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Community respiratory viruses: organ transplant recipients.

Respiratory infections are common after solid organ transplantation, but the significance of community respiratory viral infections in this patient population has not been determined. Review of the literature indicates that infection of organ transplant recipients by community respiratory viruses can result in significant morbidity with some associated mortality. These viruses include respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus. As in normal hosts, infection of organ transplant recipients by these viruses can result in limited upper respiratory tract symptoms, such as rhinorrhea, cough, and fever. Immunocompromised patients can also have lower respiratory tract infection, resulting in bronchiolitis, pneumonitis, respiratory failure, and death. The highest incidence of infection with these viruses is reported in lung transplant recipients, with an incidence up to 21%. In addition to the effects of the usual immunosuppressant regimen, lung transplant recipients have altered lung immunity due to impaired ciliary clearance, poor cough reflex, and abnormal lymphatic drainage, predisposing these patients to lower respiratory tract infections. Of additional importance to organ transplant recipients is the correlation of organ rejection to recent viral infections with these agents. Influenza A and B, PIV, and adenovirus have been reported to be associated with acute rejection in renal transplant recipients. Diagnosis of these infections is often made by positive respiratory cultures, often with a delay between symptom onset and diagnosis. Clinical trials of antiviral agents in this patient population have not been carried out, and treatment has often been limited to severe, life-threatening cases.

Adenoviridae↗

Role of respiratory viruses in exacerbations of primary nephrotic syndrome.

To determine whether respiratory virus infections (URI) are associated with exacerbation of nephrotic syndrome (NS) in childhood, a prospective two-winter study of 32 children with NS was done. We obtained pre- and post-season viral serologic studies, biweekly nose and throat viral cultures, daily urinalysis, biweekly telephone follow-up for URI and renal complaints, and clinical assessments as indicated. When a URI occurred, viral cultures were done weekly if the child was at home and twice weekly if hospitalized. Sixty-one URIs occurred; the agent was identified in 33 (51.6%) (respiratory syncytial virus 14, influenza virus five, parainfluenza virus five, varicella zoster virus four, adenovirus three, Mycoplasma pneumoniae one, and Chlamydia trachomatis one). Forty-one exacerbations occurred, 71% with URI; 29% had no URI during the preceding 10 days (P less than 0.01). Total relapse occurred in 29 of 41 exacerbations, 69% with URI and 31% without URI (P less than 0.01). Patients with unstable NS had more exacerbations than those with stable NS (15 of 19 (79%) vs four of 13 (31%), P less than 0.001) and more URI (2.32 vs 1.46 per child, P less than 0.05). Exacerbations in patients with minimal change, mesangioproliferative, and focal glomerulosclerosis occurred in 40%, 60%, and 64%, respectively. We conclude that exacerbations and relapses of childhood NS are temporally related to URI. Inasmuch as multiple viral agents were associated with exacerbations, nonspecific host response to infection, not viral antigen or antibody response, may be the link to NS.

Adolescent↗

Viral and bacterial infections in the development and progression of asthma.

Viral respiratory infections produce wheezing illnesses in patients of all ages. In infancy, infections with respiratory syncytial virus and parainfluenza virus are the major cause of bronchiolitis and croup, whereas infections with common cold viruses such as rhinoviruses are the principal triggers for wheezing in older children and adults with asthma. In addition to causing increased wheezing in asthma, there is mounting evidence that infections early in childhood can affect the development of the immune system and thereby modify the risk for the subsequent development of allergies and asthma. Both of these effects appear to be mediated by virus-induced immune responses. Early during the course of viral infection, resident cells in the airway are activated in an antigen-independent fashion, triggering antiviral responses but also activating and recruiting cells to the airway that could contribute to airway obstruction and respiratory symptoms. Virus-specific T- and B-cell responses may also have dual effects in the presence of preexisting airway inflammation. Finally, there is evidence of synergistic interactions between allergen- and virus-induced airway inflammation. It is likely that greater definition of mechanisms of virus-induced inflammation will provide therapeutic targets for the treatment and possibly the prevention of allergies and asthma.

Animals↗

Continuous porcine cell lines developed from alveolar macrophages: partial characterization and virus susceptibility.

Porcine monomyeloid cell lines were established following transfection of primary porcine alveolar macrophage cultures with plasmid pSV3neo, carrying genes for neomycin resistance and SV40 large T antigen. The parental clone 3D4 exhibited a relatively rapid doubling time (25.5 h), high plating efficiency and mixed phenotype with respect to growth on a solid support. Single cell cloning of the 3D4 parent resulted in establishment of several cell lines; three of them designated 3D4/2, 3D4/21 and 3D4/31 were selected for further characterization. All three clones supported the replication of vesicular stomatitis virus (VSV), pseudorabies virus (PRV), classical swine fever virus (CSFV), swine vesicular disease virus (SVDV), swine poxvirus, African swine fever virus (ASFV), herpes simplex virus (HSV), parainfluenza virus, bovine adenovirus (BAV), vaccinia virus (VV), and porcine adenovirus (PAV). Under the conditions tested the cells did not support replication of porcine reproductive and respiratory syndrome virus (PRRSV). The swine myeloid character was confirmed for all three clones by fluorescence activated cell scanning (FACS) analysis using monoclonal antibodies 74-22-15 and DH59B, which recognize the pan-myeloid antigen cluster SWC3a. A subpopulation of each cell line was positive for nonspecific esterase activity and phagocytic activity to varying degrees depending on the media formulation. Cells from all three lines exhibited anchorage dependent growth when maintained in RPMI 1640 medium supplemented with 5-15% fetal bovine serum (FBS) and nonessential amino acids. Propagation in commercially formulated serum free media resulted in colony formation and growth in suspension. The addition of dimethyl sulfoxide (DMSO) or phorbol 12-myristate 13-acetate (PMA) to serum free media restored cell attachment. DMSO was also able to induce expression of CD14 monocyte marker in the 3D4/31 cell line maintained in FBS containing medium, as determined by FACS with monoclonal antibody CAM36A. Supplementation of RPMI medium with 10% porcine serum upregulated the expression of CD14 and induced expression of porcine macrophage markers recognized by antibodies 2B10 and 2G6 (Vet. Immunol. Immunopathol. 74 (2000) 163) in all three cell lines. The porcine myelomonocytic cell lines obtained may have a wide variety of applications in porcine virology and immunology.

Animals↗

Broad spectrum anti-RNA virus activities of titanium and vanadium substituted polyoxotungstates.

Seven polyoxotungstates substituted with vanadium or titanium atoms were examined for their activity against Flaviviridae (Dengue fever virus, DFV), Orthomyxoviridae (influenza virus type A, fluV-A), Paramyxoviridae (respiratory syncytial virus, RSV, parainfluenza virus type 2, PfluV-2 and canine distemper virus, CDV) and Lentiviridae (human immunodeficiency virus type 1, HIV-1) families. Among the seven polyoxotungstates examined, PM-43 [K(5)[SiVW(11)O(40)]], PM-47 [K(7)[BVW(11)O(40)]], and PM-1001 [K(10)Na(VO)(3)(SbW(9)O(33))(2)]26H(2)O contained vanadium. PM-1002 had the same core structure of (VO)(3)(SbW(9)O(33))(2) as PM-1001; however, three V atoms of PM-1001 consisted of two V(IV) and one V(V) and those of PM-1002 consisted of three V(IV). On the other hand, PM-518 [[Et(2)NH(2)](7)[PTi(2)W(10)O(40)]], PM-520 [Pri(2)NH(2)](5)[PTiW(11)O(40)] and PM-523 [PriNH(3)](6)H[PTi(2)W(10)O(38)(O(2))(2)]H(2)O all contained titanium. All compounds showed broad spectrum antiviral activity against all viruses examined except for PMs-43, -518 and -523 which did not exhibit inhibitory activity at >/=50 microM against PfluV-2, CDV and DFV, respectively. All compounds were inhibitory against HIV replication at an EC(50) of less than 2.0 microM. Among them, PMs-1001 and -1002 showed the most potent inhibition. The compounds were not toxic for MDCK, HEp-2 and Vero cells at a concentration of 200 microM. For the exponentially growing MT-4 cells, the vanadium containing polyoxometalates (PMs-43, 47, 1001, 1002) showed toxicity at concentrations between 41 and 47 microM. On the other hand, titanium containing polyoxometalates (PMs-518, -520, -523) were not toxic at 100 microM. The mechanism of anti-HIV action of PM-1001 was analyzed: it affected the binding of HIV to the cell membrane and syncytium formation between HIV-infected and uninfected cells.

Animals↗

Transcriptional control of the RNA-dependent RNA polymerase of vesicular stomatitis virus.

The nonsegmented negative strand (NNS) RNA viruses include some of the mosr problematic human, animal and plant pathogens extant: for example, rabies virus, Ebola virus, respiratory syncytial virus, the parainfluenza viruses, measles and infectious hemapoietic necrosis virus. The key feature of transcriptional control in the NNS RNA viruses is polymerase entry at a single 3' proximal site followed by obligatory sequential transcription of the linear array of genes. The levels of gene expression are primarily regulated by their position on the genome. The promoter proximal gene is transcribed in greatest abundance and each successive downstream gene is synthesized in progressively lower amounts due to attenuation of transcription at each successive gene junction. In addition, NNS RNA virus gene expression is regulated by cis-acting sequences that reside at the beginning and end of each gene and the intergenic junctions. Using vesicular stomatitis virus (VSV), the prototypic NNS, many of these control elements have been identified.The signals for transcription initiation and 5' end modification and for 3' end polyadenylation and termination have been elucidated. The sequences that determine the ability of the polymerase to slip on the template to generate polyadenylate have been identified and polyadenylation has been shown to be template dependent and integral to the termination process. Transcriptional termination is a key element in control of gene expression of the negative strand RNA viruses and a means by which expression of individual genes may be silenced or regulated within the framework of a single transcriptional promoter. In addition, the fundamental question of the site of entry of the polymerase during transcription has been reexamined and our understanding of the process altered and updated. The ability to engineer changes into infectious viruses has confirmed the action of these elements and as a consequence, it has been shown that transcriptional control is key to controlling the outcome of a viral infection. Finally, the principles of transcriptional regulation have been utilized to develop a new paradigm for systematic attenuation of virulence to develop live attenuated viral vaccines.

Base Sequence↗

Response of the ruminant respiratory tract to Mannheimia (Pasteurella) haemolytica.

Pneumonia is a leading cause of loss to the sheep and cattle industry throughout the world. Mannheimia (Pasteurella) haemolytica is one of the most important respiratory pathogens of domestic ruminants and causes serious outbreaks of acute pneumonia in neonatal, weaned and growing lambs, calves, and goats. M. haemolytica is also an important cause of pneumonia in adult animals. Transportation, viral infections with agents such as infectious bovine rhinotracheitis virus, parainfluenza-3 virus or bovine respiratory syncytial virus, overcrowding, housing of neonates and weaned animals together and other stressful conditions predispose animals to M. haemolytica infection [1, 2]. This review assimilates some of the findings key to cellular and molecular responses of the lung from a pathologist's perspective. It includes some of what is known and underscores areas that are not fully understood.

Animals↗

Rapid detection of respiratory viruses by centrifugation enhanced cultures from children with acute lower respiratory tract infections.

BACKGROUND: Acute respiratory tract infection (ARI) is the major cause of morbidity and mortality in young children in developing countries. Information on viral aetiology in ARI in India is very limited. OBJECTIVE: The aim of the study was to define the role of viruses in acute lower respiratory tract infections (ALRTI) in children in India using centrifugation enhanced cultures followed by indirect immunofluorescence (IIF). STUDY DESIGN: Nasopharyngeal aspirates (NPAs) were collected from children from September 1995 to April 1997, attending paediatric clinic of All India Institute of Medical Sciences (AIIMS) with symptoms of ALRTI. Virus isolation was done by centrifugation enhanced cultures using HEp-2, LLC-MK2 and MDCK cells. The viruses were identified at 24-48 h post inoculation by IIF staining using monoclonal antibodies to respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus and adenovirus. RESULTS: Of 200 NPA samples, 89 (44.5%) were positive for one or more viral pathogens. RSV was detected in 34 (17%) of all ALRTI cases followed by influenza viruses in 29 (14.5%), PIVs in 23 (11.5%) and adenoviruses in three (1.5%). In 79 children with bronchiolitis, RSV was most frequently isolated (25%) pathogen, while in bronchopneumonia cases (101) the most common viral pathogen was influenza virus (17%). In eight cases (4%) of ALRTI dual infections were detected. In 100 NPA specimens IIF staining on direct cell smears was carried out and viruses were detected in only 17%. RSV and influenza virus infection peaked from September to December, where as PIV infections were more frequent from January to April. CONCLUSION: Respiratory viruses accounted for 44.5% of cases of ALRTI in India and the results of viral aetiology could be given in 24-48 h using centrifugation enhanced cultures. RSV was the most common viral agent associated with ALRTI in children under 5 years of age with greater association with bronchiolitis.

Adenoviruses, Human↗

Immunology of viral respiratory tract infection in infancy.

Respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza viruses (PIV) and the influenza viruses cause severe lower respiratory tract disease in infants and children throughout the world. We discuss the recent discovery of the epidemiologic importance of the human metapneumoviruses, first reported in 2001. Experimental live-attenuated vaccines for each of these viruses are being developed for intranasal administration in the first weeks or months of life. The immunology of these infections in humans is poorly defined but many studies are ongoing. A significant obstacle to successful immunisation of infants against respiratory-virus-associated disease early in life may be the relatively poor immune response of very young infants to primary virus infection. This paper reviews the immune correlates of protection against disease caused by these viruses, immune responses of infants to naturally acquired infection or experimental infection with candidate vaccine viruses and the genetics of susceptibility to severe disease.

Animals↗

Inactivation of S-adenosyl-L-homocysteine hydrolase and antiviral activity with 5',5',6',6'-tetradehydro-6'-deoxy-6'-halohomoadenosine analogues (4'-haloacetylene analogues derived from adenosine).

Treatment of a protected 9-(5, 6-dideoxy-beta-D-ribo-hex-5-ynofuranosyl)adenine derivative with silver nitrate and N-iodosuccinimide (NIS) and deprotection gave the 6'-iodo acetylenic nucleoside analogue 3c. Halogenation of 3-O-benzoyl-5,6-dideoxy-1, 2-O-isopropylidene-alpha-D-ribo-hex-5-enofuranose gave 6-halo acetylenic sugars that were converted to anomeric 1,2-di-O-acetyl derivatives and coupled with 6-N-benzoyladenine. These intermediates were deprotected to give the 6'-chloro 3a, 6'-bromo 3b, and 6'-iodo 3c acetylenic nucleoside analogues. Iodo compound 3c appears to inactivate S-adenosyl-L-homocysteine hydrolase by a type I ("cofactor depletion") mechanism since complete reduction of enzyme-bound NAD+ to NADH was observed and no release of adenine or iodide ion was detected. In contrast, incubation of the enzyme with the chloro 3a or bromo 3b analogues resulted in release of Cl- or Br- and Ade, as well as partial reduction of E-NAD+ to E-NADH. Compounds 3a, 3b, and 3c were inhibitory to replication of vaccinia virus, vesicular stomatitis virus, parainfluenza-3 virus, and reovirus-1 (3a < 3b < 3c, in order of increasing activity). The antiviral effects appear to correlate with type I mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase. Mechanistic considerations are discussed.

Adenosine↗

Antiviral flavonoids from the seeds of Aesculus chinensis.

A bioassay-guided fractionation of an ethanol extract of the seeds of Aesculus chinensis led to the isolation of two new flavanoids (1 and 2), along with eight known ones (3-10). The structures of the new compounds were elucidated by spectroscopic methods including 2D NMR. All compounds were tested for antiviral activity against respiratory syncytial virus (RSV), parainfluenza virus type 3 (PIV 3), and influenza virus type A (Flu A). Compounds 1, 2, and 6 showed significant antiviral activities against RSV with IC(50) values of 4.5, 6.7, and 4.1 microg/mL and selective index (SI) values of 15.8, 32, and 63.8, respectively. Compound 8 demonstrated significant antiviral activity against Flu A with an IC(50) of 24.5 microg/mL and a SI of 16.0, respectively.

Aesculus↗

Community respiratory virus infections following lung transplantation.

Respiratory infections remain a significant cause of morbidity and mortality after lung transplantation. In addition to cytomegalovirus, the community respiratory viruses such as respiratory syncytial virus (RSV), parainfluenza virus (PIV), influenza virus, and adenovirus, are important causes of infection in transplant recipients, often involve the lower respiratory tract, and may be associated with significant morbidity and mortality. In this review, we summarize the current state of knowledge regarding the epidemiology, clinical manifestations, diagnosis, treatment and outcomes associated with RSV, PIV, influenza virus, and adenovirus infections in lung transplant recipients.

Adenoviridae Infections↗

Infectious etiology of bronchiolitis obliterans: the respiratory viruses connection - myth or reality?

A variety of viruses, such as the influenza viruses A and B, the human respiratory syncytial virus, the parainfluenza viruses, and the adenoviruses, cause seasonal respiratory tract infections in young children and adults. Also, studies indicate that these viruses are an important group of pathogens in pediatric and adult lung transplant recipients. More importantly, accumulating data on these infections among lung transplant patients suggest that these illnesses may have immediate and long-term implications for the function of the transplanted lung, including the development of bronchiolitis obliterans. This is important because patient survival and allograft function in lung transplantation remain limited by the development of bronchiolitis obliterans. Models of lung transplantation indicate that respiratory viral infections cause acute and chronic airway damage after transplantation. The mechanism leading to allograft damage by respiratory viruses may be related to the production of alloreactive cytokines such as interleukin (IL)-1, tumor necrosis factor, IL-6 and IL-8 during viral replication. Current clinical data are suggestive of a possible role for respiratory viruses in the development of bronchiolitis obliterans, but further control studies are required to evaluate the significance of respiratory virus infections as a causal factor in the development of bronchiolitis obliterans in lung transplantation.

Bronchiolitis Obliterans↗

The impact of influenza viruses on hospitalizations in infants younger than two years old during epidemics of respiratory syncytial virus infection.

In order to evaluate the association of influenza viruses with hospitalizations for acute respiratory infection in infants younger than two years old during epidemics of respiratory syncytial virus infection, we studied 512 nasal washes from this population. The samples were obtained from 1997 to 2000. A total of 337 viruses were isolated: 264 respiratory syncytial viruses, 62 influenza viruses, eight parainfluenza viruses, two adenovirus and one rhinovirus. Hospitalizations for acute respiratory infection were owing to influenza and respiratory syncytial viruses in 18.3% vs. 78.3% of all cases, and 32.5% vs. 65.8%, respectively, in the group of infants between 6 months and 2 years old.

Hospitalization↗

Diagnosis and epidemiology of community-acquired respiratory virus infections in the immunocompromised host.

Infections due to community-acquired respiratory viruses are important causes of morbidity and mortality among immunocompromised patients. Respiratory syncytial virus, influenza viruses, and parainfluenza viruses are the most frequent causes of serious lower respiratory tract infections in this patient population. Early diagnosis, often possible with the use of rapid detection assays, is essential for optimal management and prevention of the spread of these serious infections to other vulnerable patients.

Bone Marrow Transplantation↗

Bronchiolitis obliterans and lung transplantation: evidence for an infectious etiology.

Bronchiolitis obliterans (OB) or bronchiolitis obliterans syndrome (BOS) remains a major hurdle in the long-term survival of lung transplant recipients. The pathogenesis of OB or BOS remains to be fully discerned, but it is hypothesized that allogenic or nonallogenic insults result in the release of chemokines and T lymphocytes propagating the injury and ultimately recruiting fibroblasts culminating in intraluminal proliferation. Infectious agents, with or without other exogenous factors, have been proposed to have a contributory role in the development of OB or BOS. Cytomegalovirus (CMV) is an immunomodulating virus that may lead to persistent stimulation of T cells with the release of chemokines that may promote OB. Animal studies have correlated the development of OB with CMV infection. However, assessment of CMV as a risk factor for the development of OB or BOS in clinical studies has yielded conflicting results. CMV infection was noted to have a hazard ratio of 1.62 in one study, whereas CMV pneumonitis was associated with relative risk of 2.3. Additional studies did not find a higher risk for developing OB or BOS with CMV. Other viruses including respiratory syncytial virus and parainfluenza viruses can promote epithelial damage and act synergistically with chronic rejection in the development of OB. A higher (47%) incidence of BOS has been noted during the respiratory virus season. The evidence of Pneumocystis carinii pneumonia or other infectious episodes causing OB is lacking. Thus, although the role of infectious agents in the development of OB or BOS is biologically plausible, an incontrovertible association between infection and OB or BOS has not been documented. This is a US government work. There are no restrictions on its use.

Bronchiolitis Obliterans↗

The role of viral respiratory infections in the pathogenesis and exacerbation of asthma.

Respiratory viral infections are implicated in both the pathogenesis and exacerbation of asthma. Infections with respiratory syncytial virus and parainfluenza virus are the major cause of wheezing-related respiratory infections early in life. Infections in early childhood affect the immune system and modify the risk for subsequent development of allergies and asthma. Later in life, rhinovirus and influenza are implicated frequently in the exacerbation of asthma. The management of respiratory viral infections includes adequate prophylaxis and treatment of acute infections. Insights into the mechanism of viral respiratory tract infections will provide therapeutic targets for treatment and possibly the prevention of virus-induced asthma.

Asthma↗

An outbreak of coronavirus OC43 respiratory infection in Normandy, France.

The 2 groups of human coronaviruses (HCoVs) represented by the prototype strains HCoV 229E and HCoV OC43 are mostly known as viruses responsible for common cold syndrome. HCoVs are difficult to detect, and epidemiological data are rare. From October 2000 through April 2001, we tested 1803 respiratory samples for HCoV by reverse-transcriptase polymerase chain reaction. From 8 February through 27 March 2001, HCoV OC43 was detected in samples obtained from 30 (6%) of 501 patients. The other viruses detected were respiratory syncytial virus (6.1%), parainfluenza virus 3 (1%), influenza virus A (7.8%), influenza virus B (7.2%), rhinovirus (6.4%), enterovirus (1%), and adenovirus (2%). Infection with HCoV OC43 was detected in patients of all age groups. The following clinical symptoms were noted: fever (in 59.8% of patients), general symptoms (in 30%), digestive problems (in 56.8%), rhinitis (in 36.6%), pharyngitis (in 30%), laryngitis (in 3.3%), otitis (in 13.3%), bronchitis (in 16.6%), bronchiolitis (in 10%), and pneumonia (in 6.6%). This study shows that an outbreak of HCoV OC43 respiratory infection was responsible for the lower respiratory tract symptoms observed in nearly one-third of patients identified by active surveillance for coronavirus infection.

Adolescent↗