Edward E. Walsh

Pattern recognition receptors TLR4 and CD14 mediate response to respiratorysyncytial virus

The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.

Respiratory Syncytial Virus Infection in Adults

Originally considered as only a paediatric pathogen, respiratory syncytial virus (RSV) has recently been shown to be a significant cause of respiratory illness among elderly and high-risk adults. Approximately 170,000 hospitalizations and 10,000 deaths associated with RSV occur annually in people over the age of 65 years in the United States. Although rhinorrhoea and wheezing are common symptoms among adults, the clinical syndrome associated with RSV is not distinctive and thus laboratory methods are required for specific diagnosis. Presently, the combination of reverse transcription PCR and enzyme immunoassay serology offers the best sensitivity and specificity for diagnosis of RSV. Treatment options are limited at present, with inhaled ribavirin being the only licensed drug for use in hospitalized children. Vaccines against RSV remain an unachieved goal. Promising new agents that inhibit the virus-cell fusion, cell-cell fusion, or viral gene expression are currently in development.

Human Metapneumovirus Infections in Young and Elderly Adults

Human metapneumovirus virus (hMPV) is a newly discovered respiratory pathogen with limited epidemiological data available. Cohorts of young and older adults were prospectively evaluated for hMPV infection during 2 winter seasons. Patients hospitalized for cardiopulmonary conditions during that period were also studied. Overall, 44 (4.5%) of 984 illnesses were associated with hMPV infection, and 9 (4.1%) of 217 asymptomatic subjects were infected. There was a significant difference in rates of hMPV illnesses between years 1 and 2 (7/452 [1.5%] vs. 37/532 [7.0%]; P<.0001). In the second year, 11% of hospitalized patients had evidence of hMPV infection. Infections occurred in all age groups but were most common among young adults. Frail elderly people with hMPV infection frequently sought medical attention. In conclusion, hMPV infection occurs in adults of all ages and may account for a significant portion of persons hospitalized with respiratory infections during some years.

Aerosolized Ribavirin Treatment of Infants with Respiratory Syncytial Viral Infection: A Randomized Double-Blind Study

We evaluated a new antiviral agent, ribavirin, in the treatment of infants hospitalized with lower-respiratory-tract disease from respiratory syncytial virus. Ribavirin or placebo was administered to 33 infants in a double-blind manner by continuous aerosol for three to six days. Seventeen infants were treated with placebo, and 16 with ribavirin. By the end of treatment, infants receiving ribavirin had significantly greater improvement in their overall score for severity of illness, in lower-respiratory-tract signs, and in arterial oxygen saturation. Viral shedding was also diminished in the treated groups as compared with the placebo group. No side effects or toxicity were associated with the aerosol therapy. Isolates of respiratory syncytial virus obtained from the infants over the course of therapy showed no change in sensitivity to ribavirin.

Protection of Mice Against Dengue 2 Virus Encephalitis by Immunization with the Dengue 2 Virus Non-structural Glycoprotein NS1

Immunization of mice with the dengue 2 virus (DEN 2)-specified non-structural protein NS1 provided significant protection against intracerebral challenge with the virus in the absence of detectable neutralizing or other anti-virion antibody. NS1, purified from lysates of infected Vero cells by immunoaffinity chromatography, expressed an antigenic site(s) common to each of the four DEN serotypes, and hyperimmunization of rabbits with NS1 stimulated production of complement-fixing (CF) antibody with broad DEN serotype specificity. However, cross-protection was not observed: mice immunized with DEN 2 NS1 developed little or no heterologous CF antibody and were not protected against challenge with neurovirulent DEN 1. Induction of a protective immune response by NS1 suggests that it be considered for incorporation into possible synthetic or recombinant DNA DEN vaccines.

Severity of Respiratory Syncytial Virus Infection Is Related to Virus Strain

The relationship between respiratory syncytial virus (RSV) strain and disease severity was assessed in 265 hospitalized infants over a 3-year period (1988-1991). A severity index of clinical and physiologic parameters was used to grade illness severity. Multivariate analysis of 134 infants infected with group A RSV strains and 131 infants infected with group B strains indicated that prematurity, underlying medical conditions, group A RSV infection, and age < or =3 months were independently associated with severe disease. Odds ratios for severe disease for these risk factors were 1.83, 2.84, 3.26, and 4.39, respectively. Among infants without underlying medical conditions, group B RSV infection rarely required ventilatory support, in contrast to group A infections (1/90 vs. 13/107; P < .006), and had significantly lower severity indices (mean +/- SD, 0.6 +/- 9 vs. 1.3 +/- 1.9; P = .05). Results confirm earlier findings that group A RSV infection results in greater disease severity than group B infection among hospitalized infants.

Viral Respiratory Infections in the Institutionalized Elderly: Clinical and Epidemiologic Findings

To prospectively evaluate the incidence and impact of viral respiratory infection in the institutionalized elderly during a winter season.

Variation in severity of respiratory syncytial virus infections with subtype

Two major subtypes of respiratory syncytial virus have been identified. This study assessed the hypothesis that A-subtype infections were more severe than B-subtype infections among the 157 infants hospitalized in two hospitals in Rochester, N.Y., during two winters. Severity was measured both by specific clinical observations and by a severity index that was derived empirically. Among all subjects, several clinical observations suggested that A-subtype infections were more severe. For example, mechanical ventilation was required in 12.6% of those with A-subtype compared with 1.6% of those with B-subtype infection (relative risk = 7.88; p = 0.01). Among high-risk infants (infants with underlying conditions or age 3 months or less at admission), carbon dioxide tension greater than 45 mm Hg was found in 37.0% of those with A-subtype compared with 12.0% of those with B-subtype infection (relative risk = 3.08; p = 0.04). In discrete multivariate (logit) analysis, effects of subtype (odds ratio = 6.59; p less than 0.01) on severity remained after adjustment for other statistically significant effects of age less than 3 months, underlying condition, and premature birth. The finding that A-subtype infections were more severe might have important implications for vaccine development, studies of the virulence of respiratory syncytial virus, clinical management (e.g., selection for antiviral therapy), and long-term prognosis.

Viral Pneumonia in Older Adults

Abstract Viruses account for a substantial portion of respiratory illnesses, including pneumonia, in the elderly population. Presently, influenza virus A H3N2 and respiratory syncytial virus are the most commonly identified viral pathogens in older adults with viral pneumonia. As diagnostic tests such as reverse-transcription polymerase chain reaction become more widely used, the relative importance of additional viruses (such as parainfluenza, rhinoviruses, coronaviruses, and human metapneumovirus) will likely increase. Influenza virus should be considered as a cause of pneumonia during the winter months, especially during periods of peak activity. Patients with high-grade fever, myalgias, and cough should arouse the highest suspicion. Respiratory syncytial virus pneumonia should also be suspected during the winter in patients with coryza, wheezing, low-grade fever, and patchy infiltrates, especially if negative for influenza on rapid testing. Because clinical features and periods of activity for many viruses overlap, laboratory confirmation of influenza is recommended for cases involving seriously ill or institutionalized patients.

Rhinovirus and Coronavirus Infection-Associated Hospitalizations among Older Adults

Abstract Rhinoviruses and coronaviruses are recognized as the major causes of the common cold syndrome. The role of these viruses in more serious respiratory illnesses resulting in hospitalization is less well defined. During a winter when influenza A infection was prevalent, 100 elderly adults hospitalized because of cardiopulmonary illnesses were evaluated for rhinovirus and coronavirus infection. Patients who tested negative for influenza or respiratory syncytial virus had nasal swab samples tested for rhinovirus, coronavirus OC43, and coronavirus 229E by reverse-transcription polymerase chain reaction and for coronaviruses by serologic testing. Twelve percent of patients had rhinovirus or coronavirus identified (rhinovirus, 4 patients; coronavirus 229E, 4 patients; coronavirus OC43, 3 patients; and mixed rhinovirus/coronavirus 229E infection, 1 patient). All patients had significant underlying diseases. Although all patients recovered, the mean length of stay was 8 days; 4 persons had pneumonia, and 1 required ventilator support. These data suggest that rhinoviruses and coronaviruses may be associated with serious respiratory illnesses in frail older adults.