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1 Running Head: EPSTEIN-BARR VIRUS Melisa Dervisevic Epstein - Barr virus Written Protocol SUNY IT 2 EPSTEIN-BARR VIRUS Epstein - Barr virus Written Protocol Definition of Problem, Pathophysiology, Etiology Epstein-Barr virus (EBV), also called human herpes virus 4 (HHV-4) is part of the herpes virus family. The virus was first revealed in 1964 by Michael Epstein and Yvonne Barr during their research on Burkett’s lymphoma (Grywalska et al, 2013). EBV virions have a doublestranded, linear DNA genome encoding approximately 100 genes surrounded by a protein capsid. A protein tegument lies between the capsid and the envelope (2013). The EBV genome convert a series of products interacting with or exhibiting homology to a wide variety of antiapoptotic molecules, cytokines, and signal transducers, therefore promoting EBV infection, immortalization, and transformation (Carbone, Gloghini, & Dotti, 2008). There are three types of latent gene expression in the EBV genome: latency I, latency II, and latency III (2008). In latency I, there is an Epstein- Barr nuclear antigen I (EBNA-1) and two small noncoding Epstein-Barr RNAs (EBERs). The gene expression in latency II includes the EBNA-1, the EBERs, latent membrane protein (LMP)-1, LMP-2A, and LMP-2B. Latency III involves all of the EBNAs, EBERs, and LMPs (2008). Most primary EBV infections in healthy individuals are asymptomatic but occasionally can cause acute infectious mononucleosis, which clears on its own. Once the individual has the EBV infection, they become lifelong carriers of the virus. EBV then continues latently in the host within long-life memory B cells. In a normal response, the growth of B cells latently infected with EBV is controlled by the host immune response, mainly by virus- specific T cells. However, in some individuals, the virus is implicated in the development of malignancy (Grywalska et al, 2013). In the immunocompromised hosts, the interaction between EBV replication, latency, and immune control can be interrupted and induces extended proliferation of 3 EPSTEIN-BARR VIRUS EBV-infected lymphocytes and their malignant transformation (2013). EBV has been classified as class I carcinogen and is associated with multiple malignancies and lymphoproliferative disorders (Grose & Schub, 2013). There is strong evidence that shows association between EBV and Burkitt’s lymphoma, NK/T-cell lymphoma, nasopharyngeal carcinoma (NPC), Hodgkin’s lymphoma, and malignant lymphoma (2013). Also there has been some relations between EBV and gastric carcinoma and breast carcinoma. Incidence The incidence of EBV is higher now than it was before because of all the detection tests and studies being done that show correlation with different disease processes. Many children become infected with EBV, and these infections are usually mild and cause no symptoms. When adolescence and young adults get EBV infections, it causes infectious mononucleosis in 35-50% of the time. Up to 95% of American adults aged 35-40 have been infected with EBV (Zhong, 2012). According to Centers for Disease Control and Prevention (CDC), infants become susceptible to EBV as soon as maternal antibody protection disappears (2013). Burkitt’s lymphoma is broken down into three different variants: endemic (affecting children in equatorial Africa and New Guinea), sporadic (affecting children and young adults throughout the world), and immunodeficiency related (HIV infection). Based on the different variants, EBV has been identified in all cases of endemic variant, 15-20% of sporadic variant cases, and 30-40% of the cases of the immunodeficiency variant (Carbone, Gloghini, & Dotti, 2008). There are different types of Hodgkin’s lymphoma and all have different degrees of EBV in the tissue. EBV was found in lymphoma tissue in 70% of mixed cellularity (MC) Hodgkin’s disease, 95% of lymphocyte depleted (LD), and 10-40% of nodular sclerosing (Grywalska et al, 4 EPSTEIN-BARR VIRUS 2013). AIDS-related lymphomas show an EBV infection in 40-90% of all cases (Leruez-Ville et al, 2012). Screening/Risk Factors There are no current screenings done to test for EBV. The diagnosis is made by symptoms and laboratory studies. EBV infections are most common in developing countries and populations of low socioeconomic status (Grywalska et al, 2013). The areas with poor hygiene practices have also shown to have an increased risk of developing EBV. Gender is not a risk factor due to males and females both having the same chance of developing the virus. The geographic location is another risk factor, regions such as central Africa, Papua New Guinea and Alaska have higher percentages of EBV (2013). The virus can be spread through oral contact, therefore sharing food, utensils, dishes, or glasses with an infected person is a risk factor. Kissing an individual that has the virus is another risk factor. There are groups of individuals that are at risk for developing a serious illness caused by EBV. Those people are organ transplant recipients, those who are human immunodefiency (HIV) positive, those receiving chemotherapy, or have other immune system disorder (Grose & Schub, 2013). Those individuals with Duncan’s disease such as X-linked lymphoproliferative syndrome may also develop a serious illness because they have weakened immune response (2013). Clinical Findings Infectious mononucleosis (IM) is the most common cause of EBV. The clinical findings of the virus will depend on what illness/disease they have caused and it could be different with the other diseases such as lymphoma. The classic three symptoms that characterize IM are fever, pharyngitis, and lymphadenopathy (Marshall & Foxworth, 2012). Cervical lymph 5 EPSTEIN-BARR VIRUS nodes are enlarged in majority of the cases. Before the patient develops any of these three symptoms, they usually start with prodrome symptoms that last about a week. The nonspecific clinical findings are headache, anorexia, malaise, and fatigue. There could be associated signs and symptoms such as splenomegaly, hepatomegaly, rhinitis, cough, rash, abdominal pain, and periorbital edema. This presentation usually represents adolescents. Older adults are less likely to have sore throat and lymphadenopathy instead they have hepatomegaly and jaundice (Ebell, 2004). When young children get infected with the virus, they show minimal to no symptoms. If they do have any symptoms it will present as a viral upper respiratory infection or gastrointestinal illness. IM in many cases could be confused with group A streptococcal pharyngitis because they both can have palatal petechiae and tonsillar exudates on the posterior oropharynx. Rash is normally not see with EBV, however a muculopapular rash can occur in more than 90% of those patients treated with an aminopenicillin antibiotic (ampicillin, amoxicillin) (Marshall & Foxworth, 2012). In this case the provider might have treated the patient for group A streptococcal pharyngitis instead of IM. Differential Diagnosis When the virus is in the body the individual can present in many different ways. The provider won’t always have a clear diagnosis from the start and will think about other reasons why the patient is having the symptoms. The list of differential diagnosis that can come to mind are: 1. Streptococcal pharyngitis and tonsillitis 2. Diphtheria 3. Blood dyscrasias 6 EPSTEIN-BARR VIRUS 4. Rubella 5. Measles 6. Viral Hepatitis (hepatitis A or B) 7. Cytomegalovirus 8. Toxoplasmosis 9. Acute HIV infection (Marshall & Foxworth, 2012) Social/Environmental Considerations Based on the risk factors, good hand washing and hygiene is important to minimize the chances of spreading or getting infected with the virus. Every person should avoid close contact with a person that is infected and symptomatic. Transmission of this virus involves intimate contact with saliva of an infected person. Transmission of this virus through the air or blood does not normally occur (Centers for Disease Control and Prevention, 2013). The incubation period is usually 4-6 weeks. There is no special precautions or isolation procedures required because the virus is also found frequently in the saliva of healthy people (2013). These people can carry and spread the virus sporadically throughout their life. They are usually the reservoir for person-toperson transmission. That is the prime reason why transmission of the virus is almost impossible to prevent. Laboratory Tests When symptoms are not enough to make a clear diagnosis, laboratory studies might need to be done to confirm before treatment is started. The most frequently used and rapid test is the heterophil antibodies, also known as the monospot test. This test has great specificity because a 7 EPSTEIN-BARR VIRUS positive result usually indicates infection with EBV, however the sensitivity ranges from 70-90% (Marshall & Foxworth, 2012). Providers can also use viral capsid antigen of EBV to differentiate between acute, recent, and past infections. The presence of IgM antibodies to the viral capsid antigen of EBV happens within the first few weeks of the infection and disappears after 3 months. The occurrence of IgG antibodies to the viral capsid antigen of EBV is seen early in the disease but is also stays in the system for life. Antibodies to EBV early antigen (anti-EA) occur weeks to months after infection and may exist for 6 months to years after the infection (2012). Another laboratory test that could be done is a CBC with differential that would show an elevated white blood cell (WBC) count, decreased hematocrit, and decreased platelet count. Liver function tests should be done to see if the liver enzymes are elevated. Peripheral blood smears can be used in evaluating if there are any atypical large lymphocytes. If there are any respiratory symptoms, a chest x-ray should be done to rule out infiltrates or pneumonia. If a splenic rupture is questionable then an abdominal ultrasound must be done (Grose & Schub, 2013). Management/Treatment Non-Pharmacological The ultimate treatment for IM is supportive care for symptomatic relief and promote physiologic recovery. Adequate hydration and rest are the two main recommendations. Encourage patients to do warm saline gargles for sore throat at least three times a day. The patients should be provided writing material if they difficulty with verbal communication because of the swelling. Vital signs should be monitored frequently. Humidification and head of 8 EPSTEIN-BARR VIRUS the bed should be elevated to help patients breathe easier. Patients should be provided assistance if they need it with hygiene and re-positioning themselves to prevent skin breakdown. All physiological systems should be assessed especially neurological, lymphatic, and respiratory to prevent further complications from occurring. Intake and output monitoring is important to prevent dehydration. Pharmacological Pharmacological treatment is not recommended for a patient with IM but can be used to treat some of the discomfort. Nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen can be used for fever and myalgias. If the patient has moderate-severe sore throat, they can use throat lozenges, sprays, or gargle with 2% lidocaine (Xylocaine) solution to relieve pharyngeal discomfort (Ebell, 2004). Acyclovir (antiviral) can be used early in the course to reduce some of the symptoms. However according to Ebell, a meta-analysis of five randomized controlled trials involving 339 patients found that patients who took acyclovir had less oropharygneal shedding at the end of therapy but it provided no significant or consistent clinical benefit (2004). If the patient has a secondary bacterial infection such as streptococcal pharyngitis, an antibiotic can be used. Corticosteroids are not recommended but can be used with severe complications such as hematologic or neurologic complications or when the airway is compromised (severe pharyngotonsillitis and oropharyngeal edema). The typical dose of corticosteroids is 1mg/kg/day (with a maximum dose of 20mg/day) for 7 days. After the 7 days, the dosing should be tapered before discontinuation. A small, double blinded, randomized trial of 33 confirmed IM children was done, those who were given dexamethasone orally had less pain at 12 hours but not at 24,48,and 72 hours (Ebell,2004). This finding shows that more doses would be needed and is not the best treatment. 9 EPSTEIN-BARR VIRUS Complications The two most serious complications of IM caused by EBV are airway obstruction and splenic rupture. Airway obstruction can occur because of palatal and tonsillopharyngeal hypertrophy. This could be very serious and might require an emergency tracheal insertion for open airway. Splenic rupture is rare, it occurs in 0.1% of all cases but can be fatal if it does occur (Marshall & Foxworth, 2012). In a review of 55 athletes with splenic rupture, almost all of the ruptures occurred in the first three weeks of the illness. In the same group one half of the ruptures didn’t cause any trauma (Ebell, 2004). The presence of acute abdominal pain that localizes to the left quadrant and radiating to the left shoulder is a positive Kehrs sign and indicates splenic rupture. The most common complications of EBV infections are mild laboratory abnormalities. There could be neutropenia and thrombocytopenia that occurs early in the infection. Severe autoimmune thrombocytopenia and autoimmune hemolytic anemia are less common. Many patients have elevated transaminases but most of the time are asymptomatic. EBV has been found to be a major cause of viral-induced hemophagocytic lymphohistiocytosis (HLH) and is often associated with fatal IM (2012). Neurologic complications are rare but can occur. These are encephalitis, meningitis, Guillain-Barre syndrome, cranial nerve palsies, and transverse myelitis. Cardiac complications are also rare but EBV can cause pericarditis and myocarditis. Even though it’s very uncommon, EBV can cause malignancies such as Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin disease, T-cell lymphoma, and gastric carcinoma (2012). Follow-up 10 EPSTEIN-BARR VIRUS Since EBV can cause many different complications, the patients should be monitored closely during the first 2-3 weeks after the onset of symptoms. Then continue following the patient until the symptoms subside completely. The patient should be closely monitored for physical and laboratory evidence of splenic rupture, severe hemolytic anemia, thrombocytopenia purpura, and encephalitis. Counseling/Education Education is very important in a patient who has IM caused by EBV in order to prevent worsening symptoms or complications. You want to instruct the patient to avoid any contact sports, heavy lifting, and excess exertion until spleen and live have returned to normal size. It usually takes 3-4 weeks. It is difficult to depend on the physical exam alone in determining if the patient has splenomegaly. In one study, an ultrasound detected splenomegaly in all affected individuals with IM compared with 17% found by palpation only (Marshall & Foxworth, 2012). The individual needs to eliminate alcohol and any other exposure to hepatotoxic drugs until liver function tests are back to normal. They need to avoid oral (kissing) and physical contact with others for several weeks during the active infection. Patients need to be educated on the complications that could occur with IM and to call if they develop any new or worsening signs/symptoms. Consultation/Referral Other specialist might need to be involved in the care of the patient with IM caused by EBV if severe complications occur. A list of potential consults are: 1. Surgeon ( splenic rupture) 2. Ears, nose, throat (ENT) specialist ( airway obstruction) 11 EPSTEIN-BARR VIRUS 3. Hematologist ( anemia or thrombocytopenia) 4. Neurologist (Encephalitis) 5. Cardiologist (Pericarditis) (Domino, 2010) Literature Review The majority of the articles were obtained from CINAHL databases. Some articles were found at Medline plus, SAGE journals, and google scholar. It was difficult finding 25 peer reviewed studies because there were too many case studies and descriptive articles. The key terms used were Epstein - Barr virus, EBV, EBV diseases, EBV treatment, EBV education, and EBV complications. A librarian helped out by guiding me in the right direction and showing me how to search key terms suggested by the database. Most of the articles were found using CINAHL’s suggested terms. The limitations that were used were the year from 2008-2013, English language, peer reviewed, journal articles, and full text. This helped narrow the search down to the articles that were most helpful. EBV can cause many different diseases or complications to the patient. After the 25 articles were obtained, I narrowed it down to the most common themes and used the information from there to develop the Appendix table. The state of the science in most of the articles for EBV were related to infectious mononucleosis as the most popular one but it also had different malignancies that were related to EBV. The ones most commonly mentioned are lymphoma, childhood leukemia, laryngeal carcinoma, breast cancer, multiple myeloma, nasopharyngeal carcinoma, and Hodgkin’s. There were no specific guidelines that were mentioned, just the different 12 EPSTEIN-BARR VIRUS correlations that were made between EBV and other medical illnesses. The major credible authorities for the topic were department of cancer, pathology and microbiology, surgery, hematology and research, and biomedical imaging. The similarities that were often include the age group they used, population, where information was obtained from, and the positive correlations between EBV and cancers. The differences are the different malignancies that were mentioned in each article. I think this created the gaps in the studies. There were way too many different diseases that were mentioned and small studies that were done. The largest population size that was used was 108 and smallest was 10. Cancer was the common theme in majority of the articles. There were a few studies that were done on the pediatric population but the age group most often seen was 30’s-50’s. There some that were done on men only and others that were done on female only. Refer to appendix for more information on the different articles. 13 EPSTEIN-BARR VIRUS Questions 1. How is the EBV transmitted? a. Fecal-oral route b. Blood/bodily fluids c. Saliva or close oral contact ( EBV cells live in the mouth and spread by saliva) d. Not contagious 2. What is the most common cause of EBV? a. Hodgkin's b. Infectious mononucleosis (EBV shown to cause most frequently) c. Burkitt’s Lymphoma d. Breast carcinoma 3. The highest incidence of EBV is between what age group? a. 15-24 ( college students most at risk) b. 40-60 c. 10-20 d. 6-8 4. Which individual is at most risk for getting EBV? a. 12 month old that just started walking b. 40 y.o that works at the hospital c. 20 y.o in college ( most at risk because they share drinks, utensils, and risky behavior) d. 10 y.o that plays three different sports 5. What is the most common clinical finding in Infectious mononucleosis? a. RLQ pain and fever b. Nausea/vomiting, increased WBC’s, abdominal pain c. Jaundice and increased LFT’s d. Fever, pharyngitis, and lymphadenopathy ( the classic triad of symptoms for Mono) 6. Discharge teaching should include? 14 EPSTEIN-BARR VIRUS a. Appropriate follow-up b. Teaching on EBV and how to prevent complications c. Avoid physical contact d. All of the above ( teaching should include ways to prevent splenic rupture) 7. What is the major reason you want the pt. to avoid physical contact? a. So they don’t spread the infection to other teammates b. They need their rest c. Prevent dehydration d. Prevent splenic rupture (one of major complications of Mono) 8. What would the CBC look like with a pt. with mono? a. Elevated WBC’s, decreased Hct and platelets b. Hct and Hgb decreased c. Normal d. WBC’s increased 9. The best treatment for Mono is? a. Antibiotics b. Antivirals c. Oral or IV hydration and rest (supportive therapy best treatment) d. Analgesics 10. Why might a person with mono need a surgical consult? a. Possible tonsillectomy b. Just to establish care c. Possible spleenectomy ( if the person ruptures the spleen) d. Not necessary 15 EPSTEIN-BARR VIRUS Appendix A Study Focus Dohno et al Evaluate the (2010) rate of VCAIgM and/or VCA-IgG negative Japanese patients during the acute phase of IM Subjects N= 104 Japanese children with EBV-IM Population Department of Pediatrics at Kochi Medical School Hospital from 19882003 Age 2month s-13 years LeruezVille et al (2012) Investigate whether the risk of developing lymphoma was increased when blood EBV DNA load was high in previous years N= 43 cases of AIDSrelated lympho ma (ARL) diagnose d between 19882007 French Agence Nationale de Rechercher sur le SIDA (ANRS) PRIMO and SEROCO HEMOCO No age group identifi ed Koh et al (2012) Evaluate the potential roles of age, gender, stage, and subtype in the effect of EBV on overall, diseasespecific, and N= 159 patients with Hodgkin ’s Lympho ma (HL) Patients diagnosed at Asan Medical Center, Seoul, Korea 4-77 years old. Male= 94 Female s= 65 The median Method EBV genome in peripheral blood mononuclea r cells was measured. Serology was based on lab immunefluorescence assay Two case controls matched for the cohort and CD4 cell count in the year of ARL. EBV DNA was measured in PBMC’s and serum samples Clinical information was obtained via medical records Finding Anti VCAIgM was positive rate in acute phase was only 25% in fants but 80% in patients >4years of age High levels of EBV DNA in PBMCs collected a median of 10 months before diagnosis were associated with increased risk of system B lymphoma Tumor cell EBV was + in 34.5% EBV + HL was associated with age of >25, male gender, B symptoms, advanced 16 EPSTEIN-BARR VIRUS event free survival Wu et al, (2013) Sehgal et al, (2010) Rota et al, (2010) age was 35.5 Demonstrate that a substantial percentage of the immune thrombocytop enia cases are associated with EBV and CMV Investigate the association of EBV in childhood leukemia N= 42 patients at Sichuan Universit y Patients clinically diagnosed with ITP and received a lap splenectom y 20082012 N=29 25 patients consecuti with acute ve lymphocytic patients leukemia (ALL) and 4 with Hodgkin’s Determine the serum levels of cytokines in EBV DNA positive patients with laryngeal carcinoma N=10 patients Biopsy tested positive for laryngeal CA and tumor tissue positive for EBV age stage, high risk IPS, tx with chemo Averag Retrospectiv Nine e= 36 e report on (21.4%) and 42 ITP pts eight (19%) Male=1 and 20 ITP pts had 0 healthy a positive Female control EBV and = 32 cases CMV 2-14 years old. Averag e was 6.5 All were male Averag e age 54.6 EBV studies using sensitive polymerase chain reaction followed by hybridizatio n for presence of Bam H1-W region of EBV genome and detection of anti Z EBV replication activator The PCR for EBV was + in 8/25 patients of ALL, Western blot test using anti Zebra antibodies was + in 5/25, and 32% of children with ALL had evidence of active EBV replication Serum No cytokine difference levels were between determined serum by enzyme- levels of linked interleukin immunosorb 1B, 2, 6, ent assay and 12. Serum levels of interleukin 10 and B1 17 EPSTEIN-BARR VIRUS Aguayo et al, (2011) Analyze the presence of HPV and EBV in breast cancer N= 55 Agborsang aya et al, (2011) Evaluate the association between serum antibodies indicating EBV infection or reactivation and risk of pregnancyassociated breast cancer (PABC) N=108 density sampled PABC casecontrols that were previousl y used Investigate whether there are differences between two groups of Multiple myeloma (MM) and control group for presence of EBV DNA N=60 patients (30 MM and 30 control group) Sadeghian et al, (2011) Breast cancer patients of different hospitals from Santiago of Chile Case and controls were used from a linkage of the Finnish Maternity Cohort (FMC) in Finland <65= 34 patients >65=12 patients 60 formalinfixed paraffin embedded bone marrow biopsies in pathology lab, Ghaem, Iran Averag e age control group = 40-80 Averag e age= 34.4 All females Averag e age in MM 58-66 Histological classificatio n was made using the guidelines of the Japan Cancer Society Nested casecontrol that looked at vitamin D and antibodies to EBV for PABC Casecontrol study was done. Several sections were cut from each paraffin blocks, and then DNA was extracted by non-heating extraction method. were higher in EBV DNA +laryngeal CA HPV-16 was detected in 4/46 BCs (8.7%) and EBV 3/46 (6.5%) BCs Immunologi cal markers of EBV reactivation status among individuals with sufficient vit D levels were consistently associated with increased risk of the disease DNA of EBV was detected in 10 patients of case control (5 males and 5 females) and 3 subjects (2 males and 1 female) of control group 18 EPSTEIN-BARR VIRUS Ferrari et al, (2012) Evaluate EBV DNA levels before treatment and during followup of Western pts with locoregionally advanced nasopharynge al carcinoma (NPCs) N= 36 consecuti ve patients Patients treated with induction chemothera py followed by chemoradiat ion 29-58 All Italian men PCR was carried out for detection of EBV genome and analyzed by electrophore sis Prospective study, EBV copy numbers were determined after DNA extraction using realtime quantitative polymerase chain reaction The study confirmed that patients from a Western country affected by locoregionally NPCs have high plasma EPV DNA levels at diagnosis. All but one patient has a plasma EBV DNA concentratio n of >350 copies/ml 19 EPSTEIN-BARR VIRUS References Agborsangaya, C.B., Lehtinen, T., Toriola, A.T., Pukkala, E., Surcel, H.M., Tedeschi, R. & Lehtinen, M. (2011) Association between epstein-barr virus infection and risk for development of pregnancy-associated breast cancer: joint effect with vitamin d. European Journal of Cancer. 47, 116-120. Aguayo, F., Khan, N., Koriyama, C., Gonzalez, C., Ampuero, S., Padilla, O., Solis, L., Elizuru, Y., Corvalan, A. & Akiba, S. (2011) Human papillomavirus and Epstein-barr virus infections in breast cancer from chile. Infectious Agents and Cancer. 6(7), 1-7. Bathoorn, E. Vlaminckx, B.M., Schoondermark-Stolk, S., Donders, R., Van Der Meulen, M. & Thijsen, S.F.T. (2011) Primary epstein-barr virus infection with neurological complications. Scandinavian Journal of Infectious Diseases. 43, 136-144. Bayram, A., Erddogan, M.B., Eksi, F. & Yamak, B. 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Grose, S. & Schub, T. (2013) Epstein-barr virus infection. CINAHL International Systems. 1-3. Gujral, S., Gandhi, J.S., Valsangkar, S., Shet, T.M., Epari, S. & Subramanian, P.G. (2010) Study of the morphological patterns and association of Epstein-barr virus and human herpes virus 8 in acquired immunodeficiency deficiency syndrome-related reactive lymphadenopathy. Indian Journal of Pathology and Microbiology. 53(4), 723-728. Jin, C.Q., Liu, F., Dong, H.X., Zhang, J., Zhou, J.W., Song, L., Xiao, H. & Zheng, B.Y. (2011) Type 2 polarized immune response holds a major position in Epstein-barr virus-related idiopathic thrombocytopenic purpura (ebv-itp). International Journal of Laboratory Hematology. 34, 164-171. Fagundes, C.P., Alfano, C.M., Bennett, J.M., Glaser, R., Povoski, S.P., Lipari, A.M., Agnese, D.M., Yee, L.D., Carson III, W.E., Farrar, W.B., Malarkey, W.B., Chen, M. & KiecoltGlaser, J.K. (2012) Social support and socioeconomic status interact to predict Epstein-barr virus latency in women awaiting diagnosis or newly diagnosed with breast cancer. American Psychological Association. 31(1), 11-19. Ferrari, D., Codeca, C., Bertuzzi, C., Broggio, F., Crepaldi, F., Luciani, A., Floriani, I., Ansarin, M., Chiesa, F., Alterio, D. & Fao, P. (2012) Role of plasma ebv dna levels in predicting recurrence of nasopharyngeal carcinoma in a western population. Biomed Central. 12, 1- 21 EPSTEIN-BARR VIRUS 7. Grywalska, E., Markowicz, J., grabarczyk, P., Pasiarski, M. & Rolinski, J. (2013) Epstein-barr virus-associated lymphoproliferative disorders. Postepy Hig Med Dosw. 67, 481-490. Kannangai, R., Sachithanandham, J., Kandathil, A.J. Ebenezer, D.L., Danda, D., Vasuki, Z., Thomas, N., Vasan, S.K. & Sridharan, G. (2010) Immune responses to Epstein-barr virus in individuals with systemic and organ specific autoimmune disorders. Indian Journal of Medical Microbiology. 28(2), 120- 123. 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