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[The pathogenesis and therapy of virus infection-induced senile bronchial asthma].

We investigated the pathogenesis and therapy of virus infection-induced senile bronchial asthma in vitro. To examine the effects of rhinovirus infection on the production of cytokines and intercellular adhesion molecule-1 (ICAM-1), human tracheal epithelial cells and submucosal gland cells were cultured, and infected with human rhinovirus. Rhinovirus upregulated the production of interleukin (IL)-1 beta, IL-6, IL-8, tumor necrosis factor (TNF)-alpha in supernatants of epithelial cells and submucosal-gland cells, and IL-1 alpha and granulocyte macrophage colony-stimulating factor (GM-CSF) in supernatants of submucosal gland cells. Rhinovirus upregulated the expression of ICAM-1 mRNA. Rhinovirus infection also increased epithelial permeability. These events may be important for the spread of airway inflammation after rhinovirus infection. Furthermore, we studied the effects of dexamethasone and erythromycin on the modulation of virus infection and induction of cytokines and ICAM-1 in tracheal epitherial cells. Both of them reduced viral titers of rhinovirus type 14, a major group rhinovirus, and cytokine production of supernatants, and ICAM-1 mRNA expression in the cells. Because it is known that acidic conditions by proton pumps are needed for rhinovirus entry into the cells, we studied the effects of H+ ATPase inhibitor bafilomycin A1. Bafilomycin A1 reduced the virus titers of both rhinovirus type 2 and 14 in supernatants. These findings in our in vitro study suggest that dexamethasone, erythromycin and bafilomycin A1 may inhibit rhinovirus infection and modulate airway inflammation induced by rhinovirus infection.

Aged↗

Use of monoclonal antibodies to identify four neutralization immunogens on a common cold picornavirus, human rhinovirus 14.

A collection of 35 mouse monoclonal antibodies, raised against human rhinovirus 14 (HRV-14), was used to isolate 62 neutralization-resistant mutants. When cross-tested against the antibodies in a neutralization assay, the mutants fell into four antigenic groups, here called neutralization immunogens: NIm-IA, -IB, -II, and -III. Sequencing the mutant RNA in segments corresponding to serotype-variable regions revealed that the amino acid substitutions segregated into clusters, which correlated exactly with the immunogenic groups (NIm-IA mutants at VP1 amino acid residue 91 or 95; NIm-II mutants at VP2 residue 158, 159, 161, or 162; NIm-III mutants at VP3 residue 72, 75, or 78; and NIm-IB mutants at two sites, either VP1 residue 83 or 85, or residue 138 or 139). Examination of the three-dimensional structure of the virus (M. G. Rossmann, E. Arnold, J. W. Erickson, E. A. Frankenberger, J. P. Griffith, H.-J. Hecht, J. E. Johnson, G. Kamer, M. Luo, A. G. Mosser, R. R. Rueckert, B. Sherry, and G. Vriend, Nature [London], 317:145-153, 1985) revealed that each of the substitution clusters formed a protrusion from the virus surface, and the side chains of the substituted amino acids pointed outward. Moreover, four of the amino acid substitutions, which initially appeared to be anomalous because they were encoded well outside the cluster groups, could be traced to surface positions immediately adjacent to the appropriate viral protrusions. We conclude that three of the four antigens, NIm-IB, -II, and -III, are discontinuous. Thus, the amino acid substitutions in all 62 mutants fell within the proposed immunogenic sites; there was no evidence for alteration of any antigenic site by a distal mutation.

Antibodies, Monoclonal↗

[Smoking and lower respiratory tract infection].

Cigarette smoking exerts deleterious effects not only on the respiratory tract, but also on the lung's parenchyma. The FEV is reduced in heavy chronic smokers. Persistent smoking has an unfavourable influence on mucociliary activity. According to the results of recent research almost 8 million people in the U.S. were suffering from chronic bronchitis in 1981. There is a direct correlation between the number of cigarettes smoked, over what period of time, and the incidence of chronic bronchitis. In studies with patients suffering from exacerbations of chronic bronchitis the most common bacterial pathogens found were Haemophilus influenzae, Streptococcus pneumoniae and Branhamella catarrhalis. Mycoplasma pneumoniae and certain viruses are counted amongst the non-bacterial pathogens. Antibiotics should be effective against such possible pathogens. The resistance of H. influenzae to ampicillin/amoxicillin is currently observed in at least 12% of cases, whilst H. influenzae is regularly observed to be resistant to erythromycin. Cefaclor, trimethoprim/sulphamethoxazole and amoxicillin/clavulanic acid offer satisfactory forms of treatment. Pneumonia caused by S. pneumoniae, H. influenzae, B. catarrhalis and Legionella pneumophila is often seen in smokers and patients with COLD. Haemocultures should be prepared for all hospitalized patients. Penicillin G and/or V is the agent of choice. Cefaclor or trimethoprim/sulphamethoxazole can be given to counter beta-lactamase producing H. influenzae whilst cefaclor, erythromycin, tetracycline or trimethoprim/sulphamethoxazole are used for the treatment of B. catarrhalis infections. In Legionella infections erythromycin is the preferred treatment. A combination of erythromycin and cefamandole or ceftriaxone is indicated for empirical management. Patients with COLD should be immunised with pneumococcus and influenza vaccines.

Bacterial Infections↗

[Epidemic typhus in Africa].

Epidemic typhus is caused by a small strictly intracellular virus named Rickettsia prowazekii, a member of the Rickettsial family. It is transmitted to man by the body louse, Pediculus humanus. Although now rare in Western countries, exanthematic typhus remains common in the Southern hemisphere due to poverty, inadequate clothing hygiene, and poor socioeconomic conditions. In Africa, outbreaks have historically occurred in Burundi, Rwanda, southwest Ouganda, and Ethiopia. The largest outbreak of epidemic typhus since the World War II was reported in Burundi where ongoing civil war since October 1993 has forced 10 p. 100 of the population of Burundi to live in cold, promiscuity, and malnutrition of makeshift refugee camps. The purpose of this report based on our two-year experience working with this unfortunate population is to describe the characteristics of this disease in Africa where the epidemic form had become rare until recently. Indeed political unrest as well as numerous civil wars are now epidmiological factors favorizing outbreaks of epidemic typhus at any time. This overview also provides an opportunity to recall epidemiological, bacteriological, and clinical aspects of typhus as well as diagnosis and treatment of the disease in the context of Africa.

Africa↗

Antiviral agents in respiratory infections.

Viral respiratory illnesses are among the most common afflictions in the United States. Until recently, few agents were available to control these infections. Now, there are specific and nonspecific agents either to prevent or treat viral respiratory infections. For example, a better understanding of the pathogenesis of the common cold provided new insights into therapeutic intervention for that entity. In other instances (eg, influenza), the antiviral agent is so specific that there is a need for diagnostic information to guide therapy. Epidemiological clues, clinical symptoms, and some newer laboratory methods all contribute to the clinician's understanding of the cause of an individual respiratory illness and guide the choice of therapy. In other circumstances, information is being gradually developed that points toward the availability of a broad-spectrum antiviral drug with activity against at least five of the important respiratory viruses; its major limitation is that a cumbersome and expensive means of delivery to the patient is required. For such a drug to gain widespread use, a more practical method of delivery is necessary.

Antiviral Agents↗

A Ca(2+)-dependent protein kinase that endows rice plants with cold- and salt-stress tolerance functions in vascular bundles.

A rice Ca(2+)-dependent protein kinase, OsCDPK7, is a positive regulator commonly involved in the tolerance to cold and salt/drought. We carried out in situ detection of the transcript and immunolocalization of the protein. In the wild-type rice plants under both stress conditions, OsCDPK7 was expressed predominantly in vascular tissues of crowns and roots, vascular bundles and central cylinder, respectively, where water stress occurs most severely. This enzyme was also expressed in the peripheral cylinder of crown vascular bundles and root sclerenchyma. Similar localization patterns with stronger signals were observed in stress-tolerant OsCDPK7 over-expressing transformants with the cauliflower mosaic virus 35S promoter. The transcript of a putative target gene of the OsCDPK7 signaling pathway, rab16A, was also detected essentially in the same tissues upon salt stress, suggesting that the OsCDPK7 pathway operates predominantly in these regions. We propose that the use of the 35S promoter fortuitously strengthened the localized expression of OsCDPK7, resulting in enhancement of the stress signaling in the inherently operating regions leading to improved stress tolerance.

Adaptation, Physiological↗

Recombinant human interferon-gamma as prophylaxis against rhinovirus colds in volunteers.

The first evaluation of intranasal (i.n.) recombinant human interferon-gamma (rHuIFN-gamma) as prophylaxis against experimental rhinovirus (RV) infection and illness in volunteers is reported. In two studies, 7 of 27 (26%) of the volunteers who received rHuIFN-gamma (2 Mu i.n. 3 x /day) had either blood stained nasal secretions or nose bleeding which was not observed in any of the 26 placebo recipients. Some volunteers given rHuIFN-gamma showed increased nasal secretion and the majority complained of slight nasal stuffiness, whereas only a few of those receiving placebo complained of these symptoms. In the prophylactic study, 17 volunteers were given the above regimen of rHuIFN-gamma and 17 placebo; after the fourth dose all were challenged with RV9, followed 1 h later with RV14 (100 TCID50 of each virus). Compared with the placebo-treated controls, interferon recipients showed no significant reduction in the proportion who developed colds or became infected, and there was an increase in both their mean clinical scores and mean nasal secretion weights. Thus i.n. rHuIFN-gamma did not prevent rhinovirus infection or illness and may enhance the symptoms.

Administration, Intranasal↗

Low grade rhinovirus infection induces a prolonged release of IL-8 in pulmonary epithelium.

Rhinoviruses are important respiratory pathogens implicated in asthma exacerbations. The mechanisms by which rhinoviruses trigger inflammatory responses in the lower airway are poorly understood, in particular their ability to infect the lower airway. Bronchial inflammatory cell (lymphocyte and eosinophil) recruitment has been demonstrated. IL-8 is a potent proinflammatory chemokine that is chemotactic for neutrophils, lymphocytes, eosinophils, and monocytes and may be important in the pathogenesis of virus-induced asthma. Increased levels of IL-8 have been found in nasal samples in natural and experimental rhinovirus infections. In these studies we therefore examine the ability of rhinovirus to infect a transformed lower airway epithelial cell line (A549) and to induce IL-8 protein release and mRNA induction. We observed that rhinovirus type 9 is able to undergo full viral replication in A549 cells, and peak viral titers were found 24 h after inoculation. Rhinovirus infection induced a dose- and time-dependent IL-8 release up to 5 days after infection and an increase in IL-8 mRNA expression that was maximal between 3 and 24 h after infection. UV inactivation of the virus completely inhibited replication, but only reduced IL-8 protein production and mRNA induction by half, while prevention of virus-receptor binding completely inhibited virus-induced IL-8 release, suggesting that part of the observed effects was due to viral replication and part was due to virus-receptor binding. These studies demonstrate that rhinoviruses are capable of infecting a pulmonary epithelial cell line and inducing IL-8 release. These findings may be important in understanding the pathogenesis of rhinovirus-induced asthma exacerbations.

Cells, Cultured↗

Biting in day care centers: incidence, prevention, and intervention.

Analysis of accident logs in child day care centers indicates that biting is common, especially among toddlers 13 to 30 months of age. Children of this age often lack appropriate verbal skills and resort to aggressive means to achieve their goals. Still awkward in gross-motor skills, toddlers can also suffer self-bites following accidental falls. According to medical reports, human bites sometimes are more virulent than animal bites and can cause severe trauma. Although the AIDS virus has been cultured from saliva, transmission from saliva alone has not been documented. Bite injuries in day care, however, usually are minor and can be treated by washing, applying cold compresses, and comforting the child. Suggested methods to diminish the frequency of biting in day care include physical changes within the room, behavior modification, and other classroom management techniques.

Bites, Human↗

Ambroxol for the prevention of acute upper respiratory disease.

Although acute upper respiratory diseases (AURDs) such as common cold and influenza are common, few interventions have been proven to be effective in their prevention and treatment. The aim of this study was to assess the efficacy of ambroxol for preventing AURD. Fifty-four patients were randomly divided into 3 groups: a rebamipide (non-mucoactive drug) group (300 mg/day), carbocisteine group (1500 mg/day) and ambroxol group (45 mg/day). The study was divided into 2 terms, the first half-year (summer season) and the second half-year (winter season). In the preceding winter, only 19.5% of the patients had been vaccinated against influenza viruses (flu). The primary goal of this study was to evaluate the effectiveness of mucoactive drugs in decreasing the frequency of AURD. Treatment with ambroxol, but not carbocisteine, significantly reduced the median number of AURD episodes (P=0.0049 vs. rebamipide). Thirty-three patients without vaccination against flu were assessed especially during the second half-year. Treatment with ambroxol also significantly reduced the median number of AURD episodes in this assessment (P=0.0028 vs. rebamipide in the second half-year). In conclusion, ambroxol may be useful for preventing AURD.

Aged↗

Influenza vaccines in children.

Influenza is a common disease of childhood. Young children and children with high-risk medical conditions are at increased risk of being hospitalized when infected with influenza virus. Children of all ages have excess physician visits and receive excess antibiotic prescriptions during influenza season. The safety, immunogenicity, and efficacy of influenza vaccines in children are described in this review. Clinical trials and postlicensure experience have demonstrated that trivalent inactivated influenza vaccine is well-tolerated in children. Efficacy of the inactivated vaccine also has been demonstrated in numerous clinical trials. In comparison to trivalent inactivated influenza vaccine, investigational cold-adapted, live-attenuated influenza vaccine (LAIV) has the advantage of an intranasal route of administration. A large clinical trial demonstrated the tolerability and efficacy of the trivalent live, attenuated product in children 15 to 71 months of age. Pending information on safety and coadministration of this vaccine with other childhood vaccines will determine if it is licensed and recommended for use in children, including possible expanded indications for routine yearly administration to young children.

Administration, Intranasal↗

Intranasal pirodavir (R77,975) treatment of rhinovirus colds.

A randomized, double-blind, placebo-controlled trial assessed the therapeutic efficacy of intranasal pirodavir in naturally occurring rhinovirus colds. Adults with symptoms of < or = 2 days' duration were randomly assigned to intranasal sprays of pirodavir (2 mg per treatment) or placebo six times daily for 5 days. In people with laboratory-documented rhinovirus colds (53 in the pirodavir group, 55 in the placebo group), no significant differences in the resolution of respiratory symptoms were apparent between the groups. The median duration of illness was 7 days in each group. Similarly, scores for individual symptoms found no differences in favor of pirodavir during or after treatment. In contrast, reduced frequencies of rhinovirus shedding were observed in the pirodavir group on day 3 (70 versus 23%; P < 0.001) and day 5 (38 versus 12%; P = 0.002) but not after the cessation of treatment, on day 7 (19 versus 21%). No pirodavir-resistant viruses were recovered from treated individuals. The pirodavir group had higher rates of nasal dryness, blood in mucus, or unpleasant taste on several study days. In summary, intranasal sprays of pirodavir were associated with significant antiviral effects but no clinical benefit in treating naturally occurring rhinovirus colds.

Administration, Intranasal↗

Broad antigenic relationships among rhinovirus serotypes revealed by cross-immunization of rabbits with different serotypes.

The rhinoviruses are a large group of at least 89 serotypes and extensive cross-relationships have been demonstrated among these serotypes using both rabbit and human antisera. The extent of these cross-relationships was further investigated by sequential intravenous immunization of rabbits with different virus serotypes, known to be both related and unrelated. In all cases in which a relationship had previously been demonstrated with monovalent antiserum, after heterotypic stimulation with the related virus, the antibody titer to the virus used as primary immunogen showed an anamnestic response, whereas the antibody response to the secondary immunogen was good, but resembled a primary response. In some instances when immunized rabbits were injected with an unrelated antigen, previously unsuspected relationships were revealed. A number of clusters of related rhinoviruses were demonstrated: 5, 17, 42; 3, 4, 6, 14; 9, 32, 67; and 13, 14, 41. Heterotypic immunization proved to be a powerful biologic probe for detecting relationships among the rhinoviruses, and together with newly available epidemiologic data it offers a possible approach for design of a vaccine for the common cold.

Animals↗

Post-polio syndrome: an update.

The PPS is now a well-recognized entity encompassing the late manifestations that occur because of previous poliomyelitis. Common signs and symptoms include fatigue, cold intolerance, joint deteriorations with pain, and prominent neurologic problems that include new weakness, muscle pain, atrophy, respiratory insufficiency, dysphagia, and sleep apnea. It is estimated that there are 1.63 million polio survivors in the United States and that half of them will develop PPS. PPS and PPMA usually begin 30 to 40 years after the acute illness and are very slowly progressive. The etiology is unclear, although premature exhaustion of the new sprouts that develop after acute poliomyelitis and of their motor neurons appears most likely. Less likely is a persistent polio-virus infection or an immune-mediated problem. Treatment is primarily supportive, although nonfatiguing strengthening exercise may improve strength over the short term. The long-term effects of this type of exercise remain to be clarified.

Humans↗

Vitamin C for preventing and treating the common cold.

BACKGROUND: The role of oral vitamin C (ascorbic acid) in the prevention and treatment of the common cold has been a subject of controversy for at least sixty years. Public interest in the topic continues to be high and vitamin C continues to be widely sold and used as a preventive and therapeutic agent for this common ailment. OBJECTIVES: To discover whether oral vitamin C in doses of 200 mg or more daily, reduces the incidence, duration or severity of the common cold when used either as continuous prophylaxis or after the onset of cold symptoms. SEARCH STRATEGY: This updated review added to earlier searches, a full search of the following electronic databases: the Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2004); MEDLINE (January 1966 to June 2004); and EMBASE (1990 to June 2004). SELECTION CRITERIA: Papers were excluded if a dose less than 200 mg daily of vitamin C was used; if there was no placebo comparison; if methods of outcome assessment were inadequately described; and if the report did not record any of the three study outcomes (incidence, duration or severity) in sufficient detail to enter into the meta-analysis. Three criteria of study quality were assessed: Jadad scores, placebo distinguish-ability, and allocation concealment. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. 'Incidence' of colds during prophylaxis was assessed as the proportion of participants experiencing one or more colds during the study period. 'Duration' was the mean days of illness of cold episodes and 'severity' of these episodes was assessed by days confined indoors, off work or school. or by symptom severity scores. MAIN RESULTS: Twenty-nine trial comparisons involving 11,077 study participants contributed to the meta-analysis on the relative risk (RR) of developing a cold while taking prophylaxis. The pooled RR was 0.96 (95% CI 0.92 to 1.00). A subgroup of six trials that involved a total of 642 marathon runners, skiers, and soldiers on sub-arctic exercises reported a pooled RR of 0.50 (95%CI 0.38 to 0.66). Thirty comparisons that involved 9,676 respiratory episodes contributed to the meta-analysis on common cold duration during prophylaxis . A consistent benefit was observed, representing a reduction in cold duration of 8% (95% CI 3% to 13%) for adult participants and 13.5% (95% CI 5% to 21%) for child participants. Fifteen trial comparisons that involved 7,045 respiratory episodes contributed to the meta-analysis of severity of episodes experienced while on prophylaxis. The pooled results revealed a difference favouring those on vitamin C when days confined to home and off work or school were taken as a measure of severity (p = 0.02), and when restricting to studies which used symptom severity scores (p = 0.16), and for the both measures of severity combined (p = 0.004). Seven trial comparisons that involved 3,294 respiratory episodes contributed to the meta-analysis of cold duration during therapy with vitamin C that was initiated after the onset of cold symptoms, and no significant difference from placebo was seen. Four trial comparisons that involved 2,753 respiratory episodes, contributed to the meta-analysis of cold severity during therapy and no significant difference from placebo was seen.In laboratory studies, differing methods of artificial transmission of virus to vitamin C or placebo treated volunteers in residential experiments gave different results. Volunteers infected by nasal installation showed small or no benefit from vitamin C, whereas a group who were infected more naturally, reported less severe symptom severity scores (p = 0.04). REVIEWERS' CONCLUSIONS: The failure of vitamin C supplementation to reduce the incidence of colds in the normal population indicates that routine mega-dose prophylaxis is not rationally justified for community use. But evidence shows that it could be justified in persons exposed to brief periods of severe physical exercise and/or cold environments. Also, the consistent and statistically significant small benefits on duration and severity for those using regular vitamin C prophylaxis indicates that vitamin C plays some role in respiratory defence mechanisms. The trials in which vitamin C was introduced at the onset of colds as therapy did not show any benefit in doses up to 4 grams daily, but one large trial reported equivocal benefit from an 8 gram therapeutic dose at onset of symptoms.

Administration, Oral↗

Isolation of rhinoviruses and coronaviruses from 38 colds in adults.

Nasal washings were collected from 27 normal adults during 38 naturally acquired colds. The washings were exhaustively tested using tissue cultures, organ cultures and electron microscopy. Washings yielding no identifiable agent were inoculated into human volunteers, and further specimens obtained from the latter were examined by the same techniques in vitro. Viruses were identified in association with 25 of the original 38 colds (65.7%). Fifteen were rhinoviruses (39.5%), seven coronaviruses (18.4%), two were para-influenza viruses, and one was influenza virus. Use of organ cultures and of volunteers significantly increased the isolation rate. No agent was cultivated from the remaining 13 specimens, although tests in volunteers showed that cold-producing agents were present in five of them (13%). Three specimens gave doubtful results in volunteers, and five others, all collected within a period of six weeks in December and January, apparently contained no infectious agent.

Adult↗

Transmission and control of rhinovirus colds.

With the expanding knowledge of rhinovirus transmission and rhinovirus chemistry, the outlook for control of infections with these agents has brightened considerably. Although rhinoviruses are probably the world's leading cause of respiratory illness, they are surprisingly reluctant transmitters, infecting only about 50% of susceptibles in family-like settings. Current research suggests that rhinoviruses are spread chiefly by aerosol, rather than by fomites or personal contact. It has been possible to interrupt rhinovirus transmission completely by careful use of virucidal facial tissues, which, presumably, smothered aerosols generated by coughing, sneezing and nose blowing. Accordingly, it may be feasible to control rhinovirus (and perhaps other virus) dissemination by appropriate air handling and filtration systems in combination with careful nasal sanitation. Anti-rhinovirus drug development is also moving forward. Although there are over 100 rhinovirus serotypes, it has been found that most rhinoviruses attach to a single cell receptor by a single binding site on the virus. Also, the structure of the rhinovirus capsid is now known at the atomic level. These two pieces of knowledge about basic viral architecture appear to open new vistas for reasoned synthesis of antiviral drugs, and some promising compounds are now under investigation. Even interferon has been demonstrated useful in a family setting. On several research fronts, there are good grounds for optimism about control of rhinovirus colds.

Ascorbic Acid↗

Cytotoxic T cell lines recognize autologous and allogeneic melanomas with shared or cross-reactive HLA-A.

Cytotoxic T lymphocytes (CTL), CD3+, alpha/beta T-cell-receptor-positive, are important effector cells with specific immunity in melanoma patients. The establishment and expansion in vitro of CTL of a specific phenotype to tumor cells strongly depends on the method of activation and sensitization with tumor cells. We generated CD3+ CTL lines to melanoma by co-culturing peripheral blood lymphocytes with autologous irradiated melanoma cells and repetitive stimulation with high-dose interleukin-4 in a "cocktail" culture medium. CTL lines were investigated for their specificity to kill autologous and allogeneic melanoma. Histocompatibility locus antigen (HLA) class I (A, B) molecules are important restrictive recognition antigens for CTL. Although these antigens are highly polymorphic, they can share a similar immunogenic molecular epitope(s) and can be immunologically cross-reactive. The CTL lines generated were found to kill not only autologous melanoma, but also allogeneic melanomas having class I HLA-A antigens shared or "cross-reactive" with autologous HLA-A. These CTL lines were poor killers of melanomas bearing non-shared or non-cross-reactive HLA-A. Cold-target inhibition assays demonstrated this CTL cross-reactivity to allogeneic melanoma specificity. Epstein-Barr-virus-transformed autologous and allogeneic B lymphoblastoid cell lines failed to block autologous melanoma killing, indicating that CTL were not recognizing major histocompatibility complex antigens, serum proteins or culture medium products as the primary target antigen. HLA-A2 was the major shared HLA-A antigen recognized by CTL lines on the melanoma lines studied. CTL lines also recognized shared HLA-A11 and A24 on allogeneic melanoma. There were no CTL lines showing restriction to HLA-B. These results suggest that common tumor-associated antigens are present on melanomas and are recognized in association with distinct HLA-A epitopes by CTL.

Antigens, Neoplasm↗