Internal Amplification Control for PCR Should Not Be Mandatory in the Clinical Medical Environment

Hoorfar et al. propose making internal amplification control (IAC) mandatory for diagnostic PCR (J. Hoorfar, N. Cook, B. Malorny, et al., Letter, J. Clin. Microbiol. 41:5835, 2003). This proposal appears to be specific to foodstuffs, but it might also be applied to clinical diagnostics. It is interesting to consider IAC for PCR in light of other methods in clinical microbiology, where it is uncommon to test for the presence of inhibitors despite numerous false negatives. For example, 51% of urine specimens were shown to contain antibiotics, with a 78% loss of expected positive cultures (unpublished data).

With foodstuffs, “a false negative turns a risk into a threat for the population” (Hoorfar et al., letter), as it might allow contaminated foods to reach the market. In clinical medicine a test result is merely one piece of evidence and should always be interpreted in view of the clinical assessment. We do not withdraw treatment from patients whose tests are negative. We may repeat the test, try another method of confirming the clinical suspicion, pursue an alternative diagnosis, or do nothing! I don't deny that false negatives are undesirable. They are damaging. They prevent us from focusing on a specific disease, bringing the extra costs and complications of continuing with unnecessary drugs and investigations while searching for a diagnosis. This damage extends from all test types, not just PCR. Don't doubt that we are working to improve the collection of urine samples!

Insisting that internal controls are included in articles on PCR is less attractive than encouraging reports on whether a test is “robust” enough for use in the intended environment, with data produced by diagnostic staff working in real-life situations on unselected clinical samples. This would be much more helpful to clinical diagnostic laboratories assessing the literature. Knowing the reason for a false negative is helpful, as it may provide an opportunity to correct the problem, but it is not an essential piece of information when considering implementing a test in medicine. It is the overall use and clinical performance of the test in field conditions that interests us.

PCR is relatively new but is not so special that it deserves an IAC in preference to other tests. If the standards organizations were to require IAC for PCR in clinical work, then surely, for the sake of standardization, they should also require similar controls for culture methods; perhaps we have accepted undetected false negatives for too long. However, this added cost might prevent the introduction of a test that otherwise outperforms alternative methods. In medicine the benefit of extra diagnoses with a sensitive system such as PCR may outweigh losses due to some false negatives caused by inhibition, which is only one of the causes of a false negative.