Testing vs diagnosis
Physicians are enamored of blood tests, as are patients. They seem so clear and unequivocal. But any good doctor knows that blood results do not a diagnosis make. Diagnosis is a complex, multivariate consideration. In the case of infection, serology can contribute significantly to making a diagnosis, but many factors go into whether serology is accurate or not.
In the case of Chlamydia pnemoniae, there are significant difficulties in obtaining accurate tests. In addition to the accuracy issue, individual's may not respond antigenically. All of this means that having a negative blood test for Cpn does not mean that you don't have Cpn infection. Tests can be inaccurate for the following, and other, reasons:
- The test may not be sensitive enough. Antigen tests for Cpn are said to be relatively inaccurate. PCR tests are the most sensitive, but dependent on the particular primers used, whether the dna used by the test matches the particular strain of Cpn one has, whether the test used accounts for the type of sample well (blood, sputum, cerebrospinal fluid, etc), the accuracy of the technician (PCR is particularly trickey in a technical sense), and so on.
- If the infection is predominantly in cryptic phase, there is no serology evident.
- If the patient's immune system is significantly depleted, they will not show positive antigens for the organism infecting them (they are immuno-incompetant).
Since many asymptomatic persons show existing antibodies to Cpn, and many with symptoms show no positive Cpn serology, blood tests are not the last word in diagnosis. Diagnosis requires a physician to put together the whole symptom picture: the suggestive evidence of infectious involvement, serology and other tests, to diagnose and treat a condition.
Stratton and Wheldon (draft paper) argue that symptomatic suspicion may be enough to warrant an empirical antichlamydial therapy even in the absence of positive serology. Dr. Wheldon's wife, Sarah, is a case in point: worsening symptoms of MS completely reversed and put into remission through use of his protocol, despite no serological indications. Endotoxin reactions to antichlamydial abx's (see below) followed by symptomatic improvement are often taken as a confirmation that the infection exists. The argument, in the absence of serology for Cpn, is that the treatment is low risk.
Serology is an inadequate indicator of chronic infection (Saikku 1999). It does not indicate the locality of the possible chronic process, and the high frequency of C. pneumoniae antibodies in people makes it difficult to prove an association with a specific disease.
Tiina Sävykoski nee Huittinen
A sophisticated technical commentary on serology and diagnostic difficulties is provided from:
We have already seen that the 'gold standard' micro immunofluorescence (MIF) test is actually not a good test for diagnostic purposes because of its lack of specificity, objectivity, reproducibility and agreed protocol. While expert chlamydiologists might be happy to use the test for comparative epidemiology, most would agree it is quite a different matter to be confident about the meaning of a result in an individual patient. A priori one might expect some of the newer tests with defined antigens to be more specific, but there is little evidence for this at the moment and it is a difficult thing to prove. In studies of the association of antibody to C. pneumoniae with coronary heart disease, the choice of test appears to be very important [Halvorsen et al, 2002; Schumacher et al., 2001]. The newer serological tests based on synthetic or recombinant antigens have largely been evaluated against the classic MIF as gold standard. It is important to remember that no test can perform better than the selected gold standard and, since MIF is a far from perfect test, it may be that the apparent performance of some of the newer tests is constrained by this choice of gold standard. However further evaluation of these new tests and their application is required before they enter routine diagnostic practice...
What is the effect of differing antibody and infection kinetics? When individuals acquire a chlamydial infection, there is a lag period before they make an antibody response. Similarly antibody persists for long after an infection is resolved. High or persisting antibody in an individual does not necessarily mean current or persistent infection. [Nor do persisting symptoms]. Persisting or lagging antibody will further confound the positive and negative predictive value of serology. The evidence, such as it is, is that serology and direct evidence of infection are not well correlated [Rabenau et al., 2000]. ...
...Bas et al., 2002 tried to determine the most sensitive and specific method of measuring antibody to C. trachomatis in reactive arthritis. A panel of serum samples were chosen from 17 patients with C. trachomatis reactive arthritis and twenty patients with other inflammatory arthritic conditions not involving chlamydiae. Chlamydial IgG, IgM and IgA antibody was measured by immunoblotting, by various enzyme-linked immunosorbent assays using six synthetic peptides or recombinant antigens and microimmunofluorescence. The best association of sensitivity (76%) and specificity (85%) was obtained when IgG and/or IgA reactivity to two species-specific antigens was determined. These antigens were synthetic peptides, derived from species-specific epitopes in the variable domain IV of the major outer membrane protein (Labsystems, Finland) and recombinant polypeptide encoded by open reading frame 3 of the plasmid (pgp3). For the impact of sensitivity and specificity on predictive values see: worked examples. [Comment: This was a good study based on a chronic condition where it might reasonably be expected that specific antibody should be associated with infection. Given that the best that could be achieved using multiple tests was a sensitivity of 76%, (which would not give an impressive negative predictive value) and a specificity of 85% (which would give poor positive predictive value) this reviewer concludes, unlike the authors, that serology has little role to play in the laboratory diagnosis of reactive arthritis]...
...Conclusion: There is inadequate scientific justification for making serious clinical decisions about patient management on the basis of chlamydial serology. New generation recombinant or peptide-based tests for antibody to C. trachomatis are likely to be more specific than tests based on whole chlamydial antigens. Where other diagnostic methods are lacking or it is not possible to obtain relevant samples, the new serology tests with their high negative predictive value may be of use for identifying patients in whom it is unlikely that C. trachomatis infection is playing a role. Given that much better methods are available for detecting current chlamydial infection, clinicians are strongly recommended to focus their efforts on seeking direct evidence of chlamydial infection wherever possible, using the best locally available test, preferably one using nucleic acid amplification. Chlamydial serology continues to have a role in research [Moss & Darougar, 2001].
According my recent conversations with Dr. Stratton (2008), he does not consider PCR tests useful for diagnosing Cpn as the primers used can differ from lab to lab and the technique is less standardized and dependent more on operator accuracy. Serology tests have become more accurate and reliable in recent years and would be preferred to PCR tests. Mayo Clinic Lab and Quest Lab both appear to have more reliable tests in the USA. One clinician reported Mayo Clinic Cpn tests as catching about 95% of the Cpn cases in his practice. Many of our members have had Cpn detected through Quest Labs serology tests. Your mileage may vary.