Serious respiratory tract disease caused by respiratory syncytial virus: prospects for improved therapy and effective immunization.
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Intranasal deposition of Sendai virus (SV) in C57BL/6 mice provokes an Ab-forming cell (AFC) reaction in mediastinal (MLN) and cervical lymph nodes (CLN), which drain the lungs and upper respiratory tract, respectively. While the majority of AFC elicited by infectious SV at both sites produced IgG, the CLN response to SV rendered inactive in replication was restricted almost entirely to IgA, although isotype switching in mediastinal continued to be skewed heavily to IgG. However, in vitro restimulation of the accompanying virus-specific T cell populations from the two sites did not reveal any significant difference in lymphokine output, and isotype expression was not altered substantially in mice lacking IL-4 or IL-6 genes. To dissociate the response to specific Ags from the inflammatory reaction to viral infection, we examined the response to inactivated SV in the face of infection with influenza virus A/HKx31. The magnitude and IgA dominance of the anti-SV AFC population in the CLN were unaffected by a simultaneous, vigorous, IgG-dominated CLN anti-influenza reaction. Evidently, the characteristics of this antiviral response are determined primarily by cognate interactions. Moreover, the IgA bias of the CLN AFC response to inactivated SV was observed only when the virus was delivered intranasally: injection under the epidermis of the cheek, a site that has a lymphatic drainage into the CLN, resulted in an IgG-dominated CLN AFC reaction, lacking IgA. The site of deposition of a vaccine can thus have more influence on the pattern of isotypes induced than the site at which the immune response is initiated.
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Bacterial infection of the lower respiratory tract is initiated by colonization of the upper respiratory tract followed by aspiration of small volumes of contaminated secretions into the lungs. Failure of lung antibacterial defenses results in pneumonia. Strategies for prevention involve prevention of colonization, avoidance of aspiration, or enhancement of lung defenses. Effective prevention against specific organisms can be provided by immunization which enhances lung defenses for vaccinated strains. This approach has limited applicability because of the time required for development of protective antibody and the selective spectrum of protection. Aspiration of small quantities of oropharyngeal secretions is probably unavoidable in seriously ill patients. Prevention of colonization of the upper respiratory tract by pathogenic organisms would provide an effective prophylactic strategy. Although much has been learned about the role of bacterial adherence to regional epithelial cells in determining colonization, manipulation of this adherence phenomenon in the respiratory tract is not clinically possible at this time. The use of topical antimicrobial agents provides another means of preventing colonization with susceptible organisms. In human subjects and experimental animals, topical polymyxin B has successfully reduced cases of pneumonia due to Pseudomonas aeruginosa and Klebsiella pneumoniae, although colonization and occasional infections with resistant organisms occur. However, prevention of pneumonia by manipulation of the bacterial flora of the upper respiratory tract is an approach that warrants further investigation.
The respiratory tract of male and female Syrian golden hamsters was treated intratracheally with 7H-dibenzo[c,g]carbazole (DBC), a tobacco smoke component. The carcinogen was given by multiple instillations at two dose levels. At the lower dose (9 mg), 35 of 46 hamsters (72%) developed respiratory tract tumors. The group receiving treatment at the higher dose level (30 mg) died earlier because of the toxicity of the compound. In this group, 15 of 45 animals (33%) had respiratory tract tumors. These occurred in the larynx, trachea, bronchi, and lungs, but predominated in the trachea and bronchi. Morphologically, most tumors were papillomas and squamous cell carcinomas. This study indicates the highly potent carcinogenic effect of DBC and that respiratory tumors can be induced in this model system without any carrier dust.
In 1984, the International Commission on Radiological Protection (ICRP) appointed a task group of Committee 2 to review and revise, as necessary, the ICRP Dosimetric Model for the Respiratory System. The model was originally published in 1966, modified slightly in Publication No. 19, and again in Publication No. 30 (in 1979). The task group concluded that research during the past 20 y suggested certain deficiencies in the ICRP Dosimetric Model for the Respiratory System. Research has also provided sufficient information for a revision of the model. The task group's approach has been to review, in depth, morphology and physiology of the respiratory tract; deposition of inhaled particles in the respiratory tract; clearance of deposited materials; and the nature and specific sites of damage to the respiratory tract caused by inhaled radioactive substances. This review has led to a redefinition of the regions of the respiratory tract for dosimetric purposes. The redefinition has a morphologic and physiological basis and is consistent with observed deposition and clearance of particles and with resultant pathology. Regions, as revised, are the extrathoracic (E-T) region, comprising the nasal and oral regions, the pharynx, larynx, and upper part of the trachea; the fast-clearing thoracic region (T[f]), comprising the remainder of the trachea and bronchi; and the slow-clearing thoracic region (T[s]), comprising the bronchioles, alveoli, and thoracic lymph nodes. A task group report will include models for calculating radiation doses to these regions of the respiratory tract following inhalation of representative alpha-, beta-, and gamma-emitting particulate and gaseous radionuclides. The models may be implemented as a package of computer codes available to a wide range of users. This should facilitate application of the revised human respiratory tract model to worldwide radiation protection needs.
Respiratory tract papillomas are associated with human papillomavirus (HPV) types 6 and 11; these HPV types are also commonly associated with genital warts (condyloma acuminata). Although most commonly seen in young children, the incidence of respiratory tract papillomas in young adults is increasing. It has been postulated that orogenital contact is the means of transmission in this age group. We performed a survey of adults with genital warts to assess the prevalence of respiratory tract papillomatosis in relation to sexual behaviour and other factors. Fifty-three adult patients (35 male, 18 female) with genital warts attending a genitourinary medicine clinic agreed to examination of the mouth and throat, including indirect laryngoscopy. Seventy per cent of the group had participated in oral sex. Two patients (3.8%) had lesions attributable to HPV infection of the oropharynx and larynx (one with laryngeal keratosis, one with papilloma of the pharynx). There was no specific risk factor identified to predict respiratory tract disease. In view of the high infectivity of genital warts, it is interesting to note the low prevalence of oropharyngeal warts in adults indulging in orogenital contact. Since malignant transformation is known in respiratory tract papillomas, we would recommend that any patient with genital warts who develops unexplained hoarseness has a specialist examination of the upper respiratory tract.
Symptomatic respiratory tract involvement with granulomatous bronchial lesions has not yet been described in Crohn's disease. We report two patients with colonic Crohn's disease and severe respiratory symptoms (dyspnoea associated in one of the patients with voicelessness); erythema, aphthoid and superficial ulcerations were found in the colon and whitish granulations in the bronchi at endoscopy. Non-caseating tuberculoid granulomas were found in the colonic mucosa of both patients, as well as in the bronchial mucosa of one of them; in the second a diffuse inflammatory infiltrate including epithelioid cells was found underneath an erosion of bronchial epithelium. Both patients improved on oral prednisone. These two patients probably had bronchial involvement by Crohn's disease.
In the virological surveillance of children with acute respiratory tract illnesses, five human respiratory coronaviruses (HRCV) were recovered. Three of these strains were isolated from nasopharyngeal swabs of patients with influenza-like illness collected in Kuji City on March 29, 1979. This may suggest the association of HRCVs and influenza-like illness. The other 2 strains were yielded from nasopharyngeal swabs of patients with afebrile acute upper respiratory tract illness collected in Morioka City on March 16 and April 27, 1979. These 5 isolates exhibited typical properties of HRCV; distinctive morphology, resistant to BUDR, chloroform sensitivity, and electron microscopic features of growth in L132 cells. These isolates were identified as 229E-like HRCV by indirect immunofluorescence test, but these were considerably different to HRCV (strain 229E) in antigenicity. Reciprocal neutralization titers of antisera against HRCV (strain 229E) and each isolate were determined by 50% plaque reduction tests in monolayers of L132 cells. The neutralizing activities of anti-HRCV (strain 229E) serum against each isolate were 40- to 100-fold lower than that of homologous reaction. The remarkable differences of antigenicity among the isolates did not be observed.
Most respiratory tract infections are viral in origin, yet until recently only a few effective therapies had been developed. This reflected the large number of causative agents and the generally benign course of most infections. However, increasing numbers of serious respiratory infections have been seen in recent years, due to the rising prevalence of immunodeficient patients and the emergence of previously unrecognised pathogens. Better understanding of viral structure, and novel methods of drug design and discovery are leading to the development of potentially valuable new treatments, particularly for influenza and respiratory syncytial virus infection.
Diseases of the respiratory tract commonly occur in captive chelonians, and several diseases also have occurred in wild chelonians. Infectious causes include viruses, bacteria, fungi, and parasites. Herpesviruses have surfaced as important pathogens of the oral cavity and respiratory tract in Hermann's tortoise (Testudo hermanii), spur-thighed tortoise (Testudo graeca), and other tortoises in Europe and the United States. Herpesvirus-associated respiratory diseases also have been reported in the green turtle, Chelonia mydas, in mariculture in the Cayman Islands. Of diseases caused by bacteria, an upper respiratory tract disease caused by Mycoplasma sp has been reported in free-hanging and captive gopher tortoises in the southeastern United States and in desert tortoises in the Mojave Desert of the southwestern United States. Mycotic pulmonary disease is commonly reported in captive chelonians, especially in those maintained at suboptimal temperatures. An intranuclear coccidia has been seen in several species of captive tortoises in the United States, and, in one case, a severe proliferative pneumonia was associated with organisms in the lung. The most common noninfectious cause of respiratory disease in chelonians results from trauma to the carapace. Although pulmonary fibromas commonly occur in green turtles with fibropapillomatosis, for the most part, tumors of the respiratory tract are uncommon in chelonians.
During colonization of the respiratory tract by Bordetella pertussis, virulence factors contribute to adherence of the bacterium to the respiratory tract epithelium. In the present study, we examined the roles of the virulence factors filamentous hemagglutinin (FHA), fimbriae, pertactin (Prn), and pertussis toxin (PT) in the adherence of B. pertussis to cells of the human bronchial epithelial cell line NCI-H292 and of the laryngeal epithelial cell line HEp-2. Using B. pertussis mutant strains and purified FHA, fimbriae, Prn, and PT, we demonstrated that both fimbriae and FHA are involved in the adhesion of B. pertussis to laryngeal epithelial cells, whereas only FHA is involved in the adherence to bronchial epithelial cells. For PT and Prn, no role as adhesion factor was found. However, purified PT bound to both bronchial and laryngeal cells and as such reduced the adherence of B. pertussis to these cells. These data may imply that fimbriae play a role in infection of only the laryngeal mucosa, while FHA is the major factor in colonization of the entire respiratory tract.
Acute respiratory infections cause considerable morbidity among Inuit children, but there is very little information on the risk factors for these infections in this population. To identify such factors, the authors performed a prospective community-based study of acute respiratory infections in an open cohort of 288 children aged 0-2 years in the town of Sisimiut, Greenland. Between July 1996 and August 1998, children were monitored weekly, and episodes of upper and lower respiratory tract infections were registered. Risk factor analyses were carried out using a multivariate Poisson regression model adjusted for age. Risk factors for upper respiratory tract infections included attending a child-care center (relative risk = 1.7 compared with home care) and sharing a bedroom with adults (relative risk = 2.5 for one adult and 3.1 for two adults). Risk factors for lower respiratory tract infections included being a boy (relative risk = 1.5), attending a child-care center (relative risk = 3.3), exposure to passive smoking (relative risk = 2.1), and sharing a bedroom with children aged 0-5 years (relative risk = 2.0 for two other children). Breastfeeding tended to be protective for lower respiratory tract infections. The population-attributable risk of lower respiratory tract infections associated with passive smoking and child-care centers was 47% and 48%, respectively. The incidence of acute respiratory infections among Inuit children may be reduced substantially through public health measures.
The respiratory tract mucosa is not only the site of infection for influenza viruses but also the site of defense against virus infection. Viruses are initially detected and destroyed non-specifically by innate immune mechanisms, but if the viruses escape the early defense mechanisms, they are detected and eliminated specifically by adaptive immune mechanisms. The major adaptive immune mechanisms are as follows. (i) Specific secretory-IgA (S-IgA) antibodies (Abs) and CTLs (CD8+ cytotoxic T lymphocytes) are involved in the recovery from influenza following viral infection of naive mice. (ii) Preexisting specific S-IgA and IgG Abs in the immunized animals are involved in viral elimination by forming virus-Ig complexes shortly after re-infection. By their polymeric nature, the S-IgA Abs, which are carried to the mucus by transepithelial transport used for dimeric IgA (dIgA) Abs, provide not only protection against homologous virus infection but also cross-protection against drift virus infection. The IgG Abs, which transude from the serum to the mucus by diffusion, provide protection against homologous virus infection. They are largely distributed on the alveolar epithelia to prevent influenza pneumonia. (iii) In the absence of Abs in the pre-immunized animals, the production of specific IgA and IgG Abs by B memory cells is accelerated after re-infection, and these antibodies play a role in viral elimination from day 3 onwards after re-infection. (iv) In epithelial cells of infected animals, specific dIgA Abs being trafficked through the epithelial cells may be involved in the prevention of viral assembly by binding to newly synthesized viral proteins. (v) In the pre-immunized animals, CTL production by memory T cells is also accelerated and these cells appear to participate in the killing of the host cells infected with different subtype viruses (within the same type) from day 3 onwards after re-infection. (vi) Similarly, memory Th1 cells that mediate an accelerated delayed-type hypersensitivity response are involved in blockade of virus replication by secreting IFN-gamma in mice challenged with different subtype viruses. These defense mechanisms suggest that the development of a mucosal vaccine, capable of inducing S-IgA Abs, which provide cross-protection against variant viruses within the same subtype, serum IgG Abs to prevent lethal influenza pneumonia and CTLs, which provide broad cross-protection against different subtype viruses, is strategically important to control influenza.