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
Corresponding author
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
Phone: 615-322-3412
Fax: 615-936-1269
E-mail: tina.hartert@vanderbilt.edu
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.
REFERENCES
1. Hammad H, Lambrecht BN. Dendritic cells and epithelial cells: linking innate and
adaptive immunity in asthma. Nat Rev Immunol 2008;8:193-204.
2. Schleimer RP, Kato A, Kern R, Kuperman D, Avila PC. Epithelium: at the interface
of innate and adaptive immune responses. J Allergy Clin Immunol 2007;
120:1279-84.
3. Johnston SL. Innate immunity in the pathogenesis of virus-induced asthma exacerbations.
Proc Am Thorac Soc 2007;4:267-70.
4. Holt PG, Upham JW, Sly PD. Contemporaneous maturation of immunologic and
respiratory functions during early childhood: implications for development of
asthma prevention strategies. J Allergy Clin Immunol 2005;116:16-24.
5. Cardozo DM, Nascimento-Carvalho CM, Andrade AL, Silvany-Neto AM, Daltro
CH, Brandao MA, et al. Prevalence and risk factors for nasopharyngeal carriage
of Streptococcus pneumoniae among adolescents. J Med Microbiol 2008;57:185-9.
6. Bisgaard H, Hermansen MN, Buchvald F, Loland L, Halkjaer LB, Bonnelykke K,
et al. Childhood asthma after bacterial colonization of the airway in neonates. N
Engl J Med 2007;357:1487-95.
7. Almirall J, Bolibar I, Serra-Prat M, Roig J, Hospital I, Carandell E, et al. New evidence
of risk factors for community-acquired pneumonia: a population-based
study. Eur Respir J 2008;31:1274-84.
8. Miller EK, Lu X, Erdman DD, Poehling KA, Zhu Y, Griffin MR, Hartert TV, Anderson LJ, Weinberg GA,
Hall CB, Iwane MK, Edwards KM, New Vaccine Surveillance Network. Rhinovirus-associated
hospitalizations in young children. J Infect Dis 2007;6(195):773-81.
9. Hartert TV, Neuzil KM, Shintani AK, Mitchel EF Jr, Snowden MS, Wood LB, Dittus RS, Griffin MR.
Maternal morbidity and perinatal outcomes among pregnant women with respiratory hospitalizations
during influenza season. Am J Obstet Gynecol 2003;6(189):1705-12.
10. Talbot TR, Hartert TV, Mitchel E, Halasa NB, Arbogast PG, Poehling KA, et al.
Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med 2005;
352:2082-90.
11. Juhn YJ, Kita H, Yawn BP, Boyce TG, Yoo KH, McGree ME, et al. Increased risk
of serious pneumococcal disease in patients with asthma. J Allergy Clin Immunol
2008;122:719-23.
12. Xatzipsalti M, Kyrana S, Tsolia M, Psarras S, Bossios A, Laza-Stanca V, et al. Rhinovirus
viremia in children with respiratory infections. Am J Respir Crit Care Med
2005;172:1037-40.
13. Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices.
Updated recommendations for prevention of invasive pneumococcal disease among adults using the 23valent pneumococcal polysaccharide vaccine (PPSV23). MMWR Morb Mortal Wkly Rep
2010;34(59):1102-6.
14. Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, Iskander JK, Wortley PM, Shay DK,
Bresee JS, Cox NJ; Centers for Disease Control and Prevention (CDC). Prevention and control of
influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP),
2010. MMWR Recomm Rep. 2010 Aug 6;59(RR-8):1-62. Erratum in: MMWR Recomm Rep. 2010 Sep
10;59(35):1147. MMWR Recomm Rep. 2010 Aug 13;59(31):993.