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Dr. Hammerschlag is the Professor of Pediatrics and Medicine and the Director of Pediatric Infectious Diseases, Department of Pediatrics, SUNY Downstate Medical Center.
Correspondence to: Margaret R. Hammerschlag, MD, Department of Pediatrics, Box 49, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203-2098; e-mail: mhammerschlag{at}pol.net
One of the distinguishing characteristics of members of the genus Chlamydia is the ability to cause prolonged, often subclinical infection. It has been recognized for years that the majority of genital infections with Chlamydia trachomatis are asymptomatic, especially in women.1 It is also recognized that asymptomatic C trachomatis infections are not trivial; they can be associated with significant sequelae.2 In this issue of CHEST (see page 1416), Miyashita et al add to the growing number of studies that demonstrate that Chlamydia pneumoniae is also capable of causing asymptomatic infection, but in the respiratory tract. The data presented by Miyashita et al are not new but represent the largest prospective evaluation of asymptomatic infection presented thus far. They screened 1,028 healthy, asymptomatic adults over a 6-year period by obtaining nasopharyngeal swabs for C pneumoniae culture and polymerase chain reaction (PCR) testing, as well as obtaining sera for anti-C pneumoniae antibodies, using the microimmunofluorescence (MIF) method. The overall rate of C pneumoniae infection was 1.4%, ranging from 0 to 3.2% over the 6 years of the study. These numbers are very similar to the 2 to 5% rates of asymptomatic infection in adults and children reported in several studies3 4 from the United States. Of the 14 culture-positive and/or PCR-positive individuals reported by Miyashita et al, 3 of 10 patients from whom follow-up specimens were obtained remained positive for periods up to 12 weeks. The other patients appeared to have spontaneously cleared their infections. Persistent respiratory infection with C pneumoniae has been documented for periods up to 8 years.5
Unlike C trachomatis, the complications or long-term sequelae of persistent asymptomatic respiratory infection are not really known. Persistent C pneumoniae infection has been hypothesized as being responsible or associated with several chronic diseases, most notably atherosclerosis.6 Asymptomatically infected individuals may also be a reservoir for transmission of infection in the community.
Very little is known about the natural course of C
pneumoniae infection in general. When does infection first occur?
Is it always associated with illness? How long can it persist?
Seroepidemiologic studies7
8
suggested that C
pneumoniae infection occurs primarily in school-aged children and
the prevalence of infection increases with increasing age. Following
the criteria proposed by Grayston et al,9
acute infections
were defined by a fourfold rise in IgG titer between consecutive
specimens or a single IgM titer of 
16 or a single IgG of 512.
An IgG titer 
256 was considered to indicate past exposure. However,
subsequent studies4
10
that have utilized culture and PCR
for detection of C pneumoniae suggest that infection may
occur at earlier ages than implied by MIF serology. The most
interesting observation was the lack of correlation between positive
culture results and serology; approximately 70% of culture-positive
children in these studies were MIF negative, and < 5% met the
serologic criteria for acute infection.10
Hyman et
al3
reported that 18% of a group of culture-negative,
subjectively healthy adults met the serologic criteria for acute
infection with a single serum sample, IgG 512 and/or IgM 16.
Two subjects in this study3
had nasopharyngeal swab
specimens that were culture positive and/or PCR positive; one subject
was seronegative and one subject had an IgG titer of 256 in a single
serum specimen. The results of other studies11
12
13
in
adults suggest that some high anti-C pneumoniae IgG antibody
detected by MIF may be heterotypic, either due to infection with other
chlamydial species or other organisms, including Bartonella and
Bordetella pertussis. Chlamydial heat shock protein
(HSP) 60 is almost identical to that of Escherichia
coli,14
and a recent study15
found
picornavirus proteins also share antigenic determinants with
HSP60/HSP65, including C pneumoniae HSP60.
The major obstacle to understanding the natural history of C
pneumoniae infection and its potential role in disease is the lack
of standardized diagnostic methods, including serology and PCR. Because
of the perceived difficulty in culturing C pneumoniae,
serology using the MIF test was promoted as the diagnostic method of
choice.9
Some of the limitations of MIF are illustrated by
Miyashita et al in the present study. Of the 14 culture-positive and/or
PCR-positive individuals in their study, none met the serologic
criteria for acute infection.9
Five subjects had IgG
titers believed to be indicative of past infection, and the remainder
were seronegative. In addition to the issue of correlation with culture
and/or PCR, the MIF assay is also not standardized. It has a
significant subjective component, and performance can vary
significantly from laboratory to laboratory, even when the same assay
kits are used.16
Recently, the Centers for Disease Control
and Prevention recommended that the serologic criteria using the MIF
assay be made more stringent.17
Acute infection required
demonstration of a fourfold increase in IgG or IgA, and/or an IgM
16. In addition, the panel believed that there were no reliable
serologic markers for past or persistent infection.
Although at least 18 in-house PCR assays for detection of C pneumoniae in clinical specimens have been reported in the literature, none have been adequately validated compared to either culture or another PCR assay using a different target.18 There are no standardized, commercially available nucleic acid amplification assays (NAAs) for detection of C pneumoniae, whereas there are now four NAAs approved by the US Food and Drug Administration for the detection of C trachomatis.19 Data are emerging that suggest that there is substantial variation in performance of in-house PCR assays for detection of C pneumoniae in clinical specimens, even between laboratories using the same assay with the same specimens.20 In that study,20 identical sets of 15 human atheroma specimens and 5 spiked control specimens were analyzed by 16 PCR assays in nine laboratories. The number of atheroma specimen results reported as positive ranged from 0 to 60% from laboratory to laboratory, and the maximum concordant result for positivity was only 25% for one specimen. In addition, 3 of 16 negative control specimens (19%) were reported as positive in two of the laboratories. Of the 14 asymptomatically infected individuals identified by Miyashita et al, 13 were PCR positive, 3 of whom were also culture positive and 1 was PCR negative and culture positive. Does this mean that PCR is superior to culture? Not necessarily; it may be that their culture methods were suboptimal. Other laboratories using culture have reported higher prevalences of asymptomatic infection.3 4 10 Use of NAAs has revolutionized the diagnosis and treatment of genital C trachomatis infections; one would expect that such an assay would accomplish the same for C pneumoniae.
References
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