Guide to the Application of Genotyping to Tuberculosis Prevention
Applying Genotyping Results to Tuberculosis
Evaluating Nonmatching Genotypes
The previous discussion focused on genotyping matches. The following
discussion will describe possible action steps for isolates that
have nonmatching genotypes. If the genotyping laboratory reports
that an isolate has a unique genotype that does not match any other
isolates from the TB programís jurisdiction, no further genotyping
tests are required to conclude that the isolate is genetically distinct.
Specifically, there is no reason to request RFLP if PCR tests have
shown that an isolate has a unique genotype pattern.
Nonmatching Genotypes with Known Epidemiologic Links
Results from the NTGSN study show that patients with nonmatching
genotypes often had known epidemiologic links identified during
previous contact investigations. In these cases, three possibilities
exist: a) the genotypes changed slightly over time, b) the previously
identified epidemiologic links are misleading and do not reflect
recent transmission, or c) the genotyping results are erroneous
or misleading. Although there is little information available about
the relative frequencies of these three possibilities, the standardized
nature of the genotyping tests and the ambiguities involved in conducting
contact investigations suggest that misleading epidemiologic links
are much more common than incorrect genotyping results.
The possibility that genotypes have changed slightly over time
is easy to evaluate. Isolates that match in all but one digit in
the MIRU type or that have spoligotypes that differ in one region
(as a result of loss of one or more spacers) should be considered
closely related. Programs should consult with the genotyping
laboratory or CDC to determine if RFLP typing of such isolates is
warranted. RFLP patterns can also change slightly over time. In
these cases, the RFLP patterns will differ by only a single band.
There are two common characteristics of patients identified with
known epidemiologic links and nonmatching genotypes; if either of
these characteristics is present, the probability that the epidemiologic
links are incorrect or misleading is even higher. As discussed in
Chapter 4, Combining Genotyping and Epidemiologic
Data to Improve Our Understanding of Tuberculosis Transmission,
epidemiologic links that have later been shown to be inconsistent
with genotyping results have occurred when the presumed secondary
case-patient was born in a foreign country or when the presumed
source case-patient was culture-positive but sputum smear-negative.
If either of these characteristics is present, these epidemiologic
links presumably do not indicate recent transmission.
Incorrect or misleading genotyping results are not common. They
can, however, occur under unusual circumstances. Persons can be
infected with more than one strain of M. tuberculosis at
the same time. If an infection with two strains of M. tuberculosis
is suspected, the TB program should consult with the genotyping
laboratory about testing additional isolates from that person. Finally,
a genotyping laboratory error can occur. A specimen might be mislabeled,
an isolate might be contaminated, or there might be an error in
reporting. If any of these are suspected, the genotyping laboratory
should be consulted.
Nonmatching Genotypes and No Known Epidemiologic Links
If a particular isolate shows a unique genotype pattern that has
not been reported from a jurisdiction in the past, and if the contact
investigation of the person with the non-matching genotype did not
reveal any epidemiologic links with other cases or only possible
epidemiologic links, there is insufficient evidence of recent transmission
to support additional investigations. Although future genotyping
reports might identify new patients with matching genotypes (and
if they do, additional investigations might be required at that
point), at this point in the decision analysis there is little additional
work that is necessary, except to ensure that routine TB control
measures have been taken.
Concluding Remarks on Decision Analysis
At this point in the decision analysis, genotyping data have been
combined with information about possible epidemiologic links in
order to determine what specific action steps are needed. The following
sections describe the goals, steps, and the expected outcome of
those action steps.