1. Fever ≥38.5°C |
2. Splenomegaly |
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 |
Drug | Recommendation |
No proven worth in IM other than a reduction in oral shedding. | |
Though more active than acyclovir for EBV, there is no proven worth in IM other than a reduction in oral shedding. Some use it to treat CNS EBV acute infections, but controversial. |
Comment: Direction to frequent clinical diagnostic and therapeutic problems and return to sports that face practitioners. 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: Meta-analysis of eight trials with more adults than children found a modest benefit. The issue is that with IM, there is some evidence that the use of steroids may heighten risk for outcomes such as lymphoma and autoimmune disease when population databases are analyzed.
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 entirely 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 a 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: HLH should be considered patients with IM who don’t improve after four weeks with continued fever, perhaps progressive jaundice, LFT abnormalities and severe cytopenias.
Comment: Infections were 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 considered responsible for 27%.
Comment: Seven RCTs were examined that judge the effectiveness of antivirals (acyclovir, valganciclovir 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, 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 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 acquiring primary EBV. These authors had a prospective longitudinal cohort and could 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 results from the loss of viral replicative control backed up by finding only high levels of the virus just about the same time or at the time of clinical presentation. Very low levels of EBV in blood were detected ~ 3 wks prior. There was no cytotoxic T cells (CD8) expansion in this early period and only upon the 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), and gastric carcinomas.
Comment: A prospective study starting with US college freshmen/women demonstrated that IM is still the "kissing disease." In this study, 546 students were 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. The severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003).
The study take-home point 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, the severity of infection is likely a consequence of a vigorous, mainly cytotoxic T-cell immune response.
Rating: Important
Comment: A small prospective study of primary EBV infection in children with renal transplants found no correlation with the intensity or duration of EBV viral load for post-transplant lymphoproliferative disorder. The study was too small to determine if other factors were at play.
Comment: A helpful and thorough review of PTLD management, which is beyond the scope of this module. Traditionally, lowering immunosuppression is the key strategy, although other therapies, including rituximab (anti-CD20 monoclonal antibody) and traditional chemotherapy, are sometimes used.
Comment: A small study suggested benefits in patients with elevated titers to EBV and HHV-6. Small studies (n=30) don’t hold up usually in larger studies when considering this likely heterogeneous disorder.
Comment:
Authors expand upon a prior meta-analysis but incorporate newer, larger studies. They found a risk (RR) 2.17 for MS following IM.
Comment: One of several studies perhaps suggests the 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 by immunizing 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, 1 month and 5 months, with follow-up for a total of 18 months. The authors found that vaccination 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 endpoint of preventing IM showed an efficacy of 78% (95% CI, 1- 96%) but did not halt the asymptomatic acquisition of EBV. Adverse side effects were no differences 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 safe, generating 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, the 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 the 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 be worthwhile in industrialized countries where there is some evidence suggesting that IM is increasing in incidence and severity. Given the immunological complexity of EBV infection, whether a vaccine strategy can be safely employed will not be quickly answered, as long-term studies will likely be needed.
Comment: Taller/larger people may have spleens bigger than customary ultrasound measurements. This doesn’t mean they must 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 were studied with CNS processes but PCR only had 29% positive predictive value, and a specificity 79%. This study more likely reflects real-life statistics in evaluating a diffuse set of CNS conditions in HIV. Authors suggest tests useful for ruling out lymphoma but not diagnosing it without a brain biopsy.
Rating: Important
Comment: The study suggests an approximately 40x increased risk of HL after IM during four year study period.
Rating: Important
Comment: British series suggests that the infection is causing increased hospitalization rates of adolescents and adults compared to surveys of IM in the 1970s and 1980s. The authors suggest that there has been a dramatic decline in 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, it is incumbent upon the physician suspicious of IM to ask for a manual differential that may 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-aged to elderly patients with definitive evidence of a current EBV primary infection. Protracted fever, jaundice, pleural effusion, anemia, or Guillain-Barre syndrome were dominant clinical findings among these patients. Clinically, older patients appear to have less pharyngitis, LN, and 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 instead highly activated cytotoxic T lymphocytes (CTL) important for clearly lytic phase primary infection. Investigators have sought to control the problematic problem of EBV-related lymphoproliferative disorders by using CTL infusion in bone marrow transplant candidates, which may hold some success by immunomodulation of this challenging problem.
Comment: Splenic rupture in IM has traditionally been handled by splenectomy. However, recognizing the long-term risks of overwhelming sepsis due to the post-splenectomy state, this case series and literature review advocate 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 of 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 IM may precipitate anxiety and depressive disorders, 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 the criteria for DSM-III-R psychiatric illness. Problems regarding anxiety, depression or fatigue that persisted beyond two or six months were 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, which rarely occurs beyond the third week of the 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