The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
Editorials
B ACTERIA AND E XACERBATIONS
OF C HRONIC O BSTRUCTIVE
P ULMONARY D ISEASE
P ATIENTS with chronic obstructive pulmonary
disease have exacerbations characterized by in-
creased dyspnea, accompanied by increases in cough-
ing, sputum production and purulence, and wheezing.
Although most of these episodes are self-limited, they
are associated with substantial decrements in the qual-
ity of life1 and account for a large fraction of expend-
itures for the treatment of chronic obstructive pulmo-
nary disease, since exacerbations are the most common
cause of hospitalization among patients with this dis-
ease. The precise nature of these episodes is not well
understood; their characteristics suggest that they are
acute infections of the intrapulmonary airways, but
this is extremely difficult to demonstrate because pa-
tients with chronic obstructive pulmonary disease of-
ten have pathogens in their airways in the absence of
exacerbations. Moreover, changes in airway flora have
not been closely correlated with symptoms.
The report by Sethi et al.2 in this issue of the Journal
materially advances our understanding of these events.
On the basis of careful serial studies of sputum spec-
imens from patients with chronic obstructive pulmo-
nary disease, obtained during both stable periods and
exacerbations, the authors found that the appearance
of Streptococcus pneumoniae or Moraxella catarrhalis
in sputum cultures was significantly associated with
symptoms of exacerbation. Furthermore, they subject-
ed the sputum isolates to molecular typing in order
to identify different bacterial strains. Exacerbations
were more strongly associated with changes in the bac-
terial strain than with the simple presence or absence
of a pathogen in cultured sputum. Most striking was
the case of Haemophilus influenzae; the presence or ab-
sence of this pathogen in sputum was not related to
the risk of an exacerbation, but the presence of a new
strain of the organism was.
These results are unique, and there is no reason to
believe that they cannot be generalized. The patients
were well described and had moderate or severe airway
obstruction, with an average of two exacerbations per
year characteristics that are similar to those of pa-
tients in other prospective studies of exacerbations.3,4
The organisms associated with exacerbations were the
usual suspects, previously identified by many investi-
gators. Sethi et al.2 interpret their findings as sugges-
tive of a bacterial origin of some exacerbations. They
hypothesize that new pathogens, including new strains
of the same organism, are capable of evading host
526 N Engl J Med, Vol. 347, No. 7 August 15, 2002 www.nejm.org
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defenses, infecting the airways, and causing inflam-
mation.
Although this interpretation is plausible, the find-
ings reported by Sethi et al. do not constitute defin-
itive evidence, as they acknowledge. Applying Kochs
postulates to exacerbations of chronic obstructive pul-
monary disease is a nearly impossible task. However,
trials of antibiotic therapy provide empirical evidence
that bacterial infection plays a part in exacerbations of
chronic obstructive pulmonary disease. Patients with
exacerbations recover more quickly with antibiotic
therapy than without it, especially if the exacerbations
are accompanied by purulent sputum.3,5 It is difficult
to interpret these results as indicating anything other
than a role of bacterial infections in exacerbations. An-
tibiotic therapy is recommended for the management
of exacerbations, usually without sputum cultures.6
However, bacterial infection of the airways is not the
only cause of exacerbations of chronic obstructive pul-
monary disease. In the series described by Sethi et al.,2
18 percent of exacerbations occurred in the absence
of any identifiable bacterial pathogens in the sputum.
There is good evidence7 that approximately one third
of exacerbations are associated with evidence of viral
respiratory infection. It seems likely that some exac-
erbations occur in the absence of any infection, as
is the case in asthma. Indeed, the evidence favoring
the use of systemic glucocorticoids to treat exacerba-
tions of chronic obstructive pulmonary disease may
point to a common mechanism underlying exacerba-
tions of the two disorders.8 Multiple causes are entirely
consistent with the usual definition of an exacerbation,
which is simply an increase in symptoms. The most
common and distressing symptom of chronic obstruc-
tive pulmonary disease is dyspnea, a complex sensation
thought to represent an imbalance between the pa-
tients urge to breathe and his or her ability to achieve
a satisfactory result. The most credible cause of in-
creased dyspnea in patients with chronic obstructive
pulmonary disease is an increase in airway obstruction,
which need not be large if the patient has poor lung
function to start with or is sensitive to minor alter-
ations in lung mechanics. Any agent that induces air-
way inflammation, edema, or smooth-muscle constric-
tion is likely to cause exacerbations.
Exacerbations of chronic obstructive pulmonary dis-
ease merit further study for several reasons. As noted
above, they are a major component of morbidity in
patients with the disease. Recent data indicate that
exacerbations probably contribute to the long-term
deterioration of lung function that is characteristic of
chronic obstructive pulmonary disease.4,9 Finally, pre-
vention or amelioration of exacerbations is becoming
a popular end point for trials of potential therapeutic
agents in patients with chronic obstructive pulmonary
disease.10 However, exacerbations are not easy to study,
 EDITORIALS
and many data are based on patients recall of symp-
toms. This is obviously a suboptimal approach. The
best way to study exacerbations is prospectively, which
means identifying a cohort of patients with chronic
obstructive pulmonary disease, following them close-
ly, and examining them when exacerbations occur. The
best previous studies have used this approach,3,4 which
is difficult and expensive. The study by Sethi et al.2 be-
longs in this group; its most impressive feature is the
intensity and completeness of the follow-up achieved.
Finally, should the results of the study by Sethi et
al.2 change clinical practice? Probably not, since the
findings support the current empirical use of antibi-
otics to treat exacerbations of chronic obstructive pul-
monary disease and illustrate the difficulties in inter-
preting the results of routine sputum cultures. The
study does, however, point to a major gap in our
knowledge namely, which antibiotics should be
used. The studies demonstrating the efficacy of an-
tibiotics are old and involved the use of inexpensive
agents with a relatively narrow spectrum. Bacterial re-
sistance to these antibiotics has increased, and ex-
pensive, broad-spectrum agents are often used now,
though there is little evidence that they have superi-
or benefits.
NICK R. ANTHONISEN, M.D., PH.D.
Respiratory Hospital
Winnipeg, MB R3A 1R8, Canada
REFERENCES
1. Seemungal TAR, Donaldson GC, Paul EA, Bestall JC, Jeffries DJ, Wedz-
icha JA. Effect of exacerbation on quality of life in patients with chronic ob-
structive pulmonary disease. Am J Respir Crit Care Med 1998;157:1418-22.
2. Sethi S, Evans N, Grant BJB, Murphy TF. New strains of bacteria and
exacerbations of chronic obstructive pulmonary disease. N Engl J Med
2002;347:465-71.
3. Anthonisen NR, Manfreda J, Warren CPW, Hershfield ES, Harding
GKM, Nelson NA. Antibiotic therapy in exacerbations of chronic obstruc-
tive pulmonary disease. Ann Intern Med 1987;106:196-204.
4. Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA.
Time course and recovery of exacerbations in patients with chronic obstruc-
tive pulmonary disease. Am J Respir Crit Care Med 2000;161:1608-13.
5. Saint S, Bent S, Vittinghoff E, Grady D. Antibiotics in chronic obstruc-
tive pulmonary disease exacerbations: a meta-analysis. JAMA 1995;273:
957-60.
6. Stoller JK. Acute exacerbations of chronic obstructive pulmonary dis-
ease. N Engl J Med 2002;346:988-94.
7. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses,
symptoms, and inflammatory markers in acute exacerbations and stable
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;
164:1618-23.
8. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic
glucocorticoids on exacerbations of chronic obstructive pulmonary disease.
N Engl J Med 1999;340:1941-7.
9. Kanner RE, Anthonisen NR, Connett JE. Lower respiratory illnesses
promote FEV1 decline in current smokers but not ex-smokers with mild
chronic obstructive lung disease: results from the Lung Health Study. Am
J Respir Crit Care Med 2001;164:358-64.
10. Paggiaro PL, Dahle R, Bakran I, Frith L, Hollingworth K, Efthimiou
J. Multicentre randomised placebo-controlled trial of inhaled fluticasone
proprionate in patients with chronic obstrucive pulmonary disease. Lancet
1998;351:773-80.
Copyright 2002 Massachusetts Medical Society.
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BK V IRUS N EPHROPATHY
P OLYOMAVIRUS A DDING I NSULT
TO I NJURY
V IRUSES are particularly troublesome pathogens
in transplant recipients. Viral infections enhance
susceptibility to opportunistic infection both by caus-
ing tissue injury and by contributing to systemic im-
munosuppression.1 Such infections increase the rate
of graft rejection and the risk that cancer will develop.
The problem of viral infection in transplantation re-
flects the intricate balance between lifelong viral in-
fection in tissues, the hosts antiviral immune function,
and the level of immunosuppression required to main-
tain graft function.
The likelihood that latent viral infection will be ac-
tivated is a function of the microbiologic features of
the specific virus, the presence of stimuli for the acti-
vation of virus in tissues, the amount of virus present,
and the nature of the persons immune deficits.1 Thus,
the risk of invasive infection is lower in a person who
has preexisting immunity against the pathogen (i.e.,
a seropositive host) and is higher in a person without
preexisting immunity (i.e., a seronegative host). Viral
replication is often stimulated by the allogeneic im-
mune response (e.g., graft rejection or antilymphocyte
antibodies) and by inflammation (e.g., tissue injury,
leukocyte infiltration, and the release of cytokines). As
long as the transplanted organ functions under the
protection of immunosuppressive therapy, the link be-
tween immune function and the risk of infection can-
not be broken.
Prevention of viral infection relies on the minimal
level of immunosuppressive therapy that is consistent
with graft survival and the use of antiviral therapies in
proportion to the perceived risk of infection. Prophy-
lactic therapy is based on the assumption that the en-
tire population is at substantial risk for infection and
merits preventive treatment with antimicrobial agents.
Thus, after transplantation, all patients receive prophy-
laxis against Pneumocystis carinii infection for some
period. With preemptive therapy, the use of antimi-
crobial agents to prevent a specific infection is linked
to a microbiologic assay of disease activity that predicts
the likelihood of invasive disease.1,2 Thus, quantitative
molecular or antigen-based assays are used to deter-
mine whether the level of infection (e.g., in the case of
cytomegalovirus, the number of plasma DNA cop-
ies) makes invasive disease likely. The results of such
assays, coupled with individual measures of risk (e.g.,
the number of HLA mismatches between donor and
recipient), are used to determine whether preemptive
therapy should be used. The implications of meas-
urements of circulating virus are less clear in invasive
tissue infections (hepatitis C or cytomegalovirus infec-