|Increased Risk of Infections among Persons with Asthma
Tina V Hartert, MD, MPH1
1 Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107 MCE, Nashville, TN 37232-8300
Tina V. Hartert, M.D., M.P.H.
Division of Allergy, Pulmonary and Critical Care Medicine
Center for Asthma & Environmental Sciences Research, 6107 MCE
Vanderbilt University School of Medicine
Nashville, TN 37232-8300
Keywords: asthma, infection, pneumococcal disease
Are persons with asthma at an increased risk for infections? One of the problems in answering this question is that historically studies of infections and asthma have centered on the impact of respiratory infections on asthma exacerbations, a respiratory disease, rather than focusing on infection susceptibility or infections outside of the respiratory tract. Recent investigations provide biologically plausible explanations for an increased susceptibility to certain viral and bacterial infections among persons with asthma, however, the exact mechanisms for this increased risk are not known. While we know that persons with asthma have a disrupted airway epithelial physical barrier, increased and aberrant mucous production, and other alterations in innate and adaptive immunity, whether these are the mechanisms through which asthmatics have an increased risk or more severe infections is not known. In addition, the medications used to treat asthma may also be immunosuppressive, or could possibly even enhance immune responses specifically among persons with asthma who are prescribed and compliant with their medications. Thus what we do not know, is whether the increased association of infections and infection severity in asthma is an epiphenomenon due to enhanced airway inflammation and/or allergic inflammation resulting in more severe respiratory infections in individuals with a chronic respiratory disease, or whether these differences among persons with asthma truly alter host defense rendering asthmatics more susceptible to bacterial and viral pathogens. What follows is a summary of our current understanding of the data supporting the association of asthma and serious infections, potential mechanisms of host susceptibility to infections, and preventive implications.
The data that support biologic plausibility for persons with asthma being at increased risk for particular infections come from several lines of evidence. The first is that asthmatic inflammation may inhibit or alter host defense rendering asthmatics more susceptible to infections. A second is that innate immunity may be altered in asthma and this alteration may inhibit antimicrobial host defense and/or response to injury and in this way render asthmatics more susceptible to and less able to resist infections. Lastly, in support of link between response to infections and the underlying chronic disease asthma, are the many known genetic factors that impact patterns of immune response to infectious agents, that are also strongly linked with asthma.1-4
The body of literature that actually supports an increased risk of infection among persons with asthma is relatively small, and can be conceptually grouped into evidence for increased infection-related morbidity, increased infection latency (propensity to persist and cause chronic infection), and increased invasiveness of infections among asthmatics. Importantly, as asthma is a respiratory disease, we need to understand whether infections outside of the respiratory tract are more common or severe among persons with asthma; unfortunately, in this regard there is little data to my knowledge. Persons with asthma have been shown to have increased rates of pneumococcal nasal colonization, as well as hypopharyngeal colonization as neonates before the development of asthma, which provides strong support for a pre-existing defective immune response among persons destined to develop asthma.5,6 Data also supports latency of infection among persons with asthma for a number of pathogens, including respiratory syncytial virus, adenovirus, Human rhinovirus, Mycoplasma pneumoniae and Chlamydia pneumoniae. Respiratory-related infection morbidity has also been shown to be higher among persons with asthma. Almirall and colleagues have shown that both asthma and inhaled corticosteroids are risk factors for community-acquired pneumonia in a European population based case-control study among persons age >14 years. Asthma has also been shown to be an independent risk factor for influenza-attributable morbidity among children and pregnant women.7-9 Previously, our group reported that persons with asthma had a greater than 2-fold increased risk of invasive pneumococcal disease, using the Active Bacterial Surveillance Core data from the US Centers for Disease Control and Surveillance, which identified Streptococcus pneumoniae from sterile sites, (blood cultures, cerebrospinal and joint fluid) among both children and adults.10 A follow-up study by Juhn et al also showed an increased risk of serious pneumococcal disease among persons with asthma.11 The available evidence from these studies, as is true with nearly all of the investigations looking at the relationship between infections and asthma is that they are based on observational data. While an association between asthma and a subsequent infectious event can reflect causal mechanisms, alternatively, such associations can be the result of other unmeasured factors or characteristics that are closely related to asthma (confounders). However, in both of these investigations of the association of asthma with invasive or serious pneumococcal disease, ‘‘asthma’’ identified those at high-risk, and in both of these studies, the results are strikingly consistent. The consistency of these data suggest that the increased association of clinically significant pneumococcal infection in asthma is not just an epiphenomenon caused by enhanced airway inflammation rendering persons with asthma more clinically symptomatic from pneumococcal respiratory disease, but that allergic inflammation and asthma are associated with or alter host defenses and in this way render persons with asthma more susceptible to pneumococcal disease. The strongest evidence for this true increased susceptibility to pneumococcal disease among persons with asthma lies in the data supporting an increase in invasive infections.10 This has also been recognized with rhinovirus infections, where persons with asthma are more likely to experience rhinovirus viremia, and this increased susceptibility has been shown to likely relate to defective innate immune responses.11 The association with increased risk of invasive pneumococcal disease is additionally important, as pneumococcal vaccine is most efficacious for invasive pneumococcal disease. It is important to realize that although these studies have limitations, these observational investigations are likely to be the extent of the available human evidence to support the association between asthma and an increased risk of serious infectious diseases, as randomized trials of most infections are unethical to conduct for obvious reasons. For these reasons, these data were used by the Advisory Committee on Immunization Practices (ACIP) to make new recommendations for pneumococcal vaccination for persons with asthma.13 What we still lack is information on the asthmatic response to pneumococcal vaccination, and to determine if the protection that it confers, is as robust as that in non-asthmatic hosts.
Although it is imperative for us to understand the mechanisms underlying why persons with asthma are at increased risk for vaccine preventable diseases in order to identify novel targets for treatment, to further understand the disease, and to advance preventive efforts, we do not need these answers now to put these findings into clinical context. Whether the disease, and/or the medications used to treat the disease put individuals at risk, asthmatics have an increased risk of serious pneumococcal disease, and increased morbidity from a variety of respiratory viral and atypical pathogens. The risk of invasive pneumococcal disease among asthmatics is similar to persons with chronic obstructive pulmonary disease (COPD) in whom pneumococcal vaccination has been recommended; the risk for significantly increased morbidity related to influenza, particularly among pregnant women, and especially those with asthma is well recognized, and both of these findings have led to new vaccine recommendations.13,14
In sum, the available evidence suggests that asthmatics are at increased risk of enhanced morbidity, latency, and susceptibility to a variety of bacterial and viral pathogens. This recognition has established asthma as a disease in which possibly the aberrant immune response to pathogens leads to suboptimal viral/bacterial clearance and/or host response to infection. These findings have led to vaccine policy changes for selected infections, but a deeper comprehension of why asthmatics are at increased risk for these infections should lead us to a better understanding of asthma, and means to prevent the significant increased morbidity associated with selected viral and bacterial infections among persons with asthma.
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