Epstein-Barr virus and the elderly host

The ability of the Epstein-Barr virus (EBV) to cause latent lifelong infection in the host and its capabilities of transformation may have important implications for the elderly host. Reports in the literature and hospital records were reviewed to determine the activity of EBV in the elderly. Seroepidemiologic surveys demonstrated that 90%-97% of adults more than 60 years old were seropositive for EBV. Geometric mean antibody titers and the percentage of individuals with high antibody titers to EBV increased with age--changes that were not associated with clinical illness. Only 29 cases of infectious mononucleosis have been reported in adults more than 60 years old. The elderly with infectious mononucleosis had significantly fewer occurrences of pharyngitis, lymphadenopathy, and splenomegaly when compared with young adults. The cases of two patients with illnesses that did not meet full criteria for infectious mononucleosis but may still have represented clinical manifestations of EBV infection are presented. Other EBV-associated diseases reported in the elderly include nasopharyngeal carcinoma and possibly B cell lymphoproliferative disease but not a chronic mononucleosis-like syndrome.     

Bone Marrow Findings in Infectious Mononucleosis and Mononucleosis-Like Diseases in the Older Adult

The bone marrow findings in 5 older adults with infectious mononucleosis or mononucleosis-like illnesses are presented. These individuals were initially considered to have lymphoproliferative disorders which often have similar constitutional signs and symptoms. All had atypical lymphocytosis of the peripheral blood. In addition, there were also abnormalities in the bone marrow. The most common findings included focal collections of lymphocytes and the presence of granulomas. The granulomas were small without caseous necrosis and giant cells were infrequent. This is in contrast to the idea that the bone marrow is normal in infectious monoculeosis and gives support to performing core biopsies as the aspirate smears in these individuals did not demonstrate the focal lymphocytosis or granulomas. Whereas, infectious mononucleosis and mononucleosis-like illness may be uncommon in the older individual, they certainly are not rare and it is important to differentiate these benign disorders from the more serious lymphoproliferative diseases. Heterophil test and/or Epstein Barr titers are important confirmatory tests.     

Hepatic encephalopathy in primary human immunodeficiency virus type 1 (HIV-1) infection

Primary infection of human immunodeficiency virus type 1 (HIV-1) is occasionally associated with common cold-like symptoms, and rarely with a self-limited illness resembling infectious mononucleosis. We report a 32-year-old man who presented with infectious mononucleosis-like blood picture on admission. Five days after admission he developed hepatic encephalopathy, which was ameliorated by administration of bolus corticosteroid. Based on the results of serologic studies, we diagnosed that he had primary HIV-1 infection. To our knowledge, this is the first published report of hepatic encephalopathy as a clinical manifestation of primary HIV-1 infection.     

Primary infection with Epstein-Barr virus in infants in the United States: clinical and serologic observations.

Previous studies in Ghana had shown that primary infections with Epstein-Barr virus in infants under the age of two years remain silent and evoke antibody responses different from those seen in infectious mononucleosis. In order to determine whether or not these observations were limited to Africa, 80 American infants presenting with minor infectious complaints were studied serologically; 14 (17.5%) showed evidence of recent or current primary infections with Epstein-Barr virus. The clinical features of these 14 infants were similar to those of the other 66 and did not suggest a diagnosis of infectious mononucleosis, nor were there histories of a recent infectious mononucleosis-like illness. Ten (72%) had antibodies to the early antigen complex induced by Epstein-Barr virus; however, these antibodies were directed, as in the Ghanaian infants, against the restricted rather than the diffuse components, in contrast to the pattern generally observed in infectious mononucleosis. Possible reasons for the differences between the responses of infants and those of older individuals to primary infection with Epstein-Barr virus and to the early antigen complex are discussed.     

Heterophil-negative infectious mononucleosis and mononucleosis-like illnesses. Laboratory confirmation of 43 cases.

During a 50-month period the diagnosis of heterophil antibody negative infectious mononucleosis or of a mononucleosis-like illness was made in 43 patients with a variable clinical picture and significant numbers of atypical lymphocytes. Epstein-Barr virus (EBV)-related serologic tests revealed that seven patients had primary EBV infections based on the detection of immunoglobulin M (IgM) antibodies to EB-viral capsid antigens (IgM-VCA) and the absence of anti-Epstein-Barr virus associated nuclear antigen (EBNA) on most initial specimens (six of seven cases). Thirty cases were due to active cytomegalovirus (CMV) infections and both detectable CMV-macroglobulins (≧1:32) and significant anti-CMV titers were present by a complement fixation technic. Abnormalities in liver function were less marked in CMV than in EBV infections in age-matched subjects. Of the remaining six cases, one was due to rubella and one to toxoplasmosis. Four cases were of undetermined etiology. Serums from 38.1 per cent of the patients with heterophil-antibody positive infectious mononucleosis were found to “cross react” in the IgM-CMV test, but serums from patients with acute CMV infection did not cross react in the VCA-specific IgM test. In nine of 36 cases without heterophil antibody (six due to CMV, one due to toxoplasmosis and one apparent infectious hepatitis), anti-D or -R of the early-antigen (EA) complex was detected (1:10 to 1:40), raising the question of reactivation of the EBV-carrier state by intervening infections mainly of viral origin.     

Autoimmune neutropenia and thrombocytopenia associated with development of antibodies to human immunodeficiency virus

We report on two patients with acute human immunodeficiency virus (HIV) infection, who developed an infectious mononucleosis-like clinical episode with thrombocytopenia and granulocytopenia. In both cases we detected the presence of IgG antigranulocyte antibodies and in one case the presence of IgG, IgM and IgA antiplatelet antibodies. The mechanisms of these cytopenias are discussed. The association between such autoimmune cytopenias and acute HIV infection has not been previously reported. We suggest testing for HIV seroconversion in patients with a seronegative infectious mononucleosis-like syndrome belonging to groups with a high risk for HIV infection.     

Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes.

Cold agglutinins (CA) were evaluated prospectively in patients with various mononucleosis syndromes and in a large control group. Cold agglutinins with anti-i specificity were seen mainly in heterophil-positive or -negative Epstein-Barr virus (EBV)-induced infectious mononucleosis (31.8% of cases). Unclassified CA with equal reactivity against cord and adult erythrocytes were seen in 56 of 150 (37.3%) cases of heterophil-antibody-positive infectious mononucleosis (IM), in 1 of 7 (14.3%) cases of heterophil-negative EBV-induced IM, and in 12 of 31 (38.7%) cases of the heterophil-negative mononucleosis-like syndrome due to cytomegalovirus or other unspecified agents. One patient with heterophil-positive IM had a persistent, partially papain sensitive CA with anti-Pr-like activity. Anti-i CA were seen in less than 1.0% of healthy young adults (500) or patients without mononucleosis (500) submitted for heterophil studies. Unclassified CA were noted in 3.2% of the latter 1000 samples.     

A case with infectious mononucleosis-like syndrome caused by human herpes virus-6 infection

A 26-year-old female was admitted because of multiple fractures in lower extremities. While in the hospital, she developed a high fever and generalized skin eruption. Physical examination revealed bilateral cervical lymphadenopathy and mild hepatosplenomegaly. The white cell count was 11,200 with 11% atypical lymphocytes. Serum GOT, GPT, LDH were markedly elevated. Infectious mononucleosis was suspected, but the serological test for EB virus did not show evidence of acute EB virus infection. Anti-HSV, CMV, hepatitis A virus antibody titers also did not show significant change during the coarse. The serological test for HHV-6 only showed increased titer of IgM and IgG antibodies. Rapidly elevated IgG antibody titer was indicative of reactivation of HHV-6. So, she was diagnosed as mononucleosis-like syndrome caused by HHV-6, probably reactivated infection. Her symptoms gradually disappeared during a month.     

Drug-induced mononucleosis-like hepatic injury in a patient with systemic lupus erythematosus

A case of systemic lupus erythematosus (SLE) with mononucleosis-like hepatic injury was described. An emergent cesarean section was performed in a 25 yr-old house wife at 34 weeks gestation, followed by administration of several antibiotics. After the surgery she complained of high fever, hepatomegaly and dull right hypochondralgia, and mild liver dysfunction was also found. The liver biopsy showed prominent mononuclear cell infiltration in the sinusoids with minimum hepatocellular necrosis and mild triaditis, resembling hepatic lesion in infectious mononucleosis (mononucleosis-like injury). There were no clinical and serological features suggestive of infectious mononucleosis. This hepatic lesion was thought to be a manifestation of allergic reaction to drugs to which the lymphocyte stimulation test was found to be positive. Immunological abnormalities inherent in SLE might be related to occurrence of such allergic drug reaction.     

Adverse virus-drug interactions

Over the last 3 decades, epidemiologists and clinicians have identified a few clinical entities that appear to result when a viral infection and a chemical exposure overlap and interact. Ampicillin rash during infectious mononucleosis, Reye's syndrome following salicylate ingestion and certain viral infections, and the association of AIDS-related Kaposi's sarcoma with abuse of nitrite inhalants and infection due to human immunodeficiency virus are examples of such phenomena. Preclinical research provides additional evidence that viruses and chemicals may interact and produce illnesses in animals. We hypothesize that other virus-drug interactions may exist. Identifying such interactions may lead to a better understanding of the pathogenesis of currently baffling illnesses and may provide insights into ways of preventing and/or treating diseases that appear uncontrollable now.     

Drug-induced mononucleosis-like hepatic injury in a patient with systemic lupus erythematosus

A case of systemic lupus erythematosus (SLE) with mononucleosis-like hepatic injury was described. An emergent cesarean section was performed in a 25 yr-old house wife at 34 weeks gestation, followed by administration of several antibiotics. After the surgery she complained of high fever, hepatomegaly and dull right hypochondralgia, and mild liver dysfunction was also found. The liver biopsy showed prominent mononuclear cell infiltration in the sinusoids with minimum hepatocellular necrosis and mild triaditis, resembling hepatic lesion in infectious mononucleosis (mononucleosis-like injury). There were no clinical and serological features suggestive of infectious mononucleosis. This hepatic lesion was thought to be a manifestation of allergic reaction to drugs to which the lymphocyte stimulation test was found to be positive. Immunological abnormalities inherent in SLE might be related to occurrence of such allergic drug reaction.     

Indirect immunofluorescence test for detection of IgM antibodies to cytomegalovirus.

A technique for the detection of IgM antibodies to cytomegalovirus (CMV) by immunofluorescence was developed. In order to prevent interference by rheumatoid factor in the sera, IgG was removed by prior immunoabsorption with antiserum to gamma Fc. Sera from 63 patients with a rise in titer of antibody to CMV, indicated by complement fixation, were IgM-positive, but yielded negative results on the Paul-Bunnell-Davidsohn test for infectious mononucleosis. Convalescent-phase serum samples from 20 patients with a seroconversion to herpes simplex virus and from 20 patients with a seroconversion to varicella-zoster virus also had no IgM antibodies to CMV. Sera from six of 10 patients with infectious mononucleosis and two of 100 normal blood donors were positive for IgM antibodies to CMV. In 38 of 63 patients, the diagnosis of CMV infection could be made several weeks earlier by the immunofluorescence test than by the complement-fixation test. IgM antibodies to CMV persisted for more than two months after onset of symptoms of the infection.     

Positive Epstein-Barr virus heterophile antibody tests in patients with primary human immunodeficiency virus infection

PURPOSE: To describe three cases of primary human immunodeficiency virus (HIV) infection in patients who had laboratory studies consistent with infectious mononucleosis. SUBJECTS: We describe 3 patients who presented with a viral syndrome, had a positive heterophile antibody test, and were diagnosed with primary HIV infection. RESULTS: The results of Epstein-Barr virus serology studies in each of these patients were consistent with chronic, but not acute, Epstein-Barr virus infection. HIV antibody tests were negative, and HIV RNA was >500,000 copies/mL in each patient. CONCLUSIONS: Clinicians should recognize that a positive heterophile antibody test in the setting of an acute viral illness does not exclude the diagnosis of primary HIV infection, although reactivation of latent Epstein-Barr virus infection cannot be ruled out. Patients presenting with nonspecific viral syndromes should be assessed for HIV risk behaviors and tested for primary HIV infection when appropriate.     

SH2D1A mutations in Japanese males with severe Epstein-Barr virus--associated illnesses

X-linked lymphoproliferative disease (XLP), a genetic disorder characterized by immunodeficiency to Epstein-Barr virus (EBV) infection, has been linked to mutations in the SH2D1A gene. To search for the occurrence of SH2D1A mutations in Japan, we performed genetic analysis of the SH2D1A gene in 40 males presenting with severe EBV-associated illnesses, including fulminant infectious mononucleosis, EBV-positive lymphoma, and severe chronic active EBV infection. SH2D1A mutations were detected in 10 of these 40 patients. Five of these 10 cases were sporadic. Patients with SH2D1A mutations displayed severe acute infectious mononucleosis with hyperimmunoglobulin M, hypogammaglobulinemia, and B-cell malignant lymphoma. By contrast, chronic active EBV infection was not associated with SH2D1A mutations. XLP survivors exhibited normal levels of circulating EBV-DNA during convalescence, suggesting that SH2D1A protein is not directly responsible for control of EBV replication. Thus, genetic analysis of the SH2D1A gene is particularly useful in the diagnosis of sporadic cases and carriers of XLP. (Blood. 2001;98:1268-1270)     

Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies

Forty-four patients, including 26 adults and 18 children under 15 years of age, were referred for evaluation of recurrent or persistent illnesses, with symptoms including pharyngitis, lymphadenopathy, fever, headaches, arthralgia, fatigue, depression, dyslogia, and myalgia. Thirty-nine patients were positive for Epstein-Barr virus antibody with antibody levels compatible with active infection for at least 1 year. Antiviral capsid antigen and anti-early antigen titers of patients were significantly greater (p less than 0.001) than age-group-matched controls. The frequency, number, duration, and patterns of symptoms, as well as patient sex, were compared by age in study patients seropositive and seronegative for Epstein-Barr virus. Illness patterns were not associated with changes in specific antibody titers or clinical findings. Lymphocyte phenotype and function analyses were done in 11 of the 39 patients positive for Epstein-Barr virus antibody; no consistent differences from normal were found. Only 1 of 32 patients had circulating interferon, in contrast to 7 of 7 patients with acute infectious mononucleosis. There were many adverse consequences of the illness. Epstein-Barr virus infection may not be self-limiting, and the virus may be associated with clinically recognizable illness other than infectious mononucleosis in children as well as in adults.     

Manifestations of Epstein-Barr virus-associated disorders in liver

Abstract: Epstein-Barr virus is a ubiquitous virus associated with a variety of different diseases and disorders. The manifestations of Epstein-Barr virus-associated diseases or disorders within the liver, which involve a broad spectrum of histologic and clinical features, ranging from hepatitis through lymphoproliferative disorders to lymphoma, are presented. An important aspect of Epstein-Barr virus expression and infection is the biology of the Epstein-Barr virus. Documentation of infection can be performed using serology to detect the interaction of Epstein-Barr virus with the immune system, and the detection of EBV proteins and use of molecular biologic techniques to identify the presence of EBV RNA, and DNA sequences. Of particular utility are in situ hybridization, Southern blot analysis, and polymerase chain reaction as diagnostic methods to identify specific RNA or DNA sequences. Epstein-Barr virus-associated diseases and disorders including infectious mononucleosis, sporadic fatal infectious mononucleosis, X-linked proliferative disorder (Duncan's disease), post-transplant lymphoproliferative disorders, lymphoma, and AIDS are discussed. The histopathologic findings present in liver associated with each disease are presented with illustrative examples. Handling the tissue and interaction with clinical services are also discussed as a method for appropriate diagnosis of Epstein-Barr virus-driven processes affecting the liver.     

Metagenomic Analysis Reveals High Abundance of Torque Teno Mini Virus in the Respiratory Tract of Children with Acute Respiratory Illness

Human Anelloviridae is a highly prevalent viral family, including three main genera—Alphatorquevirus (Torque teno virus, TTV), Betatorquevirus (Torque teno mini virus, TTMV), and Gammatorquevirus (Torque teno midi virus, TTMDV). To date, the characterization of Anelloviridae in the respiratory tract of children with acute respiratory infection (ARI) has been poorly reported and mainly focused on TTV. We performed a metagenomic analysis of eight respiratory samples collected from children with an ARI of unknown etiology (eight samples tested negative with a multiplex PCR assay, out of the 39 samples initially selected based on negative routine diagnostic testing). A total of 19 pediatric respiratory samples that tested positive for respiratory syncytial virus (RSV, n = 13) or influenza virus (n = 6) were also sequenced. Anelloviridae reads were detected in 16/27 samples, including 6/8 negative samples, 7/13 RSV samples and 3/6 influenza samples. For samples with a detection of at least one Anelloviridae genus, TTMV represented 87.1 (66.1–99.2)% of Anelloviridae reads, while TTV and TTMDV represented 0.8 (0.0–9.6)% and 0.7 (0.0–7.1)%, respectively (p < 0.001). Our findings highlight a high prevalence of TTMV in respiratory samples of children with an ARI of unknown etiology, as well as in samples with an RSV or influenza infection. Larger studies are needed to explore the role of TTMV in childhood respiratory diseases.     

Lymphocyte reactivity in infectious mononucleosis

Reactivity of lymphocytes to a purified preparation of Epstein-Barr virus (EBV) was studied in 17 healthy individuals and 15 patients with primary EVB infection and clinical signs of infectious mononucleosis. Lymphocyte reactivity to EBV was negative in individuals who were seronegative for antibody to EBV and in seven of 15 patients examined less than or equal to 21 days after onset of clinical signs of illness. Positive lymphocyte reactivity was observed in all patients by day 36; once it was established, it remained in individual patients for up to 480 days. During the acute phase of infectious mononucleosis, negative lymphocyte reactivity was always associated with a strong antibody response to EBV capsid antigens. This disparity was paralleled by the inability of lymphocytes to respond to recall antigens and mitogens, especially concanavalin A. Positive lymphocyte reactivity to EBV indicates a specific cellular memory function, probably of thymus-cell origin, which is acquired following primary EBV infection, and may be retained into later life.     

A rapid slide test for heterophile antibody in infectious mononucleosis

The sera of 473 individuals were examined for sheep cell agglutinins both by theslide test and the Paul-Bunnell method. In this group there were 46 patients withpositive slide tests and 35 of these individuals also had a diagnostic serum dilutiontest for heterophile antibody. In 11 cases the slide test was positive but the Paul-Bunnell test gave very low serum dilution values. However, when the slide testwas carried out at 37 C, it was negative in 9 of the 11 cases. In the remaining 2instances, one patient had a Forssman type of antibody which gave a 1:64 titer insaline and the slide test was positive at 37 C. In the other case no studies were madeon the effect of temperature and the nature of the agglutination reaction wasunfortunately not determined.

Using human and bovine albumen, sheep serum and human AB serum absorbedwith sheep cells as a diluent no evidence for blocking or hyperimmune antibodywas discovered in the cases of infectious mononucleosis studied in this series.Moreover, of the 6 patients with negative serology but with strong clinical andhematological evidence for the disease, no blocking or hyperimmune antibodywas disclosed by the slide test or by the use of absorbed human AB serum. Theconclusion seems justified that blocking, incomplete or hyperimmune heterophileantibody must be rather uncommon in infectious mononucleosis.

In the use of the rapid slide test it has been pointed out that cold agglutinins,(which may be abolished by warming to 37 C) and Forssman antibodies (whichmay be absorbed by guinea pig kidney) can give positive results. However, diseases in which cold agglutinins are strong enough to give a positive slide testare relatively rare and the occurrence of Forssman antibodies of a strength likely togive a positive slide test would be decidedly uncommon. In any event unless furtherexperience reveals more serious discrepancies, the rapid slide test as described inthis paper seems to offer a practical screening test to detect clinically significantamounts of heterophile antibody in cases of infectious mononucleosis.

     

Virologic diagnosis,viral monitoring,and treatment of epstein-barr virus infectious mononucleosis

Epstein-Barr virus (EBV) is the cause of infectious mononucleosis and is associated with severe infections in immunocompromised patients. EBV is also causally linked with several human malignancies. The heterophile antibody test and EBV-specific antibody tests remain the principal means of diagnosis of initial infection in otherwise healthy patients. Enzyme-linked immunosorbent assays have replaced the traditional immunofluorescence assays for EBV-specific antibodies. Several newer molecular diagnostic tests have become available that facilitate accurate monitoring of infection. The role of these tests for patients with uncomplicated infectious mononucleosis is limited, although these tests are being increasingly used to monitor the state and level of EBV replication for severe infections and among immunocompromised patients. Antiviral therapy has a limited, short-term effect on oropharyngeal shedding but has proven ineffective for the clinical manifestations of infectious mononucleosis. Patients with selected complications frequently benefit from short-term corticosteroid therapy.