Características de la infección por metapneumovirus humano, ¿es importante la edad? / Characteristics of human metapneumovirus infection, is it important the age?

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[Metapneumovirus infection in an adult]. / Metapnevmovirusnaya infektsiya u vzroslogo.

The paper briefly characterizes human metapneumovirus, a newly discovered pathogen of acute respiratory infections, and gives brief clinical, virological, and pathological data concerning a fatal outcome of a 51-year-old obese woman without severe background pathology. Metapneumovirus infection has been verified by real-time PCR. Morphological examination revealed the signs of subtotal diffuse alveolar damage, ciliary epithelial cell overgrowths, and binucleated macrophages. The changes revealed in the lungs are similar to those as previously described in paramyxovirus infections, but are accompanied by severe nonspecific changes that have been recently observed in swine influenza. Those in the brain meninges, kidneys, pancreas, and intestine may be suggestive of the generalization of the infection. It has been proposed that the properties of the virus may vary.

The role of influenza and parainfluenza infections in nasopharyngeal pneumococcal acquisition among young children.

BACKGROUND: Animal models suggest that influenza infection favors nasopharyngeal acquisition of pneumococci. We assessed this relationship with influenza and other respiratory viruses in young children. METHODS: A case-control study was nested within a prospective cohort study of acute respiratory illness (ARI) in Andean children <3 years of age (RESPIRA-PERU study). Weekly household visits were made to identify ARI and obtain nasal swabs for viral detection using real-time reverse-transcription polymerase chain reaction. Monthly nasopharyngeal (NP) samples were obtained to assess pneumococcal colonization. We determined whether specific respiratory viral ARI episodes occurring within the interval between NP samples increased the risk of NP acquisition of new pneumococcal serotypes. RESULTS: A total of 729 children contributed 2128 episodes of observation, including 681 pneumococcal acquisition episodes (new serotype, not detected in prior sample), 1029 nonacquisition episodes (no colonization or persistent colonization with the same serotype as the prior sample), and 418 indeterminate episodes. The risk of pneumococcal acquisition increased following influenza-ARI (adjusted odds ratio [AOR], 2.19; 95% confidence interval [CI], 1.02-4.69) and parainfluenza-ARI (AOR, 1.86; 95% CI, 1.15-3.01), when compared with episodes without ARI. Other viral infections (respiratory syncytial virus, human metapneumovirus, human rhinovirus, and adenovirus) were not associated with acquisition. CONCLUSIONS: Influenza and parainfluenza ARIs appeared to facilitate pneumococcal acquisition among young children. As acquisition increases the risk of pneumococcal diseases, these observations are pivotal in our attempts to prevent pneumococcal disease.

Role of Bibersteinia trehalosi, respiratory syncytial virus, and parainfluenza-3 virus in bighorn sheep pneumonia.

Pneumonic bighorn sheep (BHS) have been found to be culture- and/or sero-positive for Bibersteinia trehalosi, respiratory syncytial virus (RSV), and parainfluenza-3 virus (PI-3). The objective of this study was to determine whether these pathogens can cause fatal pneumonia in BHS. In the first study, two groups of four BHS each were intra-tracheally administered with leukotoxin-positive (Group I) or leukotoxin-negative (Group II) B. trehalosi. All four animals in Group I developed severe pneumonia, and two of them died within 3 days. The other two animals showed severe pneumonic lesions on euthanasia and necropsy. Animals in Group II neither died nor showed gross pneumonic lesions on necropsy, suggesting that leukotoxin-positive, but not leukotoxin-negative, B. trehalosi can cause fatal pneumonia in BHS. In the second study, two other groups of four BHS (Groups III and IV) were intra-nasally administered with a mixture of RSV and PI-3. Four days later, RSV/PI-3-inoculated Group IV and another group of four BHS (Group V, positive control) were intra-nasally administered with Mannheimia haemolytica, the pathogen that consistently causes fatal pneumonia in BHS. All four animals in group III developed pneumonia, but did not die during the study period. However all four animals in Group IV, and three animals in Group V developed severe pneumonia and died within two days of M. haemolytica inoculation. The fourth animal in Group V showed severe pneumonic lesions on euthanasia and necropsy. These findings suggest that RSV/PI-3 can cause non-fatal pneumonia, but are not necessary predisposing agents for M. haemolytica-caused pneumonia of BHS.

Fatal human metapneumovirus and influenza B virus coinfection in an allogeneic hematopoietic stem cell transplant recipient.

Human metapneumovirus (hMPV) infection can occur in all age groups with significant morbidity and mortality. Coinfection with influenza virus occurs mainly with influenza type A and all reported cases recovered completely. We report the case of a 61-year-old man who had hematopoietic stem cell transplant for myelodysplastic syndrome. He was admitted to hospital for septic shock and neutropenia, and blood culture was positive for Pseudomonas aeruginosa. He rapidly developed respiratory failure and required ventilator support. His respiratory culture grew P. aeruginosa and hMPV. His course was complicated by persistent shock requiring vasopressor support, and repeat nasopharyngeal swab was positive for influenza type B and hMPV. His condition rapidly deteriorated, his family elected comfort care, and the patient died shortly thereafter. Coinfection with hMPV and influenza virus type B may have a poor outcome and can be fatal, especially in immunocompromised patients.

Long-term impairment of Streptococcus pneumoniae lung clearance is observed after initial infection with influenza A virus but not human metapneumovirus in mice.

Human metapneumovirus (hMPV) is a paramyxovirus responsible for respiratory tract infections in humans. Our objective was to investigate whether hMPV could predispose to long-term bacterial susceptibility, such as previously observed with influenza viruses. BALB/c mice were infected with hMPV or influenza A and, 14 days following viral infection, challenged with Streptococcus pneumoniae. Only mice previously infected with influenza A demonstrated an 8% weight loss of their body weight 72 h following S. pneumoniae infection, which correlated with an enhanced lung bacterial replication of >7 log(10) compared with pneumococcus infection alone. This enhanced bacterial replication was not related to altered macrophage or neutrophil recruitment or deficient production of critical cytokines. However, bacterial challenge induced the production of gamma interferon in bronchoalveolar lavages of influenza-infected mice, but not in those of hMPV-infected animals. In conclusion, hMPV does not cause long-term impairment of pneumococcus lung clearance, in contrast to influenza A virus.

Human metapneumovirus subgroup changes and seasonality during epidemics.

BACKGROUND: Human metapneumovirus (HMPV) is a major cause of respiratory tract illness in young children and causes annual outbreaks in winter and spring seasons. We evaluated the subgroups of HMPV that caused annual outbreaks and its seasonal occurrence during a 21-year period. METHODS: Real-time PCR was used for detection of HMPV in 3576 nasopharyngeal aspirates that had been continuously collected year-round for the years 1987 to 2008 from infants hospitalized with acute respiratory tract illness. Phylogenetic analysis was used to assess HMPV subgroups. RESULTS: Of the 3576 samples obtained, 202 (5.6%) tested positive for HMPV. All known HMPV subgroups (A1, A2a, A2b, B1, B2) could be identified as important respiratory tract pathogens in infants. We found that one HMPV subgroup predominated each year, and it was displaced by another subgroup every 1 to 3 years. Besides the frequent change in predominant HMPV subgroups, we observed a yearly shift in the seasonal occurrence, with a strong peak of HMPV activity in late spring-summer months every second year. CONCLUSION: HMPV activity is characterized by a periodic change in the predominant subgroup and it shows a stable seasonal rhythm of alternating winter and spring activity.

Estudio comparativo de inmunofluorescencia directa, enzimoinmunoanálisis y cultivo para el diagnóstico de las infecciones por metapneumovirus humano / A comparative study of direct immunofluorescence, enzyme immunoassay, and culture for diagnosing metapneumovirus infection

Introducción: El metapneumovirus humano (hMPV) es el causante de un número importante de infecciones en pediatría, entre un 14 y un 22% de las infecciones respiratorias víricas con diagnóstico etiológico establecido. Se presenta un estudio comparativo entre una técnica de inmunofluorescencia directa (IFD), una de enzimoinmunoanálisis (EIA) y el cultivo según la técnica de shell vial. Métodos: Se procesaron 124 aspirados nasofaríngeos pertenecientes a 108 lactantes con infecciones respiratorias de vías bajas. Durante su recepción se los procesó para la IFD, para lo que se utilizó un anticuerpo anti-hMPV comercial (Diagnostic Hybrids Inc.) y se sembró en la línea celular LLC-MK2 (sólo 76 muestras) para fijarse y teñirse a las 48h con el mismo suero citado. El resto de la muestra se procesó según la rutina diagnóstica habitual y se congeló en alícuotas para posterior estudio con EIA (Biotrin®).Resultados: Veinte muestras (16,12%) fueron positivas al hMPV mediante la IFD, 27 muestras (21,77%) fueron positivas mediante el EIA y 15 muestras (19,73%) fueron positivas mediante cultivo. La IFD y el EIA coincidieron en un 92,73% de las 124 muestras. Al considerar las 3 pruebas (76 muestras) se consiguió una concordancia del 90,78%. Al considerar sólo las primeras muestras de cada enfermo (fase aguda), la sensibilidad, los valores predictivos y el índice Kappa de la IFD mejoraron y se acercaron a los obtenidos con el EIA. Conclusión: Ambas pruebas de detección de antígeno son útiles en el diagnóstico de la infección aguda por hMPV en aquellos hospitales pediátricos que no dispongan de las técnicas de amplificación para este virus y necesiten un diagnóstico etiológico con urgencia, con la salvedad de que la IFD está indicada sólo en la fase inicial de la infección (AU)

Introduction: Human metapneumovirus (hMPV) is an important cause of lower respiratory tract infections in children, accounting for 14% to 24% of all viral respiratory infections with an etiological diagnosis. This study compares a direct fluorescent antibody (DFA) test, enzyme immunoassay (EIA), and shell-vial culture for diagnosing acute bronchiolitis in infants.Methods: A total of 124 nasopharyngeal aspirates from 108 infants with lower respiratory tract infection were analyzed. Incoming samples were processed for DFA using a commercial anti-hMPV antibody (Diagnostic Hybrids Inc.®); 76 were inoculated in an LLC-MK2 cell line, and after an incubation period of 48h, were stained and fixed with the aforementioned serum. The remaining sample was processed according to the routine diagnostic procedure and aliquots were frozen for EIA analysis (Biotrin®).Results: Twenty (16.12%) samples were positive for hMPV by DFA, 27 (21.77%) by EIA, and 15 (19.73%) by culture. DFA and EIA results were consistent in 92.73% of the 124 samples. Considering the 3 techniques, the same results were obtained in 90.78% of the 76 specimens. Considering only the first specimen from each patient (acute phase), the sensitivity, predictive values, and Kappa index for DFA improved and were very close to the EIA values.Conclusion: DFA and EIA are useful for antigen detection in the diagnosis of acute hMPV infection, particularly in pediatric hospitals that do not have amplification techniques for this virus, and when a rapid diagnosis is required. It should be kept in mind that DFA analysis is a suitable test for this purpose only in the acute phase of the infection (AU)

Detection of human metapneumovirus in hospitalized children with acute respiratory tract infection using real-time RT-PCR in a hospital in northern Taiwan.

BACKGROUND/PURPOSE: Human metapneumovirus (hMPV) is a newly discovered respiratory pathogen. This prospective hospital-based study investigated the clinical role and features of hMPV in Taiwan. METHODS: Respiratory specimens collected from hospitalized children with acute respiratory tract infection between September 1, 2003 and April 10, 2005 were screened for metapneumovirus using real-time reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: During the study period, 930 specimens were obtained from 926 hospitalized children. After exclusion of 200 cases due to lack of clinical evidence of airway infection or diseases with known etiology, 726 were included in the analysis. Among these, 33 children had a positive result for hMPV infection. The majority of these patients were admitted during spring and early summer. Twenty-one (63.6%) were younger than 2 years of age. hMPV accounted for 13.3% of respiratory infections occurring between the ages of 18 and 24 months and was as common a respiratory pathogen as respiratory syncytial virus (RSV) in that age group. The 11 patients (33.3%) with underlying diseases had a similar disease course to those without underlying diseases. A co-pathogen was found in 11 patients (33.3%). Infected children between 2 and 5 years of age had significantly higher titers of hMPV in their respiratory specimens (103.88 copies/microL) than children younger than 2 years (102.26 copies/microL) (p = 0.013) and children older than 5 years (102.25 copies/microL) (p = 0.005). hMPV positive cases were significantly older than those with RSV infection (p = 0.002) and had a shorter duration of hospitalization (p = 0.001), fewer days of oxygen use (p = 0.001) and higher levels of C-reactive protein (p = 0.004). CONCLUSION: Metapneumovirus circulates in children in northern Taiwan during spring and early summer. hMPV was the most common respiratory pathogen in children aged between 18 and 24 months hospitalized with acute respiratory tract infection. Real-time RT-PCR is a sensitive method for investigating the epidemiology and diseases associated with hMPV.

Bordetella pertussis and mixed infections.

AIM: In pertussis-like respiratory infections, once pertussis has been laboratory confirmed, other potential causative pathogens will seldom be looked for. Probably most mixed infections are found accidentally and since these mixed infections might cause a more severe disease we performed a retrospective study of their incidence. METHODS: We selected from 2 groups of patients with serologically confirmed Bordetella (B.) pertussis infection those in whom serology for other respiratory pathogens had also been performed. Group 1 consisted of 50 pertussis patients with 51 episodes of B. pertussis infection selected from 100 patients with serologically confirmed pertussis. They participated in a long-term follow-up after a B. pertussis infection. In group 2, 31 pertussis patients were selected from 98 consecutive patients with positive pertussis serology from one routine practice. RESULTS: In 23 of 82 pertussis infections (28%) serological evidence of 1 (n = 21) or 2 (n = 2) additional infections were demonstrated. These involved para-influenza virus (n = 6), respiratory syncytial virus (RSV) (n = 6), Mycoplasma pneumoniae (n = 5), adenovirus (n = 4), influenza A virus (n = 3) and influenza B virus (n = 1). CONCLUSIONS: We conclude that in patients with B. pertussis infection, coinfection with another respiratory pathogen is often present.

Human metapneumovirus infections cause similar symptoms and clinical severity as respiratory syncytial virus infections.

Human metapneumovirus (hMPV) is a recently discovered pathogen in respiratory tract infection. The published literature suggests milder illness severity in hMPV compared with respiratory syncytial virus (RSV) infection. In two consecutive seasons, 637 nasopharyngeal aspirates from pediatric patients were tested by hMPV polymerase chain reaction, and risk factors and clinical and laboratory items were analyzed. The hMPV patients were compared with hMPV-negative but RSV-positive patients by matched pair analysis. HMPV was detected in 17.9% of all samples. In total, 88 hMPV-infected patients with complete datasets were considered. More than half of all hMPV patients were older than 12 months, 45.5% had at least one risk factor for a severe course of viral respiratory tract infection, and 27.3% were born prematurely, 15.9% with a birth weight <1,500 g. At least one other virus was also detected in 39 patients (44.3%; RSV in 29.5%). Coinfection did not result in greater severity of illness. On matched pair analysis (hMPV-positive/RSV-negative vs. hMPV-negative/RSV-positive), the epidemiological and clinical features of hMPV infection were similar to those of RSV infection, as in the hMPV group higher proportions of patients with hypoxemia on admission (33% vs. 21%) and of intensive care treatment (20.8% vs. 10.4%) were observed. More hMPV patients showed lobar infiltrates in radiological chest examination. In 60% of all hMPV infections, the attending physicians prescribed antimicrobial chemotherapy. We conclude that in hospitalized children, hMPV infection is as serious as RSV infection and therefore deserves the same attention. Virologic diagnosis from respiratory secretions is mandatory because clinical, laboratory, and radiological signs cannot sufficiently discriminate between viral and bacterial respiratory tract infection in infants and children.

Novel and re-emerging respiratory infections.

Over the last decade a number of novel viral respiratory pathogens have appeared or been recognized. Most of these are zoonoses, which have the capacity to infect humans directly or via an intermediate host. All but metapneumovirus are known to have caused epidemics of severe disease and at least two (the severe acute respiratory syndrome-coronavirus and influenza H5N1) have the potential to cause global pandemics. Possible preventive measures and treatment options against these new diseases are discussed in this review.

The effect of leukocyte depletion on pulmonary M2 muscarinic receptor function in parainfluenza virus-infected guinea-pigs.

1. Parainfluenza infections of the airways cause dysfunction of inhibitory M2 muscarinic receptors on the pulmonary parasympathetic nerves. To distinguish the direct effects of virus from the effects of virus-induced airway inflammation on M2 muscarinic receptor function, guinea-pigs were depleted of leukocytes by pretreating with cyclophosphamide (30 mg kg-1, i.p. daily for 7 days) after which they were infected with parainfluenza virus type 1 (Sendai virus). 2. Guinea-pigs were anaesthetized, tracheotomized, and ventilated. The vagus nerves were isolated and cut, and the distal ends were electrically stimulated causing bronchoconstriction. In control animals, pilocarpine (1-100 micrograms kg-1, i.v.) inhibited and gallamine (0.1-10 mg kg-1, i.v.) potentiated vagally-induced bronchoconstriction by stimulating or blocking M2 muscarinic receptors on the vagus. These effects of pilocarpine and gallamine were almost completely lost in virus-infected animals, demonstrating loss of M2 receptor function. 3. Cyclophosphamide depleted peripheral blood leukocytes and inhibited the virus-induced influx of inflammatory cells into the lung. Depletion of leukocytes protected M2 receptor function from viral infection in some, but not all, guinea-pigs tested. 4. Among infected animals that had been depleted of leukocytes, the viral content (expressed as the log of the number of tissue culture infectious doses per g lung tissue) of those that retained normal M2 receptor function was 4.29 +/- 0.05 (mean +/- s.e. mean), while the viral content of those that lost M2 receptor function despite leukocyte depletion was 5.45 +/- 0.20 (P = 0.011). Thus the viral content of the lungs in which M2 receptor function was lost was 16 times greater than that of the lungs in which M2 receptor function was preserved. Viral content correlated with the inhibition of vagally-mediated bronchoconstriction after the maximum dose of pilocarpine (100 Microg kg-1; r2 = 0.81, P =0.0004).5. In antigen-challenged animals, inhibitory M2 muscarinic receptor function is restored when positively charged inflammatory cell proteins are bound and neutralized by heparin. However, heparin(2000 micro kg-1, i.v.) did not reverse virus-induced loss of M2 muscarinic receptor function, even in those guinea-pigs with a lower viral titer.6. Because leukocyte depletion protected M2 muscarinic receptor function only in animals with mild viral infections, it appears that viruses have both an indirect, leukocyte-dependent effect on M2 receptors and, in animals with more severe infections, a leukocyte-independent effect on M2 receptors. The failure of heparin to restore M2 receptor function demonstrates that the leukocyte-dependent loss of M2 receptor function is not mediated by positively charged inflammatory cell proteins.

Epidemiology and cost of infection with human parainfluenza virus types 1 and 2 in young children.

To determine the morbidity, costs, and epidemiological features of lower respiratory tract infections (LRIs) due to human parainfluenza virus types 1 and 2 (HPIV-1 and HPIV-2), we evaluated 1,213 children < 6 years of age who were seen for LRIs in the emergency room of the Children's Hospital of Wisconsin and/or were admitted to the hospital for LRIs during the fall quarter of 1991. The age, sex, race, and respiratory syndrome were recorded for each child; 158 patients (13%) had respiratory samples cultured for viruses and were followed clinically for the duration of their illness. Caucasian children had croup diagnosed more often than did African-American children (relative risk [RR] = 3.12; 95% confidence interval [CI], 2.43-4.00; P < .001), while African-American children more often had pneumonia (RR = 1.85; 95% CI, 1.36-2.5; P < .001). Forty-five of 70 viruses recovered were HPIV-1 (17 cases) or HPIV-2 (28 cases). Together these two viruses were recovered from 49% of children presenting with croup, 10% of those presenting with bronchiolitis, and 12% of those presenting with pneumonia. Gender- and race-associated differences were documented in the group of children infected with HPIV-2: specifically, this group included more girls than boys (RR = 1.99; 95% CI, 1.02-3.88; P < .04) and more Caucasian than African-American children (RR = 2.64; 95% CI, 1.05-6.63; P = .027). These data extrapolate nationally to approximately 250,000 emergency-room visits and approximately 70,000 hospitalizations due to HPIV-1 and HPIV-2, with a cost of $50 million for the former and $140 million for the latter.

Parainfluenza viral infections in pediatric outpatients: seasonal patterns and clinical characteristics.

Parainfluenza types 1, 2 and 3 were studied in a pediatric outpatient population from 1976 to 1992 to compare seasonal patterns over time and to define better the spectrum of illness in all ages of children caused by these viruses. Parainfluenza type 1 occurred in the fall of odd numbered years; parainfluenza type 2 was less predictable; and parainfluenza type 3 appeared yearly with peak activity in spring or summer. The parainfluenza viruses were the major cause of croup and also accounted for one-half of the cases of laryngitis and over one-third of all lower respiratory tract illness in children from whom a virus was isolated. The major clinical manifestations of infection with parainfluenza types 1 and 2 were croup, upper respiratory infections and pharyngitis; for parainfluenza type 3 upper respiratory tract infection was predominant in all age groups. The parainfluenza viruses cause appreciable respiratory morbidity each year among infants and young children. They are the major cause of croup but also produce a spectrum of diseases ranging from mild upper respiratory tract infection to bronchiolitis and pneumonia. Most studies have focused on the morbidity of parainfluenza viruses in infants and young children who are hospitalized. Less appreciated is the impact of parainfluenza viral infections in outpatients and in older children. The parainfluenza viruses have a striking epidemiologic pattern which has evolved over the past 30 years. In the early 1960s parainfluenza types 1, 2 and 3 were all reported to be endemic.(ABSTRACT TRUNCATED AT 250 WORDS)

Biology of parainfluenza viruses.

Parainfluenza virus types 1 to 4 (PIV1 to PIV4) are important human pathogens that cause upper and lower respiratory tract infections, especially in infants and children. PIV1, PIV2, and PIV3 are second only to respiratory syncytial virus as a cause of croup in young children. Although some clinical symptoms are typical of PIVs, etiologic diagnosis always requires detection of infectious virus, viral components, or an antibody response. PIVs are typical paramyxoviruses, causing a syncytial cytopathic effect in cell cultures; virus growth can be confirmed either by hemadsorption or by using immunological reagents. Currently, PIV is most often diagnosed by demonstrating viral antigens in clinical specimens by rapid and highly sensitive immunoassays. More recently, PCR has been used for the detection of PIVs. Serological diagnosis is made by detecting a rising titer of immunoglobulin G or by demonstrating immunoglobulin M antibodies. PIVs infect species other than humans, and animal models are used to study the pathogenesis of PIV infections and to test candidate vaccines. Accumulating knowledge on the molecular structure and mechanisms of replication of PIVs has accelerated research on prevention and treatment. Several strategies for vaccine development, such as the use of live attenuated, inactivated, recombinant, and subunit vaccines, have been investigated, and it may become possible to prevent PIV infections in the near future.

Human parainfluenza virus type 1 evolution combines cocirculation of strains and development of geographically restricted lineages.

The hemagglutinin neuraminidase (HN) glycoprotein of human parainfluenza virus type 1 (HPIV-1) mediates attachment to the host cell and is the target of protective antibody. Since the efficacy of a potential vaccine depends on antigenic constancy, the antigenic and genetic stability of the HPIV-1 HN glycoprotein was examined for 13 isolates obtained between 1981 and 1989. Antigenic analysis with a panel of 11 monoclonal antibodies demonstrated a single change among 3 isolates from 1989 that distinguished them from all other isolates. The HN genes from all 13 isolates and 13 previously published HN gene sequences shared > 95% homology. Evolutionary analysis demonstrated cocirculation of strains, without a dominant lineage. The 1989 isolates and the previously proposed subtype A isolates occupied distinct evolutionary branches, indicating geographically limited evolution. The slow rate of evolution and HN homogeneity may allow development of a single vaccine formulation for the prevention of disease.