1284 THE LANCET Vol 351 April 25, 1998

CORRESPONDENCE
The generalisation that pneum-
ococcal vaccine did not prevent
pneumonia overall or pneumococcal
pneumonia in middle-aged and elderly
individuals cannot be justified by the
design or results of the study.
Does it matter that yet another
inadequate study of pneumococcal
vaccination has been published? Yes!
Publication of this article reflects badly
on the peer-review and editorial
processes of The Lancet. More
importantly, knowledge of this study
has already had a substantial adverse
effect on the uptake of pneumococcal
vaccine in Sweden. Unlike all other
countries, use of pneumococcal vaccine
has declined in Sweden in each of the
past 2 years. It is ironic that this poorly
designed and inadequately described
study should be published 1 week after
the publication in The Lancet of the
excellent study by E J Gangarosa and
colleagues (Jan 31, p 356).
2
Ronald Gold
Faculty of Medicine, University of Toronto,
Toronto, Ontario M5G 1X8, Canada
(e-mail: rongold@netcom.ca)
1 rtqvist , Hedlund J, Burman L-, et al.
Randomised trial of 23-valent
pneumococcal capsular polysaccharide
vaccine in prevention of pneumonica in
middle-aged and elderly people. Lancet
1998; 351: 399403.
2 Gangarosa EJ, Galazka AM, Wolfe CR, et
al. Impact of anti-vaccine movements on
pertussis control: the untold story. Lancet
1998; 351: 35661.
SirThe incidence of pneumococcal
pneumonia reported by ke rtqvist
and colleagues
1
of 600 per 100000
people is unusually high for
immunocompetent adults in a
developed country. This high rate may
reflect inadvertent inclusion of
immunocompromised individuals or
the use of unconventional diagnostic
indices with poor specificity and,
consequently, a high number of false-
positive results. Over 70% of the
vaccinees were smokers or alcoholics,
both risk factors for pneumococcal
disease. The high incidence of
recurrence over 25 years of follow-up
(30% of all patients with pneumonia
had more than one episode) suggests
that a substantial proportion of the
vaccinees may be immuno-
compromised. Thus, the observed
poor efficacy may result from poor
immune response or other mechanical
factors associated with these risk
factors.
The diagnostic criteria used by the
investigators are contentious. In 29
cases pneumococcal pneumonia was
diagnosed by sputum culture and in 21
by a positive antibody test. Sputum
examination in the diagnosis of
community-acquired pneumonia can
yield misleading results. Although
detection of pneumolysin antigen
antibody complex is useful, it has been
assessed on a very limited scale and no
field studies have evaluated its
specificity or sensitivity. The use of an
increasing antibody titre is also
unreliable since carriage has been
shown to result in a substantial rise in
concentrations of serotype specific
antibody;
2
carriage might also affect
other pneumococcal serology assays.
These methods may have contributed
to overdiagnosis of pneumococcal
pneumonia since carriage or
colonisation could confound either of
these criteria when used as a diagnostic
variable. Perhaps analysis of the
documented cases of invasive
pneumococcal disease by the different
diagnostic criteria may alter their
conclusion.
Steven Obaro
Division of Infectious Diseases, Childrens
Hospital Medical Center, Cincinnati, OH
45229-3039, USA
1 rtqvist , Hedlund J, Burman L-, et al.
Randomised trial of 23-valent
pneumococcal capsular polysaccharide
vaccine in prevention of pneumonia in
middle-aged and elderly people. Lancet
1998; 351: 399403.
2 Musher DM, Groover JE, Reichler MR,
et al. Emergence of antibody to capsular
polysaccharides of Streptococcus pneumoniae
during outbreaks of pneumonia: association
with nasopharyngeal colonization. Clin Infect
Dis 1997; 24: 44146.
SirThe lack of benefit found by ke
rtqvist and colleagues
1
for the
admission of 23-valent pneumococcal
vaccine in middle-aged and elderly
individuals reinforces the uncertainties
that surround this intervention. The
1996 Report of the US Prevention
Services Task Force
2
listed
pneumococcal vaccination in this
population as only a B
recommendation: There is fair
evidence to support the
recommendation that the condition be
specifically considered in a periodic
health examination.
2
Even this level of
endorsement seemed based on only
one meta-analysis.
3
Furthermore, those
groups at highest risk of infection (and
with greatest need for effective
prevention measures) are acknow-
ledged, in the meta-analysis, to have no
proven benefit from pneumococcal
vaccination.
rtqvist and colleagues finding of
5080% effectiveness in the prevention
of invasive pneumococcal disease is
admirable. Given current evidence,
however, an evangelical stance is
inappropriate when we advise our
immunocompetent middle-aged and
elderly patients to submit to
pneumococcal vaccination. In addition,
the strongly recommended use of
vaccination in high-risk groups, for
whom no benefit has been proven, is
puzzling.
4
Irrespective of its proven
safety in these high-risk populations,
one must question the value of such
treatment.
Stuart Keith Sutton
Internal Medicine, 530 Wainwright Building,
Norfolk VA 23510-1405, USA.
(e-mail: sksutton@sentara.com)
1 rtqvist , Hedlund J, Burman L-, et al.
Randomised trial of 23-valent
pneumococcal capsular polysaccharide
vaccine in prevention of pneumonia in
middle-aged and eldeerly people. Lancet
1998; 351: 399403.
2 US Preventive Services Task Force. Guide
to clinical preventative services. Baltimore:
Williams & Wilkins, 1996.
3 Fine MJ. Efficacy of pneumococcal
vaccination in adults: a meta-analysis of
randomised controlled trials. Arch Intern
Med 1994; 154: 266677.
4 US Department of health and Human
Services, Public Health Service. 1997
USPHS/IDSA guidelines for the prevention
of opportunistic infections in persons
infected with HIV. Am Fam Physician 1997;
56: 113146.
Authors reply
SirE Hak and colleagues, Ronald
Gold, and Steven Obaro criticise our
study, whereas Stuart Keith Sutton
believes that our findings lend support
to the view that one must question the
value of pneumococcal vaccination.
We selected patients who had had
a community-acquired pneumonia
because the incidence of a new
pneumonia is high in such patients.
However, this fact does not per se
indicate that they differ significantly
from other patients who develop
pneumonia in the community. We
excluded patients with known
immunocompromising disease, only
1% of patients were alcoholics,
1520% were smokers, and 40% were
previously healthy. We know that this
category of patients have an adequate
antibody response to the vaccine,
2
and
we are currently comparing the
response in patients with and without
pneumonia recurrences.
We encouraged doctors to carry out
chest radiography on any clinical
suspicion of pneumonia to detect as
many patients as possible with
penumonia. Since it was a double-blind
study, the risk of bias caused by
different indications for chest
radiography seems negligible. All the
patients had a baseline chest
radiograph on inclusion and new
infiltrates could therefore be detected
with confidence. Invasive diagnostic
THE LANCET Vol 351 April 25, 1998 1285
CORRESPONDENCE
methods could have provided a
superior specificity, but were not a
practical alternative.
To avoid unnecessary bias, we did
not actively seek information on side-
effects, and the few severe reactions
were recorded separately from the
patients medical records.
The methods we used for the
diagnosis of non-bacteraemic
pneumonia are not universally
accepted. However, to our knowledge
there are no other methods available,
and again, the study was double-blind.
We do not believe that we over-
diagnosed pneumococcal pneumonia
in our study. The rate of bacteraemic
and non-bacteraemic pneumococcal
pneumonia was about 1 and 56,
respectively, a figure similar to earlier
reports. It is unfortunate that the full
set of tests was not obtained in all
patients. However, since streptococcus
is the main pathogen of community-
acquired pneumonia, and it is not
possible to obtain an aetiological
diagnosis in all patients with this
infection, the primary endpoint of
pneumonia is probably the most
important one.
The power of our study was less than
expected because the incidence of
pneumococcal pneumonia in our
population was lower than our pretrial
calculations. However, the Kaplan-
Meier survival curve clearly spoke
against the possibility that the vaccine
was efficacious against pneumococcal
pneumonia in this population. Further,
until recently the only basis for a
possible protective efficacy against
pneumococcal pneumonia in the
elderly has been data obtained from
efficacy studies on invasive disease, and
not from clinical studies of pneumonia.
There is one recent exception
(published after our study was
submitted) in which elderly high-risk
patients had a 59% (95% CI 6 to 82),
protective efficacy in the prevention of
pneumococcal pneumonia.
3
However,
this study, conducted more than 10
years ago with the 14-valent vaccine,
yielded conflicting results, since nearly
the opposite results (although not
statistically significant) were observed
in low-risk patients, with a protective
efficacy of 66% (257 to 23).
Finally, our study lends support to
earlier findings that the vaccine is
effective in the prevention of invasive
pneumococcal disease in elderly
patients. Unlike Sutton, we believe
that this is the indication for using
the vaccine. The incidence of
invasive pneumococcal disease and
of antibiotic-resistant pneumococci
is increasing in most parts of the
world. These factors, together with
the safety and low costs associated with
the pneumococcal vaccine, make a
general vaccination in the elderly
advisable.
*kke rtqvist, Jonas Hedlund,
Mats Kalin
Department of Infectious Diseases, Karolinska
Institute, Danderyd Hospital, S-18288
Danderyd, Sweden
1 Hedlund JU, rtqvist B, Kalin Me, Scalia-
Tomba G, Giesecke J. Risk of pneumonia in
patients previously treated in hospital for
pneumonia. Lancet 1992; 340: 39697.
2 Hedlund JU, Kalin ME, rtqvist B,
Henrichsen J. Antibody response to
pneumococcal vaccine in middle-aged and
elderly patients recently treated for
pneumonia. Arch Intern Med 1994; 154:
196165.
3 Koivula I, Stn M, Leinonen M, Mke PH.
Clinical efficacy of pneumococcal vaccine in
the elderly: a randomised, single-blind
population-based trial. Am J Med 1997; 103:
28190.
about the benefits and risks of lung
transplantation in the clearest possible
terms.
*Scott D Ramsey, Eric Larson
Center for Cost and Outcomes Research,
School of Medicine, School of Public Health
and Community Medicine, University of
Washington, Box 358853, Seattle,
WA 98195, USA
1 Hosenpud JD, Bennett LE, Keck BM,
Edwards EB, Novick RJ. Effect of diagnosis
on survival benefit of lung transplantation
for end-stage lung disease. Lancet 1998; 35:
2427.
2 Ramsey SD, Patrick DL, Albert RA,
Larson EB, Wood DE, Raghu G. The cost-
effectiveness of lung-transplantation: a pilot
study. Chest 1995; 108: 1594601.
3 Reassessing the cost-effectiveness of lung
transplantation. Chest 1996; 110: 577.
Lung transplantation
SirJeffrey Hosenpud and colleagues
(Jan 3, p 24)
1
find that survival for most
lung-transplant patients does not
exceed survival for patients on the
waiting list for transplants. With
mathematical techniques to project
short-term survival statistics, we
reported similar findings in our
costeffectiveness analysis of lung-
transplantation 3 years ago.
2
This
finding was the primary reason that
lung transplantation proved cost-
ineffective compared with other organ-
transplant technologies. Our study was
greeted with scepticism and hostility by
many in the transplant community.
3
Since there are limitations on the
resources that can be allocated for
health care, policy makers should ask
whether expensive new interventions
provide good health value for
expenditure. So far, the limited supply
of donor lungs had not made this an
especially important issuetransplant
demand will continue to greatly exceed
supply for the foreseeable future. At the
level of doctor and patient, however,
it is most important to provide clear
information about the health value of
a particular treatment relative to the
alternatives. For patients considering
lung transplantation, the most relevant
question is whether they will be willing
to accept the up-front mortality risks
(and out-of-pocket expense) for
improved quality of life without a
high likelihood of longer survival.
Economics aside, the data provided by
the United Network for Organ Sharing
team compel clinicians to speak openly
Do Asian HBV carriers
differ from non-Asian
carriers?
SirIn his Jan 17 commentary, Robert
Carithers
1
expresses concerns about
our report
2
of spontaneous rates of
seroconversion in hepatitis B virus
(HBV) carriers from HBeAg-positive to
HBeAg-negative. We compared
spontaneous seroconversion rates in a
cohort of Asian-American carriers with
those reported for carriers treated with
interferon- in randomised clinical
trials, most of whom were non-Asian.
3
As a guide to physicians in advising
patients whether to undergo this
difficult, expensive, and often
unsuccessful treatment, we presented
a natural history of spontaneous
seroconversion in carriers (aged 550
years) with raised serum alanine
aminotransferase (ALT) over the
average treatment and follow-up period
used in clinical trials compared with
treatment-associated seroconversion
rates. We showed that seroconversions
continue to occur at a substantial rate
throughout adulthood in carriers, and
concluded that treatment therefore
results in an average acceleration of
seroconversion usually of only 818
months.
Because studies differ greatly in their
initial populations, follow-up methods,
and prevalence of raised ALT, there is
great variation in published rates of
spontaneous seroconversion for both
Asian and non-Asian patients.
Carithers suggests that our
seroconversion rates in people with
raised ALT (1523% in 15 months)
are substantially higher than those seen
in carriers of European origin who
generally acquire infection later in life.
He cites an average rate of 9% in 15
months for European carriers on the