1. Fever ≥38.5°C
3. Cytopenias (affecting at least 2 lineages)
Hemoglobin < 9 g/dL (in infants < 4 weeks: hemoglobin < 10 g/dL)
Platelets < 100 × 103/mL
Neutrophils < 1 × 103/mL
4. Hypertriglyceridemia (fasting, >265 mg/dL) and/or hypofibrinogenemia (< 150 mg/dL)
5. Hemophagocytosis in bone marrow, spleen, lymph nodes, liver, or other tissue
6. Low or absent NK cell activity
7. Ferritin >500 ng/mL
8. Elevated sCD25 (soluble IL-2 receptor): >2,400 U/mL or elevated based on the laboratory-defined normal range
Comment: Direction to frequent clinical diagnostic, therapeutic problems as well as return to sports that face practioners. Most is expert opinion based on thin data such as retrospective or observational studies rather than RCTs.
Comment: The combination of corticosteroid and acyclovir offered no clinical benefit in IM.
Comment: As existing antivirals have little effect on EBV, there is much interest in new approaches especially for PTLDS, HLH-related disease and CAEBV.
Comment: General overview of HLH including genetic and sporadic.
Comment: Dr. Cohen has the most experience with CAEBV in the U.S. HSCT is the only true curative option suggesting that early diagnosis is important to allow sufficient health for good outcomes.
Comment: Mechanisms are not completely understood, but in CAEBV, host responses don’t control the virus resulting in markedly elevated levels of EBV DNA in the blood and infiltration of organs by EBV-positive lymphocytes. Patients often present with fever, lymphadenopathy, splenomegaly, EBV hepatitis, or pancytopenia. Over time, these patients develop progressive immunodeficiency and if not treated, succumb to opportunistic infections, hemophagocytosis, multiorgan failure, or EBV-positive lymphomas. Patients with CAEBV in the United States most often present with disease involving B or T cells, while in Asia, the disease usually involves T or NK cells. The only proven effective treatment for the disease is hematopoietic stem cell transplantation
Comment: Consider in patients with IM who don’t improve after 4 weeks with continued fever, perhaps progressive jaundice, LFT abnormalities and severe cytopenias.
Comment: Infections was the leading category in the 41.3% of patients with diagnosed entities (of 218 total) in this study from Turkey. Of the 27% (n = 59) with infections, EBV was thought to be responsible for 27%.
Comment: Seven RCTs examined that judge the effectiveness of antivirals (acyclovir, valomaciclovir and valacyclovir) in IM. Authors judge the quality of evidence as very low. The majority of included studies were at unclear or high risk of bias and so questions remain about the effectiveness of this intervention. Although two of the 12 outcomes have results that favor treatment over control, the quality of the evidence of these results is very low and may not be clinically meaningful.
Comment: This 2015 update of earlier 2012 did not find any new data compared to the earlier Cochrane review that examined seven trials with a total of 362 participants. Available data was low quality with nothing to support their use; however, this is due to the paucity of trials.
Comment: On average, patients come to clinical attention about six weeks after acquisition of primary EBV. These authors had a prospective longitudinal cohort and were able to follow events in the pre-patent period. They found little virus in oral secretions until 1 week before symptom onset. Authors postulate that clinical EBV therefore is a result of the loss of viral replicative control backed up by finding only high levels of virus just about the same time or at the time of clincial presentation. Very low levels of EBV in blood were detected ~ 3 wks prior. There was no expansion of cytotoxic T cells (CD8) in this early perior and only upon onset of high level virus and clinical disease.
Comment: Review of malignancies with certain and associated EBV including Burkitt’s lymphoma, Hodgkin’s disease , post-transplant lymphoproliferative disorders (PTLD) and T-cell lymphomas (e.g. Peripheral T-cell lymphomas; PTCL and Anaplastic large cell lymphomas; ALCL). It is also linked to epithelial tumors such as nasopharyngeal carcinoma (NPC), gastric carcinomas.
Comment: Small prospective study of primary EBV infection in children with renal transplants found no correlation with intensity or duration of EBV viral load for post-transplant lymphoproliferative disorder. Study was too small to determine if other factors at play.
Comment: Prospective study starting with US college freshmen/women demonstrated that IM is still the "kissing disease." In this study, 546 students screened, 202 (37%) were antibody negative and 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003).
Study take home points for this author is that this is one of the first "modern" studies in years. Over one-third of US students in this Midwest university were EBV seronegative. Also, the majority were symptomatic with infection. Although some have suggested EBV is an STD, this was not supported in this study. As others have found, severity of infection is likely a consequence a vigorous, mainly cytotoxic T cell immune response.
Comment: Helpful and thorough review of PTLD management, which is beyond the scope of this module. Traditionally, lowering immunosuprpression is the key strategy, although other therapies, including the rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy are used at times.
Comment: Small study suggesting benefit in patients with elevated titers to EBV and HHV-6. IFteb sycg small studies (n=30) don’t hold up in larger studies when considering this likely heterogenous disorder.
Authors expand upon a prior meta-analysis but incorporating newer, larger studies. They found a risk (RR) 2.17 for MS following IM.
Comment: One of several studies perhaps suggesting a role of sexual transmission for EBV. What is difficult is to divorce potential oral from genital exposures.
Comment: This phase II vaccine study sought to determine whether acute EBV infection or IM could be prevented through the immunization of naive young adults. This was a randomized, double-blind trial using a recombinant gp350 vaccine that prompts antibody development against a key viral antigen that facilitates EBV entry into B lymphocytes. Immunizations were carried out at initiation, and at 1 month and 5 months, with follow-up for a total of 18 months. The authors found that immunization with the gp350 vaccine yielded detectable antibody response in 98.7% of subjects (95% CI, 85.5-97.9%). By the end of the 18 month study period, the primary end point of preventing IM showed an efficacy of 78% (95% CI, 1- 96%), but did not halt asymptomatic acquisition of EBV. Adverse side effects were no different between the vaccine and placebo groups. The group receiving the gp350 vaccine had no cases of IM once the three series of immunizations were completed, compared to the placebo group that continued to develop IM. This trial suggests that in the intent-to-treat analysis, the gp350 vaccine was protective against the development of IM — although the small study design guaranteed wide confidence intervals. Immunization appeared to be safe and it generated reliable seroconversion, suggesting that the vaccine is a candidate for study in larger populations. Whether such a vaccine can interrupt the malignancy potential of EBV depends on whether the significant immune dysregulation as a consequence of IM is a leading driver. If, instead, oncogenic potential is related to viral infection alone, then this vaccine is unlikely to yield this specific benefit, since it does not appear to halt acquisition of the EBV virus. Regardless, since there is no reliable medical therapy for IM that shortens illness or postinfectious fatigue duration, a vaccine strategy could well be worthwhile in industrialized countries where there is some evidence suggesting that IM is increasing in incidence as well as severity. Given the immunological complexity of EBV infection, the question of whether a vaccine strategy can be safely employed will not be quickly answered, as longterm studies will likely be needed.
Comment: Taller/larger people may have spleens bigger than customary ultrasound measurements. This doesn’t mean they need to refrain from activities beyond 4-6 weeks after IM.
Comment: Small series refuting the claimed high sensitivity/specificity of EBV CSF PCR. Here 26 patients studied with CNS processes but PCR only 29% positive predictive value, and specificity 79%. This study more likely reflects real-life statistics in evaluating a diffuse set of CNS conditions in HIV. Authors suggest test useful for ruling out lymphoma, but not diagnosing it without brain biopsy.
Comment: Study suggests an approximately 40x increased risk of HL after IM during four year study period.
Comment: British series suggesting that the infection is causing increased rates of hospitalization of adolescents and adults compared to surveys of IM in the 1970's and 1980's. The authors suggest that there has been a dramatic decline in the number of childhood infections of low severity while infection acquired later in life is more likely to yield severe symptoms.
Comment: Cases of primary EBV with unusual features are particularly challenging diagnostically especially when automated hematologic analyzers do not flag leukocyte counts to be inspected manually for the presence of atypical lymphocytes. When wbc #'s are within normal range, then it is incumbent upon the physician suspicious of IM to ask for a manual differential that may then visualize circulating atypical lymphocytes.
Comment: Although Epstein-Barr-virus (EBV)-induced infectious mononucleosis usually occurs in young adults between the ages of 15 and 30 if it occurs in older individuals, it frequently presents diagnostic problems. These two reports described middle-age to elderly patients all of whom had definitive evidence of a current EBV primary infection. Protracted fever, jaundice, pleural effusion, anemia, or the Guillain-Barre syndrome were dominant clinical findings among these patients. Clinically, older patients appear to have less pharyngitis, LN, splenomegaly while fever & hepatitis is more prominent.
Comment: The circulating atypical lymphocytes of IM have long been known to be not EBV-infected B lymphocytes, but rather highly activated cytotoxic T lymphocytes (CTL) important for clearly lytic phase primary infection. Investigators have sought to control the difficult problem of EBV-related lymphoproliferative disorders by using CTL infusion in bone marrow transplant candidates which may hold some success by immunomodulation of this difficult problem.
Comment: Splenic rupture in IM has traditionally been handled by splenectomy. However, recognizing the long-term risks of overwhelming sepsis due to post-splenectomy state, this case series and review of the literature advocates conservative management only if hemodynamics are stable, and the blood transfusion requirement does not exceed two units of blood.
Comment: The study compared nine commonly used kits and EBV-specific serology for infectious mononucleosis. The sensitivities and specificities of the rapid kits (Monospot and similar) varied from 63 to 84% and 84 to 100%, respectively.
Comment: Retrospective analysis of autopsy proven cases of AIDS related CNS lymphoma documenting that PCR for EBV DNA in CSF was 100% sensitive and 98.5% specific. For these patients, the EBV CSF PCR may be useful as a diagnostic tumor marker obviating the need for brain biopsy in a patient with compatible neuroimaging.
Comment: One of a number reports highlighting that acute HIV seroconversion must be entertained as a diagnosis of heterophile negative mononucleosis-like illnesses.
Comment: Five patients followed for >4yrs with persistently positive rapid heterophile (Monospot) tests without evidence of illness, thereby emphasizing that false positives unassociated with any illnesses may occur.
Comment: Although anecdotal reports suggest that anxiety and depressive disorders maybe precipitated by IM, this has not been examined rigorously. This study in high school and college students found that although transient psychological distress was common during acute infection, few patients met criteria for DSM-III-R psychiatric illness. Problems that regarding anxiety, depression or fatigue that persisted beyond two or six months was best correlated with lower psychosocial premorbid functioning rather than any severity index regarding acute IM.
Comment: Though dated from an imaging perspective, this study examines some of the thorny issues regarding restriction from athletic training and participation. The most fearsome complication is splenic rupture, and it rarely occurs beyond the third week from onset of clinical symptoms.
A. Normal Lymphocyte
B. Enlarged, atypical lymphocyte with more cytoplasma and bilobed nucleous
C. So-called "Dutch Skirting" caused by red blood cells indenting lymphocyte outer membrane
Source: Paul G. Auwaerter, MD
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