Chin DP, Crane CM, Diul MY, Sun SJ, Agraz R, Taylor S, Desmond E, Wise F. Spread of Mycobacterium tuberculosis in a Community Implementing Recommended Elements of Tuberculosis Control. JAMA. 2000;283(22):2968-2974. doi:10.1001/jama.283.22.2968
Author Affiliations: Tuberculosis Control Branch and Microbial Disease Laboratory, California Department of Health Services, Berkeley (Drs Chin and Desmond and Messrs Sun and Agraz); Tuberculosis Programs, Contra Costa Public Health, Martinez, Calif (Dr Crane and Mss Taylor and Wise); and the World Health Organization, Geneva, Switzerland (Dr Diul).
Context Despite improvements in tuberculosis (TB) control during the past decade, Mycobacterium tuberculosis transmission and resulting disease
continue to occur in the United States.
Objective To determine the primary reasons for disease development from a particular
strain of M tuberculosis.
Design Population-based, molecular epidemiological study.
Setting Urban community in the San Francisco Bay area of California with recommended
elements of TB control in place.
Patients Seventy-three TB cases were reported in 1996-1997 that resulted from
1 strain of M tuberculosis as identified by TB genotyping
and epidemiological linkage.
Main Outcome Measures Transmission patterns involving source and secondary case-patients;
primary reasons for disease development.
Results Seventy-three (33%) of 221 TB case-patients in this community resulted
from this strain of M tuberculosis. Thirty-nine (53%)
of the 73 case-patients developed TB because they were not identified as contacts
of source case-patients; 20 case-patients (27%) developed TB because of delayed
diagnosis of their sources; and 13 case-patients (18%) developed TB because
of problems associated with the evaluation or treatment of contacts; and 1
case-patient (1%) developed TB because of delay in being elicited as a contact.
Of the 51 TB cases identified with sources, 49 (96%) were infected within
the 2 years prior to diagnosis.
Conclusions Our results indicate that in a community that has implemented the essential
elements of TB control, TB from ongoing transmission of M tuberculosis will continue to develop unless patients are diagnosed
earlier and contacts are more completely identified.
During the past decade, the application of molecular epidemiology to
the field of tuberculosis (TB) has advanced our understanding of the dynamics
of TB transmission. Numerous descriptions of TB outbreaks have identified
hospitals, prisons, congregate living settings, and homeless shelters as sites
for TB transmission, to name only a few such settings.1- 4
Population-based studies have identified the characteristics of cases associated
with the clustering of patients with the same strain of Mycobacterium tuberculosis, which is believed to indicate the recent
transmission of M tuberculosis.5- 8
Despite improved understanding of the dynamics of TB transmission and
improvements in TB control, transmission of M tuberculosis and disease resulting from such transmission continue to occur.7 To date, a comprehensive assessment of why our current
public health interventions have failed to eliminate TB from this mechanism
has not been reported. Such an assessment can guide the development or implementation
of interventions so that cases of TB from ongoing transmission can be reduced
in our communities.
Since 1996, we have conducted a population-based molecular epidemiological
study of TB in the San Francisco Bay area. As part of this study, we identified
a large cluster of TB case-patients infected with a single strain of M tuberculosis in 1 county. Because we determined that
from 1992 to 1993 a number of case-patients in this community had the same
strain of M tuberculosis, we investigated the current
cluster to identify the factors responsible for the propagation of this strain
of M tuberculosis.
Contra Costa County, California, is located in the San Francisco Bay
Area with a population of around 900,000 persons and an area of 720 square
miles. The western part of the county is densely populated and there are high
rates of poverty, homelessness, substance abuse, and human immunodeficiency
virus (HIV) infection. The remainder of the county, which is much more sparsely
populated, has suburban and rural communities.
During 1996-1997, 221 TB cases (annual rate of 12.5 cases/100,000 population)
were reported in the county.9 Of these, 160
were culture-confirmed cases. M tuberculosis isolates
were collected for IS6110-based restriction fragment-length polymorphism analysis
for 151 of the culture-confirmed cases (93.8%).10,11
The restriction fragment-length polymorphism pattern from 72 isolates (45%)
was identical to at least 1 other isolate and these were designated as clustered
isolates. Sixty-five (90%) of the clustered isolates had less than 6 copies
of IS6110 (5 with 1 copy, 58 with 2 copies, and 2 with 3 copies). These isolates
were further analyzed with a second genotyping technique using a probe for
the polymorphic guanine-cytosine rich sequence (PGRS) (previously described).12 All isolates with 1 copy of IS6110 had unique PGRS
patterns. The 2 isolates with 3 copies of IS6110 had an identical PGRS pattern.
Of the 58 isolates with 2 copies of IS6110, 56 isolates had the same PGRS
pattern, and this cluster was given the designation PG004; the remaining 2
isolates had unique PGRS patterns.
We reviewed the public health record of all TB cases to identify additional
cases in 1996-1997 that had epidemiological linkages to cases in the PG004
cluster. Epidemiological linkages were identified with 17 additional case-patients
in whom cultures were either negative or not collected, for example, pediatric
case-patients. Our final study population consisted of all 56 case-patients
in the PG004 cluster and the 17 case-patients with epidemiological linkages
to case-patients in the PG004 cluster.
We reviewed all available public health and medical records to collect
the following data: demographic and clinical information, risk factors for
TB, HIV infection, laboratory and radiographic results, date of symptom onset,
date of TB diagnosis, reasons for delay in diagnosis, estimated period of
communicability, treatment information, use of directly observed therapy,
adherence to treatment, and information on contact investigation, including
the evaluation of each contact. Additional information on acquired immunodeficiency
syndrome was obtained by cross-matching these case-patients with the AIDS
Registry in the California Department of Health Services.13
A contact investigation was routinely performed on all case-patients with
pulmonary TB and a source case-patient investigation was performed for all
pediatric and extrapulmonary TB case-patients. The concentric-circle approach
to contact investigation was used. Identified contacts were evaluated for
TB and tuberculous infection and then given treatment when appropriate. The
routine use of directly observed therapy and contact investigation as outlined
has been in place since 1985.
For our analysis, a source case-patient was defined as a patient who
was determined to have transmitted M tuberculosis
to another person. A secondary case-patient was defined as a patient who was
infected by an identifiable source. A secondary case-patient who transmitted M tuberculosis to other case-patients was also defined
as a secondary source case. Using predetermined criteria, 3 investigators
independently reviewed all available data to determine transmission linkages
among patients. Results from these independent reviews were compared and differences
between reviewers were resolved in a meeting. These results were presented
in a cluster conference to all public health nurses and disease investigators
involved with these patients. During the conference, additional information
on epidemiological linkages was collected and used to form the final assignment
of source and secondary case-patients.
For each case, we sought to determine the primary reason for disease
development. Secondary case-patients not identified as contacts during the
investigation of their sources were considered to have developed disease because
they were not identified as contacts in relation to their sources. All case-patients
not linked to any known source were assumed to have developed disease as a
result of failure to be elicited as a contact to an unidentified source.
For those secondary case-patients who were elicited as contacts of their
sources, we assumed their disease could only have been prevented if there
had been sufficient time for them to be identified, evaluated, and given preventive
treatment. According to established guidelines in California,14
contacts should have been elicited and evaluated, and receiving treatment
within 2 to 4 weeks after the initial report of suspected or confirmed TB.
The exact duration depends on the communicability of the index case-patient
and the risk characteristics of the contact. Based on these guidelines, secondary
case-patients were defined as having resulted from delayed diagnosis of their
source case if they developed disease before their sources were reported to
the health department or within 30 days following such reports. For each of
these secondary case-patients, TB could not have been prevented unless their
sources had been diagnosed and reported earlier.
For the remaining secondary case-patients, we compared their date of
disease onset to the date when contact investigation was initiated for their
sources, the date when each secondary case-patient was identified as a contact,
and the date when medical evaluation for each secondary case-patient was initiated
and completed. This allowed us to identify those case-patients who developed
disease because of delay in being elicited as contacts and delay in initiating
or completing medical evaluation of these contacts.
Among those secondary case-patients who had not developed TB by the
end of their medical evaluation as a contact, we assessed whether they were
given appropriate treatment for tuberculous infection and whether they completed
their treatment. Thus, we identified secondary case-patients resulting from
failure to start or complete treatment for tuberculous infection. For those
secondary case-patients who completed a course of treatment for tuberculous
infection but still developed TB, we initially concluded that such treatment
had failed. For case-patients with a prior history of TB, we also initially
concluded that they had a relapse of TB. For these last 2 categories of case-patients,
we placed them into the category of exogenous reinfection if 2 conditions
were met: the case-patient had contact with another infectious TB patient
after the completion of their treatment for TB infection or disease; and the M tuberculosis isolates from the case-patient and his/her
putative source had the same genotype. We used the above criteria to determine
why their disease was not prevented after reinfection.
Statistical software (SAS, version 6.12, SAS Institute Inc, Cary, NC;
Epi Info, version 6, Centers for Disease Control and Prevention, Atlanta,
Ga) was used to calculate relative risks and to generate 95% confidence intervals
of point estimates, including use of exact methods when appropriate.
Of the 221 patients with TB reported in Contra Costa County during 1996-1997,
73 (33%) were linked by TB genotyping or an epidemiological relationship,
or both, to a single strain of M tuberculosis. This
strain was susceptible to all first-line anti-TB drugs. The 73 case-patients
did not include 3 case-patients determined to have resulted from laboratory
cross-contamination. The demographic, sociobehavioral, and disease characteristics
of the 73 case-patients are reported in Table 1. Eighty-five percent of these case-patients were reported
from 3 ZIP codes in the densely populated western part of the county. The
involved areas had high rates of poverty, homelessness, substance abuse, and
Initially, the 3-person review group separated the 73 case-patients
into 13 epidemiologically linked clusters and was left with 20 unlinked case-patients.
Based on additional information gathered at the cluster conference, the final
grouping of clusters was established: 57 case-patients in 13 epidemiologically
linked clusters and 16 unlinked case-patients.
Among the 57 case-patients in linked clusters, there were 6 source case-patients
and 51 secondary case-patients (Figure 1).
However, 9 of the 51 secondary case-patients also became secondary source
case-patients, giving rise to other cases during 1996-1997. Ten of the 57
clustered case-patients resulted from 7 source case-patients reported prior
to 1996, with 5 of 7 reported in 1995. Overall, only 2 (4%) of 51 secondary
case-patients resulted from remote infection (transmission that occurred >2
years ago). When we included the case-patients reported prior to 1996 into
the 13 clusters, our clusters ranged in size from 2 to 19 case-patients (median,
For 20 case-patients, the primary reason for disease development was
delayed diagnosis of their sources (Table
2). These case-patients were identified and immediately evaluated
during the contact investigation of their sources, but they had already developed
TB. Among the cases resulting from delayed diagnosis of their sources, 12
(60%) case-patients were pediatric and 7 (35%) were not culture-confirmed.
Pediatric case-patients were more likely than adult case-patients to have
developed TB from delayed diagnosis of their sources (12/19 vs 8/32; relative
risk [RR], 2.5; 95% confidence interval [CI], 1.2-5.0).
Problems associated with elicitation of contact resulted in discovery
of 40 cases. Seventeen case-patients were not identified during the contact
investigation of their sources. Therefore, the primary reason for disease
development was failure to be elicited as a contact. For the 22 cases with
no identifiable source (16 unlinked case-patients and 6 source case-patients
reported in 1996-1997), we assumed that their primary reason for disease development
was also failure to be elicited as a contact. A delay in eliciting a contact
led to 1 case-patient. In this instance, the contact investigation surrounding
the source case-patient occurred within 1 day of case report to the health
department, but it took 72 days for the health department to elicit the contact
and the patient developed TB during this period of delay.
Problems associated with evaluation of contacts resulted in 6 case-patients.
Four contacts developed TB because they failed to complete their recommended
evaluation—1 contact could not be located, a second contact refused
any medical evaluation, and 2 other contacts were determined to have a tuberculin
skin test but failed to keep multiple medical appointments. Another contact
developed TB because of delay in completing his medical evaluation. At the
time of initial evaluation, the patient was asymptomatic but had a positive
tuberculin skin test result. However, the patient missed appointments for
a chest radiograph and was found to have TB when evaluation was completed.
One other contact developed TB because of improper evaluation. In this case,
the health department did not repeat the tuberculin skin test in the contact
who had a negative initial skin test result.
Problems associated with treatment of contacts for tuberculous infection
resulted in 7 cases. Isoniazid treatment was recommended to 2 contacts, but
they did not keep their medical appointments and subsequently developed TB;
another contact was not offered isoniazid treatment because he had completed
treatment for a prior episode of TB. One case-patient did start isoniazid
treatment but discontinued her treatment and subsequently developed TB. Three
contacts developed TB after completing 6 to 12 months of isoniazid treatment
for tuberculous infection. Only 1 of the 3 case-patients was certain to have
adhered to his treatment since he was receiving directly observed preventive
therapy; the other 2 case-patients completed their self-administered preventive
Three case-patients had prior treatment for TB, but all had evidence
of exogenous reinfection. They all had new exposure to an infectious case
of TB after completing appropriate treatment for their prior episode of TB.
One case-patient received directly observed therapy; the second case-patient
did not receive directly observed therapy but had no documented treatment
nonadherence. The isolates from the 2 case-patients had the same genotype
as the isolates from their current putative source case-patients. Although
reinfection is likely in these 2 case-patients, endogenous relapse with the
original strain cannot be ruled out. One other case-patient had a history
of TB but with an isoniazid-monoresistant organism. Because the case-patient's
current isolate was pan-sensitive, we concluded that reinfection was likely.
None of the 3 case-patients was immunocompromised.
Of the 51 case-patients with identifiable sources, 17 were not elicited
as contacts to their sources. Out-of-household contacts were less likely than
household contacts to be elicited (15/31 vs 19/20; RR, 0.51; 95% CI, 0.35-0.74).
Among the out-of-household contacts, some came in contact with their sources
in home settings and others occurred in nonhome settings, with illicit drug
use locations being the most common sites. Out-of-household contacts in nonhome
settings were less likely to be elicited than out-of-household contacts in
home settings (3/13 vs 12/18; RR, 0.35; 95% CI, 0.12-0.98).
Twenty of the 23 identifiable sources were reported from 1995 to 1997.
Information on their treatment and contact investigation showed that they
were well managed from a public health perspective (Table 3). In 8 of the 12 case-patients with longer than 60 days
from symptom onset to diagnosis, secondary cases of TB had already developed
among their contacts by the time the diagnosis was established. In contrast,
only 2 of the 8 case-patients with 60 days or less from symptom onset to diagnosis
had secondary cases of TB among their contacts by the time they were diagnosed
(RR, 0.38; 95% CI, 0.11-1.33).
Overall, of the 10 sources with secondary cases that resulted from their
delayed diagnosis, 8 took longer than 60 days from symptom onset to diagnosis.
For 9 of these 10 sources, we determined that patient delay in seeking medical
evaluation was the main cause of the delay in establishing the diagnosis.
In 1992, a strain of M tuberculosis that had
2 copies of IS6110 was isolated from Contra Costa County. Bradford et al15 reported a cluster of 19 cases with this strain as
part of a larger study. Using the pTBN12 method, one investigator (Don Cave,
PhD, University of Arkansas for Medical Sciences, Little Rock) compared the
current strain of M tuberculosis to the prior strain
and they had the same restriction fragment-length polymorphism pattern. Case-patients
in the 2 clusters resided in the same area and had similar patient demographics.
We did not attempt to find direct epidemiological linkages between the 2 clusters.
In this study, we used molecular and conventional epidemiological methods,
along with a detailed assessment of program data, to determine the factors
responsible for the spread of a strain of M tuberculosis in a community. Over a 2-year period, this strain of M tuberculosis was responsible for one third of all cases in a community
that has implemented the key elements of TB control. These cases did not result
from a single source outbreak or institutional transmission but rather from
multiple sources infecting others in community settings, with the vast majority
of transmission occurring within the 2 years prior to disease development.
A detailed examination of why this strain of M tuberculosis successfully propagated in this community revealed it was largely
due to failure in contact elicitation and delay in diagnosis of infectious
More than 50% of the case-patients were not elicited as contacts to
their sources. This finding of TB among unidentified contacts is consistent
with other studies, which showed that routine contact investigation identified
epidemiological linkages in only a small percentage of case-patients with
the same strain of M tuberculosis.4,5,7
Such results have led some investigators to recommend that contact investigation
activities, at least in our urban communities, should be intensified.5,7 Our results lend support to this recommendation
since nearly half of the missed epidemiological linkages could be established
in retrospect. We believe an intensification of contact identification activities
in this community can identify more infected contacts before they become TB
Such intensification, at least in this community, will have to focus
on out-of-household contacts because the vast majority of cases from failed
contact elicitation occurred in this population. In particular, contacts in
settings other than the typical household accounted for a large proportion
of the TB cases from failed contact elicitation. Special effort should be
targeted toward the population with a high prevalence of substance abuse and
homelessness. To identify this group of contacts, investigations based on
location or social network may be useful.4,16,17
Clearly, the traditional concentric-circle approach is inadequate in this
Although secondary cases occurred from problems in contact elicitation,
it is important to point out that the county's contact investigation program
was functioning properly. The health department initiated contact investigation
for all infectious TB case-patients and this was done in a timely manner for
nearly all identified sources in this study. Both the mean and median number
of contacts identified was high. Despite this, cases of TB due to recent infection
continued to occur.
In this study, at least one quarter of the patients developed TB because
of delayed diagnosis of their sources. Although delayed diagnosis of TB is
believed to contribute to the transmission of M tuberculosis, the importance of this to the development of TB in a given community
has not been well described. Delayed diagnosis has been identified as a major
reason for community-based TB outbreaks.18
Studies on delayed diagnosis of TB have focused on determining the risk factors
for delayed diagnosis, such as older age, atypical radiographic presentation,
or extrapulmonary TB.19- 21
Other studies have explored patients' attitudes and beliefs to determine how
they may lead to delays in diagnosis.22 To
our knowledge, this is the first study to actually quantify the contribution
of delayed diagnosis to the development of secondary case-patients with TB.
In this community, delayed diagnosis of TB disproportionately affected
the development of TB in children. Two thirds of the pediatric case-patients
with this strain of M tuberculosis developed disease
because of delayed diagnosis of their sources. Pediatric case-patients were
5 times more likely than adult case-patients to have TB that resulted from
delayed diagnosis of their sources.
Some studies have defined delay in diagnosis of TB by a period of at
least 60 days from symptom onset to diagnosis.23
Our study did not focus on absolute delay but instead focused on whether any
delay, regardless of duration, resulted in secondary cases. We found that
even though 60% of the sources had a delay from symptom onset to diagnosis
of at least 60 days, not all such delays led to secondary cases. In contrast,
some secondary case-patients did develop TB even though their sources were
diagnosed within 60 days from symptom onset. Although sources with delays
in TB diagnoses were more likely to be linked to secondary case-patients,
this association was not statistically significant. In this study, patient
delay in seeking medical care was more important than physician delay as a
factor for disease development. Therefore, interventions to reduce delayed
diagnosis in this community will have to include efforts to get patients to
seek health care earlier.
Less than 20% of the case-patients resulted from problems with the evaluation
or treatment of identified contacts. Several contacts developed TB because
they were nonadherent to various steps in their evaluation despite efforts
by the health department. Some contacts also failed to start treatment or
did not complete treatment for tuberculous infection. A few contacts developed
TB after completing a course of preventive therapy; however, the degree of
adherence to such therapy is unknown. Although improvement in contact evaluation
and treatment should be encouraged, it is important to point out that such
improvement will only prevent a small percentage of cases in this community.
The propagation of this strain of M tuberculosis
in this community is likely to have been going on for several years. The most
convincing evidence of this is the identification of a cluster of case-patients
with this strain of M tuberculosis dating back to
1992.15 Although this strain appears to be
endemic in this community, most of the patients with disease from this strain
were recently infected. Therefore, the presence of an endemic strain of M tuberculosis does not preclude the possibility that disease
from the strain is due to recent infection.
There are limitations to this study. First, these results do not tell
us how well the program actually performed in contact investigation activities,
it only tells us about the cases that develop from gaps in contact investigation
activities. We also cannot determine the number of cases prevented because
of current activities. A control group of case-patients would be needed to
determine this. Second, we could not evaluate all factors contributing to
the successful propagation of this strain of M tuberculosis. The organism's virulence or the genetic susceptibility of individuals
to TB may play a part in the successful propagation of the strain of M tuberculosis.24,25
Neither of these factors was assessed. Third, we cannot be certain that case-patients
with epidemiological linkages to this strain of M tuberculosis, but without culture confirmation, were infected by the same strain.
A recent study found that a third of the TB case-patients with epidemiological
linkages were infected with a different strain of M tuberculosis.26 However, case-patients born in the
United States (as with our study population) were more likely to have the
same strain. In addition, the high number of pediatric case-patients among
the culture-unconfirmed case-patients also increases the likelihood that these
case-patients were infected by the same strain. Fourth, the epidemiology of
TB tends to vary from location to location. Therefore our results may not
be generalizable to all communities in which there is ongoing transmission
of M tuberculosis. However, the methods used in this
study can be used to determine why disease due to recent infection continues
to occur in other communities.
Our results are consistent with molecular epidemiological studies from
TB control programs in San Francisco and Baltimore, Md.7,27
These studies found that even when the treatment completion rate for TB is
high and contact investigation is performed, disease due to ongoing transmission
could not be eliminated and, in fact, accounted for a substantial proportion
of cases. Our results extend these findings by identifying key reasons for
the development of TB. Unless we can identify cases earlier and elicit a complete
list of contacts, we will not be able to eliminate TB from ongoing transmission
of M tuberculosis in this and likely other communities
using currently available tools.