This approach produced a pool of 96 relevant research articles including one umbrella review, six systematic reviews including one Cochrane review , three meta-analyses, 36 reviews and 11 case reports, with publishing span from to Contradicting results and alternative perspectives on the subject were noted and presented. Low amounts of EBV may be detected in saliva throughout life in infected individuals.
After successful transmission, EBV infects epithelial cells and resting B-cells in the oropharynx, starts replicating and thereby spreads throughout the body. This process represents the incubation period, which lasts about six four to seven weeks [ 8 ] and leads to an activation of cytotoxic T-lymphocytes CTL and natural killer cells.
The activation of CTL in primary infection leads to cell-mediated immune response causing the clinical presentation of IM.
However, when EBV infects B cells, the virus is able to restrict its expression of genes to nine proteins out of approximately thereby avoiding recognition of CTLs, and thus resulting in latent infection in the affected B-cells. Different patterns of these expressed so-called latency proteins have been described and seem to associate to different EBV-associated lymphoproliferative conditions such as Hodgkin Lymphoma HL , Burkitt Lymphoma BL and post-transplant lymphoproliferative disorder PTLD depending on the expression pattern, please refer below.
Reactivation of EBV may also occur in later life in the immunocompromised as seen after transplants, due to immunosuppressive medication, acquired immune deficiency syndrome AIDS , etc.
Whether an individual develops IM primarily depends on the timing of exposure to the virus. The risk of severe symptoms is positively correlated to the age of the patient at time of primary infection [ 11 ]. White tonsillar exudates, sometimes even covering the tongue may be seen and distinguish IM from the more spotted coverings seen in bacterial tonsillitis [ 6 ].
Hepatosplenomegaly and some degree of hepatitis are also common findings. Splenomegaly may not be noticeable upon physical examination, but ultrasonic assessment of splenic size during acute IM has shown that all patients develop splenomegaly in varying degrees [ 12 ]. Patients with IM are therefore routinely advised to limit physical activity for at least 1 month after the onset of symptoms, however, there is yet to be developed a method of predicting the risk of splenic rupture [ 13 ].
Though patients with IM often present with the aforementioned triad of symptoms, a GP should always consider the array of illnesses that can cause IM-like symptoms. A thorough history of the patient should elucidate recent travel- and sexual history, contact with animals, previous medical problems and family history of disease.
An excellent review from concerning the diagnostic process for IM-like disease, has summarized conditions that may mimic IM, and that should be considered depending on the medical and personal history of the patient [ 5 ].
An algorithmic approach to the patient at this point is recommendable. Pregnancy, intravenous drug use or men having sex with men should prompt the GP to be even more alert. The latter two groups should be tested for HIV as well [ 6 ].
If a patient does not classify as high risk, as defined above, the next step is blood testing heterophile antibody test Monospot test as well as a complete blood count CBC. VCA and EBNA antibody tests offer higher sensitivity and specificity, but come at a higher price and take longer to analyze. A diagnostic algorithm for use in primary care has been summarized in a recently published clinical review Fig. Algorithm for diagnosing IM. Adapted with permission from Lennon et al.
There is currently no specific treatment for IM. Management focuses on symptomatic relief and patients are therefore treated with simple analgesics, antipyretics, hydration and rest. Of interest, a systematic review from advises against prolonged rest due to possible deconditioning. Deconditioning may cause prolonging of symptoms including fatigue and increases recovery time and patients should be allowed out of bed as soon as they feel fit enough [ 16 ].
There has been controversy surrounding a possible link between acute viral infections, such as IM, and chronic fatigue syndrome CFS , but at present, it is unlikely that an acute EBV infection leading to IM can cause CFS by itself [ 6 ]. Antivirals for IM has been proposed for some time. However, there has not been any firm evidence to support this notion. A Cochrane review from concluded that the effectiveness of antiviral agents acyclovir, valomaciclovir and valacyclovir in acute IM is uncertain and that the quality of the evidence was low [ 17 ].
Thus, at the moment treatment should focus on supportive care which in severe cases may require hospitalization for intravenous fluids due to dehydration or monitoring for impeding respiratory failure. Cholestatic liver disease and chronic hepatitis due to EBV are rare complications, but have been described in the literature [ 19 — 21 ].
The hepatic changes are therefore usually transient and self-limiting, but cases of liver failure with fatal outcomes - even in immunocompetent patients - have been reported [ 22 , 23 ] which is why it is advisable to order liver tests upon diagnosis and during monitoring of patients with more severe IM. Splenic rupture, as a result of splenomegaly and altered splenic architecture [ 24 ], is probably the most feared and acute complication to IM.
It is, however, a very rare complication with an incidence varying from 0. This is supported by a study of the ultrasonic assessment of splenic size during IM in athletes, which showed a peak increase The risk of splenic rupture is anecdotally highest in patients who are involved in contact sports like martial arts, football, hockey, etc.
Athletes are withheld from practice and competition during this phase of the infection, which may have implications for their academic- and athletic career, especially in countries like the US where athletic scholarships can determine whether a student goes to college. Much literature has therefore focused on the safe return to sports. There seems to be a current consensus that return to non-contact activities can commence 3 weeks after symptomatic onset [ 25 ].
On the other hand, recommendations regarding the return to contact sports vary, ranging from three to 5 weeks to 6 months [ 27 ]. Multiple attempts have been made to make clinical guidelines, but none have been accepted as general practice. One of the more sophisticated attempts was made by McKeag et al who focused on time from onset of symptoms and criteria such as fever, lymphadenopathy, bilirubin- and liver enzyme levels and absence of splenomegaly verified radiographically [ 27 ].
Still, several cases of spontaneous splenic rupture have been reported [ 28 ] and splenic rupture should therefore be suspected in all patients presenting with acute abdominal- or chest pain and with confirmed- or suspected IM. Cervical lymphadenopathy is a hallmark in IM and involves the nasopharyngeal and palatal tonsils. Swelling has been estimated to cause airway compromise in 1—3.
Symptoms include stridor, cyanosis and tachypnea and should lead to immediate admittance and treatment. Early treatment with systemic corticosteroids may therefore limit the need for surgical intervention in severe cases [ 29 ]. Tracheotomy has only been used in extremely severe and exceptionally described cases, where treatment with systemic corticosteroids have failed [ 29 ]. Selected use of acute tonsillectomy in patients who have not responded satisfactorily to systemic corticosteroids has been proposed by some groups [ 30 , 31 ], but has been a topic of debate, due to the conflicting data on the risk of bleeding.
These results were not supported by those advocating for selected use of acute tonsillectomy [ 30 , 31 ] and it seems that more research on this topic is warranted.
Of importance, treatment with systemic corticosteroids is only warranted in an emergency setting, in the case of acute complications such as impending airway compromise. Systemic corticosteroids should not be instituted for symptomatic relief as it does not affect the incidence of complications nor rates of admission or length of hospitalization [ 32 ].
Lymphoproliferative cancers are the most well-established late-onset complication to IM and have been investigated in several different cohorts since the s. A British study from found similar results in two different cohorts. Both showed elevated risk of HL with rate ratios of 3.
An Italian multicenter case-control study from also observed an increased risk, with an age-adjusted OR of 4. Overall, published data seem to agree on a strong correlation between IM and HL where results concerning NHL in general are more conflicting.
On the other hand, for certain NHL subtypes a strong correlation seems to exist. This highly aggressive type of B-cell lymphoma has since been strongly correlated to EBV. There are three subtypes of BL; endemic, sporadic and immunodeficiency-associated, where the endemic subtype has shown the strongest correlation with EBV [ 35 ].
This condition has shown to impair prognosis as these patients tend to respond poorly to conventional therapy [ 36 ]. As previously discussed, IM may lead to airway compromise as the mentioned lymphoproliferative cancers may themselves cause airway obstruction.
However, this is not within the scope of this review nor relevant to a GP. It seems clear, however, that there is an association. Furthermore, the risk of MS was 2. A large umbrella review published in , studying 44 different proposed risk factors for MS found similar results, with strong epidemiological evidence for IM as a risk factor for MS [ 38 ]. A study of the correlation of IM and initial symptoms of MS from supports a causative relationship between IM and MS and state that the rate of which MS develops could depend on genetically susceptibility to EBV infection as well as time of infection, with postpubescent infection being critical for the initiation and rapid development of MS [ 39 ].
Despite the published data, it is a challenge to prove underlying mechanisms. Humanized mouse models have been studied, but graft-versus-host reactions have been major confounders in these studies [ 40 ].
A study from on this controversy summarized the key issues in the debate: There is currently no consensus as to whether patients with MS has EBV-infected B-cells in the CNS [ 41 ].
If there indeed exits a causal link between EBV and MS, this would support that vaccination against EBV could have the potential to eliminate MS as one study suggests or, that insuring early life exposure to EBV could decrease the risk of developing MS, as individuals with a history of symptomatic IM exhibit a 2. A causal link between RA and IM has been proposed alongside several other autoimmune diseases.
However, a large systematic review and meta-analysis from found no significant association. The authors concluded, however, that several of the included studies had limitations and that more data on the subject was needed [ 45 ].
At present, no data demonstrate a clear association between EBV and RA, but it is worth acknowledging the increasing amount of literature suggesting diverse roles of EBV in autoimmune disease. Although rare, a GP should be aware of this as a differential diagnosis in patients with IM-symptoms persisting for more than 3 months, after exclusion of IM, autoimmune disease and immunodeficiency disorders congenital or acquired [ 46 ]. Further diagnostic work should be performed by a specialist in haematology.
The expanding roles of EBV in both benign and malignant disease bear witness of a viral species with diverse effects on the human body. GPs of today therefore need to be aware of not only the classical early complications to IM, but also late complications and potential associated conditions as patients are entitled to evidence-based risk estimates of such outcomes.
Encephalitis is a term that means inflammation of the brain tissue, and is accompanied by typical signs of this inflammation. A change in level of consciousness, behavioral changes, difficulty walking or talking, and even strange sensations of tingling and numbness--called paresthesias--may be seen. In addition, a person with encephalitis may experience hemiparesis, which is a weakness along an entire side of the body.
Infection with EBV may result in this neurological symptom, especially if the eye is infected with the virus. In this case, eye pain and gradual loss of vision may occur. According to Drs. Osborne and Balcer, writing in UpToDate, vision usually diminishes over a course of hours to days; the peak of vision loss occurs within one to two weeks.
Flashes of light, light flickers and loss of color vision are also potential indicators of optic neuritis. A cranial nerve palsy is a disorder of one of the nerves of the head. In patients infected with EBV, the most common nerve to be affected is the facial nerve; this is another neurological symptom of EBV. Indications of a facial nerve palsy include an abrupt onset of paralysis of one side of the face--the side in which the nerve is affected.
A sagging eyebrow and inability to close one eye are other clues that a facial nerve is being affected by EBV. A mononeuropathy is a disease or disorder of a single nerve. It is often caused by compression, entrapment or trauma to a specific nerve; for instance, carpal tunnel syndrome occurs when the median nerve of the wrist becomes entrapped.
Outcomes: Multiplex PCR detected 5. Lessons: Elderly patients under immunosuppression may be susceptible to develop retinitis associated with infection of multiple HHVs, and multiplex PCR is an excellent tool to diagnose an unidentified panuveitis resembling this case. Abstract Rationale: Chronic uveitis with immunosuppressive agents could develop chronic herpetic retinitis with varicella-zoster virus VZV or herpes simplex virus HSV.
Publication types Case Reports.
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