Respiratory Infection and the Impact of Pulmonary
Immunity on Lung Health and Disease
Joseph P. Mizgerd1
1Departments of Medicine, Microbiology, and Biochemistry, Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts
Acute lower respiratory tract infection is responsible for an in-
ordinate disease burden. Pulmonary immunity determines the
outcomes of these infections. The innate and adaptive immune re-
sponses to microbes in the lung are critical to maintaining a healthy
respiratory system and preventing pulmonary disease. In addition
to balancing antimicrobial defense against the risk of lung injury
during the immediate infection, the shaping of pulmonary im-
munity by respiratory infection contributes to the pathophysio-
This Pulmonary Perspective aims to communicate two intercon-
nected points. First, tremendous morbidity and mortality result
from inadequate, misguided, or excessive pulmonary immunity.
stage of rapid developments and discoveries, but many questions
remain. Further advances in pulmonary immunity and elucidation
of the cellular and molecular responses to microbes in the lung
are needed to develop novel approaches to predicting, prevent-
ing, and curing respiratory disease.
Keywords: respiratory tract infections; pneumonia; acute lung injury;
innate immunity; adaptive immunity
Each day, a typical human adult inhales all the contaminants
of approximately 11,000 liters of air, the equivalent of two ele-
terials from the upper airways are frequently aspirated into the
lungs. Pulmonary immunity has evolved to respond to these
challenges, in most cases protecting the lung from infection and
maintaining respiratory function. However, when responses
designed to protect the lungs during infection go awry, pulmo-
nary disease develops.
ACUTE LUNG INFECTIONS
The World Health Organization uses the metric of disability-
adjusted life-years to assess burden of disease, quantifying life-
years lost to mortality or compromised by morbidity. Since first
analyzed for 1990 (1), the greatest disease burden worldwide
has consistently been reported as acute lower respiratory infection
(Figure 1A, from World Health Organization data ). Impres-
sive as they are, these figures underestimate the full impact of
such infections, because intersections with comorbidities (such as
HIV/AIDS, chronic obstructive pulmonary disease [COPD], or
asthma) tend to be attributed to the underlying disease rather
than lung infection.
The U.S. mortality rate due to pneumonia and influenza (3)
declined through the first half of the 20th century in conjunction
with sanitation, pollution, nutrition, hygiene, and education
improvements that anteceded medical strategies specific to lung
infection (Figure 1B, purple line). Healthier hosts better resist
and overcome infection, which may be the most significant rea-
son acute lower respiratory tract infections exert disproportionate
tolls in the poorest communities (4). The trend of improvement
was dramatically broken in 1918, when an influenza pandemic
suddenly quadrupled the death rate (Figure 1B, red line). The
general course of improvement was interrupted again in the
middle of the century, in this case beneficently (Figure 1B, green
line). During this time, basic research on antibiotics was effec-
tively translated into therapies that became widely applied, and
the mortality rate from pneumonia and influenza plummeted,
a stirring testament to the potential for biomedical discoveries
to transform the public’s health. In contrast to the rapid progress
in the middle of the last century, the latter half of the century
might by comparison be considered bleak. The remaining mortal-
ity rate is substantial, as detailed in the next paragraph, but there
has been little or no improvement for decades (Figure 1B, black
line). Some evidence suggested that pneumonia mortality was
recently decreasing (5), but this apparent trend was attributed
to artifactual changes in diagnostic coding rather than improve-
ments in pneumonia outcome (6).
Acute lung infections remain a substantial concern, even in
wealthycountries. Ofinfectious diseases,acute lower respiratory
infections cause the most deaths (Figure 1C) and are the largest
burden of disease (4, 7) in the United States. Among pulmonary
diseases, acute lung infection is the third greatest killer (Figure
1C). Subpopulations are especially prone to pneumonia, such as
the elderly and those with comorbidities (8). For those older
than 65 years, pneumonia hospitalizations are increasing, and
hospitalization for pneumonia carries a significantly increased
risk of mortality compared with other hospitalizations (8). At
the other end of the age spectrum, pneumonia is the most com-
mon reason that U.S. children become hospitalized ( and
Figure 1D). Acute bronchitis and influenza, also acute lung infec-
tions, are third and tenth, respectively (Figure 1D). These findings
are not particular to the United States, as pneumonia exerts a sim-
ilarly heavy burden in Europe (10). Thus, acute lung infections
are a terrible problem even in the wealthiest societies, and
improved abilities to prevent or treat respiratory infection would
have a profound impact. Unfortunately, in comparison with other
diseases, pneumonia is dramatically understudied and receives
disproportionately little attention from biomedical researchers
and funding bodies (4, 11). Increased attention will improve pneu-
monia outcomes, as has occurred with HIV/AIDS (12), myocardial
infarctions (13), and other diseases. The substantial public health
consequences combined with the failure to improve pneumonia
(Received in original form June 14, 2012; accepted in final form July 2, 2012)
Supported by National Institutes of Health grants R01-HL068153 and R01-
Correspondence and requests for reprints should be addressed to Joseph P. Mizgerd,
Sc.D., Boston University School of Medicine, The Pulmonary Center, 72 East
Concord Street, Boston, MA 02118. E-mail: firstname.lastname@example.org
Am J Respir Crit Care Med
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201206-1063PP on July 12, 2012
Internet address: www.atsjournals.org
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