T cell-mediated immune response enhances the severity of myocarditis in secondary cardiotropic virus infection in mice

In this report, we showed that a previous enterovirus exposure in ordinary mice with normal T cell function, but not in T cell-deficient mice, can influence development of myocardial inflammation with a second virus exposure. Inoculation of 4-week-old male BALB/c-nu/+ (euthymic and normal T cell function) mice with amyocarditic Coxsackie virus B1 (CB1), followed by inoculation 28 days later with myocarditic variant of Coxsackie virus B3 (CB3-m) resulted in more intense myocardial inflammation and injury than was seen in BALB/c-nu/+ inoculated with CB1, followed by inoculation with non-enterovirus, i.e., encephalomyocarditis virus (EMC) or influenza A virus and in age-matched BALB/c-nu/+ mice secondary inoculated with CB3-m alone. In contrast, this phenomenon of the enhancement of the severity of myocarditis by a secondary CB3-m inoculation was not seen in BALB/c-nu/nu (athymic and T cell- deficient) mice. Interestingly, inoculation of BALB/c-nu/+ mice with CB1, followed by inoculation 28 days later with another amyocarditic variant of Coxsackie virus B3 (CB3-o), resulted in more severe myocarditis than was seen in age-matched BALB/c-nu/+ mice secondary inoculated CB3-o alone. Myocardial-activated T cells and elevated serum interleukin-6 were involved in the exacerbation of the disease during the reinfection. T cell-mediated immune responses to a conserved antigenic epitope among the enteroviruses may be involved in the exacerbation of myocardial inflammatory disease during a second enterovirus infection. Received: 14 December 2000, Returned for revision: 19 January 2001, Revision received: 30 January 2001, Accepted: 31 January 2001     

Cellular immune response in virus infections

Two levels of specificity exist in the killing of virus infected target cells by immune effector T cells. One relates to the classic specificity for the virus, and the second involves the necessity for sharing expression of genes mapping in K and D but not I regions. Among the theories that could explain this is that of dual recognition with separate T-cell receptors detecting H-2 and viral antigen. Support for this possibility was provided by experimental influenza virus infection where evidence of specific recognition of viral products was obtained.     

Cellular immune activation in children with acute dengue virus infections is modulated by apoptosis

Apoptosis is an important modulator of cellular immune responses during systemic viral infections. Peripheral-blood mononuclear cell (PBMC) apoptosis and plasma soluble levels of CD95, a mediator of apoptosis, were determined in sequential samples from children participating in a prospective study of dengue virus (DV) infections. During the period of defervescence, levels of PBMC apoptosis were higher in children developing dengue hemorrhagic fever (DHF), the most severe form of illness, than in those with dengue fever (DF) and other, nondengue, febrile illnesses. CD8(+) T lymphocytes made up approximately half of the peak circulating apoptotic PBMCs in DHF and DF. Maximum plasma levels of soluble CD95 were also higher in children with DHF than in those with DF. The level of PBMC apoptosis correlated with dengue disease severity. Apoptosis appears to be involved in modulation of the innate and adaptive immune responses to DV infection and is likely involved in the evolution of immune responses in other viral hemorrhagic fevers.     

The reappearance of dengue-3 and a subsequent dengue-4 and dengue-1 epidemic in Puerto Rico in 1998

In January 1998, dengue-3 (DEN)-3 (group III genotype) was detected in Puerto Rico after an absence of 20 years. Public health officials intensified education efforts to promote community participation in dengue control. Virologic surveillance revealed an unexpected paradox: DEN-4 and DEN-1 produced a large epidemic overlaying the DEN-3 epidemic. In 1998 there were 17,000 reported cases of dengue (4.8/1,000 persons), and among all virus isolations (n = 960), DEN-4 (419, 43.6%), DEN-1 (337, 35.1%), and DEN-2 (143, 14.9%) were detected much more frequently than DEN-3 (61, 6%). Age group-specific attack rates were highest for persons 10-19 years old, followed by infants less than a year of age. Nineteen fatal cases (median = 37 years old, range = 8 months to 90 years) had a positive laboratory diagnosis of dengue. Among DEN-3 cases no fatalities were documented, 50 were hospitalized, and 10 of 48 (21%) fulfilled the criteria for dengue hemorrhagic fever (four had primary infections and six had secondary infections). During 1999, DEN-3 became the predominant serotype isolated (182 of 310 isolations, 59%). The reappearance of DEN-3 and its subsequent circulation from 1999 to 2001 produced no changes in dengue incidence that could have been detected in the absence of virologic surveillance.     

Early immune activation in acute dengue illness is related to development of plasma leakage and disease severity

T lymphocyte activation and increased cytokine levels have been described in retrospective studies of children presenting with dengue hemorrhagic fever (DHF). Serial plasma samples obtained in a prospective study of Thai children presenting with <72 h of fever were studied. Plasma levels of 80-kDa soluble tumor necrosis factor receptors (sTNFRs) were higher in children who developed DHF than in those with dengue fever (DF) or other nondengue febrile illnesses (OFIs) and were correlated with the degree of subsequent plasma leakage. Soluble CD8 and soluble interleukin-2 receptor levels were also elevated in children with DHF compared with those with DF. Interferon-gamma and sTNFR 60-kDa levels were higher in children with dengue than in those with OFIs. TNF-alpha was detectable more often in DHF than in DF or OFIs (P<.05). These results support the hypothesis that immune activation contributes to the pathogenesis of DHF. Further studies evaluating the predictive value of sTNFR80 for DHF are warranted.     

Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children

Please cite this paper as: Martin et al. (2012) Multiple versus single virus respiratory infections: viral load and clinical disease severity in hospitalized children. Influenza and Other Respiratory Viruses 6(1), 71–77. Background Molecular testing for viral pathogens has resulted in increasing detection of multiple viruses in respiratory secretions of ill children. The clinical impact of multiple virus infections on clinical presentation and outcome is unclear. Objectives To compare clinical characteristics and viral load between children with multiple virus versus single virus illnesses. Patients/methods Eight hundred and ninety‐three residual nasal wash samples from children treated for respiratory illness at Children’s Hospital, Seattle, from September 2003 to September 2004 were evaluated by quantitative PCR for respiratory syncytial virus (RSV), human metapneumovirus (hMPV), influenza (Flu), parainfluenza, adenoviruses, and coronaviruses (CoV). Illness severity and patient characteristics were abstracted from medical charts. Results Coinfections were identified in 103 (18%) of 566 virus‐positive samples. Adenovirus was most commonly detected in coinfections (52%), followed by CoV (50%). Illnesses with a single virus had increased risk of oxygen requirement (P = 0·02), extended hospital stays (P = 0·002), and admissions to the inpatient (P = 0·02) or intensive care units (P = 0·04). For Adv and PIV‐1, multiple virus illnesses had a significantly lower viral load (log₁₀ copies/ml) than single virus illnesses (4·2 versus 5·6, P = 0·007 and 4·2 versus 6·9, P < 0·001, respectively). RSV, Flu‐A, PIV‐3, and hMPV viral loads were consistently high whether or not another virus was detected. Conclusions Illnesses with multiple virus detections were correlated with less severe disease. The relationship between viral load and multiple virus infections was virus specific, and this may serve as a way to differentiate viruses in multiple virus infections.     

Moraxella catarrhalis in chronic obstructive pulmonary disease: burden of disease and immune response

RATIONALE: Moraxella catarrhalis is frequently present in the sputum of adults with chronic obstructive pulmonary disease (COPD). Little is known about the role of M. catarrhalis in this common disease. OBJECTIVE: To elucidate the burden of disease, the dynamics of carriage, and immune responses to M. catarrhalis in COPD. METHODS: Prospective cohort study of 104 adults with COPD in an outpatient clinic at the Buffalo Veterans Affairs Medical Center. MEASUREMENTS: Clinical information, sputum cultures, molecular typing of isolates, and immunoassays to measure antibodies to M. catarrhalis. MAIN RESULTS: Over 81 months, 104 patients made 3,009 clinic visits, 560 during exacerbations. Molecular typing identified 120 episodes of acquisition and clearance of M. catarrhalis in 50 patients; 57 (47.5%) of the acquisitions were associated with clinical exacerbations. No instances of simultaneous acquisition of a new strain of another pathogen were observed. The duration of carriage of M. catarrhalis was shorter with exacerbations compared with asymptomatic colonization (median, 31.0 vs. 40.4 days; p = 0.01). Reacquisition of the same strain was rare. The intensity of the serum IgG response was greater after exacerbations than asymptomatic colonization (p = 0.009). Asymptomatic colonization was associated with a greater frequency of a sputum IgA response than exacerbation (p = 0.009). CONCLUSIONS: M. catarrhalis likely causes approximately 10% of exacerbations of COPD, accounting for approximately 2 to 4 million episodes annually. The organism is cleared efficiently after a short duration of carriage. Patients develop strain-specific protection after clearance of M. catarrhalis from the respiratory tract.     

Glycaemic status influences the nature and severity of coronary artery disease

Aims/hypothesis  

We sought to understand the relationships between glycaemic status and both severity and progression of coronary artery disease (CAD), the leading cause of death in diabetes.     

Hepatitis B and C virus infections in the immune compromised

PURPOSE OF REVIEW: This review compares and contrasts the natural history and treatment of hepatitis B and C virus infections in three principal populations of immune compromised individuals: (1) patients co-infected with HIV; (2) patients with liver failure secondary to hepatitis B or C virus infection who undergo liver transplantation, and (3) patients with hepatitis B or C virus infection who undergo anticancer chemotherapy. RECENT FINDINGS: Chronic liver disease resulting from hepatitis B or C virus infection progresses more rapidly in patients co-infected with HIV than in HIV negative patients. Treatment protocols for antiviral therapy are, however, similar to those used in immunocompetent individuals and although few long-term results are available, the efficacy of interferon and ribavirin therapy in hepatitis C virus/HIV infection and lamivudine in HIV/hepatitis B virus infection has been proven in the short-term. Perhaps the most important consideration is the timing of administering treatments to co-infected patients. For patients with well preserved CD4 counts and hepatitis C virus/HIV co-infection, the hepatitis infection should be treated as early as possible to avoid drug interactions of hepatitis C virus antivirals with antiretroviral therapy. Also, response to hepatitis C virus treatment appears better when treatment is administered in the context of preserved immune function. Conversely, in hepatitis B virus/HIV co-infection, hepatitis B virus antivirals are best administered with anti-retroviral therapy, thus preventing the selection of HIV viral species which may be resistant to the drugs used for hepatitis B virus. Improved graft and patient survival after liver transplant and with anticancer chemotherapy in hepatitis B virus infected patients has been proven using lamivudine prophylaxis. However, although therapy for hepatitis C virus recurrence after liver transplantation would seem rational, limited success with current treatment protocols has been achieved. SUMMARY: Although the prognosis of hepatitis B and C virus infections in the immune compromised may be inferior to that of immunocompetent individuals, such patients should have full evaluation of their viral hepatitis, and antiviral therapy should be considered.     

Phylogenetic study of dengue-3 virus in Taiwan with sequence analysis of the core gene

Dengue virus serotype 3 (dengue-3) has been classified into five genotypes (I-V) by phylogenetic analysis based on different viral genes. To investigate the genetic variability and evolutionary character of the dengue-3 isolates in southern Taiwan from 2005 to 2006, we analyzed the 290 nucleotides of the core (C) gene of 12 dengue-3 isolates and compared them with the published C gene sequences of global dengue-3 strains available in GenBank, including four isolates from 1998 and one isolate from 1999, from Taiwan. The dengue-3 viruses from 2005 to 2006 were not from continuous spread of an epidemic strain or re-emergence of the 2005 strains in the 2-year period because there was a 5.4-6.2% difference in the 290 nucleotides of the C gene and different genotypes between the 2005 and 2006 strains. Most of the nucleotide changes, compared with a prototype dengue-3 virus, H87, occurred in the third codon position and were non-synonymous mutations occurring naturally in the C gene. In addition, there was no consistent difference in the 290 nucleotides of the C gene between eight dengue fever and two dengue hemorrhagic fever isolates from 2006. The phylogenetic analysis indicates that the isolates from the 1998, 1999 and 2006 Taiwan dengue-3 epidemics are phylogenetically related and belong to genotype III. It was noted that the 2005 Taiwan dengue-3 isolates belong to another genotype. This molecular epidemiology study of dengue-3 viruses in Taiwan helps to elucidate whether there is a continuation of outbreaks in consecutive years, re-emergence of endemic dengue virus, or introduction of strains from other countries.     

B-cell responses during primary and secondary dengue virus infections in humans

Low-avidity serotype-cross-reactive antibodies are hypothesized to play a key role in triggering severe disease in patients with secondary dengue virus (DENV) infection. However, there is little systematic information about the frequency, avidity, and cross-reactivity of DENV-specific B cells in individuals experiencing primary instead of secondary infection. We compared DENV-specific B-cell responses in a cohort of Thai children with primary or secondary DENV infection. B cells specific for DENV precursor membrane protein, envelope (E) protein, and nonstructural protein 1 were detectable in immune peripheral blood mononuclear cells with the highest frequencies of DENV E-specific B cells detected in patients experiencing primary DENV-1 infections. DENV E-specific B cells were highly serotype-specific after primary DENV infections, whereas most E-specific B cells in patients with secondary infection were serotype-cross-reactive and secreted antibodies with higher avidity to heterologous DENV serotypes. Our data suggest that the minor populations of serotype-cross-reactive B cells generated by primary DENV infection are preferentially expanded during secondary DENV infection.     

Intrauterine virus infections and congenital heart disease

The etiologic basis for the vast majority of cases of congenital heart disease remains largely undefined. Viruses have been considered to be likely candidates since the recognition of the association between intrauterine rubella and congenital heart disease. Although the pathogenesis of cardiovascular defects is poorly understood, information gained from the study of congenital rubella syndrome suggests that mechanisms such as focal endothelial cell damage, resulting in obliteration of vascular supply, decreased growth rate, and shortened survival time of certain cells, and disturbed DNA replication in cells whose chromosomes were damaged secondary to the effects of virus replication may be operative in the production of defects in the developing fetus. In addition to rubella there is suggestive, but not conclusive, evidence that Coxsackie B3 and B4 virus infections during pregnancy can result in the birth of infants with a variety of types of congenital heart lesions and that intrauterine mumps virus infection may be etiologically related to the postnatal development of endocardial fibroelastosis (EFE). Although there are a number of other viruses that are potential etiologic agents of congenital heart disease, the current status of information is inadequate to allow even suggestive associations to be made. The most profitable areas for future investigation appear to be: (1) the epidemiology of congenital heart disease, (2) prospective studies of the association of maternal viral infection with abnormal offspring, (3) the in-depth virologic investigation of the infant with a cardiac defect, and (4) the development of experimental animal models of congenital heart disease. Successful control of virus-induced congenital heart disease will depend on the results of these investigations and the development of vaccines against the identified causative viruses and/or safe and effective antiviral chemotherapy for the woman in early gestation who is infected with a known teratogenic agent.     

Chronic hepatitis C virus infections in leukemia survivors: prevalence, viral load, and severity of liver disease.

The natural history of chronic hepatitis C (HCV) infections in long-term leukemia survivors has not been well characterized. We studied the prevalence of HCV infections, measured HCV RNA levels, and evaluated the severity of liver disease in patients with leukemia who achieved long-term remissions after intensive chemotherapy or bone marrow transplantation (BMT). HCV antibody tests were performed by the enzyme-linked immunosorbent assay (ELISA) and positive tests confirmed by the recombinant immunoblot assay (RIBA). HCV RNA levels were measured by the branched DNA (bDNA) assay. Seventy-five leukemia survivors with 25 or more blood donor exposures were identified. Nine (12%) were anti-HCV positive. All were infected before 1992 when second generation HCV screening tests were implemented. Mean HCV RNA levels were 10.3 x10(6) eq/mL versus 3.2 x 10(6) eq/mL (P =.056) in a control group of 20 anti-HCV positive immunocompetent individuals of comparable age who were infected twice as long (17.8 +/- 6.5 years v 9.0 +/- 4.4 years in leukemia survivors, P =.001). Liver biopsies were performed on six of the nine anti-HCV positive leukemia survivors. All showed at least moderate portal inflammation and half had evidence of bridging fibrosis. We conclude that viral loads in anti-HCV positive leukemia survivors are markedly higher than in immunocompetent controls. Our results suggest that long-term leukemia survivors with chronic HCV may have more rapidly progressive liver disease than has been previously recognized.