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TB Guidelines
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Guidelines (by subject) > Guide to the
Application of Genotyping to Tuberculosis Prevention and Control
> Definitions
Guide to the Application of Genotyping to Tuberculosis Prevention
and Control
Combining Genotyping and Epidemiologic
Data to Improve Our Understanding of
Tuberculosis Transmission
Definitions
Matching Versus Nonmatching Genotypes
The first objective in interpreting genotyping results is to decide
if an isolate has a genotype pattern that matches any other isolate
in the genotyping results database. Isolates that show a genotyping
pattern that matches at least one other isolate in the database
are referred to as belonging to the same genotyping cluster. An
isolate with at least one other genotype match is also referred
to as being clustered. If an isolate has a genotyping pattern that
does not match any other isolate in the database, that isolate is
referred to as having a nonmatching or unique genotype.
In general, the determination of whether an isolate has a matching
or a nonmatching genotype is straightforward, since the genotyping
laboratory report will provide a PCR cluster designation for all
isolates that have a matching spoligotype and MIRU type. If the
genotyping laboratory report lists no PCR cluster designation, the
isolate has a nonmatching or unique genotype. TB program staff can
determine for themselves if there are any matching PCR genotypes
by performing a simple Excel SORT command on the spoligotype and
MIRU type results, since that command will group all matching isolates
together.
Two factors, however, complicate this picture. First, while all
isolates will have genotyping results from the two PCR tests, only
a subset of isolates will have IS6110–based RFLP results.
When interpreting genotyping results from isolates that belong to
a PCR cluster, it is important to remember that a subsequent RFLP
analysis may reveal that some or all of the isolates have different
RFLP patterns and do not, therefore, belong to the same genotyping
cluster. In a more general sense, when one speaks of isolates belonging
to the same genotyping cluster, it is important to clarify if the
isolates belong to the same PCR cluster (and RFLP has not been performed)
or if the isolates belong to the same PCR/RFLP cluster (Table 4.1).
Table 4.1. Genotyping cluster designations based
on results of the three genotyping methods (spoligotyping, MIRU
analysis, and IS6110-based RFLP). Only isolates that match
by the two PCR methods should be analyzed by IS6110-based
RFLP.
| PCR-based test results |
IS6110-based RFLP
results |
|
Not performed |
Performed |
|
RFLP patterns match |
RFLP patterns do not match |
| PCR cluster |
PCR/RFLP cluster |
Nonmatching (or
unique) genotypes |
| * Nonmatching (or
unique) genotypes |
* Nonmatching
(or unique) genotypes |
* Nonmatching
(or unique) genotypes |
*RFLP not indicated in this situation
The second factor that complicates the definition of nonmatching
genotypes involves the possibility that other isolates, either isolates
in another TB program’s database or ones that may be genotyped in
the future, may reveal matching genotypes. For example, consider
a source patient, who lived and worked in Kansas City, Missouri
and transmitted TB to one secondary patient at their place of work.
If the secondary patient lived in Kansas City, Kansas, a search
of the Kansas TB program’s genotyping database would not reveal
a genotype match, nor would a search of the Missouri TB program’s
genotyping database. If the two programs routinely compared their
data, however, the match would be identified at that time. Similarly,
if a source patient transmits TB to a secondary patient, and that
secondary patient is not diagnosed at the same time, the initial
review of the genotyping data will show that the source patient’s
isolate has a nonmatching genotype. When the secondary case is diagnosed
and the isolate genotyped, the source case’s status will change
from nonmatching to matching.
In summary, it is important to bear in mind that the classification
of an isolate as matching or nonmatching is provisional and can
change as new data become available.
Infectious Period
The infectious period is a key part of determining if epidemiologic
links exist between TB patients because it describes when a TB patient
was most likely capable of transmitting TB to others. We will provide
an operational definition of the term here, presented by whether
the case was sputum smear positive or smear negative.
- Sputum smear-positive cases: the infectious period
extends from 3 months before the first positive smear or symptom
onset (whichever is earlier) until 2 weeks after the time of the
start of appropriate TB treatment or until the patient is placed
into isolation or the date of the first negative smear that is
followed by consistently negative smears.
- Sputum smear-negative cases: the infectious period is
defined as beginning 1 month before symptom onset or start of
appropriate TB treatment or when the patient was placed into isolation
(whichever was earlier) until 2 weeks after the start of appropriate
treatment or until isolation began.
Epidemiologic Links
Information on epidemiologic links between two patients with TB
comes from data collected during the initial case interviews, the
contact investigations, and a subsequent cluster investigation,
if one is undertaken.
Key data that help define epidemiologic links collected during
the case interviews include the following: a) location where patients
lived, worked, and spent time (in order to determine if the patients
in a genotyping cluster were also clustered in space); b) the times
that each patient was present at each of the locations (in order
to determine if the patients were clustered in time); c) the infectious
period; and d) social and behavioral traits that the patients might
share that could increase the chance of TB transmission (e.g., drug
use, homelessness, incarceration). Key data collected during contact
or cluster investigations include the following: a) whether either
patient named the other one as a contact; and b) whether the patients
lived, worked, or spent time at the same place (this information
may come from the initial case interview or from the contact investigation).
During cluster investigations field staff members seek the same
information, but because genotyping results are already available
and describe the patients as belonging to the same genotyping cluster,
cluster investigations are more focused and search for possible
links that might have occurred farther in the past.
What constitutes a known as compared with a possible epidemiologic
link cannot be defined as precisely as a genotyping match. The text
box, Summing Up: Defining Epidemiologic Links, lists general
guidance about definitions that have proven helpful to some TB programs.
As we learn more about how to interpret genotyping data, these definitions
may need to be revised. And as with genotyping data, epidemiologic
links are provisional at any point in time. A contact investigation
might fail to identify an epidemiologic link that is discovered
only during a subsequent cluster investigation. Similarly, a link
may only become apparent when additional cases are added to a cluster
and new information about how all the cases are related becomes
apparent. Table 4.2 lists commonly identified relationships and
locations that were found to represent known epidemiologic links
in the NTGSN study.
Table 4.2: Commonly identified relationships
and settings that represent known epidemiologic links between
TB patients.*
| Relationship |
Frequency |
| Household member |
47% |
| Common source† |
27% |
| Friend or contact outside the home |
23% |
| Co-worker |
3% |
| Total |
100% |
| Setting |
Frequency
|
| Emergency shelter |
18% |
| Group quarters |
11% |
| Prison or jail |
7% |
| Nursing home |
3% |
| Hospital |
1% |
| School/day care |
1% |
| Nontraditional setting§ |
59% |
| Total |
100% |
*This analysis of unpublished NTGSN data includes 1,485 epidemiologic
links between TB patients who had matching genotypes and for whom
a contact or cluster investigation identified a likely location
and relationship of transmission.
† A common source was defined as two TB patients who
were in the same place at the same time but did not fit into any
of the other categories.
§ Common nontraditional settings included bars/social
clubs, churches/temples, drug/crack houses, and other locations
not typically asked about in routine contact investigations.
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Summing Up: Defining epidemiologic links
Based on the information collected during case interviews,
contact investigations, cluster investigations, and record
reviews, TB patients in a genotyping cluster can be characterized
by the strength of the epidemiologic links between them.
Known epidemiologic link
Two patients are said to have a known epidemiologic link
if either of the following two conditions apply:
- One of the patients named the other as a contact during
one of the patient’s infectious period
OR
- The two patients were at the same place at the same time
during one of the patient’s infectious period
Possible epidemiologic link
Two patients are said to have a possible epidemiologic link
if any one of the following conditions apply:
- The two patients spent time at the same place around
the same time, but the timing of when they were there or
the timing of the infectious period was not definite enough
to meet the criteria for a known epidemiologic link
OR
- The two patients lived in the same neighborhood around
the same time
OR
- The two patients worked in or were at the same geographic
area around the same time and shared social or behavioral
traits that increased the chances of transmission
No identified epidemiologic link
Two patients should be classified as having no identified
epidemiologic link if they do not meet the criteria listed
above. |
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