Some of these cells demonstrate plasmacytoid morphology with eccentric nuclei and perinuclear hof Fig 1B. Some show visible nucleoli resembling immunoblasts Fig 1C. It appears that the percentage of atypical lymphocytes in total lymphocytes does not correlate with the severity of the disease Table I. Additionally, two cases of bronchial alveolar lavage smears from two patients no accompanying blood smear review were reviewed due to the presence of numerous atypical lymphocytes with the same morphology as those found in the blood smear Fig 1E.
Differential count of the indicated lymphocytes was performed; lymphocytes were counted in each patient. Their morphology is different from Downey type II reactive lymphocytes Fig 1F that are commonly seen in other viral infections such as Epstein—Barr virus.
Additionally, lymphopenia is frequently seen in SARS and influenza and in both diseases has been recognised as a negative predictor of outcomes. However, presence of atypical lymphocytes is not a laboratory feature of influenza. Future studies in the characterisation of these cells could be helpful in our understanding of the pathophysiology of the disease. National Center for Biotechnology Information , U. Br J Haematol.
Samuel E. Studies in immunodeficient mice reconstituted with human cells indicate that NK cells are particularly important in controlling lytic EBV infection NK cells also appear to have a role in controlling chronic viral infection.
It will be important in future studies to gain more insight into the molecular interactions that occur between NK cells and EBV-infected cells, especially given the panoply of NK cell receptors and the ability of viruses to modulate NK cell ligands. Like other herpes viruses, EBV utilizes a multitude of strategies to evade detection and elimination by the host immune system Immune evasion strategies of EBV have been recently reviewed 19 , 20 and will not be extensively detailed here, but can be broadly classified into three categories, those that modulate: 1 immune cell function, 2 antigen presentation pathways or 3 apoptotic pathways.
A variety of EBV proteins target the processing and presentation of viral antigens thereby promoting immune evasion. Finally, EBV has evolved several tactics to prevent apoptosis of the infected cell in order to augment viral persistence. A functional bcl-2 homolog encoded by BHRF1 can inhibit apoptosis induced by a range of stimuli at least in part by binding to the pro-apoptotic protein Bim LMP1 signaling in human B lymphoma cell lines induces expression of the cellular protein c-FLIP that interferes with formation of the death inducing signaling complex DISC , required to initiate activation of caspase 8 following ligation of death receptors.
LMP1 modulation of cell death pathways may be especially relevant to the germinal center model for EBV discussed above. In this scenario LMP1, a functional homologue of CD40, can provide survival signals, in concert with another latent cycle protein, LMP2a, which mimics B cell receptor BCR signaling, to infected B cells that are otherwise destined to die in the absence of encounter with antigen.
These are just a few salient examples of the myriad maneuvers through targeting of immune cell function, antigen presentation, and cell death pathways, by which EBV modulates the host immune response. Understanding the manner in which EBV-encoded proteins cooperate to evade and subvert the immune response during lytic and latent infection is crucial to advancing new approaches to vaccine development and to understand the pathogenesis of EBV-associated malignancies. LMP1 is required for transformation of human B cells 35 and is sufficient to transform rodent fibroblasts in vitro LMP1 is an integral membrane protein containing six transmembrane-spanning domains and a long C-terminal tail Fig.
The transmembrane domain acts to induce oligomerization of LMP1 complexes in the membrane to aggregate in lipid rafts. This clustering of LMP1 proteins brings individual C-terminal tails into proximity, creating suitable docking sites for cytoplasmic signaling adaptor proteins, thereby allowing LMP1 to signal in a constitutive fashion. We have examined in detail the signal transduction pathways elicited by LMP1 and the corresponding downstream functions in latently infected B cells.
It is likely that IL produced by EBV infected B cells also acts to negatively regulate the immune response, akin to regulatory IL producing B cells, that have been more recently described to play a role in peripheral tolerance in autoimmunity, cancer, and organ transplantation By understanding the signal transduction pathways elicited by LMP1 we have been able to pinpoint specific molecules within key signaling nodes as potential therapeutic targets.
EBV was the first virus shown to encode microRNA miRNA 46 , a family of small, approximately 22 nucleotide, non-coding RNA that post-transcriptionally regulate gene expression for control of cellular events. Subsequently it has been established that virally-encoded miRNA participate in viral-host cell interactions including immune evasion, prolonging survival of infected cells, regulation of viral genes and potentially in the pathogenesis of viral-associated disease Interestingly, overexpression of miR is characteristic of many B cell lymphomas 50 , 51 and in a mouse model constitutive expression of miR in B cells lead to uncontrolled proliferation of pre-B cells and subsequent malignancy We and others have found that EBV infection induces the expression of specific host B cell miRNAs, including miR and miR, which potentially play a role in viral oncogenesis These studies suggest that further analysis of viral diversity and the impact on cellular function may provide new insights in to the underlying viral mechanisms that drive B cell lymphomagenesis and may be exploited to develop biomarkers for disease.
In particular, a high proportion of LMP1 molecules isolated from cell lines derived from Chinese patients with NPC were shown to have a characteristic 30 base pair deletion, compared to the B Consequently, it was proposed that the 30 base pair deletion may be important in development of NPC, however, subsequent studies showed a similarly high frequency of this deletion in LMP1 isolated from healthy, seropositive Chinese subjects Several other classification schemes for EBV have been described and at least three systems are based on amino acid changes in the C-terminal region of LMP1.
Raub-Traub and colleagues 62 proposed a system based on sequences from aa—aa of LMP1 variants compared to the laboratory strain, B Another classification scheme focused on amino acid sequences in short segments surrounding the 33 bp repeat and identified 25 variant forms The various criteria used for each of these classification schemes and the limited number of samples that were analyzed make it challenging to draw comparisons across studies and to establish whether specific variants or sequences of the EBV genome are linked to disease.
With respect to the immune response, there is evidence that genetic diversity can correlate with differences in T cell immunity such that LMP1 variants derived from NPC tumors elicit augmented T regulatory cell function and diminished cytokine production 66 , The full impact of variation in EBV genotypes, with respect to the immune response and to disease, has not likely been appreciated yet, in part, because the analyses have focused on distinct parts of the viral genome.
The whole genome sequence of the B Current technologies including high throughput sequencing platforms are likely to provide a more comprehensive, integrated assessment of EBV genotypes and may lead to an improved understanding of the relationship between EBV diversity, health, and disease.
In conclusion, EBV infection initiates a complex, ongoing interplay between the virus, the host B cell and the immune response. EBV has successfully employed a variety of strategies to promote viral persistence in healthy individuals, however, dysregulation of these pathways, or perturbation of host immunity, may contribute to the development of EBV-associated malignancies. Future studies to elucidate the mechanisms by which EBV coopts B cell function, the immune response to EBV, and the significance of viral diversity will be important in understanding the outcome of EBV disease.
National Center for Biotechnology Information , U. Immunol Res. Author manuscript; available in PMC Oct Olivia L. Krams , and Olivia M. Author information Copyright and License information Disclaimer.
Corresponding author: Olivia M. Martinez, Ph. Copyright notice. The publisher's final edited version of this article is available at Immunol Res. See other articles in PMC that cite the published article. The Viral Life Cycle To fully understand the host-viral interactions following infection with EBV requires a closer look at the complex life cycle of this virus Fig 1.
However, diagnostic testing is warranted in pregnant women because toxoplasmosis and acute human immuno-deficiency virus HIV and CMV infections are associated with significant pregnancy complications. Symptoms of acute HIV infection can resemble those of infectious mononucleosis. If acute HIV infection is suspected, a quantitative polymerase chain reaction test should be performed.
The differential diagnosis for suspected infectious mononucleosis is summarized in Table 1. Cytomegalovirus infection Patient is less likely to have adenopathy, tonsillar exudates, fever, or absence of cough than patients with streptococcal pharyngitis or infectious mononucleosis. Some information from reference Few well-designed studies have been conducted to determine the value of clinical examination in patients with infectious mononucleosis in the primary care setting.
The best study is a series including more than patients 16 years of age and older with sore throat, 15 of whom were found to have infectious mononucleosis on the basis of a positive heterophile antibody test.
Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med ; The presence of splenomegaly, posterior cervical adenopathy, axillary adenopathy, and inguinal adenopathy is most useful in considering the possibility of infectious mononucleosis, while the absence of cervical adenopathy and fatigue is most helpful in dismissing the diagnosis.
Infectious mononucleosis should be suspected and a diagnostic evaluation obtained in febrile patients who have sore throat plus splenomegaly, palatal petechiae, or posterior, axillary, or inguinal adenopathy.
The accuracy of diagnostic tests for infectious mononucleosis is summarized in Table 3. When a higher cutoff point is used to define an abnormal number of atypical lymphocytes, the sensitivity decreases i. Patients with clinically suspected IM; reference standard is positive heterophile antibody Patients over age 16 with sore throat; reference standard is positive heterophile antibody 6.
Patients with suspected IM; reference standard is positive heterophile antibody and an EBV-VCA antibody pattern compatible with recent infections 15 - NOTE : If the specificity was percent, The midpoint was within 2 percent of the mean in each case. The sensitivity is the percentage of patients with IM who have a positive test. Information from references 6 , 10 , and 15 through The original serologic test for infectious mononucleosis, the Paul-Bunnell test, detected heterophile antibodies by agglutination of sheep or horse red blood cells.
Although they are relatively specific, heterophile antibody tests are somewhat insensitive, particularly in the first weeks of illness. The false-negative rate is as high as 25 percent in the first week, approximately 5 to 10 percent in the second week, and 5 percent in the third week of illness. When the results are negative, these tests are better than heterophile antibody tests in ruling out infectious mononucleosis caused by EBV negative likelihood ratio, 0.
Antibody to Epstein-Barr nuclear antigen EBNA , while typically not detectable until six to eight weeks after the onset of symptoms, can help distinguish between acute and previous infections. If EBNA is positive in a patient with acute symptoms and suspected infectious mononucleosis, previous infection is suggested. Elevated hepatic transaminase levels are relatively common in patients with infectious mononucleosis, occurring in approximately one half of patients.
No evidence-based or consensus guidelines have been proposed to guide the evaluation of patients with suspected infectious mononucleosis; the following recommendations are based on a synthesis of the available evidence Figure 1. Patients between 10 and 30 years of age with sore throat, fever, and significant anterior cervical adenopathy, fatigue, posterior cervical adenopathy, inguinal adenopathy, palatal petechiae, or splenomegaly are at high risk for infectious mononucleosis.
A white blood cell count with differential or a heterophile antibody test should be obtained in these patients, as well as a rapid test for streptococcal pharyngitis. Algorithm for the management of suspected infectious mononucleosis. If the patient has more than 20 percent atypical lymphocytes or more than 50 percent lymphocytes with at least 10 percent atypical lymphocytes, infectious mononucleosis is quite likely, and further confirmation of the diagnosis is not needed.
A positive result of a heterophile antibody test also is strong evidence in favor of a diagnosis of infectious mononucleosis. A negative result of an antibody test, particularly during the first week of illness, may indicate that the patient does not have infectious mononucleosis. However, it also could be a false-negative result or could indicate that the patient has an infectious mononucleosis—like syndrome caused by CMV or toxo-plasmosis.
The patient should be treated symptomatically, and if the patient does not clinically improve within five to seven days, a second heterophile antibody test should be performed. If an accurate diagnosis is urgently required for example, in a competitive athlete who wants to return to competition as soon as possible , a VCA-IgM test may be selected. A negative result is strong evidence against the diagnosis of infectious mononucleosis. The mainstay of treatment for infectious mononucleosis is good supportive care, including adequate hydration; nonsteroidal anti-inflammatory drugs or acetaminophen for fever and myalgias; and throat lozenges or sprays, or gargling with a 2 percent lidocaine Xylocaine solution to relieve pharyngeal discomfort.
An older, quasi-experimental study 21 found that enforced bed rest slowed recovery. Given the lack of evidence for bed rest in many other conditions, it seems sensible to recommend that patients base their return to usual activities on their energy levels. A meta-analysis 22 of five randomized controlled trials involving patients found that patients who took acyclovir Zovirax had less oropharyngeal shedding at the end of therapy, but this treatment provided no significant or consistent clinical benefit and is therefore not recommended.
Another trial found no significant benefit from the use of ranitidine Zantac in patients with infectious mononucleosis. Corticosteroids have been advocated for the treatment of patients with infectious mononucleosis, 8 and some early studies 24 , 25 seemed to show a benefit from these agents with regard to normalization of temperature and laboratory values.
However, these studies had significant methodologic limitations. A more recent and better-designed study 26 found no benefit from a combination of acyclovir and prednisone. In a small, double-blind, randomized trial 27 of 40 children with suspected infectious mononucleosis 33 of whom had confirmed infectious mononucleosis , those who were given oral dexamethasone 0.
This finding indicates that repeated doses may be needed. Based on clinical experience and case reports, corticosteroids are recommended in patients with significant pharyngeal edema that causes or threatens respiratory compromise.
Two other studies 29 , 30 reported GABHS pharyngitis rates of only 3 to 4 percent in studies of more than patients. The true rate of concomitant infectious mononucleosis and GABHS pharyngitis probably lies between these extremes and may depend on the time of year. It seems prudent to obtain a rapid strep test in patients with infectious mononucleosis and to treat them with antibiotics only if the strep test result is positive. Amoxicillin and ampicillin should not be used because they may cause a morbilliform rash in patients with infectious mononucleosis.
Patients with infectious mononucleosis are likely to have splenomegaly. Although most patients do not have a palpable spleen on physical examination, a study 31 of 29 patients who were hospitalized with infectious mononucleosis and who therefore may have had more severe disease found that all patients had splenomegaly on ultrasound examination and that one half of them had hepatomegaly.
Only 17 percent of the enlarged spleens and 8 percent of the enlarged livers were palpable on physical examination, a finding that is consistent with other studies. The risk of splenic rupture is estimated at 0. Interestingly, in the same series, one half of ruptures were atraumatic.
These data suggest that patients should be kept out of athletics for at least three to four weeks and until they are asymptomatic. Some experts suggest a longer duration of restricted activity of five to six weeks 35 or even six months, 36 although data from natural history studies do not necessarily support these recommendations.
Because the physical examination is so insensitive, ultrasound imaging to assess the size of the spleen at three weeks may be a better guide for determining whether a patient should return to athletics. Although the strategy may make sense when used selectively e. Several cohort studies have examined the long-term outcomes of infectious mononucleosis. Between 9 and 22 percent of patients reported persistent fatigue or hypersomnia six months after clinical infectious mononucleosis, compared with zero to 6 percent of patients following uncomplicated upper respiratory infection.
In this study, sore throat, fever, headache, rash, cough, and nausea largely had resolved one month after the onset of symptoms. Fatigue resolved more slowly 77 percent initially, 28 percent at one month, 21 percent at two months, and 13 percent at six months , as did sleeping too much 45 percent initially, 18 percent at one month, 14 percent at two months, and 9 percent at six months and sore joints 23 percent initially, 15 percent at one month, 6 percent at two months, and 9 percent at six months.
The association between EBV infection and chronic fatigue syndrome remains uncertain, and a positive IgG test for EBV does not imply a causal relationship. In addition, evidence of EBV infection is not part of the definition of chronic fatigue syndrome. Information from references 1 and 38 through Already a member or subscriber? Log in. Interested in AAFP membership? Learn more. MARK H. Primary Care. Ebell received his medical degree from the University of Michigan Medical School, Ann Arbor, where he also completed a family practice residency.
He is the developer of the InfoRetriever software and deputy editor for evidence-based medicine for American Family Physician. Address correspondence to Mark H. Ebell, M. Reprints are not available from the author. The author indicates that he does not have any conflict of interest. Source of funding: none reported.
Bailey RE. Diagnosis and treatment of infectious mononucleosis.
0コメント