严重慢性活动性EB病毒感染12例临床回顾与随访

目的 报告12例符合诊断标准的严重慢性活动性EB病毒感染(SCAEBV).方法 回顾性分析12例SCAEBV患儿的临床资料、实验室、血清学、影像学和病理学检查以及初步随访的结果.结果 SCAEBV临床主要表现为发热、脾肿大、肝肿大、淋巴结肿大,其他表现有皮疹、黄疸、肺动脉高压、口腔溃疡和胆囊炎等.辅助检查的异常包括乳酸脱氢酶升高、肝功能异常、贫血、白细胞降低、中性粒细胞降低、血小板减少以及胸部X线的异常等.所有患者均有抗EB病毒衣壳抗原IgG抗体的升高,而其IgM和IgA的阳性率分别为33.3%和66.7%;检测5例EB病毒早期抗原IgG均为阳性,而其IgA的阳性率为40.0%.实时定量聚合酶链反应检测外周血EB病毒DNA载量(中位数)为8.12×10~6copies/ml.12例患者中4例死亡,其中2例死于噬血细胞综合征,1例死于多重感染,1例死于多脏器功能衰竭;其余病例随访中1例发生了T细胞性非霍奇金淋巴瘤,1例脾切除术后发生了肝肺综合征.结论 SCAEBV临床表现多样,常伴有各系统严重并发症,预后差,死亡率高,应引起儿科临床医师的关注.     

Encephalitis in infectious mononucleosis: diagnostic considerations.

Four atypical cases of presumed infectious mononucleosis (IM) encephalitis are presented. To establish an etiologic diagnosis, Paul-Bunnell-Davidsohn heterophil titers (PBD), antibody titers to the antigens of the Epstein-Barr virus (EBV), and oropharyngeal excretion of EBV were determined. Criteria for a primary EBV infection are (1) an antiviral capsid antigen titer of 1:160 or greater, (2) the presence of antibody to the diffuse component of the early antigen, (3) absence of antibody to the nuclear antigen, and (4) excretion of the virus from the oropharynx. Three of the four cases met these criteria; of the three, one did not have a positive heterophil titer. The fourth case turned out not to be IM; there was a positive PBD heterophil, but there was no evidence of primary EBV infection. Although the PBD heterophil is usually a reliable test to diagnosis IM, it is not always present in children, and it is sometimes nonspecifically elevated. Some EBV titers can be nonspecifically elevated as well; however, the above criteria are diagnostic of primary EBV infection.     

Possible Role of Streptococcus pyogenes in Mucocutaneous Lymph Node Syndrome VII. A Weak Response to Epstein-Barr Viral Capsid Antigen in Mice Infected Neonatally with S. pyogenes

A negligible, if not entirely negative, production of antibody to Epstein-Bart virus(EBV)-associated antigens in patients with mucocutaneous lymph node syndrome(MCLS) has been a perplexing problem for investigators who are in favor of a streptococcal etiology of the disease. In the present investigations, antibody formation to EB viral capsid antigen (VCA) was assessed by the use of the indirect immunofluorescence technique in mice which had been subjected to neonatal infection with an attenuated strain of Streprococcus pyogenes or inoculation with either heat-killed streptococci or streptolysin-O, both of which were emulsified in Freund's complete adjuvant (FCA). Each mouse of these groups was inoculated 30 days or so later with EBV dilution in FCA, blood was collected about three weeks after virus infection, and antibody titers were assessed individually. According to the results of these experiments, no apparent difference was detected among the mice, irrespective of the methods of their neonatal treatment concerning their refractoriness to EB-VCA; the majority of the animals showed titers of less than 1:8, no case having a titer above 1:30. In contrast, all sera from control mice yielded positive responses showing antibody titers of 1:250 and over. Such an immunological character is an exact counterpart of that of MCLS patients. Accordingly, the recent research focus on EBV as a possible etiological agent of MCLS seems to be too restrictive.     

Burkitt's lymphoma following a pediatric liver transplantation: predictive negative value of serologic response to Epstein-Barr virus

Post-transplant lymphoproliferative disorder (PTLD) represents a spectrum of Epstein-Barr virus (EBV)-related clinical diseases, from a benign mononucleosis-like illness to a fulminant non-Hodgkin's lymphoma. Because a large proportion of children are seronegative at the time of transplantation, recipients are at high risk of contracting primary EBV infection and subsequently developing PTLD. Surveillance techniques with antibody titers and/or polymerase chain reaction (PCR) may have a role in some high-risk settings. A 12-year-old boy whose serologic response to EBV was negative during follow-up after liver transplantation (LTx) developed Burkitt's lymphoma, a rare and the most severe variant of EBV-related PTLD, 32 months after LTx. He expired possibly due to side effects of treatment. We recommend that viral monitoring must be done using PCR during follow-up of pediatric LTx to prevent dramatic outcomes.     

Clinical, virologic, and serologic evidence of Epstein-Barr virus infection in association with childhood pneumonia

To explore the association of Epstein-Barr virus infection with childhood pneumonia we studied two patients whose mononucleosis-like illnesses were accompanied by pneumonia; both had virologic and serologic evidence of current or recent EBV infection. We then analyzed the sera of 71 children (age range, 14 months to 9 years) with pulmonary infiltrates for the presence of four classes of antibody to EBV. Antibody responses consistent with current or recent EB virus infection were found in 15. Two children had IgM antibodies to the EBV viral antigen at titers greater than or equal to 1:160, indicating current infection, and all 15 patients had antibody to components of the early antigen complex, suggesting recent infection. A fourfold rise or drop in one or more EBV-specific antibody classes was noted in eight patients within 30 days following onset of clinical illness. Few patients had clinical features suggesting infectious mononucleosis. Eight of the 15 with serologic evidence of current or recent EBV infection also had clinical or serologic evidence of infection with another pathogen--bacterial, viral, or mycoplasmal. Thus, in childhood pneumonia, EBV may be a primary, co-primary, or secondary pathogen; it may be reactivated in the course of infection with another agent, or possibly, by suppressing immune function, it may precipitate infection with some other organism.     

Severe chronic active Epstein-Barr virus infection syndrome and adenovirus type-2 infection

Four patients from 4 to 24 years of age (3 males, 1 female) with generalized lymphadenopathy, hepatosplenomegaly, and intermittent fever associated with chronic active Epstein-Barr virus (EBV) infection were investigated. Laboratory data showed polyclonal gammopathy and a tendency for bone marrow suppression. Noteworthy were the extremely elevated immunoglobulin G (IgG) antibody titers to Epstein-Barr viral capsid antigen (VCA) (range, 10,240-81,920) and early antigen (EA) (range, 1,280-40,960). All patients had IgA antibodies to VCA and EA. Subtle, heterogeneous immune functional defects were observed in all four patients. Another unusual feature was our inability to establish spontaneous or B95-8 EBV-immortalized lymphoblastoid cell lines (LCLs) due to a marked cytopathic effect (CPE). Thus, we investigated for other viruses. Both IgG and IgM antibodies to adenovirus type-2 (Ad-2) were positive by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence (IF) test, suggesting recent or activated Ad-2 infection had occurred. Dual active EBV and Ad-2 infections were likely etiologic in this severe chronic active EBV infection syndrome.     

Primary Epstein-Barr virus infections in children.

During a serioepidemiologic survey of a community, 13 (6.2%) of 209 children were found to be experiencing a current or recent primary Epstein-Barr virus (EBV) infection. The sera contained elevated antibody titers to viral capsid antigen of EBV, antibodies to early antigen (EA) of EBV, and specific IgM. The frequency of primary infections was highest in the first decade of life. The primary EBV infections were usually asymptomatic. The antibody to EA was directed predominantly to the R component. A heterophil antibody response was not detected.     

Antibody response to herpes simplex virus type 1 polypeptides and glycoproteins in primary and recurrent infection

Sequential sera from a patient with primary Herpes Simplex Virus type I (HSV-1) encephalitis and a patient with HSV-1 recurrent oral lesions were collected. Sera were analyzed quantitatively by radioimmunoassay and qualitatively by electrophoresis and autoradiography of immune precipitates to determine the sequence of antibody production to specific radiolabeled HSV-1 polypeptide and glycoprotein antigens. The major antibody response in both primary and recurrent sera was against HSV-1 envelope antigens and the major capsid polypeptide. Sequential sera showed a significant correlation between neutralizing antibody titers and quantitative antibody to HSV-1 glycoproteins. Qualitative electrophoretic analysis of primary infection sera showed sequential appearance of antibodies to increasing numbers of HSV-1 polypeptides by the fourteenth day of infection. A corresponding qualitative antibody response to glycoproteins was not seen. Sequential sera obtained before, during, or after a recurrent lip lesion in another patient showed no significant quantitative or qualitative changes in antibodies to either HSV-1 glycoproteins or polypeptides.     

Association of Epstein-Barr virus infection and pulmonary exacerbations in patients with cystic fibrosis.

We observed severe pulmonary exacerbations during primary Epstein-Barr virus (EBV) infection in adolescent patients with cystic fibrosis. Since EBV is not a known respiratory tract pathogen in cystic fibrosis, we studied retrospectively all EBV-susceptible patients ages 6 to 18 years with chronic Pseudomonas respiratory tract colonization hospitalized for a pulmonary exacerbation during an 18-month period. Patients with serologic evidence of primary EBV infection (n = 5) were compared to control patients without EBV (n = 7). Before admission the groups had similar pulmonary function tests, clinical scores and frequency of hospitalization. On admission patients with EBV had significant weight loss, lower pulmonary function tests and lower clinical scores compared with controls. All remained significantly different 6 months after admission. Frequency of exacerbations requiring hospitalization increased after EBV infection but remained unchanged in controls. Primary EBV infection can be associated with severe pulmonary exacerbations and subsequent deterioration in clinical course in cystic fibrosis patients.     

Impact of FK506 and steroids on adaptation after intestinal resection or segmental transplantation

Segmental small intestinal transplantation (SIT) using living related donors (LRD) is being evaluated as a therapy, clinically. Advantages of this technique include an increase in the donor pool, optimization of the timing of transplants, and potential immunologic benefits. However, the ability of a short segment of intestine to function after transplantation has not been investigated in large animal models. This study evaluates the impact of immunosuppression on the adaptive process and the ability of a transplanted segment of intestine to adapt. A pig model of segmental SIT was used. Animals were resected, leaving 150 cm of distal ileum (n = 5), resected and treated with FK506 (n = 4), or steroids (n = 4), or with FK506 + steroids (n = 7), or transplanted using a similar segment of ileum and treated with FK506 + steroid immunosuppression (n = 9). Animals undergoing resection, or resection plus steroid treatment, did well, gaining weight post-operatively (37% and 15% of preoperative weight, respectively). However, animals undergoing resection and treated with FK506 or FK506 + steroids did poorly, losing weight (-14% and -22% of preoperative weight, respectively) and showing significant impairment of intestinal adaptation, morphologically and functionally. Furthermore, FK506-treated animals developed inflammatory changes in the intestinal mucosa, mimicking rejection. Segmental SIT animals had a high rate of rejection (66%) and showed a similar impairment in adaptation. Hence, segmental SIT is a stringent physiological test of intestinal adaptation. FK506 appears to impair gut function after resection, either directly, or by interfering with the adaptive process. In this model of segmental SIT, FK506 and steroids at the doses tested did not provide adequate immunosuppression to prevent rejection and the graft did not function adequately to allow growth. Further studies are required to evaluate the mechanisms underlying these findings, and to determine if similar effects occur in humans.     

Ataxia Telangiectasia with Persistent Epstein-Barr Virus Infection and Malignant Lymphome

Ataxia telangiectasia is agenetically determined immunodeficiency with predisposition to malignancy. Herein we report a case of ataxia telangiectasis in a child who had showed high antibody titers to viral capsid antigen (VCA), presence of antibodies to Epstein-Barr virus (EBV) induced early antigen (EA), low titers of antibodies to EBV associated nuclear antigen (EBNA), and a high incidence of EBNA-positive cells in the peripheral blood without symptoms of infectious mononucleosis before succumbing to malignant lymphoma five years later. We hypothesize the association betwen some cytogenetic defects and persistent EBV infection on the development of the malignant lymphoma in this patient.     

Vidarabine therapy for severe chronic active Epstein-Barr virus infection

PURPOSE: Severe chronic active Epstein-Barr virus infection (SCAEBV) is an intractable disease with a poor prognosis, and a definitive treatment has not been established. We administered vidarabine to patients with natural killer (NK) cell-type SCAEBV and evaluated clinical and virologic effects. PATIENTS AND METHODS: Four patients with SCAEBV were enrolled in this study. These patients had various symptoms, including fever, chronic hepatitis, hepatosplenomegaly, and hypersensitivity to mosquito bites. All patients had increased numbers of NK cells in their peripheral blood, and most of these were infected with EBV. Viral load was measured by in situ hybridization and quantitative polymerase chain reaction (PCR). RESULTS: The patients all responded to the therapy, and their symptoms improved. After the therapy, the number of NK cells in their peripheral blood decreased. In two patients who were closely monitored, the viral load measured by in situ hybridization and quantitative PCR decreased in parallel with the symptomatic improvement. After discontinuing this drug, the patient's symptoms returned and the Epstein-Barr virus load increased again. CONCLUSION: These results indicate that vidarabine therapy is a therapeutic choice to control SCAEBV, although its effect may be transient.     

Transient immunodeficiency during asymptomatic Epstein-Barr virus infection

In vivo and in vitro humoral and cellular immune responses were studied in a 2 1/2-year-old girl immediately before, during, and after an asymptomatic infection with Epstein-Barr virus. During the acute EBV infection, the patient's peripheral blood mononuclear cells were deficient in immunoglobulin synthesis and suppressed the in vitro immunoglobulin synthesis of normal allogeneic cells. In vitro mitogen transformation of lymphocytes was reduced. In vivo antibody responses to the T cell-dependent antigens bacteriophage phi X 174 and Keyhole limpet hemocyanin were markedly depressed. These studies suggest that suppressor cells induced during acute EBV infection not only suppress immunoglobulin synthesis in vitro, but also interfere with in vivo antibody synthesis.     

Chronic hepatitis associated with Epstein-Barr virus infection in an infant

A 1-year-old infant girl had a chronic illness characterized by persistent intermittent fever, thrombocytopenia, granulocytopenia, and marked hepatosplenomegaly. Histological findings on liver biopsy 307 days after the onset of her illness disclosed marked mononuclear cell infiltration and moderate fibrosis in the portal and perilobular areas. Interferon-therapy induced no clinical and laboratory improvement, whereas the patient's clinical and biochemical findings responded to prednisone. Although these findings suggested a possible autoimmune mechanism, there were no significant findings in extensive immunological and serological tests consistent with autoimmune disease. The profile of antibodies to Epstein-Barr virus (EBV)-specific antigens in the patient demonstrated that this prolonged atypical illness was the result of persistent EBV infection.     

Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis is a rare, life-threatening complication of Epstein Barr virus (EBV) infection. Current treatments are directed at reducing virus-induced immune dysregulation. Addition of agents that eliminate EBV-infected B cells may improve therapeutic efficacy. On the basis of the observations that the anti-CD-20 monoclonal antibody rituximab reduces disease burden in individuals with EBV-associated lymphoproliferative disorders, we treated a patient with severe EBV-hemophagocytic lymphohistiocytosis using a combination of rituximab and chemotherapy. This patient demonstrated a rapid clinical response and an 18-fold reduction in EBV viral load within 24 hours of receiving rituximab. He remains free of disease 8 months after completing treatment.     

A role for genetics in the immune response to the varicella vaccine

BACKGROUND: A wide range in antibody titers has been found after immunization with the varicella vaccine, although the basis for these differences has not been described. METHODS: To evaluate the contribution of a genetic component in the immune response to the varicella vaccine, concordance for six-week postimmunization antibody titers was evaluated among 248 biologic siblings who participated in varicella vaccine clinical trials by comparing all pairs of siblings (151 pairs) to all possible unrelated, nonsibling pairs created from within this same cohort (30,477 pairs). RESULTS: Postimmunization antibody titers after 1 varicella vaccine dose were within the range observed historically among healthy vaccinees, with 85.4% of subjects having antibody responses greater than the approximate correlate of protection of 5 gpELISA units. Postimmunization antibody titers within sibling pairs clustered together more than or less than 10 gpELISA units when compared with within nonsibling pairs (P < 0.0001). Postimmunization titers within sibling pairs were also quantitatively closer together than were those within unrelated, nonsibling pairs (P = 0.022). The age-adjusted intraclass correlation coefficient indicated that the heritability of the varicella vaccine immune response is 45% (95% confidence interval of 15-75%). CONCLUSIONS: Similarities in siblings' response to varicella vaccine are supportive of the hypothesis that genetic factors play a role in the antibody response to the varicella vaccine.     

Serotype-specific serum IgG antibodies to lipopolysaccharides of Pseudomonas aeruginosa in cystic fibrosis: correlation to disease, subclass distribution, and experimental protective capacity

Various studies have demonstrated pronounced systemic IgG response to Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF). However, antibody response to serotype-specific lipopolysaccharides (LPS) has never been studied. ELISA for detection of IgG antibodies to LPS of nine PA-serotypes and to toxin A were performed with serum of 78 CF patients. Anti-LPS profiles of antibodies were confirmed by SDS-PAGE and immunoblotting techniques. The most frequent PA-serotypes found were immunotypes (IT) IT-1 and IT-2, and Habs-3 and Habs-4. Ten patients without PA colonization showed no detectable antibody titers. In patients with chronic PA colonization (n = 46), these antibody titers were significantly (p less than 0.005) higher than in patients with intermittent PA colonization (n = 22). Mean serum antibody titers to LPS of PA IT-1, IT-2, Habs-3, and Habs-4 correlated with duration of PA colonization and with disease severity. Subclass analysis of anti-LPS antibodies revealed elevated levels for all four IgG subclasses and for IgA1. The IgG antibodies to LPS of PA proved to be protective in a murine burn wound sepsis model. We conclude that anti-LPS antibodies to specific PA serotypes in serum may be a sensitive measure of severity and prognosis of CF. Patients with CF show adequate functional immune response to LPS of PA, and it is possible that vaccination against PA before colonization could induce protective immunity.     

Immunodeficiency in children with acute lymphoblastic leukemia after completion of modern aggressive chemotherapeutic regimens

OBJECTIVE: To determine the prevalence, duration, and a potential cause of humoral defect(s) in children with acute lymphoblastic leukemia (ALL) at least 1 year after completion of chemotherapy. STUDY DESIGN: Antibody titers for mumps, rubeola, rubella, tetanus and diphtheria toxoid, poliovirus serotypes 1, 2,and 3, Haemophilus influenzae type b, varicella, and hepatitis B were obtained from 100 children with ALL. Children with non-protective titers to these microbial antigens were re-vaccinated and re-studied after anamnestic vaccine challenge. RESULTS: The percent of children with ALL who had protective titers was markedly less than that anticipated for immunized control subjects. Longitudinally, many titers fluctuate between protective and non-protective antibody responses after re-immunization. The chemotherapy protocol used did not affect the ability of these children to express protective antibody responses. T-, B-, and NK-cell numbers and proliferative responses to mitogens were all normal. Age correlated with titer results for certain vaccines. CONCLUSIONS: Children in remission from ALL have a high prevalence of humoral immune defects that are not related to any specific chemotherapy regimen. This antibody deficiency may place children with ALL at risk for the development of these bacterial and viral diseases, even after completion of chemotherapy. Pediatricians, oncologists, or both should periodically monitor humoral immunity after chemotherapy and re-vaccinate these children, as needed, to ensure prolonged immunoprotection.     

Antibody titers and immune response to diphtheria-tetanus-pertussis and measles-mumps-rubella vaccination in children treated for acute lymphoblastic leukemia

The objective of this study was to investigate the diphtheria-tetanus-pertussis and/or measles-mumps antibody titers before and after vaccination at various time points of acute lymphoblastic leukemia (ALL) therapy and to suggest an appropriate vaccination approach for ALL patients. The authors studied 37 ALL patients and 14 healthy control subjects, divided into three groups. In group 1 (newly diagnosed patients), baseline anti-diphtheria, anti-tetanus, and anti-pertussis titers were determined. Patients in group 2 (on maintenance chemotherapy) and group 3 (patients not receiving therapy for 3-6 months) were vaccinated with diphtheria-tetanus with or without acellular pertussis; group 3 and control subjects were also given measles-mumps-rubella vaccine. Preimmunization and 1-month postimmunization titers were drawn. Preimmunization anti-diphtheria and anti-tetanus antibody titers between the groups and the controls were statistically similar. The seropositivity rate for anti-measles antibody in group 3 was significantly lower than controls. After vaccination, all of the patients developed protective anti-diphtheria and anti-tetanus antibody titers. The seroconversion rates of group 3 and controls for anti-measles and anti-mumps antibodies were statistically similar. The results showed that patients on maintenance therapy and after cessation of therapy made good antibody responses to diphtheria and tetanus toxoids, but response to measles and mumps vaccines was not as sufficient as toxoid vaccines. Children with ALL can receive the appropriate vaccines during and after maintenance treatment.     

Comparison of the antibody response to streptococcal cellular and extracellular antigens in acute pharyngitis

The antibody response to the group A carbohydrate moiety of the streptococcal cell wall is of special interest because of its postulated role in the pathogenesis of rheumatic valvulitis. The immune response to this somatic antigen was measured in 159 children with culture-proved group A streptococcal pharyngitis and was compared with that to two extracellular antigens of the Group A streptococcus: streptolysin O and streptococcal DNase B. The data suggest that the maximum anti-A-carbohydrate rise occurs soon after the onset of streptococcal pharyngitis in a fashion similar to the response to some streptococcal extracellular antigens. However, the anti-A-carbohydrate antibody response appeared to be a less sensitive indicator of streptococcal upper respiratory tract infection.