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Respiratory syncytial virus and bronchiolitis.

Viral bronchiolitis is a common world-wide disease of infants and children resulting in respiratory failure and occasionally death. The major underlying pathophysiology is airway inflammation of peripheral airways and airway hyperresponsiveness to bronchoprovocation. Management is primarily prevention through strict hand washing and avoidance of exposures during respiratory seasons, especially in small infants who have underlying heart or lung disease. Careful supportive therapy, including fluid hydration, good nutrition, and aerosolized bronchodilators, steroids or ribavirin may be helpful. Long term follow-up for these children is important because a significant number will have recurrent episodes of bronchiolitis and wheezing, and many will develop clinical asthma. There's some evidence that long term abnormalities of airway function, perhaps secondary to airway fibrosis, may result from bronchiolitis infections. Avoidance of exposure to passive smoking, cold air and air pollutants is also beneficial to long term recovery from RSV bronchiolitis.

Bronchiolitis↗

The runny nose. Infection of the paranasal sinuses.

Infection of the paranasal sinuses is an important although infrequent complication of the common cold. This article discusses the pathophysiology, etiology, clinical presentation, complications, differential diagnosis, treatment, and prevention of these infections. Proper treatment with the appropriate antibiotic may help in avoiding irreversible mucosal damage, thus decreasing the incidence of chronic sinusitis.

Acute Disease↗

Dispersal of Staphylococcus aureus into the air associated with a rhinovirus infection.

OBJECTIVE: To determine whether healthy adult nasal carriers of Staphylococcus aureus can disperse S. aureus into the air after rhinovirus infection. DESIGN: We investigated the "cloud" phenomenon among adult nasal carriers of S. aureus experimentally infected with a rhinovirus. Eleven volunteers were studied for 16 days in an airtight chamber wearing street clothes, sterile garb, or sterile garb plus surgical mask; rhinovirus inoculation occurred on day 2. Daily quantitative air, nasal, and skin cultures for S. aureus; cold symptom assessment; and nasal rhinovirus cultures were performed. SETTING: Wake Forest University School of Medicine, Winston-Salem, North Carolina. PARTICIPANTS: Wake Forest University undergraduate or graduate students who had persistent nasal carriage of S. aureus for 4 or 8 weeks. RESULTS: After rhinovirus inoculation, dispersal of S. aureus into the air increased 2-fold with peak increases up to 34-fold. Independent predictors of S. aureus dispersal included the time period after rhinovirus infection and wearing street clothes (P < .05). Wearing barrier garb but not a mask decreased dispersal of S. aureus into the air (P < .05). CONCLUSION: Virus-induced dispersal of S. aureus into the air may have an important role in the transmission of S. aureus and other bacteria.

Adult↗

The effects of zinc on the olfactory neuroepithelium and olfactory bulbs of the Sprague-Dawley rat after oral administration of zinc-gluconate trihydrate.

BACKGROUND: The most frequent causes of upper respiratory infections are human rhinoviruses. The nasopharyngeal area, which includes the respiratory epithelium, mucosa, and the olfactory neuroepithelium (ONe), is a first-line of defense against airborne viruses and allergens, some of which manage to penetrate the nasal mucosa and invade the tissues of the nasal respiratory epithelium. Biochemical evidence from several studies suggests that zinc is an effective cold treatment and that over-the-counter (OTC) zinc-gluconate compounds may provide the high pharmacologic doses of zinc needed to act as an effective means of treating and reducing the duration and severity of symptoms of the common cold. METHODS: A series of male Sprague-Dawley rats were fed an oral preparation of zinc-gluconate trihydrate or received the equivalent through drinking water to investigate the potential cytotoxic and/or neurotoxic insult to the olfactory receptor cells and other tissue in the ONe and afferent neuronal pathways. RESULTS: Coronal sections of the rat ONe and corresponding olfactory bulbs showed consistent cellular and tissue damage of increasing severity that correlated with the duration of treatment with the zinc compound when compared with the control group animals. CONCLUSION: The results of this analysis indicate that the repeated oral administration of such zinc-containing compounds have neurotoxic effects on the ONe and to the mitral cells in the olfactory bulbs of treated rats. These findings point toward the need for increased investigation into the potential deleterious effects of zinc-containing compounds to humans as well.

Administration, Oral↗

Primary and secondary ciliary dyskinesia.

It has recently been shown that patients with Kartagener's triad and also some subjects with similar symptoms, but without situs inversus, have a congenital abnormality of cilia as an explanation for their chronic airway symptoms; this disease has been named "the immotile-cilia syndrome" or more correctly "primary ciliary dyskinesia". Studying 27 such patients, we have found daily nose blowings since birth, chronic-recurrent sinusitis, and chronic secretory otitis media highly characteristic features. The frequency of common colds was not increased, and most patients did not suffer from repeated episodes of acute purulent otitis media. The number of ciliated cells with immotile cilia was increased, but only a single patient had completely immotile cilia; also the degree of asynchrony within the single ciliated cell was increased. Electron microscopy showed a decreased number of dynein arms in some patients, and abnormal arrangement of microtubules in others. Some patients, however, had normal ultrastructure, and this appeared to be associated with a hyperfrequent beating pattern. At least three subgroups of patients with primary ciliary dyskinesia can be delineated based on the motility-ultrastructure studies. Bacterial infection tends to reduce the number of ciliated cells with motile cilia, and viral infection (common cold) gives a very marked and long-lasting reduction in the number of ciliated cells. This may account for some otherwise unexplainable subchronic symptoms from nose and throat.

Adolescent↗

Antiviral therapy for enteroviruses and rhinoviruses.

The picornaviruses are a diverse group of viral pathogens that together comprise the most common causes of infection of humans in the developed world. Within the picornavirus family are three well-known groups of human pathogens--the rhinoviruses, the enteroviruses (including polioviruses, coxsackieviruses and echoviruses) and the hepatoviruses (including hepatitis A virus). This article will focus on the rhinoviruses and enteroviruses, agents for which substantial effort has been expended, and recent successes reported, toward the development of safe and effective antiviral therapy.

3C Viral Proteases↗

Impact of coexpression and coamplification of sICAM and antiapoptosis determinants bcl-2/bcl-x(L) on productivity, cell survival, and mitochondria number in CHO-DG44 grown in suspension and serum-free media.

We have engineered dihydrofolate reductase-negative (dhfr-/-) Chinese hamster ovary (CHO) DG44 cells adapted for growth in serum-free suspension cultures for simultaneous expression of the common cold therapeutic, the soluble intercellular adhesion molecule 1 (sICAM), and the antiapoptosis determinants bcl-2 or bcl-x(L). Detailed analyses of titer and antiapoptosis characteristics of these production cell lines included an independent (sICAM; bcl-2/bcl-x(L)) as well as a cocistronic (sICAM-(bcl-2/bcl-x(L))) expression set-up in which translation-initiation of the survival cistron is driven by an internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV). In transient transfections or stable mixed populations and in comparison to isogenic sICAM-only control vectors, both bcl-x(L)-encoding configurations achieved higher sICAM yields while bcl-2 over-expression resulted in decreased product levels. Overall, the death-protective impact of bcl-2 and bcl-x(L) in engineered CHO-DG44 was not significant under typical batch-mode operation, an observation that was confirmed by clonal analysis. bcl-2 and bcl-x(L) displayed their antiapoptosis potential only following dhfr-based amplification in sICAM-producing CHO-DG44 cell lines. In all cases, bcl-x(L) outperformed bcl-2 in its cell death-protective capacity. Amplification-dependent high-level expression of mitochondria-localized bcl-2 family members required for successful antiapoptosis engineering may be essential to compensate for increased mitochondria numbers found to be associated with production cell lines grown in serum-free medium.

Animals↗

Cross-reactivity of self-HLA-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes for allo-HLA determinants.

Epstein-Barr (EB) virus-specific cytotoxic T cells, prepared from virus-immune donors by reactivation in vitro and maintained thereafter as IL-2-dependent T cell lines, have been tested against large panels of EB virus-transformed lymphoblastoid cell lines of known HLA type. Whilst the pattern of lysis of the majority of targets was always consistent with HLA-A and HLA-B antigen restriction of effector function, in several cases it was noticed that certain HLA-mismatched targets were also reproducibly lysed. When this "anomalous" lysis was investigated in detail, it was found to be directed against allodeterminants on class I HLA antigens; thus, mitogen-stimulated as well as EB virus-transformed lymphoblasts from the relevant target cell donors were sensitive to the killing, and in each case the lysis could be specifically blocked by monoclonal antibodies to class I HLA antigens. In one example the target for this alloreactive lysis could be identified as a single serologically defined antigen, HLA-Bw57, while in another example lysis was directed against a "public" epitope common to HLA-Bw35, -Bw62, and a subset of -B12 antigens. Both cold target inhibition experiments and limiting dilution analysis strongly suggested that this alloreactive lysis was being mediated by the same effector T cells that recognize EB viral antigens in the context of self-HLA. This is the first demonstration in man that alloreactive responses can be derived from within the antigen-specific, self MHC-restricted T cell repertoire.

Antibodies, Monoclonal↗

Human interferon in viral diseases.

Interferons have been studied in animals and man for local and systemic viral infections that are either rare or common. Recent clinical studies in humans with purified or recombinantly derived interferons have demonstrated significant clinical response in rhinovirus common colds, herpetic keratitis, condyloma acuminata, and laryngeal papillomatosis. However, only 40 per cent of published papers with IFN have been appropriately controlled. The toxicity of these newer preparations when administered either topically or parenterally prevents their immediate licensing for general use. The toxic to therapeutic ratio for HuIFN and rIFN appears to be close to one in most clinical situations in which it has been tested. Although interferons have not proved to be the "penicillin" for viruses many thought they would become, basic in vitro work and clinical studies have contributed greatly to our understanding of host defense and immunopathology. Future studies must focus on increasing our understanding of the mechanisms of toxicity, in addition to devising controlled clinical trials with interferon alone or in combination with other antiviral agents. Thus, after 30 years of research on interferons, it would appear our work has just begun.

Humans↗

An effective dosage regimen for prophylaxis against rhinovirus infection by intranasal administration of HuIFN-alpha 2.

Before the prophylactic effect of human interferon alpha 2 (HuIFN-alpha 2) can be tested against naturally acquired rhinovirus infection in a large-scale field trial, it is desirable to show that self-administration of the drug is practical, and to determine the smallest well-tolerated dose likely to produce a worthwhile effect. Here we report that self-administered intranasal interferon can be effective, and show how prophylaxis against rhinovirus infection is affected by both the quantity of interferon, and the interval between a dose and virus challenge. Finally, the medication regimen suggested for use in field trials (3.85 MU 3 times/day) was tested in a double-blind, placebo-controlled trial in volunteers. Although virus challenge was at a time when those being treated with interferon would be most susceptible, a substantial protective effect was still demonstrated.

Administration, Intranasal↗

The isolation of influenza viruses.

Of 129 strains of the Hong Kong variant of influenza A2 virus isolated from 176 respiratory infections, 105 (81.4%) were isolated in tissue culture, the remainder being detected only by the inoculation of fertile hen's eggs. Organ cultures of chick embryo trachea were at least as sensitive as monkey kidney tissue culture for the isolation of this virus but organ cultures of human embryonic ciliated epithelium were much less efficient. The reverse was true for strains of influenza B virus studied in 1970 and 1971 when eggs and chick embryo tracheal organ culture were of little value and organ cultures of human embryonic ciliated epithelium and monkey kidney tissue cultures were the systems of choice.

Animals↗

Nasal mucosal endorgan hyperresponsiveness.

Nonspecific hyperresponsiveness of the upper and lower airways is a well-known characteristic of different inflammatory airway diseases but the underlying mechanisms have not yet been satisfactorily explained. In attempts to elucidate the relation of hyperresponsiveness to disease pathophysiology we have particularly examined the possibility that different airway endorgans may alter their function in allergic airway disease. The nose, in contrast to the bronchi, is an accessible part of the airways where in vivo studies of airway mucosal processes can be carried out in humans under controlled conditions. Different endorgans can be defined in the airway mucosa: subepithelial microvessels, epithelium, glands, and sensory nerves. Techniques may be applied further in the nose to determine selectively the responses/function of these endorgans. Topical challenge with methacholine will induce a glandular secretory response, and topical capsaicin activates sensory c-fibers and induces nasal smart. Topical histamine induces extravasation of plasma from the subepithelial microvessels. The plasma exudate first floods the lamina propria and then moves up between epithelial cells into the airway lumen. This occurs without any changes in the ultrastructure or barrier function of the epithelium. We have therefore forwarded the view of mucosal exudation of bulk plasma as a physiological airway tissue response with primarily a defense function. Since the exudation is specific to inflammation, we have also suggested mucosal exudation as a major inflammatory response among airway endorgan functions. Using a "nasal pool" device for concomitant provocation with histamine and lavage of the nasal mucosa we have assessed exudative responses by analyzing the levels of plasma proteins (e.g., albumin alpha 2-macroglobulin) in the returned lavage fluids. A secretory hyperresponsiveness occurs in both experimental and seasonal allergic rhinitis. This type of nasal hyperreactivity may develop already 30 minutes after allergen challenge. It is attenuated by topical steroids and oral antihistamines. We have demonstrated that exudative hyperresponsiveness develops in both seasonal allergic rhinitis and common cold, indicating significant changes of this important microvascular response in these diseases. An attractive hypothesis to explain airway hyperresponsiveness has been increased mucosal absorption permeability due to epithelial damage, possibly secondary to the release of eosinophil products. However, neither nonspecific nor specific endorgan hyperresponsiveness in allergic airways may be explained by epithelial fragility or damage since nasal absorption permeability (measured with 51CR-EDTA and dDAVP) was decreased or unchanged in our studies of allergic and virus-induced rhinitis, respectively. Thus, the absorption barrier of the airway mucosa may become functionally tighter in chronic eosinophilic inflammation.

Blood Vessels↗

Interruption of experimental rhinovirus transmission.

Aqueous iodine (2%) applied to the fingers was effective in blocking had transmission of experimental rhinovirus infection. None of eight volunteers became infected when exposed to rhinovirus immediately after treatment of the fingers with iodine. All of seven similarly exposed subjects treated with a placebo preparation became infected (P less than 0.001, Fisher's exact test). One of 10 volunteers became infected when exposed 2 hr after treatment of fingers with iodine, compared with six of 10 who became infected in the control group (P = 0.06, Fisher's exact test). Virus was recovered from three (11%) of 27 hand rinses from volunteers using iodine and from 11 (41%) of 27 hand rinses from volunteers using the placebo preparation (P less than 0.03), Fisher's exact test).

Adolescent↗

Tuberculosis of the spine presenting with a cold abscess through the lumbar triangle of Petit.

The increasing incidence of human immunodeficiency virus (HIV) has resulted in an increase in the number of Mycobacterium tuberculosis (TB) infections worldwide. Musculoskeletal tuberculosis often involves the spine. Due to HIV, patients may present atypically and, as a result, a high clinical suspicion is necessary to avoid the catastrophic consequences of untreated Pott's disease of the spine. A cold abscess as a result of tuberculosis can emerge in a number of anatomical regions, and perhaps most notably as a psoas abscess. We report a less common anatomical location of a cold abscess, presenting as a mass in the inferior lumbar region through the lumbar triangle of Jean-Louis Petit. We consider the route that the pus had followed and highlight the need for vigilance when dealing with an abscess in this region, particularly in communities with a high incidence of HIV infection.

AIDS-Related Opportunistic Infections↗

Peripheral blood mononuclear cell interleukin-2 and interferon-gamma production, cytotoxicity, and antigen-stimulated blastogenesis during experimental rhinovirus infection.

To determine whether rhinovirus infection induced a systemic cellular immune response in humans, specific antigen-stimulated blastogenesis, natural killer cell activity, and mitogen-stimulated production of interleukin-2 and interferon-gamma by peripheral blood mononuclear cells (PBMC) were quantified during experimental rhinovirus infection of normal volunteers. Phytohemagglutinin-stimulated interleukin-2 production by PBMC collected on day 5 after rhinovirus inoculation was increased fourfold compared with production by PBMC collected before rhinovirus challenge (P less than .05); phytohemagglutinin-stimulated interferon-gamma production was doubled (P less than .05). An inverse relationship was observed between the increase in interleukin-2 production and both nasal mucus production (P less than .02) and the number of days virus was cultured from nasal washings (P less than .02). Natural killer cell-mediated cytotoxicity of PBMC collected on day 5 after rhinovirus challenge was also increased (P less than .01) compared with preinfection levels, as was specific antigen-stimulated blastogenesis on day 21 (P less than .05). The extent of blastogenic response correlated directly with both mucus production (P less than .05) and the number of days virus was cultured from nasal washings (P less than .05). These observations are consistent with the hypothesis that rhinovirus infection results in activation of a systemic cellular immune response.

Antibodies, Viral↗

Herpes simplex esophagitis in the immunocompetent host.

We report here a case of herpes esophagitis with Mallory-Weiss syndrome in an immunocompetent host. A 26-year-old man was admitted to our hospital because of common cold symptoms and eruptions on the body. On day 2 after hospitalization, the patient showed high-grade fever, odynophagia and hematemesis. Upper gastrointestinal endoscopic examination showed multiple ulcerations throughout the mid- and distal esophagus. Bleeding from a Mallory-Weiss tear was also seen. Follow-up endoscopic examinations showed whitish exudates on day 5. Histological examination of biopsy specimens showed Cowdry type A intranuclear inclusion bodies in epithelial cells. Positive staining of a specific antibody against herpes simplex virus-1 (HSV-1) was seen in the nuclei of esophageal epithelial cells. Primary HSV-1 infection was suspected because ELISA titers of serum IgM antibody against HSV-1 were high and titers of serum IgG antibody against HSV-1 increased from an almost cut-off ratio. A diagnosis of herpes esophagitis in an immunocompetent host was made. Our case is the first report of herpes esophagitis with Mallory-Weiss syndrome in the immunocompetent host. It is important to remind herpes esophagitis in cases of severe odynophagia even in immunocompetent hosts.

Adult↗

Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial.

OBJECTIVE: To determine whether naproxen, a propionic acid inhibitor of cyclooxygenase, alters the course of experimental rhinovirus colds. DESIGN: A randomized, double-blind, controlled trial. SETTING: Rhinovirus challenge model in volunteers cloistered in individual hotel rooms. VOLUNTEERS: Eighty-seven healthy young adults with serum neutralizing antibody titers of less than or equal to 1:2 to the challenge virus; 79 were evaluable. INTERVENTION: Thirty-nine participants received naproxen (loading dose, 400 mg or 500 mg followed by 200 mg or 500 mg three times daily for 5 days). Forty participants received placebo. Treatment was started 6 hours after viral challenge. MEASUREMENTS: Daily measurement of viral titers, symptoms, nasal mucus production, and nasal tissue use; incidence of infection and illness; and measurement of homotypic serum neutralizing antibody responses. RESULTS: Viral titers and serum homotypic antibody responses were similar in the naproxen and placebo groups. Significant reductions in headache, malaise, myalgia, and cough occurred in the naproxen group. A 29% reduction was noted in the total (5-day) symptom score in the naproxen group (95% CI, 16% to 42%). CONCLUSION: Naproxen treatment did not alter virus shedding or serum neutralizing antibody responses in participants with experimental rhinovirus colds, but it had a beneficial effect on the symptoms of headache, malaise, myalgia, and cough. Prostaglandins may be among the inflammatory mediators that play a role in the pathogenesis of rhinovirus colds.

Adult↗

Echinacea extracts modulate the pattern of chemokine and cytokine secretion in rhinovirus-infected and uninfected epithelial cells.

Extracts of Echinacea purpurea are among the most widely used herbal medicines throughout Europe and North America for the prevention or treatment of common cold, coughs, bronchitis and other upper respiratory infections. Popular preparations include expressed juice from the aerial parts of the plant (which contain polysaccharides) and alcoholic tinctures from roots (containing caffeic acid derivatives and alkylamides). Since immune modulation has been reported for similar extracts, cytokine antibody arrays were used to investigate the changes in the pro-inflammatory cytokines and chemokines released from a cultured line of human bronchial epithelial cells exposed to Rhinovirus 14 and two different chemically characterized Echinacea extracts. Virus infection stimulated the release of at least 31 cytokine-related molecules, including several important chemokines known to attract inflammatory cells. Most of these effects were reversed by simultaneous exposure to either of the two Echinacea extracts, although the patterns of response were different for the two extracts. These results could explain the antiinflammatory properties of Echinacea extracts. Furthermore, a number of these cytokines were stimulated by the same Echinacea preparations in uninfected cells. These observations therefore provide support for the alleged beneficial uses of Echinacea extracts.

Cell Line, Transformed↗