis with adenopathy, and visceral complications of IM are related to lymphoproliferation which is self-limited except in males with a rare familial defect in defense against EBV. Immune complex-mediated pathology may occur in both diseases. (5) CMV is frequently transmitted to a fetus in utero or to an infant during or after birth, and this occasionally leads to severe cytomegalic inclusion disease; vertical transmission of EBV appears to be exceptional. (6) Secondary EBV infections are associated with certain malignancies whereas such an association has not been recognized in the case of CMV.Toxoplasma gondii is another cause of HA-negative mononucleosis. Its complications in the heart, in skeletal muscle and in the central nervous system are related to direct invasion by the parasite. Cellular immunity plays an important role in defense against all three agents.     

Biological properties and viral surface antigens of Burkitt lymphoma- and mononucleosis- derived strains of Epstein-Barr virus released from transformed marmoset cells.

Three strains of Epstein-Barr virus (EBV), two from Burkitt lymphoma (BL) and one from infectious mononucleosis (IM) were used to transform separate cultures of the same batch of primary marmoset leukocytes, and the viruses released from the transformants were compared. The three viruses shared properties of the transforming biotype of EBV, namely, stimulation of DNA synthesis and immortalization of cord blood leukocytes, and failure to induce "early antigen" in lymphoblast lines. All viruses produced more virus in transformed marmoset cells than in transformed human cells, as measured by the number of EBV genomes detected by complementary RNA/DNA hybridization, by virus capsid antigen expression, or by released virions and biologically active virus. Reference human sera and sera from primary EBV infections were used to compare the three virus strains in a virus neutralization test based on inhibition of stimulation of DNA synthesis. Specimens taken late in convalescence from patients with mononucleosis and sera from marmosets experimentally infected with virus from a patient with mononucleosis neutralized the homologous virus, as well as the two virus strains isolated from patients with BL. This finding indicates that viral antigens that elicit neutralizing antibodies are shared among the strains. However, in certain sera the neutralizing-antibody titer against one strain was consistently higher than against another strain. Furthermore, sera taken early after onset of IM contained low levels of neutralizing antibody against IM-derived virus, but failed to neutralize BL-derived virus. These latter findings suggest the existence of heterogeneity among surface antigens of EBVs. The results emphasize the biological and antigenic similarity of EBV isolates from BL and IM and do not suggest major subtype variations. It remains to be determined whether antigenic diversity such as described or virus genome variation detectable by other means is epidemiologically significant.     

Hanganutziu-Deicher antibodies in infectious mononucleosis and other diseases

An enzyme immunoassay (EIA) was developed for the detection of heterophile, Hanganutziu-Deicher (H-D) antibodies in sera of patients with infectious mononucleosis (IM) and various other diseases. The EIA with a high m.w. glycoprotein (HMWGP) isolated from bovine erythrocyte stromata was shown to detect H-D antibodies directly, in spite of higher titers of Paul-Bunnell (P-B) antibodies in the IM sera. Absorption and inhibition studies of IM sera demonstrated H-D specificity of the antibodies combining with HMWGP in the EIA. The H-D antibodies were found in sera of 56% Caucasians and 27% of Japanese suffering from IM. The vast majority of the H-D antibodies in IM sera was of IgM class. Sera of patients with various other diseases also gave positive results: rheumatoid arthritis, 22%; syphilis, 19%; cancer of the gastrointestinal tract, 13%; and lepromatous leprosy 9.7%. The incidence of positive results in control sera from apparently healthy subjects was less than 4%. Results of this study confirmed our previous observation that whereas P-B antigens appear in immunogenic form in only IM, the H-D antigen is expressed as an immunogen in various diseases including IM.     

Infectious mononucleosis and Epstein-Barr virus

Epstein-Barr virus (EBV) is a gamma-herpesvirus that infects over 90% of the human population worldwide. It is usually transmitted between individuals in saliva, and establishes replicative infection within the oropharynx as well as life-long latent infection of B cells. Primary EBV infection generally occurs during early childhood and is asymptomatic. If delayed until adolescence or later, it can be associated with the clinical syndrome of infectious mononucleosis (also known as glandular fever or 'mono'), an illness characterised by fevers, pharyngitis, lymphadenopathy and malaise. EBV infection is also associated with the development of EBV-associated lymphoid or epithelial cell malignancies in a small proportion of individuals. This review focuses on primary EBV infection in individuals suffering from infectious mononucleosis. It discusses the mechanism by which EBV establishes infection within its human host and the primary immune response that it elicits. It describes the spectrum of clinical disease that can accompany primary infection and summarises studies that are leading to the development of a vaccine designed to prevent infectious mononucleosis.