Jaythoon Hassan

Elevated Serum Levels of Interferon-γ-Inducible Protein-10 in Patients Coinfected with Hepatitis C Virus and HIV

Coinfection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) is associated with an accelerated course of HCV infection and a faster progression to severe liver disease. We have investigated whether the development of liver disease in coinfected patients is associated with specific chemokine and cytokine production. Four cohorts--HCV/HIV-coinfected patients, HCV-monoinfected patients, HIV-monoinfected patients, and healthy control subjects--were studied. Serum levels of the 10-kDa interferon- gamma -inducible protein (IP-10) were higher in all 3 groups of infected patients than in control subjects (P<.0001). HCV/HIV-coinfected patients had significantly higher IP-10 levels than monoinfected patients. In HCV-monoinfected patients, liver fibrosis scores and liver enzyme levels were positively correlated with IP-10 levels. Elevated IP-10 levels are associated with and may contribute to liver damage in both HCV-monoinfected and HCV/HIV-coinfected patients.

Translational Mini-Review Series on Infectious Disease: Congenital cytomegalovirus infection: 50 years on

Cytomegalovirus (CMV) is the leading cause of congenital viral infection, with an incidence of 0·5–3% of live births worldwide. Clinical evidence has shown hearing and vision loss, mental retardation and sometimes death in affected newborns. Primary maternal CMV infection during gestation poses a 40% risk of intrauterine transmission in contrast to recurrent infection. European laboratories have made significant progress in the last decade in solving diagnostic problems linked to infection in pregnancy. With the advances in CMV serology, such as detection of anti‐CMV IgM by enzyme immunoassays (EIA), confirmed by Western blot, together with seroconversion and anti‐CMV IgG avidity evaluation in pregnant mothers, can help to identify recent infection. Preventative measures such as screening for CMV in the routine serological work‐up of pregnant women have been introduced in countries such as Spain and Italy. The development of specific T cell‐mediated immune responses in mothers, fetus and neonates is now emerging with regard to antigen‐specific CD4 and CD8 T cells, differentiation status, proliferative and cytokine responses. A protective vaccine against CMV is a major public health priority and the study of vaccines in animal model systems has identified potential strategies for interrupting transmission and preventing disease in newborns. Congenital CMV infection has a variable outcome and therefore novel diagnostic methods are required to identify those at risk and therapeutic interventions are needed to improve the long‐term prognosis of those infected. CMV was first isolated in 1957. We are now 50 years on, so procrastination is not an option.

Immunological response to cytomegalovirus in congenitally infected neonates.

Cytomegalovirus (CMV) is the most common cause of congenital infection worldwide and occurs as a result of transplacental transmission of the virus. The human neonate is highly susceptible to infection due to a combination of immaturity of the immune system and antigenic inexperience. This study uses the in vivo model of congenital CMV to examine both the humoral and cell‐mediated immune responses in vertically infected neonates and their mothers. Ten pairs of matched neonates and their mothers were evaluated for specific IgM responses to three immunodominant CMV antigens: pp38 (pUL80a), pp52 (pUL44) and pp150 (pUL32). In contrast to conventional enzyme immunoassay (EIA) testing for CMV‐specific IgM, which found five of the mothers and four of the neonates to be positive, Western immunoblotting showed all 10 adults and nine newborns to be positive. Eight mothers and nine newborns had serological evidence of primary infection. All neonates showed a response to pp38, an assembly protein, nine responded to the pp52 immediate early antigen but only four had reactivity to the pp150 tegument associated protein. Of the mothers, eight had pp38 reactivity, 10 showed a response to the pp52 antigen and seven to the pp150 antigen. T cell‐mediated immunity was assessed by measuring cytokines using a multiplex microarray assay. Levels of interferon (IFN)‐γ were high in both groups [mean ± standard error of the mean (s.e.m.): neonates = 657 ± 238 pg/ml, mothers = 1072 ± 677 pg/ml, pNS]; however, neonates had significantly higher levels of interleukin (IL)‐8 (316 ± 136 pg/ml versus 48 ± 28 pg/ml, P < 0·005). Similar levels of IL‐2, IL‐7, IL‐10 and IL‐12 were measured in both groups, but levels of IL‐1α, IL‐1β, IL‐4, IL‐6 and tumour necrosis factor (TNF)‐α were either absent or low. In response to CMV, neonates and adults mount a predominant T helper 1 (Th1) response, as evidenced by the presence of IL‐2, IL‐8, IL‐12 and IFN‐γ with concomitant lack of IL‐4. These findings suggest that the neonate, when presented with infection in utero, is capable of mounting an individual response; however, the lower IFN‐γ and higher IL‐8 levels suggest reduced immune responsiveness when compared to their adult counterparts.

Molecular Epidemiological Evaluation of the Recent Resurgence in Mumps Virus Infections in Ireland

ABSTRACT Mumps is a vaccine-preventable disease; however, outbreaks have been reported in a number of countries with childhood immunization programs, particularly among young adults at the tertiary stage of education. We have retrospectively investigated the epidemiological, virological, and serological factors associated with mumps cases identified in Ireland from 2004 to 2009. Genetic analysis of mumps virus strain variability demonstrated that a single genotype, genotype G, was circulating, and it was also detected in cerebrospinal fluid samples obtained from patients with meningitis. We observed that younger individuals were disproportionately affected with neurological sequelae following mumps virus infection, and the average age of patients with mumps virus RNA detected in cerebrospinal fluid was 19.25 years (median, 19 years; range, 14 to 24 years). Our analysis showed a 4-fold rise in mumps cases in 2008-2009 and an increased incidence in infection in those ≥30 years of age. Over a 6-year period (2004 to 2009), a total of 7,805 serum samples were investigated; of this number, 1,813 (23%) were positive for mumps virus-specific IgM. We observed a strong bias for acute mumps virus infection in males compared to females (P < 10−32) that was independent of vaccination status.

Human Cytomegalovirus UL144 Is Associated with Viremia and Infant Development Sequelae in Congenital Infection

ABSTRACT Human cytomegalovirus (HCMV) strains may be genotyped based on polymorphisms that exist within the UL144 gene, which is one of 19 viral genes lost in attenuated laboratory strains. In the present study, UL144 genotypes in congenitally infected babies (congenital cytomegalovirus [cCMV]) were determined, and the relationship between the genotype, viral load, cytokine profile, and patient developmental outcome was investigated. All cCMV infections identified during 2006 and 2007 were included (n = 29). A portion of the infants were clinically assessed at birth and at 12 to 18 months postinfection for cCMV clinical sequelae (n = 18/29). The plasma viral load (PVL) was requested for 23/29 patients, and the UL144 genotype was determined (n = 27/29). The cytokine profile in patient plasma or serum was assessed (n = 20/29). UL144 genotypes A, B, and C were detected within the cCMV population at 33.3%, 29.6%, and 25.9%, respectively. UL144 A and C were associated with a high PVL (P < 0.04). Furthermore, a significant association between the developmental outcome and UL144 A and C was observed (P < 0.04). Only patients infected with UL144 B and A/B were described as having a normal clinical outcome. In addition, a significant correlation between interleukin 10 (IL-10) levels and the PVL was observed (P < 0.04); however, there was no association between the genotype and the cytokine profile. The present study determined that the specific detection of UL144 genotypes A and C was indicative of serious cCMV infection and more likely to lead to long-term cCMV-associated clinical manifestations. The inclusion of HCMV UL144 genotyping along with the recommended PVL monitoring following cCMV diagnosis may aid prediction of the clinical outcome.

First Report of Sudden Death Due to Myocarditis Caused by Adenovirus Serotype 3

ABSTRACT Myocarditis is a rare cause of sudden death in childhood. We describe the sudden death of a child from viral myocarditis, which we demonstrate was likely caused by an uncontrolled inflammatory response to a disseminated adenovirus serotype 3 infection originating in the tonsil.

Prevalence of anti-Fab antibodies in patients with autoimmune and infectious diseases.

Sensitive ELISA were devised to examine the specificity of circulating IgM and IgA autoantibodies for whole human IgG, Fe and Fab fragments of human IgG. Sera from patients with autoimmune and infectious conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), tuberculosis (TB), infectious mononucleosis (IM) and cystic fibrosis (CF) were studied. Results of the ELISA assays using whole human IgG as antigen revealed that a proportion of patients in each of the groups studied had circulating IgM and IgA rheumatoid factors (RF). Fifteen normal individuals studied were negative. In the latex positive RA group, IgM RF and IgA RF had primarily anti‐Fc reactivity (100% and 93% respectively), although 3/15 patients also showed IgM anti‐Fab reactivity and one patient had high IgA anti‐Fab activity. Patients with SLE and TB who had detectable RF levels also revealed predominantly anti‐Fc specificity. In contrast, examination of 25 patients with IM showed positivity for IgM RF activity in 8% of patients using whole IgG as antigen, 24% positivity using purified Fc fragments as antigen and 45% positivity when plates were coated with Fab fragments. Similarly, a large number of CF patients (54%) also showed predominantly IgM anti‐Fab activity. Of interest, 69% of the CF patients who were all studied at the time of bacterial infection had detectable IgA RF levels, with 46% of these patients showing both IgA anti‐Fc and anti‐Fab activity. These findings suggest that autoantibody specificities in autoimmune and infectious diseases are different.

INCREASED CD5 + B CELLS IN PATIENTS WITH INFECTIOUS MONONUCLEOSIS

Because of the high frequency of autoantibodies associated with IM, we examined patients for the presence of CD5 + B cells and correlated these findings with serum IgM- and IgA-RF levels

Increased numbers of CD5+ B cells and T cell receptor (TCR) γδ+ T cells are associated with younger age of onset in rheumatoid arthritis (RA)

Patients presenting with RA before the age of 45 years (younger onset) are known to have more aggressive disease compared with patients presenting after the age of 65 years (older onset). Coordinated expansion of circulating CD5+ B cell and TCR γδ+ T cell levels has been reported in patients with RA. This study assesses the peripheral blood levels of these two cell types in RA patients with younger and older onset of disease. CD5+ B cell levels were significantly elevated in the younger onset RA group (26±6 γδ+4±5%) compared with the older onset RA group (14±2 γδ+1±2%; P<0±01). TCR γδ+ T cell levels were also significantly raised in the young patients (4±0 γδ+0±9%) compared with elderly patients (1±6 γδ+0±2%; P<0±01). T cell levels (CD3+) were similar in both groups (young 66±4 γδ+3±3%; old 74±3 γδ+3±4% (mean γδ+s.e.m.); NS). Total B cell levels (CD19+) were also similar in these groups (7±7 γδ+0±7%versus 8±9 γδ+1±8%; NS). A significant positive correlation was observed between the CD5+ B and TCR γδ+ T cell types in the patients (r= 0±72, P<0.05). Compared with age‐matched normal controls, the younger onset patients had similar CD5+ B cell and TCR γδ+ T cell levels to the elderly controls (CD5+ B cells 30±2 γδ+3±0%; TCR γδ+ T cells 3±0 γδ+0±8%). Conversely, older onset RA patients had CD5+ B cell levels similar to the young controls (12±3 γδ+1±9%). Spontaneous in vitro synthesis of immunoglobulins (IgM, IgA and IgG) and rheumatoid factors (IgM and IgA isotypes) were not significantly different in both patient groups. The coordinate expansion of circulating CD5+ B cells and γδ+ T cells seen in patients with RA presenting before 45 years of age and not after 65 years of age may suggest a potential role for these cells in more aggressive disease states.

Surveillance of epstein‐barr virus loads in adult liver transplantation: Associations with age, sex, posttransplant times, and transplant indications

Epstein‐Barr virus (EBV)–associated posttransplant lymphoproliferative disorder (PTLD) is a life‐threatening complication after adult orthotopic liver transplantation (AOLT). Besides EBV and immunosuppression, relatively little is known about the pretransplant clinical parameters associated with the risk of PTLD, and the benefit of using EBV surveillance to predict EBV‐associated disease in AOLT patients is uncertain. The aims of this single‐center study were to monitor EBV viral loads (VLs) in AOLT patients and to investigate any associations with age, sex, cytomegalovirus (CMV) serostatus, posttransplant times, and indications for transplantation. 1275 blood samples that were collected from 197 AOLT patients 1 day to more than 15 years after transplantation were investigated with quantitative polymerase chain reaction for EBV and CMV DNA. Seventy‐two percent of the patients had EBV DNAemia less than 100 days after transplantation without clinical manifestations. No association was observed between the EBV copy numbers and the time since transplantation. EBV DNAemia was weakly associated with male sex but was not associated with age, CMV serostatus, or indications for AOLT. The highest EBV VL levels were observed in patients who presented with congenital liver diseases, whereas patients with viral hepatitis maintained high EBV VLs after transplantation. None of the patients developed PTLD during the study period; however, 3 patients presented with EBV‐associated diseases. In conclusion, EBV DNAemia is common in AOLT patients, and routine EBV surveillance has limited value for predicting EBV‐associated morbidity or mortality. Liver Transpl, 2011.