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CORD-19:f1fd5f33dcbe0aae1ce2efb7b7d22eafb4247f02 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T1 0-53 Sentence denotes State of the Art Bugs and Asthma A Different Disease?
T2 55-63 Sentence denotes Abstract
T3 64-134 Sentence denotes The prevalence of asthma has dramatically increased in recent decades.
T4 135-276 Sentence denotes Exacerbations of asthma are a large contributor to asthma-related costs, and are primarily caused by viral and atypical bacterial infections.
T5 277-362 Sentence denotes Rhinoviruses (RVs) are the most common viruses detected after an asthma exacerbation.
T6 363-551 Sentence denotes RVs, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV) viral infections early in life can induce wheezing and are associated with the development of asthma later in life.
T7 552-709 Sentence denotes Atypical bacterial infections from Mycoplasma pneumoniae and Chlamydia pneumoniae have also been linked to chronic asthma and potential asthma exacerbations.
T8 710-999 Sentence denotes In this article, we will discuss recent developments in viral infections, specifically RV, RSV, and hMPV, and atypical bacterial infections as causes of asthma exacerbations, including new data focusing on the host immune response in airway epithelial cells and animal models of infection.
T9 1001-1269 Sentence denotes Asthma is a complex disease consisting of both genetic and environmental factors that is characterized by dyspnea, coughing, wheezing, reversible episodes of bronchoconstriction, airway hyperreactivity, chronic eosinophilic inflammation, and mucus hypersecretion (1) .
T10 1270-1421 Sentence denotes Each year 11 million asthma exacerbations occur in the United States, with viral infections causing the majority of these exacerbations (Table 1) (2) .
T11 1422-1605 Sentence denotes Atypical bacterial infections, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, have also been associated with asthma exacerbations as well as chronic asthma (Table 1) (3, 4) .
T12 1606-1919 Sentence denotes In this review article we will focus on the role of viral infections; specifically rhinoviruses (RVs), respiratory syncytial virus (RSV), and human metapneumovirus (hMPV), as causes of asthma exacerbations and also how these viral infections early in life lead to wheezing and the potential development of asthma.
T13 1920-2047 Sentence denotes In addition, we will review recent data suggesting that atypical bacterial infections have a pathogenic role in chronic asthma.
T14 2048-2288 Sentence denotes For many years viral infections were associated with asthma exacerbations (5) , but determining the specific virus present during the exacerbation was difficult, as serology and tissue culture infectivity techniques were not very sensitive.
T15 2289-2519 Sentence denotes However, the development and use of reverse transcriptase-polymerase chain reaction (PCR) has greatly facilitated an accurate, reliable, and specific way to distinguish between respiratory viruses and also to determine virus type.
T16 2520-2704 Sentence denotes Using PCR, it has been suggested that respiratory viral infections are responsible for approximately 80% of asthma exacerbations in children and 75% of exacerbations in adults (6, 7) .
T17 2705-2890 Sentence denotes Many types of viruses, such as RVs, RSV, hMPV, influenza, parainfluenza, and coronavirus, have been detected in the respiratory tract secretions from patients with asthma exacerbations.
T18 2891-3057 Sentence denotes While RV infections do not present with dramatic clinical outcomes in a normal individual, it is the most common virus detected in patients with asthma exacerbations.
T19 3058-3149 Sentence denotes In fact, approximately 60% of patients with asthma exacerbations have an RV infection (6) .
T20 3150-3310 Sentence denotes Further, wheezing induced by RV, RSV, and hMPV infections early in childhood is associated with the development of asthma later in childhood (8) (9) (10) (11) .
T21 3311-3439 Sentence denotes RVs are positive-sense, icosahedral-shaped, nonenveloped, single-stranded RNA viruses from the Picornaviridae family of viruses.
T22 3440-3564 Sentence denotes RV serotypes are categorized by many different parameters, such as receptor specificity and homology in nucleotide sequence.
T23 3565-3670 Sentence denotes Discrimination based on receptor specificity results in two groups of RVs, the major and the minor group.
T24 3671-3834 Sentence denotes The major group of RVs (e.g., RV14, 16, 39) comprises 90% of the serotypes and uses the intercellular adhesion molecule (ICAM)-1 as a means of entry into the cell.
T25 3835-3947 Sentence denotes The minor group of RVs (e.g., RV1B, 2) uses the low-density lipoprotein family of receptors as a means of entry.
T26 3948-4051 Sentence denotes Using nucleotide sequence homology and phylogenetic analysis, three species of RVs have been described.
T27 4052-4166 Sentence denotes RV serotypes were traditionally classified into two groups, RV-A and RV-B, based on the VP1 and VP4/VP2 sequences.
T28 4167-4257 Sentence denotes RV-A is composed of 74 different serotypes and RV-B is composed of 25 different serotypes.
T29 4258-4447 Sentence denotes Recently, however, using more sophisticated PCR techniques, a third species of RVs has been described that is a distinct RV-C species which contains at least nine serotypes (12) (13) (14) .
T30 4448-4566 Sentence denotes Numerous studies suggest that RV potentiates preexisting allergic inflammation, resulting in asthma exacerbations (4).
T31 4567-4846 Sentence denotes Grunberg and colleagues showed that experimental intranasal RV16 infection in adults with mild atopic asthma caused a decrease in FEV 1 that was maximal 2 days after infection and was significantly greater compared with placebo-infected individuals with mild atopic asthma (15) .
T32 4847-5143 Sentence denotes Further studies with experimental RV16 infection have shown that patients with asthma have increased levels of interleukin (IL)-8 in their nasal lavage fluid that correlates with the level of airway responsiveness (16) , in contrast to unaffected individuals in whom IL-8 does not increase (17) .
T33 5144-5411 Sentence denotes Message and colleagues showed that patients with atopic asthma experimentally infected with RV16 had increased eosinophils and increased bronchial hypersensitivity as measured by the provocative concentration of histamine required to reduce FEV 1 by 10% or 20% (18) .
T34 5412-5639 Sentence denotes While the exact mechanism remains unknown, in this study patients with asthma with the highest viral load had decreased levels of IFN-g and IL-10 and increased levels of IL-4, IL-5, and IL-13 in CD41 cells from BAL fluid (18) .
T35 5640-5845 Sentence denotes These data suggest that individuals with asthma, with increased levels of Th2 cytokines, may have increased viral replication and a subsequent increase in airway inflammation and decrease in lung function.
T36 5846-5997 Sentence denotes RV infections during early childhood are also associated with lower respiratory tract infections, wheezing, and the development of asthma (9, 10, 19) .
T37 5998-6119 Sentence denotes RV was detected in 30% of the patients with lower respiratory tract infections, and was associated with wheezing (9, 10).
T38 6120-6494 Sentence denotes Further, Miller and colleagues found that children under the age of 5 admitted to the hospital for respiratory symptoms or fever had RV-C infections in over 46% of the RV positive samples, and that patients with RV-C infections were more likely to have a diagnosis of asthma at hospital discharge compared with patients with RV-A infections (55% to 36%, respectively) (20) .
T39 6495-6755 Sentence denotes However, while RV infections during the first year of life were associated with wheezing at age 3 and asthma at age 6 (10, 19), more RSV infections induced wheezing in the first year of life compared with rhinovirus infections (50% and 25%, respectively) (10).
T40 6756-6879 Sentence denotes This may provide an explanation for why RVs were not previously determined to induce wheeze from infections during infancy.
T41 6880-6950 Sentence denotes RV infections are strongly associated with hospitalization for asthma.
T42 6951-7218 Sentence denotes In one study, adults who had been hospitalized for asthma had respiratory tract secretions examined at the time of admission and also at a 3-month follow-up; RVs were significantly associated with hospitalization for asthma, with an adjusted odds ratio of 15.1 (21) .
T43 7219-7455 Sentence denotes In this population, after adjustment for severity of asthma, subjects with RV infections were more likely to be smokers not using inhaled corticosteroids (adjusted odds ratio, 11.18; P 5 0.002) than subjects without RV infections (21) .
T44 7456-7608 Sentence denotes Green and colleagues also revealed that individuals with allergic asthma infected with RV had an increase in admission to the hospital for asthma (22) .
T45 7609-7761 Sentence denotes Further, in these patients, dust mite allergen was the primary allergen detected when these subjects were skin tested to a panel of aeroallergens (22) .
T46 7762-8057 Sentence denotes Therefore, to determine if RV infection during ongoing low dose of dust mite exposure resulted in an increase in asthma symptoms, de Kluijver and colleagues conducted a three-armed double-blind study with low-dose dust mite exposure and RV16 infections in patients with and without asthma (23) .
T47 8058-8155 Sentence denotes Dust mite exposure alone resulted in decreased FEV 1 and an increase in eosinophils in BAL fluid.
T48 8156-8244 Sentence denotes RV infection alone had decreased FEV 1 and increased production of IL-8 and neutrophils.
T49 8245-8490 Sentence denotes However, the study did not show a synergistic decrease in FEV 1 or a synergistic increase in sputum neutrophils, IL-8, or neutrophil elastase with low-dose allergen exposure and RV infection in the populations with mild to moderate asthma (23) .
T50 8491-8779 Sentence denotes While this study did not successfully develop an experimental model including both allergen exposure and RV infection, epidemiologic data and clinical data from patients with atopic asthma experimentally infected with RV show an association between RV infections and asthma exacerbations.
T51 8780-8892 Sentence denotes RSV is a single-stranded, enveloped, negative-sense RNA virus with a peak of infection during the winter months.
T52 8893-9064 Sentence denotes RSV usually results in an upper respiratory infection, but in 30 to 70% of infants, RSV infections cause lower respiratory infection leading to pneumonia or bronchiolitis.
T53 9065-9300 Sentence denotes RSV-induced bronchiolitis is the leading cause of wheeze in infants and young children, and children infected with RSV resulting in bronchiolitis are up to four times more likely to develop wheezing and asthma later in childhood (11) .
T54 9301-9465 Sentence denotes It is unknown whether RSV increases the chances of developing asthma or if people predisposed to having asthma are more likely to develop RSV-induced bronchiolitis.
T55 9466-9571 Sentence denotes Nonetheless, studies have shown a correlation between severe RSV bronchiolitis and development of asthma.
T56 9572-10211 Sentence denotes Sigurs and colleagues reported that 43% of infants with RSV bronchiolitis resulting in hospitalization had asthma or recurrent wheeze, with recurrent wheeze defined as three or more episodes of wheezing not verified by a physician in the prior year, at the age of 13, compared with 8% of control subjects (24) . hMPV hMPV, a recently isolated virus, is a paramyxovirus that is closely related to RSV by phylogenetic analysis and causes respiratory tract infections in both children and adults (25) . hMPV was isolated from children in 2001, and hMPV is associated with asthma exacerbations in both children and adults (25) (26) (27) (28) .
T57 10212-10619 Sentence denotes Studies examining respiratory viruses in nasalwash specimens from children with respiratory tract infections showed that hMPV was detected in approximately 5 to 12% of children tested (25) (26) (27) . hMPV infection was not associated with asthma exacerbations in children greater than 5 years of age (25) , but was found to be associated with wheezing in children younger than 5 years of age (26, 27, 29) .
T58 10620-10768 Sentence denotes Further, patients with a co-infection of RSV/hMPV had increased use of supplemental oxygen (26) and were associated with severe bronchiolitis (30) .
T59 10769-10916 Sentence denotes In adults, Williams and colleagues detected hMPV in the nasal washings in 6.9% of patients admitted to the hospital for asthma exacerbations (27) .
T60 10917-11086 Sentence denotes These studies show an association between hMPV and wheezing in children less than 5 years of age and also an association between hMPV and asthma exacerbations in adults.
T61 11087-11282 Sentence denotes However, children greater than 5 years of age show no significant association between hMPV infection and asthma exacerbations (25) , and the reasons for these observed differences remain unclear.
T62 11283-11439 Sentence denotes Airway epithelial cells are polarized cells with an apical and basolateral surface that provide the first line of defense for pathogens entering the airway.
T63 11440-11747 Sentence denotes RV and RSV primarily infect airway epithelial cells, activating inflammatory pathways and increasing proinflammatory cytokine and chemokine production, such as tumor necrosis factor (TNF), IL-6, CXCL8 (IL-8), CCL5 (RANTES), granulocyte macrophage colony-stimulating factor (GM-CSF), and CCL3 (MIP-1a) (31) .
T64 11748-11926 Sentence denotes This increase in cytokine and chemokine production is due to specific activation of the nuclear factor (NF)-kB and the mitogen-activated protein kinase (MAPK) pathways (32, 33) .
T65 11927-12091 Sentence denotes Increases in cytokine and chemokine production result in inflammation from the influx of leukocytes and provide a possible mechanism for the exacerbation of asthma.
T66 12092-12485 Sentence denotes Cultured 16HBE14o-airway epithelial cells and mucociliarydifferentiated primary human bronchial epithelial cells, simultaneously exposed to the proinflammatory cytokine TNF and infected with RV39, had a synergistic increase in IL-8 production and an additive increase in the transactivation of transcription factors required for maximal CXCL-8 production, NF-kB, and activator protein-1 (34) .
T67 12486-12669 Sentence denotes These data correlate with increased bronchoalveolar TNF levels and a cooperative increase with experimental RV16 infection in segmental allergen challenges of allergic patients (35) .
T68 12670-12992 Sentence denotes Together, these findings suggest that airway epithelial cells may be responsible for initiating a robust or possible synergistic immune response to an RV or RSV infection in the presence of pre-existing allergic inflammation through the activation of the NF-kB and MAPK pathways and production of cytokines and chemokines.
T69 12993-13066 Sentence denotes Until very recently a nonprimate model of RV infection was not available.
T70 13067-13209 Sentence denotes The main problem in developing a mouse model of RV infection was ICAM-1, the receptor for the major group of RVs, would not bind mouse ICAM-1.
T71 13210-13306 Sentence denotes However, in 2008 mouse models were developed for both major and minor serotypes of RV (36, 37) .
T72 13307-13430 Sentence denotes Transgenic BALB/c mice with a mouse/human ICAM-1 chimera were successfully infected with the major group virus, RV16 (36) .
T73 13431-13590 Sentence denotes Further, the minor group virus, RV1B, was capable of binding the mouse low-density lipoprotein receptor and generated a successful infection in vivo (36, 37) .
T74 13591-13891 Sentence denotes Infection with RV1B in wild-type mice or RV16 in the ICAM-1 chimera transgenic mice caused an increase in type I IFN production, augmented production of the chemokines CXCL2 and CCL5, an influx of inflammatory cells, and an increase in MUC5B expression in lung homogenates and/or BAL fluid (36, 37) .
T75 13892-14019 Sentence denotes BALB/c mice were sensitized and challenged intranasally with the allergen ovalbumin (OVA) and infected with RV1B (RV-OVA mice).
T76 14020-14261 Sentence denotes These RV-OVA mice had an increase in BAL fluid neutrophils at 1 day after infection and in lymphocytes 3 to 14 days after infection, compared with RV-infected mice or OVA-sensitized and -challenged mice receiving ultraviolet-irradiated RV1B.
T77 14262-14357 Sentence denotes Airway hyperresponsiveness was also increased in RV-OVA mice 1 day after infection in response.
T78 14358-14469 Sentence denotes Further, MUCAC and MUC5B were both increased in mice with RV1B infection during OVA-induced inflammation (36) .
T79 14470-14586 Sentence denotes Mouse models of RSV have elucidated some of the mechanisms by which virus causes inflammation and airway reactivity.
T80 14587-14731 Sentence denotes These studies reveal that RSV strain differences are an important contributor to airway inflammation and physiologic parameters after infection.
T81 14732-14935 Sentence denotes RSV strain A2 is the strain most commonly used in the laboratory, and in the absence of pre-existing allergic inflammation RSV A2 produced no lung IL-13, mucus, or airway reactivity with infection (38) .
T82 14936-15134 Sentence denotes However, infection with another RSV strain, line 19, resulted in abundant production of IL-13 in the lung, airway mucus, and an increase in airway reactivity when challenged with methacholine (38) .
T83 15135-15321 Sentence denotes Other models in which RSV infection occurs in the setting of ongoing allergic inflammation have also been useful in understanding how this virus may cause asthma exacerbations in humans.
T84 15322-15513 Sentence denotes For instance, RSV infection increased airway reactivity in response to methacholine challenge in the presence of ongoing allergic inflammation induced with OVA or cockroach antigen (39, 40) .
T85 15514-15750 Sentence denotes Mice lacking CCR1, one of the chemokine receptors for CCL3 and CCL5, had a decrease in airway resistance and CD41 or CD81 T cell infiltration into the lung with RSV infection during cockroach antigen-induced allergic inflammation (41) .
T86 15751-15866 Sentence denotes Mucus production was also increased in RSV A2 infection during ongoing allergic airway inflammation in BALB/c mice.
T87 15867-16127 Sentence denotes Unexpectedly, there was a decrease in lung IL-13, while IL-17A, a cytokine produced from Th17 cells that is also involved with mucus production, was synergistically increased in the lungs of mice infected with RSV A2 during ongoing allergic inflammation (42) .
T88 16128-16295 Sentence denotes Collectively, these data suggest that both the strain of RSV and the host immune response may be responsible for increases in mucus production and airway inflammation.
T89 16296-16428 Sentence denotes hMPV is able to infect BALB/c mice and has been shown to cause weight loss and ruffling of fur in infected mice similar to RSV (43).
T90 16429-16606 Sentence denotes However, hMPV does not replicate well in mice, a tenfold lower viral replication compared with mice infected with RSV, and does not produce a robust inflammatory response (43) .
T91 16607-16691 Sentence denotes Therefore, comparison studies between RSV and hMPV have been difficult to interpret.
T92 16692-16864 Sentence denotes Viruses have developed mechanisms to evade the immune system to establish a successful infection by down-regulating cellular transcription and the production of type I IFN.
T93 16865-17353 Sentence denotes The nonstructural (NS) proteins of RSV, NS1, and NS2 have been shown to inhibit IFN-a and IFN-b production by decreasing proinflammatory transcription factors interferon regulatory factor (IRF)-3, NF-kB, and signal transducers and activators of transcription protein (STAT)-2 (4, 44, 45) . hMPV does not contain NS proteins and has detectable levels of IFN-a in BAL fluid from 6 hours to 5 days after infection, whereas RSV does not have detectable levels at 3 days after infection (46) .
T94 17354-17535 Sentence denotes This prolonged IFN-a response provides a potential explanation for the small amount of viral replication and the low number of inflammatory cells in BAL fluid of hMPV-infected mice.
T95 17536-17755 Sentence denotes Recently, it was shown that cultured airway epithelial cells from patients with asthma had decreased IFN-b in response to RV16 infection compared with cultured airway epithelial cells from normal control subjects (47) .
T96 17756-17879 Sentence denotes This decreased type I IFN response led to an increase in viral titer and diminished airway epithelial cell apoptosis (47) .
T97 17880-17990 Sentence denotes Further, similar findings were seen in the mRNA levels of the type III interferons, IFN-l1 and IFN-l2/3 (48) .
T98 17991-18236 Sentence denotes Therefore, these data combined suggest that preexisting allergic inflammation or the host immune response in patients with asthma may lead to a decreased interferon response, resulting in a more successful infection and perhaps greater symptoms.
T99 18237-18352 Sentence denotes M. pneumoniae and C. pneumoniae are atypical bacteria that attach to airway epithelial cells and cause cell damage.
T100 18353-18494 Sentence denotes Similar to respiratory viruses, M. pneumoniae and C. pneumoniae were very difficult to detect with varying results from serology and culture.
T101 18495-18656 Sentence denotes Using PCR has made detection more sensitive, although invasive procedures, such as an endobronchial biopsy, are still normally required for definitive diagnosis.
T102 18657-18801 Sentence denotes While known to cause respiratory tract infections, the role of M. pneumoniae and C. pneumoniae in exacerbations of asthma remains controversial.
T103 18802-19091 Sentence denotes Lieberman and colleagues found that 18% of adult patients with acute asthma exacerbations had atypical bacteria infections of M. pneumoniae compared with 3% of control patients without asthma, as detected by paired sera testing using immunofluorescence or enzyme immunoassay methods (49) .
T104 19092-19181 Sentence denotes In this study there was no association with C. pneumoniae and asthma exacerbations (49) .
T105 19182-19284 Sentence denotes However, other studies revealed that C. pneumoniae infection was correlated with asthma exacerbations.
T106 19285-19427 Sentence denotes In 2001, Martin and colleagues examined C. pneumoniae or M. pneumoniae infection in the upper or lower airway of patients with chronic asthma.
T107 19428-19605 Sentence denotes Using PCR, 31 of the 55 patients with asthma (56.4%) were positive for C. pneumoniae, M. pneumoniae, or both, compared with 1 of the 11 control patients without asthma (9%) (3).
T108 19606-19795 Sentence denotes M. pneumoniae was found in 25 of the patients with asthma and in only 1 control patient by PCR, while 6 patients with asthma and no control patients were PCR-positive for C. pneumoniae (3).
T109 19796-19975 Sentence denotes Therefore, while C. pneumoniae is increased in patients with asthma compared with control patients; these data suggest that it may not be as prevalent as M. pneumoniae infections.
T110 19976-20105 Sentence denotes More clinical studies are still needed to fully determine the link between atypical bacteria infections and asthma exacerbations.
T111 20106-20374 Sentence denotes However, an animal model of OVA-induced allergic inflammation before infection with M. pneumoniae had increased collagen deposition 42 days after infection that was not seen in M. pneumoniae infection in the absence of pre-existing allergic-induced inflammation (50) .
T112 20375-20491 Sentence denotes The mechanisms describing why asthmatic airways are more susceptible to M. pneumoniae still remains largely unknown.
T113 20492-20683 Sentence denotes Wu and colleagues found that Toll-like receptor (TLR)-2 expression and IL-6 production were down-regulated with M. pneumoniae infection during ongoing OVA-induced allergic inflammation (51) .
T114 20684-20795 Sentence denotes Further, blocking IL-4 or IL-13 with neutralizing antibodies restored TLR2 expression and IL-6 production (51).
T115 20796-21021 Sentence denotes Together, these data suggest that preexisting allergic inflammation impairs the ability to up-regulate TLR-2 and IL-6 in the lungs, leading to decreased clearance of M. pneumoniae and an increase in airway inflammation (51) .
T116 21022-21208 Sentence denotes In addition, airway epithelial cells from subjects with asthma infected with mycoplasma had increased MUC5AC expression compared with epithelial cells from subjects without asthma (52) .
T117 21209-21431 Sentence denotes While there is a positive association between atypical bacteria infections and asthma exacerbations, antibiotics are generally not given in response to chronic asthma and are not recommended for asthma exacerbations (53) .
T118 21432-21674 Sentence denotes Further, macrolides and ketolides that are prescribed for M. pneumoniae and C. pneumoniae infections have antiinflammatory properties, making it difficult to determine if atypical bacteria are playing a role in asthma exacerbations (54, 55) .
T119 21675-21870 Sentence denotes However, Kraft and colleagues have shown that patients positive for M. pneumoniae and C. pneumoniae with chronic asthma had an increase in FEV 1 when treated with clarithromycin for 6 weeks (56).
T120 21871-22214 Sentence denotes The TELICAST study by Johnston and colleagues showed that patients with asthma exacerbations that were given telithromycin, a ketolide, had an increase in symptom-free days and lung function tests conducted in the clinic compared with control subjects given placebo, but did not have an increase in lung function tests conducted at home (57) .
T121 22215-22530 Sentence denotes Therefore, despite the correlation between mycoplasma infections and asthma exacerbations or chronic asthma, more research needs to be conducted to determine if atypical bacteria infections are causing the exacerbations or just another factor that persists simultaneously with, yet independent of, the exacerbation.
T122 22531-22747 Sentence denotes Although viral infections and atypical bacterial infections are associated with asthma exacerbations, not all individuals with asthma with a viral infection or atypical bacteria infection have an asthma exacerbation.
T123 22748-22876 Sentence denotes Therefore, the precise mechanisms leading to these conditions are not fully understood, and more research needs to be conducted.