Severe Infectious Mononucleosis Research Articles

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infectedtransformed B cells.

Clinical and Pathological Characteristics of Severe EBV Infection in Japanese Children; a Disease Spectrum from Acute Liver Failure to Hemophagocytic Lymphohistiocytosis

Abstract Background Epstein-Barr virus (EBV) is a ubiquitous herpesvirus known as a cause of infectious mononucleosis (IM). While most EBV infection is mild and self-limited, severe EBV diseases such as severe IM, EBV-associated hemophagocytic lymphohistiocytosis (HLH) and EBV-associated acute liver failure (ALF) may occur on rare occasions. Interestingly, the severe EBV disease with ALF may occasionally present with overlapping features of HLH; however, it remains unknown if the presence or absence of HLH reflects a distinctive underlying pathophysiology of EBV infection. To investigate the clinical and pathological characteristics of EBV-associated ALF among children, we conducted a single-center, retrospective study at the largest tertiary children’s hospital in Japan. Methods We enrolled children under 18 years old who required medical management in the intensive care unit due to primary EBV infection between January 2010 and April 2021. Patients with underlying immunodeficiencies and other medical conditions were excluded. Clinical data, type of EBV-infected cell lineage, and pathological exam were reviewed. Fourteen patients with EBV-associated ALF were identified in the initial screening, and two were excluded (due to underlying medical conditions). Thus, the details of 12 patients were further analyzed. Five patients fulfilled the criteria for HLH, while seven presented as isolated ALF only. Results The most common symptoms of these patients include fever (92%), vomiting (58%), and consciousness disturbance (100%). EBV loads were higher when HLH co-existed (median 2,700 copies/μg of DNA vs. 130,000 copies/μg of DNA, p = 0.01). Identification of EBV-infected cells revealed that the most common cell type was CD8+T cells (8/12, 80%), followed by CD3+T cells (1/12, 10%), and CD19+ cells (2/12, 20%). EBV infected in both CD8+T and CD19+ cells in one case and EBV-infected cells were not identified in two cases. In addition, an increase of activated CD8+ T cells (CD3+CD8+HLA-DR+) was observed in both HLH and ALF cases. Among 12 patients with ALF, seven patients underwent life-saving liver transplantation (LT) due to ALF. Of five patients with ALF+HLH, all patients received corticosteroid, four received cyclosporin or etoposide, and one underwent hematopoietic stem cell transplantation (HSCT). Overall mortality is 17% (2/12 patients), and both patients were complicated with HLH. Conclusion This study suggests that HLH and ALF can be an indistinguishable spectrum of severe EBV disease, and the underlying pathogenesis may be associated with the unusual type of EBV-infected cells. Hence, the identification of EBV-infected cells should be considered to guide the diagnosis and treatment. Our study also revealed that LT and cytotoxic anti-inflammatory therapy effectively treated patients with EBV-associated ALF with or without HLH, given the high mortality (>70%) of this disease spectrum. Further studies investigating EBV-associated ALF pathology are warranted to determine optimal management.

Pseudomembranous necrotic pharyngotonsillitis: a microbiologic criminal conspiracy

Within a few months, two young people were hospitalized in the infectious diseases department of Bordeaux University Hospital, France, for severe infectious mononucleosis tonsillitis. Both had fever, dysphonia, hypersialorrhea, halitosis, aphagia and activated circulating lymphocytes. Pharyngeal examination revealed a bilateral pseudomembranous and necrotic tonsillitis. Both had a good oral health and did not smoke nor reported alcohol use disorder. The diagnosis of infectious mononucleosis was confirmed by Epstein-Barr Virus serology and plasmatic PCR in both cases. The first patient was a 19-year-old man, he had received oral corticosteroids which had worsened the symptoms. The second patient was a 21-year-old woman. The rapid chromatographic immunoassay for qualitative detection of group A streptococcal antigen was negative for both patients. Necrotic pseudomembranes were swabbed, smeared on a slide before Gram staining which revealed in both cases a fusospirillar association evocative of Plaut-Vincent’s tonsillitis considered to be caused by Treponema vincentii and Fusobacterium nucleatum. Bacterial culture of necrotic pseudomembranes was negative in both cases. Both were treated by metronidazole in order to prevent the classically described amoxicillin-induced rash in infectious mononucleosis. Their symptoms rapidly improved under antibiotic therapy until full recovery. The association between infectious mononucleosis and Plaut-Vincent’s tonsillitis has seldomly been described in the literature ( 1 Pino Rivero V. González Palomino A. Pantoja Hernández C.G. Trinidad Ramos G. Marcos García M. Rejas Ugena E. et al. [Plaut-Vincent’s acute necrotizing ulcerative fusospirillum tonsillitis associated to infectious mononucleosis]. An Otorrinolaringol Ibero-Am. 2006; 33: 219-224 Google Scholar ), however Plaut-Vincent’s tonsillitis might be underdiagnosed since Gram staining on tonsil swabs is rarely performed in pharyngotonsillitis. Plaut-Vincent’s tonsillitis has been described for the first time at the end of the 19th century, first by Plaut in 1894 then by Vincent in 1898 ( 2 Harrell V. The present status of Plaut-Vincent's infection. Arch Otolaryngol. 1931 1; 14: 1-8 Crossref Google Scholar ) (Fig. 1).

Jaundice in relation to immune activation during Epstein-Barr virus-induced infectious mononucleosis

BackgroundLiver involvement during infectious mononucleosis is common, but jaundice is considered rare. This study aimed to investigate serum bilirubin concentrations in patients with infectious mononucleosis and immune abnormalities associated with jaundice. MethodsWe report on an adult patient with monoclonal B lymphocytosis and IgM-lambda gammopathy who developed a severe icteric hepatitis during infectious mononucleosis. We then reviewed the clinical records of 389 patients admitted to the hospital with infectious mononucleosis between 1995 and 2018 (51.7% male patients; median age, 19 years; range, 15-87 years) with focus on liver abnormalities and associated factors. ResultsFifty-nine patients (15.1%) had serum bilirubin concentrations between 1.5 and 3 mg/dL, and 47 patients (12.0%) had serum bilirubin >3 mg/dL. Patients with increased bilirubin concentrations had a distinct clinical presentation, with more frequent abdominal pain, nausea and vomiting, and less frequent sore throat than patients with normal bilirubin. Age and sex were not significantly different for the patients with increased and normal serum bilirubin concentrations. The patients with increased serum bilirubin concentrations showed higher levels of immune activation markers than the patients with normal bilirubin, including blood lymphocyte counts, serum IgM, and β2-microglobulin concentrations. Heterophile antibody-positive patients (88.6%) showed similar bilirubin concentrations but higher aspartate aminotransferase and alkaline phosphatase levels than their heterophile-negative counterparts. Serum bilirubin elevations normalized quickly during follow-up. ConclusionsTransient hyperbilirubinemia is common during severe (in-hospital) infectious mononucleosis in adult patients. Patients with hyperbilirubinemia have less frequent pharyngitis symptoms and more frequent abdominal symptoms. Hyperbilirubinemia during infectious mononucleosis is associated with immune activation markers.

Transient hypertriglyceridemia: a common finding during Epstein-Barr virus-induced infectious mononucleosis

BackgroundHypertriglyceridemia can occur in lymphoproliferative disorders. Infectious mononucleosis is a self-limiting, benign lymphoproliferative disorder. This study aimed to investigate the serum triglyceride concentrations and their change over time in patients with infectious mononucleosis.MethodsWe evaluated an adult patient with severe hypertriglyceridemia (>1000 mg/dL) during infectious mononucleosis and reviewed the records of 360 patients admitted to our hospital because of infectious mononucleosis (median age, 19 years; range, 15-87 years; 51.4% male). We compared the serum triglyceride concentrations with those of a control sample from the general population (n=75). A second triglyceride measurement, obtained during convalescence (median of 30 days after the initial determination), was available for 160 patients.ResultsThe triglyceride concentrations in the acute phase (median: 156 mg/dL) were significantly higher than those of the controls (median, 76 mg/dL; P<0.001). A total of 194 (53.9%) patients presented with hypertriglyceridemia (>150 mg/dL), which was more common in the patients older than 30 years than in the younger patients (78.6% vs. 50.6%; P<0.001). A significant correlation (P<0.005) was observed between the triglyceride levels and white blood cell counts, total cholesterol levels, and liver damage markers. The triglyceride concentrations decreased during convalescence (P<0.001) and were lower than the initial measurement in 83.7% of the cases. Conversely, the total cholesterol concentrations during the acute phase were lower than those of the controls and increased during convalescence (P<0.001).ConclusionsPatients with severe infectious mononucleosis frequently show mild, transient hypertriglyceridemia. Further studies are needed to elucidate the mechanisms underlying this finding.

Infectious mononucleosis in practice of otorhinolaryngologist

Infectious mononucleosis (IM) is an acute viral infection that usually occurs with fever, acute tonsillitis, affects lymph nodes, liver, spleen, and with specific changes in the hemogram. One of the most frequent symptoms of the disease is sore throat which leads people to otorhinolaryngologist. Several pathogens may be the cause of IM, but Epstein-Barr virus(EBV) plays a key role. EBV is a γ-herpes virus and about 90% of world`s population is infected with this one. Severe IM can lead to potential life-threating conditions, for example upper airway obstruction, spleen rupture. In addition to acute IM, EBV-infection can lead to a number of neoplastic and autoimmune diseases. Due to the non-specificity of IM symptoms and the emerging difficulties in laboratory and serological diagnosis of this disease, the problem of timely diagnosis and treatment in this category of patients remains very relevant.

Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency

AbstractBiallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity (IEIs) characterized predominantly by Epstein-Barr virus (EBV)-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation, and malignancy. A comprehensive understanding of the natural history, immune characteristics, and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected the clinical information of 49 patients from 29 families (CD27, n = 33; CD70, n = 16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority of patients (90%) were EBV+ at diagnosis, but only ∼30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one patients (43%) developed autoinflammatory features including uveitis, arthritis, and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

CONDITION OF LIPID PEROXIDE OXIDATION AND ANTIOXIDANT SYSTEM IN PATIENTS WITH INFECTIOUS MONONUCLEOSIS

The indicators of the activity of lipid peroxidation and the antioxidant system were studied in dynamics in 158 patients with infectious mononucleosis depending on the severity of the clinical course of the disease. It is proved that lipid peroxidation is significantly activated in patients with infectious mononucleosis as the severity of the disease increases and therefore increases the oxidative activity of blood plasma, the concentration of dyne conjugates and malondialdehyde in the blood, decreases the activity of antioxidant enzymes of erythrocytes (catalase, superoxide dismutase, glutathione peroxidase, glutathione reductase), glutathione peroxidase and glutathione reductase activity in plasma and lowering the concentration of total and reduced glutathione in the blood, as well as reduce the antioxidant activity of blood plasma and erythrocytes. Lipid peroxidation significantly increase and the activity of the antioxidant system decrease in patients with infectious mononucleosis in the acute period of the disease, as evidenced by the increased concentration of dyne conjugates, malonic dialdehyde and total oxidative plasma activity in the blood, reduced activity of the total antioxidant activity of plasma and erythrocytes, the decrease in the activity of antioxidant enzymes of erythrocytes catalase, superoxide dismutase, glutathione peroxidase, glutathione peroxidase and glutathione reductase of blood plasma, the decrease in the concentration of glutathione in the blood. The most pronounced disorders of lipid peroxidation and antioxidant system activity were found in patients with moderate-severe and severe infectious mononucleosis. The development of cytolytic syndrome in infectious mononucleosis is associated with the action of reactive oxygen forms species and lipid hydroperoxide.

Severe infectious mononucleosis in immunocompetent adults

ObjectivesTo determine the risk factors for severe infectious mononucleosis (IM) occurrence in immunocompetent adults. MethodsWe performed a multicenter, retrospective case series including immunocompetent adults presenting with confirmed IM between 2001 and 2011. Severe presentations were compared with uncomplicated presentations using Stata® 9 software. The significance level was set at 5%. ResultsIn univariate analysis, age over 30 years (n=13 or 41.9% vs. n=5 or 12.8%; P=0.006), prior use of non-steroidal anti-inflammatory drugs (NSAIDs) (n=7 or 87.5% vs. n=1 or 12.5%; P=0.009), and smoking (n=13 or 68.4% vs. n=6 or 31.6%; P=0.013) were associated with severe IM onset. In multivariate analysis, only age over 30 years (OR=3.55; P=0.05) and prior use of NSAIDs (OR=15; P=0.05) remained associated with severe IM onset, without reaching significance level (P=0.05). ConclusionOur study confirmed that age over 30 years is a risk factor for severe IM onset. Prior use of NSAIDs also seems to be correlated with severe presentations. This new data needs to be confirmed in a prospective study.

Late-Onset Non-HLH Presentations of Growth Arrest, Inflammatory Arachnoiditis, and Severe Infectious Mononucleosis, in Siblings with Hypomorphic Defects in UNC13D.

Bi-allelic null mutations affecting UNC13D, STXBP2, or STX11 result in defects of lymphocyte cytotoxic degranulation and commonly cause familial hemophagocytic lymphohistiocytosis (FHL) in early life. Patients with partial loss of function are increasingly being diagnosed after presenting with alternative features of this disease, or with HLH later in life. Here, we studied two sisters with lymphocyte degranulation defects secondary to compound heterozygote missense variants in UNC13D. The older sibling presented aged 11 with linear growth arrest and delayed puberty, 2 years prior to developing transient ischemic attacks secondary to neuroinflammation and hypogammaglobulinemia, but no FHL symptoms. Her geno-identical younger sister was initially asymptomatic but then presented at the same age with severe EBV-driven infectious mononucleosis, which was treated aggressively and did not progress to HLH. The sisters had similar natural killer cell degranulation; however, while cytotoxic activity was moderately reduced in the asymptomatic patient, it was completely absent in both siblings during active disease. Following allogeneic bone marrow transplantation at the age of 15, the older child has completely recovered NK cell cytotoxicity, is asymptomatic, and has experienced an exceptional compensatory growth spurt. Her younger sister was also successfully transplanted and is currently disease free. The current study reveals previously unappreciated manifestations of FHL in patients who inherited hypomorphic gene variants and also raises the important question of whether a threshold of minimum NK function can be defined that should protect a patient from serious disease manifestations such as HLH.

Effect of metronidazole versus standard care on length of stay of patients admitted with severe infectious mononucleosis: a randomized controlled trial

Metronidazole may be of use in the treatment of infectious mononucleosis (IM). Our aim is to show that metronidazole shortens hospital stay for patients with severe IM. A single-centre randomized controlled trial was undertaken in patients admitted with severe IM, who were with a similar group treated by the standard care. Patients were blinded to which treatment arm they were in. Forty-two of these patients were enrolled in the trial. The primary endpoint was the difference in length of stay. This was significantly less in the metronidazole group (3.67 days v 4.67) (p 0.032). This study demonstrates that metronidazole has a role to play in severe infectious mononucleosis.

Editorial Commentary: Genetics and Infectious Mononucleosis

(See the Major Article by Rostgaard et al on pages 1684–9.) The epidemiology of primary Epstein-Barr virus (EBV) infection is not completely understood. We know that kissing is the major route of transmission of primary EBV infection among teenagers and young adults [1], but we do not know the mechanism(s) of transmission among preadolescent children. In addition, we do not know why the majority of primary EBV infections in young children go unrecognized [2], whereas those in adolescents and young adults usually result in infectious mononucleosis (IM) [1]. We also do not know whether it is better to get infected by EBV early in life or later on. Evidently, much remains to be learned about the enigmatic epidemiology of EBV, but we now have some compelling information that genes are involved. In this issue of Clinical Infectious Diseases, Rostgaard and colleagues tracked familial clustering of hospitalized cases of IM [3]. Using very large Danish national databases, these investigators reported that same-sex twins had a rate ratio of 9.3 for mono, compared with 2.3 for first-degree relatives (opposite-sex twins, siblings, and parents), 1.4 for second-degree relatives (half-siblings, grandparents, uncles, and aunts), and 1.0 for third-degree relatives (first cousins). The 95% confidence intervals for those 4 classes of relationships did not overlap, supporting the conclusion that degree of relatedness increased the likelihood of contracting mono. Hwang et al, utilizing the California Twin Program registry, reported that concordance for IM in monozygotic twins was twice that of dizygotic twins [4]. They interpreted their results as consistent with a genetic contribution to susceptibility to mono. Twins certainly share the same environment and likely have similar behavior, which cannot be ruled out as risk factors. However, the significantly greater number of cases in monozygotic or same-sex twins vs dizygotic or opposite-sex twins in both the California and the Danish studies is compelling evidence that susceptibility to IM has a genetic component. A strength of both studies was the large size of the cohort investigated. A limitation of the Danish study was that only relatively severe IM was captured (85% of the cases were inpatient admissions), and therefore the results may not be applicable to typical outpatient cases of mono. Shortcomings of both studies include the lack of laboratory confirmation of EBV infection, and few data on racial groups other than whites. Rostgaard and colleagues suggest that genome-wide association studies might uncover EBV susceptibility loci that not only confer a risk for IM but also for development of EBV-associated cancer or autoimmune disease. Including diverse racial/ethnic groups in such investigations could broaden our ability to discover important genetic variants associated with acquisition, severity, and sequelae of EBV infection. In support of this, 2 separate cross-sectional surveys of US children found that early acquisition of EBV infection, as evidenced by having antibodies against EBV viral capsid antigen, was a racial disparity that could not be satisfactorily explained by socioeconomic factors alone [5, 6]. The enormous difference in overall age- and sex-adjusted EBV antibody prevalence between non-Hispanic white (32%) and non-Hispanic black children (62%) in the study by Condon et al [6] is consistent with a genetic basis for the racial clustering of EBV infection in younger children. A history of IM predisposes to Hodgkin lymphoma [7] and multiple sclerosis [8]. Why? A plausible explanation is that more severe primary EBV infection reflects dysregulated immune control of the virus (probably due to the host's genetic makeup), which persists during viral latency, eventually leading to EBV-associated malignancy or autoimmune disease. Rostgaard and colleagues have told us that susceptibility to symptomatic EBV infection is genetically influenced. Our challenge now is to find a candidate genetic marker that identifies individuals in jeopardy for serious EBV disease so that we can recognize them and potentially intervene before they get sick. These individuals would greatly benefit from a prophylactic EBV vaccine, and such vaccines are now in development [9].

Fulminant Epstein-Barr virus - infectious mononucleosis in an adult with liver failure, splenic rupture, and spontaneous esophageal bleeding with ensuing esophageal necrosis: a case report

IntroductionInfectious mononucleosis is a clinical syndrome most commonly associated with primary Epstein-Barr virus infection. The majority of patients with infectious mononucleosis recovers without apparent sequelae. However, infectious mononucleosis may be associated with several acute complications. In this report we present a rare case of esophageal rupture that has never been described in the literature before.Case presentationWe present the case of an 18-year-old Caucasian man affected by severe infectious mononucleosis complicated by fulminant hepatic failure, splenic rupture and esophageal necrosis.ConclusionsAlthough primary Epstein-Barr virus infection is rarely fatal, fulminant infection may occur - in this case leading to hepatic failure, splenic rupture and esophageal necrosis, subsequently making several surgical interventions necessary. We show here that infectious mononucleosis is not only a strictly medical condition, but can also lead to severe surgical complications.

X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis

X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n=6), severe infectious mononucleosis (n=4), isolated splenomegaly (n=3), uveitis (n=1), periodic fever (n=1), fistulating skin abscesses (n=1) and severe Giardia enteritis (n=1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.

HLA Associated Susceptibility to EBV+ Hodgkin Lymphoma: No Correlation with Infectious Mononucleosis or Number of Circulating EBV+ B Cells.

AbstractAbstract 2635EBV+ Hodgkin lymphoma (HL) arises from a latently EBV infected B cell and is associated with infectious mononucleosis (IM), a febrile illness that presents upon primary EBV infection of B cells in a proportion of adolescents and young adults. After primary infection, the virus establishes lifelong persistence in a small number of circulating B cells and this number is strongly controlled by the immune system, with a prominent role for HLA class I restricted recognition of EBV antigenic peptides by cytotoxic CD8 T cells.Interestingly, in the western European population, HLA-A1 is a susceptibility type for EBV+ HL, while HLA-A2 is protective. This corresponds well to known HLA restricted immune responses to EBV in healthy individuals, with consistent cytotoxic responses in the context of HLA-A2 and no responses in the context of HLA-A1. Because EBV+ HL tumor cells usually express all components of the antigen presenting pathway, including HLA class I, the effect of HLA type on susceptibility may act at any stage of disease pathogenesis. We therefore tested 2 hypotheses in this study: 1. HLA-A type is associated with IM risk and 2. HLA-A type determines EBV+ HL risk by influencing the number of circulating EBV+ B cells.To test the first hypothesis a total of 158 consecutive IM patients diagnosed from 1993 to 2011 at the Queen Elizabeth Hospital Birmingham, United Kingdom were included. These were all Caucasians patients with a clinical diagnosis of IM, including positive EBV antibody titers and/or Monospot test. HLA class I typing (HLA-A, B and C) was performed and allele frequencies were compared to 12,762 regional Blood Bank volunteers. The HLA-A1 type was clearly under represented in IM patients (12.3%) compared to controls (19.3%, OR 0.59; 95%CI 0.42–0.83), in sharp contrast to the situation in EBV+ HL. The uncommon HLA-B53 type was overrepresented in IM patients (1.6% vs. 0.3%, OR 5.313; 95%CI 2.14–13.2). Some other types showed borderline significance: HLA-A3 (OR 1.41; 95%CI 1.07–1.87), HLA-B14 (OR 1.68, 95%CI 1.07–2.62), HLA-C7 (OR 0.75; 95%CI 0.58–0.97) and HLA-C8 (OR 1.76, 95%CI 1.10–2.81). These data indicate that the known association of HLA-A1 and HLA-A2 with EBV+ HL is not paralleled by a similar association with IM. The unexpected negative correlation between HLA-A1 and IM may be caused by an association with less severe IM symptoms as suggested in another study (McAulay et al J Clin Invest 2007), if individuals with less severe IM symptoms did not seek medical attention.To answer the second hypothesis, first year medical students from the University of Birmingham, UK were asked to participate and donate blood in the years 2007 and 2008. EBV viral load was measured by Q-PCR using PBMC DNA from 270 students with positive EBV serology (30% of all students were serology negative) and no recent IM symptoms. Viral load was considered indicative for number of circulating EBV+ B cells. HLA-typing was done for HLA-A1, A2, B7, B8 and B35. For each type EBV loads were compared between HLA type carriers and non-carriers. Results with medians are shown in figure 1. The percentages of EBV seropositive students with detectable EBV loads per HLA-type are indicated under the x-axis (57.5% for all subjects). EBV seropositive students with undetectable EBV loads were also included in the statistical analyses. Of the individuals with HLA types previously shown to be involved in cytotoxic immune responses to latent EBV (A2, B7, B8 and B35), only HLA-B7 positive individuals had a significantly lower viral load than HLA-B7 negative individuals (p=0.038, median: 0 vs. 44). None of the other HLA types showed a significant difference between HLA type carriers and non-carriers, including HLA-A1 (expected to have higher viral loads in A1+ donors).In conclusion, the risk effect of HLA-A1 and the protective effect of HLA-A2 in the development of EBV+ HL are unlikely to be explained by differences occurring during primary EBV infection or differences in the lifelong virus-host balance. Instead, these effects probably relate to immune surveillance of EBV infected Hodgkin (precursor) cells at later stages of disease pathogenesis. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Current diagnosis and management of infectious mononucleosis

Infectious mononucleosis is a common, usually self-limited disease. However, infectious mononucleosis may present with severe manifestations. Complications may also occur. Consequently, diagnostic and treatment issues regarding infectious mononucleosis are of major importance. In this review, we focus on the evaluation of articles providing diagnosis and treatment data for infectious mononucleosis, published during the past 2 years. Twelve studies, deriving from extended search in PubMed, were included. Nine studies provided diagnosis data. The evaluated diagnostic methods were real-time PCR (RT-PCR), IgM/IgG antibodies measured with different assays [measurement of Epstein-Barr virus viral load (EBV-VL) in peripheral blood, neutrophil/lymphocyte/monocyte counts, C-reactive protein values, and monospot test]. The sensitivities reported for RT-PCR were high. The available treatment data were scarce (three studies). Two of them suggested that antivirals (mainly acyclovir and valacyclovir) may have a role in the treatment of infectious mononucleosis with complications, whereas the remaining study presented novel potential therapeutic patents including 5-substituted uracyle, azacytosine derivatives, and peptides inhibiting EBV-mediated membrane fusion. RT-PCR and measurement of EBV-VL may provide useful tools for the early diagnosis of infectious mononucleosis in cases with inconclusive serological results. Antiviral agents may provide a useful treatment option in patients with severe infectious mononucleosis.

Imaging spectrum of EBV-infection in a young patient

A wide variety of atypical presentations with complications affecting multiple organ systems during acute infectious mononucleosis (IM) is described in the literature, with an increase in the number of teenagers who are susceptible to a severe case of the disease. We report a case of a 14-year-old girl with severe IM and acute abdominal pain. Ultrasonographic (US) evaluation showed a marked thickening of the gallbladder wall (GBW) with enlargement of some mesenteric lymph nodes. CT scan showed multiple enlarged lung nodules of various sizes and a small pleural and pericardial effusion; a hypodense solid mass of unknown etiology was detected in the anterior mediastinum, mimicking a malignant tumor. Hematological analysis of peripheral blood smear was performed to exclude neoplastic pathology. IM was identified as the only underlying disease. The patient was carefully monitored: clinical evaluation, laboratory analysis and US examination were repeated at weekly intervals, until recovery.

Infectious mononucleosis-like syndrome induced by salazosulfapyridine in a patient with rheumatoid arthritis

We describe a 43-year-old woman with rheumatoid arthritis (RA), who developed severe infectious mononucleosis (IM)-like syndrome during treatment with salazosulfapyridine (SASP). She presented with fever, skin rash, lymphadenopathy, and hepatosplenomegaly. Laboratory tests revealed a marked increase of atypical lymphocytes in the peripheral blood and biphasic hepatic dysfunction. IM-like syndrome can be caused by various drugs, including SASP, and the concept of drug-induced hypersensitivity syndrome has been proposed recently. IM-like syndrome due to SASP has been reported in patients taking higher dosages for the treatment of inflammatory bowel disease, but has not been reported earlier in patients with RA. The results of the drug-induced lymphocyte stimulation test tests suggested that 5-aminosalicylic acid was a possible causative metabolite. This severe type of drug-induced hypersensitivity reaction mimicking IM due to SASP should be granted wider awareness in the field of rheumatology, because the drug is widely used for the treatment of RA.

New lights on infectious mononucleosis

This review focuses on recent studies that shed new lights on infectious mononucleosis (IM). The major transmission of Epstein-Barr virus (EBV) via saliva is opposed to the possibility of sexual transmission of EBV in developed countries. Multiple infections with different LMP-1 EBV genotypes are frequently observed during IM but with unclear significance. The strict lymphotropism of the virus during primary EBV infection is questioned. Prolonged high EBV-load in saliva is clearly demonstrated during IM and could be explained by a different immune response in tonsil versus blood. Benign and severe IM are also explained by the variability of the immune response. Correlations between severity of IM and high viral load in blood are controversial. A relationship between IM and Hodgkin's disease is suggested by several epidemiological studies. Despite potential new antiviral targets and preliminary human vaccine trials, the lack of curative or preventive treatment against IM is pointed out.

Simultaneous manifestation of fulminant infectious mononucleosis with haemophagocytic syndrome and B-cell lymphoma in X-linked lymphoproliferative disease

X-linked lymphoproliferative disease is a rare T and NK cell immune deficiency which most frequently presents as fulminant infectious mononucleosis following infection with the Epstein-Barr virus (EBV). We report the case of a 4-year-old boy from a Spanish family presenting with severe infectious mononucleosis. In the course of the disease he developed hepatic failure, pancytopenia and neurologic impairment, leading to death after less than 2 months. The results of bone marrow biopsy and autopsy indicated a histological diagnosis of both high-grade B-cell lymphoma and virus-associated haemophagocytic syndrome, thereby confirming the simultaneous presence of two different manifestations of X-linked lymphoproliferative disease (XLP) in this patient. The family history revealed four close male relatives dying under similar circumstances, one of whom died following a vaccination against measles. Molecular genetic studies identified a novel mutation in the SH2D1A gene in several members of the family, establishing the diagnosis of XLP. Fatal EBV infection in male infants is highly indicative of XLP. Virus-associated haemophagocytic syndrome and B-cell lymphoma can occur concomitantly and may be difficult to distinguish due to their similar histological pictures.