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Tuberculosis Recurrences
Reinfection Plays a Role in a Population Whose Clinical/Epidemiological Characteristics Do Not Favor Reinfection
Darío García de Viedma, PhD;
Mercedes Marín, PharmD, PhD;
Susana Hernangómez, MD;
Marisol Díaz, PharmD, PhD;
María Jesús Ruiz Serrano, PharmD;
Luis Alcalá, PharmD;
Emilio Bouza, MD, PhD
Arch Intern Med. 2002;162:1873-1879.
ABSTRACT
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Background Tuberculosis (TB) recurrences can be due to either reactivation by the
same strain (standard assumption) or reinfection by a new strain. Reinfection
has mainly been studied in selected populations with a high risk of reexposure
to TB. Our aim was to analyze the role of reinfection in TB recurrences in
unselected populations, without the clinical/epidemiological circumstances
that favor the involvement of a new different strain of Mycobacterium tuberculosis in the recurrence.
Methods A molecular typing analysis was performed with 92 sequential isolates
of M tuberculosis from 43 patients with recurrent
TB, during a 12-year period. The subjects were both positive and negative
for the human immunodeficiency virus, most did not adhere to anti-TB therapy,
and they lived in an area with a moderate incidence of TB. Recurrence was
considered as being caused by reinfection when the molecular fingerprints
for the strains involved in the sequential episodes of TB were different.
Results In 14 (33%) of the 43 patients, different M tuberculosis strains were involved in the first and in subsequent episodes of TB.
Reinfection was found for patients who were both positive and negative for
the human immunodeficiency virus, and most patients did not adhere to anti-TB
therapy. Differences between the reinfection and reactivation groups were
not significant (P = .77) according to the time interval
between episodes.
Conclusions Reinfection plays an important role in recurrent TB in a population
without the clinical/epidemiological circumstances that are usually assumed
to favor it. Reinfection should, thus, be considered as a cause of TB recurrences
in a wider context than before.
INTRODUCTION
THE PROPORTION of patients with a well-documented first episode of tuberculosis
(TB) who have a second recurrent episode is not well-known for unselected
populations, and the proportion depends on different socioeconomic conditions.
Tuberculosis recurrences are assumed to be mainly due to mismanagement of
the disease, resulting from either poor adherence to correct therapy or the
administration of inadequate treatment.
Recurrences have traditionally been considered as endogenous reactivations
of the strain that caused the primary episode. Different studies have failed
to find reinfections1-3
or have only described anecdotal cases in which different strains are isolated
from the primary and postprimary episodes.4-6
Some researchers7-8 described
a high rate of recent infections in studies of TB transmission dynamics. A
few studies9-11
have found a role for reinfection in TB recurrences, always in selected high-risk
groups of patients in whom reinfection is favored by specific epidemiological
circumstances.
Our study searches for the rate of recurrent episodes of TB occurring
in a large unselected population, not particularly prone to reinfection, during
a 12-year period, and tries to assess the role of a new strain (reinfection)
or the same strain (reactivation) in these recurrences—a key issue with
clinical, therapeutic, and epidemiological repercussions.
PATIENTS AND METHODS
PATIENTS
Our institution is a 1700-bed hospital that serves a population of 630 000.
The percentage of the working population is 77%; 74% have completed high school
studies, and 12% are educated to the university level. The percentage of immigrants
is 6%. The incidence of TB in this area from January 1, 1994, through December
31, 1999, has decreased, mainly due to the reduction of acquired immunodeficiency
syndrome–associated cases after the introduction of highly active antiretroviral
treatment, from 66 to 29 cases per 100 000 inhabitants per year.
We reviewed the records (databases) of the mycobacteriology laboratory
of our institution from January 1, 1988, to December 31, 1999. All patients
with 1 or more isolates of M tuberculosis in different
respiratory clinical samples were considered. We considered patients with
recurrent episodes, ie, all those with new isolates of M tuberculosis separated by more than 100 days (median, 430 days) from
the primary episode (day 0). Nonadherence to treatment was not a criterion
of exclusion, because our aim was to explore the role of reinfection in circumstances
in which it is not usually expected, including in those patients in whom reactivation
is usually assumed to be due to treatment failure. In the patients selected
with recurrent episodes, we collected information regarding sex, age, human
immunodeficiency virus (HIV) status, other risks for immunosuppression, anti-TB
therapy, duration of treatment, time between episodes, and physicians' opinion
regarding individual adherence to therapy. Adherence to treatment was defined
as completion of at least 6 months of combination therapy. Nonadherence was
considered exclusively when it was confirmed by the patient and the clinician.
Directly observed therapy was not available in our patients. All these data
are compiled in Table 1.
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Table 1. Epidemiological and Clinical Features of Patients With Sequential
Episodes of TB Caused by Different Strains (Reinfection)*
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The strains cultured from the first and subsequent episodes for all
patients were frozen at -70°C. For study purposes, only cultures
from respiratory specimens were considered for analysis.
METHODS
Microbiological Methods
Clinical specimens were processed according to standard methods and
inoculated in Löwenstein-Jensen slants and, since January 1, 1995, also
in mycobacteria growth indicator tube media (Becton, Dickinson and Company,
Sparks, Md). Susceptibility testing for isoniazid, rifampin, streptomycin
sulfate, and ethambutol hydrochloride was performed for all the strains involved
in reinfections. For strains before January 1, 1992, the proportions method
was applied, and from this date, it was performed by another system (MB/BacT;
Organon Teknika Diagnostics, Durham, NC). Correlations between these 2 approaches
have been proved.12 The susceptibility patterns
were confirmed by reassaying all cases in which resistance was detected.
Molecular Typing Methods
Spacer Oligonucleotide Typing (Spoligotyping) Assay.
The spoligotyping assay, which explores polymorphisms in the directed
repeats locus of Mycobacterium tuberculosis, was
performed as follows. For chromosome extractions, 1 mL of the bacteria cultured
in mycobacteria growth indicator tubes (Becton, Dickinson and Company) was
centrifuged. Cells were resuspended in lysis reagent from Gene-Probe (Accuprobe,
San Diego, Calif) and boiled for 5 minutes. Lysis beads (Gene-Probe) were
added, and the suspension was sonicated for 5 minutes. The polymerase chain
reaction (PCR) for amplifying the directed repeats region was performed using
primers of the spoligotyping kit (Isogen Bioscience, Maarssen, the Netherlands),
following the manufacturer's instructions. All spoligotypes showing differences
for the strains from each patient were reassayed to confirm reinfection. When
a spoligotype showed ambiguities in any of the boxes, the assay was repeated
to obtain definite hybridization signals.
Double-Repetitive Elements (DRE)–PCR Assay.
The DRE-PCR assay was performed as a secondary typing method on all
the isolates that were considered to be indistinguishable by spoligotyping.
The chromosome of M tuberculosis was prepared as
described for spoligotyping. The DRE-PCR assay was performed as described
elsewhere.13-14
Amplified products were loaded in precast polyacrylamide gels (GeneGel
Excel 12.5; Amersham-Pharmacia Biotech, Uppsala, Sweden) and run in an electrophoresis
instrument (GenePhore; Amersham-Pharmacia Biotech). Gels were silver stained
using a kit (Amersham-Pharmacia Biotech). These electrophoresis conditions
highly improved the reproducibility of the assay and the sensitivity of detection
of minor bands, thus eliminating the limitations of this technique when it
is performed in agarose gels and with ethidium bromide staining.15
All DRE-PCR assays showing differences between strains from each patient were
reassayed to confirm reinfection. The DRE-PCR types were considered different
when differences in more than 3 major bands were observed between strains.
This is an acceptable degree of difference because 3 bands constitute a high
proportion of the total number of bands obtained for the strains analyzed.
Interpretation of Molecular Typing Data.
Reactivation was considered the cause of the recurrence when the strains
isolated in the sequential episodes were identical, as determined by spoligotyping
and DRE-PCR. Reinfection was considered the cause of recurrence when different
typing patterns were obtained for the strains isolated from the sequential
episodes in spoligotyping or DRE-PCR assays.
To rule out cross contamination as a cause of misassignment of reinfections,
we followed 2 approaches that were applied alternatively, depending on the
availability of samples: (1) typing of the strains isolated from all the specimens
that were processed in the laboratory on the same day as the strains in the
analysis or (2) typing independent isolates for the same patient belonging
to the same episode (<7 days apart). Spoligotypes for the strains processed
on the same day from different patients were always different. For all control
samples within the same episode of each patient, the same spoligotype was
obtained. Both approaches ruled out cross contamination, indicating that the
strains assigned to each of the recurrent episodes caused by reinfections
were truly cultured from the patient's specimens.
STATISTICAL METHODS
The statistical package used for the analysis was Intercooled Stata
7.0 for Windows (Stata Corp, College Station, Tex). Because the number of
patients was small, the Fisher exact test was preferred for the comparisons
between the distribution of risk factors included in Table 2. The equality of medians was tested using the median test.
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Table 2. Comparison of the Distribution of Risk Factors Associated
With TB*
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RESULTS
In our institution, from 1988 to 1999, 2567 patients were diagnosed
as having TB based on the isolation of M tuberculosis.
Overall, 172 patients had at least a second episode of TB more than 100 days
apart (7% of the patients with a confirmed first episode). Ninety-two M tuberculosis sequential isolates from 43 patients with
more than 1 episode (range between episodes, 106-3373 days; median, 430 days)
were available for analysis.
All the 92 strains were typed by spoligotyping. Forty-six different
spoligotypes were obtained for the whole analysis group (Figure 1A and B).
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Figure 1. A, Patients with sequential episodes
caused by strains with different spacer oligonucleotide types (spoligotypes).
In patients 10 and 43, 2 of the episodes were caused by the same strain and
the other by a different strain. The number of different spacers between sequential
isolates is indicated. B, Patients with sequential episodes caused by strains
that were indistinguishable by spoligotyping. The sequential isolates that
were indistinguishable by spoligotyping but different by double-repetitive
elements–polymerase chain reaction are shaded.
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When considering the sequential isolates for each of the 43 patients,
10 (23%) showed different strains for the first and second episodes, meaning
reinfection was the cause of their recurrences. The spoligotypes for the sequential
strains considered as different showed differences in a minimum of 4 spacers
of the directed repeats locus (indicated by differences in 4 boxes in the
spoligotype) and a maximum of 20, which means that the strains were clearly
different (Figure 1A). In the other
33 patients (77%), the isolates cultured from their sequential episodes were
indistinguishable by spoligotyping (Figure
1B).
For 2 patients with 3 episodes analyzed (patients 10 and 43), their
recurrences showed a combined pattern: 2 episodes caused by reactivation,
and the other caused by reinfection (Figure
1A).
To check the typing data and to increase the discriminatory power of
the spoligotyping assay, a second molecular typing method (DRE-PCR) was performed
for the 33 patients whose sequential isolates were considered indistinguishable.
With this second-line typing assay, the presence of identical strains in the
first and postprimary episodes was confirmed for 29 of these 33 patients (Figure 2A). In the remaining 4 patients,
DRE-PCR found major differences between the patterns of the sequential isolates
(Figure 2B). Therefore, after the
second-line typing assay, an additional 4 (9%) of the 43 patients had different
strains for their first and second episodes, thus indicating reinfection.
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Figure 2. A, Typing patterns of a selection
of the sequential isolates that were indistinguishable by spacer oligonucleotide
typing and double-repetitive elements–polymerase chain reaction (DRE-PCR).
B, Sequential isolates with different DRE-PCR patterns. M indicates molecular
weight marker.
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If the data for the double-typing approach are taken together, reinfection
was found in 14 (33%) of the 43 patients analyzed. Reactivations involving
the same strain were found in the remaining 29 (67%) of the 43 patients.
For the reinfection and reactivation groups, there were no significant
differences according to HIV status or to other risk factors, such as adherence
to anti-TB therapy, intravenous drug abuse, alcoholism, homelessness, or prison
stay (Table 2). The differences
between the median (95% confidence interval) time between episodes were not
significant (reinfection vs reactivation group, 479.5 [254.0-1020.0] vs 303.0
[228.9-578.1] days; median test, continuity-corrected Pearson  21 = 0.09, P = .77). The mean (SD)
times between episodes were as follows: reinfection group, 800.1 (837.3) days;
and reactivation group, 593.7 (744.0) days. The interquartile range was 831.7
days for the reinfection group and 528.0 days for the reactivation group.
The antimicrobial susceptibility of the strains involved in the cases
of reinfection remained unchanged (drug susceptible) in all patients but 3
(Table 1). Two of these acquired
resistance (patients 10 and 28), and in the other (patient 1), reinfection
was caused by a more susceptible strain than the one from the primary episode
(Table 1).
COMMENT
Of all the patients diagnosed as having TB in our institution during
the past 12 years, 7% had a recurrent episode. Data available for comparison
are scarce, generally from old series or from selected groups of the population,
and depend on anti-TB therapeutic regimens.Figures for recurrence range from
1% to 11%,16-18
and for one of the classic studies,17 the recurrence
proportion (6%) is practically equivalent to ours, despite the availability
of anti-TB drugs, the low level of primary resistance, and the close follow-up
of patients with TB in our country.
Our study presents an analysis of 92 strains involved in sequential
episodes of TB from 43 patients, during a 12-year period. To our knowledge,
this is the longest follow-up and the largest group of patients studied in
the context of TB recurrences.
An unexpectedly high frequency of reinfection (33%) was found in our
population. A previous study by van Rie et al11
found a large proportion of reinfection in a selected population of HIV-negative
patients after curative treatment; these patients lived in an extremely high
incidence area (1000 cases per 100 000 population per year). On the contrary,
the population in our study was unselected, there were both HIV-positive and
HIV-negative patients, the patients lived in an area with a much lower incidence
of TB (mean incidence for the last 6 years of the study period, 44 per 100 000),
and the patients were not in high-exposure situations (except for 1 patient).
Nevertheless, reinfection was the cause of a high percentage of recurrences,
which suggests that reinfection should not only be considered in circumstances
that favor reexposure. In a recent report by Caminero et al,19
a high percentage of reinfection was also found among patients with recurrent
TB who lived in a geographic setting with a moderate incidence of the disease.
One feature in our study could account for the frequent finding of reinfection—the
high variability found among the strains circulating in our area. Of the 46
spoligotypes obtained, 41 were unique. In this sense, there have been reports11 on the inability to detect reinfections when 2 independent
strains of the same majority endemic clone are involved in 2 sequential episodes.
Molecular epidemiological studies1, 20
in patients with TB frequently find the presence of majority clones. This
could be the cause of an underestimation of reinfection in other studies.
It is possible that the wide variation of clones in our population provided
the optimal conditions to reveal the real proportion of reinfection in patients
with TB.
Most of the patients in our study with recurrences due to reinfection
did not adhere to anti-TB treatment. Recurrences in patients without curative
therapy of their primary TB are expected to be due to reactivations of the
same strain, which cannot be assumed to have been eliminated from the organism.
Surprisingly, all but 3 of our 14 reinfected patients did not adhere to treatment,
and this may imply a role for reinfection for more cases than previously expected.
Initially, our study could be criticized for having selected patients with
a second isolate of M tuberculosis who did not adhere
to therapy during their first episode. These patients are not usually considered
to have recurrences but are considered to be patients in whom treatment has
failed. Nevertheless, our data indicate that in many of these cases, a different M tuberculosis strain is responsible for the second isolation,
which suggests that the concepts of recurrence/reinfection could not a priori
be defined by adherence to therapy during the first episode. It is difficult
to explain reinfection in patients in whom primary TB has not been efficiently
treated. The strain involved in the first episode may not have been eliminated
by therapy, but could have been displaced after competition with the new strain,
if the new strain showed higher biological fitness or more efficient interactions
with host factors. Another explanation for reinfection in patients who did
not adhere to anti-TB therapy could be the occurrence of coinfection with
more than 1 strain and the selective growth of different strains for the first
and second episodes. We have preliminary data from a selection of these patients
in whom clonally homogeneous populations of M tuberculosis are found after typing multiple independent colonies for each of their
episodes. Thus, coinfection with more than 1 strain could reasonably be excluded.
In our study, we did not find significant differences in the distribution
of the main risk factors for TB between the reinfection and reactivation groups,
although we cannot rule out that it might be due to a lack of statistical
power to detect differences, given the small number of patients. Both HIV-positive
and HIV-negative patients were found in the reinfection and reactivation groups.
An assumption in the analysis of recurrences in patients with TB is the immune
protection that the primary episode is supposed to confer. Therefore, reinfection
is usually not considered for HIV-negative patients not living in high-exposure
situations. In our analysis, reinfection is also found for HIV-negative patients,
and differences in HIV status are not significant for the reinfection and
reactivation groups. This suggests a role of factors other than immune status
in modulating reactivation and recurrence dynamics.
Furthermore, the assumption that reinfection is more likely in episodes
farther apart in time, whereas reactivations are assumed for episodes closer
in time, should be approached with caution. Some researchers11, 21
have found cases of reinfection at the end of therapy and even during the
therapy period. In our analysis, the differences in time intervals between
reinfection and reactivation episodes were not significant. Reinfections were
found for episodes close in time, and reactivations occurred for episodes
far apart in time.
Some studies5, 10, 22-23
have found reinfection to be associated with the acquisition of strains with
higher resistance to anti-TB drugs. In our case, strains involved in reinfection
are rarely associated with a higher resistance, and in 1 case, the strain
in the second episode was more susceptible than that which caused the first
episode. This is consistent with the nonadherence to therapy generally found
in our patients. Thus, resistance confers no advantages on new strains if
treatment has not been adhered to.
In our study, the typing design is different from that of previous reports,2, 9, 11, 21 in
which restriction fragment length polymorphism was the method selected. We
performed a double-line typing assay, following previously recommended procedures.24-27 In
our case, a highly reproducible method, such as spoligotyping, was first performed15, 28 to search for differences between
strains involved in reinfection. A secondary typing method, DRE-PCR,13-14 was applied to increase the discriminatory
power of the assay to guarantee cases sharing typing patterns and, therefore,
confirm reactivation. This approach lacks the limitations that are found for
IS6110 restriction fragment length polymorphism,24, 29-31 and
has been proved to have an equivalent discriminatory power as this reference
method.25
To test the validity of our molecular data, we performed 2 alternative
approaches to rule out the potential role of laboratory cross contamination
in misassigning some cases of reinfection.11, 32
We checked that (1) the strains from specimens cultured in the laboratory
on the same day as those in analysis did not share spoligotypes or (2) the
strains cultured from other samples close in time for the same patient showed
an identical typing pattern. Both observations lead us to be confident about
the validity of our data.
In conclusion, our study shows a high proportion of TB recurrences caused
by reinfection with a new strain. Reinfection in our analysis was found in
a group of unselected patients and, therefore, they were not as homogeneous
as others in previous reports. It was detected for HIV-positive and HIV-negative
patients, in conditions in which high exposure was not expected, and in patients
who did not generally adhere to anti-TB treatment. Our data suggest that even
when clinical/epidemiological characteristics do not particularly favor reinfection,
it should not be ruled out.
AUTHOR INFORMATION
Accepted for publication January 3, 2002.
We thank Beatriz Pérez Gómez for her help with the statistical
analysis; Oscar Cuevas for his help with the typing assays; and Thomas O'Boyle
for his revision of the English in the manuscript.
Corresponding author and reprints: Darío García de
Viedma, PhD, Servicio de Microbiología y Enfermedades Infecciosas,
Hospital Gregorio Marañón, C/Dr Esquerdo 46, 28007 Madrid, Spain
(e-mail: dgviedma{at}microb.net).
From the Servicio de Microbiología y Enfermedades Infecciosas,
Hospital Gregorio Marañón, Madrid, Spain.
REFERENCES
| |
1. Soini H, Pan X, Amin A, Graviss EA, Siddiqui A, Musser J. Characterization of Mycobacterium tuberculosis
isolates from patients in Houston, Texas, by spoligotyping. J Clin Microbiol. 2000;38:669-676.
FREE FULL TEXT
2. March F, Garriga X, Rodríguez P, et al. Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency
virus–associated tuberculosis. Clin Infect Dis. 1997;25:1044-1047.
ISI
| PUBMED
3. Strassle A, Putnik J, Weber R, Fehr Merhof A, Pfyffer GE. Molecular epidemiology of Mycobacterium tuberculosis strains isolated from patients in a human immunodeficiency virus cohort
in Switzerland. J Clin Microbiol. 1997;35:374-378.
ABSTRACT
4. Godfrey Fausset P, Githui W, Batchelor B, et al. Recurrence of HIV-related tuberculosis in an endemic area may be due
to relapse or reinfection. Tuber Lung Dis. 1994;75:199-202.
FULL TEXT
|
ISI
| PUBMED
5. Shafer RW, Singh SP, Larkin C, Small PM. Exogenous reinfection with multidrug resistant Mycobacterium
tuberculosis in an immunocompetent patient. Tuber Lung Dis. 1995;76:575-577.
FULL TEXT
|
ISI
| PUBMED
6. van Rie A, Warren RM, Beyers N, et al. Transmission of a multidrug resistant Mycobacterium
tuberculosis strain resembling "strain W" among noninstitutionalized,
human immunodeficiency virus–seronegative patients. J Infect Dis. 1999;180:1608-1615.
FULL TEXT
|
ISI
| PUBMED
7. Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco. N Engl J Med. 1994;330:1703-1709.
FREE FULL TEXT
8. Alland D, Kalkut GE, Moss AR, et al. Transmission of tuberculosis in New York City. N Engl J Med. 1994;330:1710-1716.
FREE FULL TEXT
9. Chaves F, Dronda F, Alonso Sanz M, Noriega AR. Evidence of exogenous reinfection and mixed infection with more than
one strain of Mycobacterium tuberculosis among Spanish
HIV-infected inmates. AIDS. 1999;13:615-620.
FULL TEXT
|
ISI
| PUBMED
10. Nardell E, NcInnis B, Thomas B, Weidhaas S. Exogenous reinfection with tuberculosis in a shelter for the homeless. N Engl J Med. 1986;315:1570-1575.
ABSTRACT
11. van Rie A, Warren R, Richardson M, et al. Exogenous reinfection as a cause of recurrent tuberculosis after curative
treatment. N Engl J Med. 1999;341:1174-1179.
FREE FULL TEXT
12. Díaz Infantes MS, Ruiz Serrano MJ, Martínez Sánchez L, Ortega A, Bouza E. Evaluation of the MB/BacT Mycobacterium detection system for susceptibility
testing of Mycobacterium tuberculosis. J Clin Microbiol. 2000;38:1988-1989.
FREE FULL TEXT
13. Friedman CR, Stoeckle MY, Johnson WD, Riley LW. Double-repetitive-element PCR method for subtyping Mycobacterium tuberculosis clinical isolates. J Clin Microbiol. 1995;33:1383-1384.
ABSTRACT
14. Montoro E, Valdivia J, Cardoso Leao S. Molecular fingerprinting of Mycobacterium tuberculosis isolates in Havana, Cuba, by IS6110 restriction
fragment length polymorphism analysis and by the double-repetitive-element
PCR method. J Clin Microbiol. 1998;36:3099-3102.
FREE FULL TEXT
15. Kremer K, van Soolingen D, Frothingham R, et al. Comparison of methods based on different molecular epidemiological
markers for typing of Mycobacterium tuberculosis
complex strains: interlaboratory study of discriminatory power and reproducibility. J Clin Microbiol. 1999;37:2607-2618.
FREE FULL TEXT
16. Girling DJ. Hong Kong Tuberculosis Treatment Services/British Medical Research
Council study of short-course regimens of streptomycin, isoniazid and pyrazinamide:
latest results. Tubercle. 1975;56:81-96.
FULL TEXT
|
ISI
| PUBMED
17. Hong Kong Tuberculosis Treatment Services and East African and British
Medical Research Councils. First-line chemotherapy in the retreatment of bacteriological relapses
of pulmonary tuberculosis following a short-course regimen. Lancet. 1976;1:162-163.
FULL TEXT
| PUBMED
18. Hong Kong Chest Service/British Medical Research Council. Controlled trial of four thrice-weekly regimens and a daily regimen
all given for 6 months for pulmonary tuberculosis. Lancet. 1981;1:171-174.
FULL TEXT
| PUBMED
19. Caminero JA, Pena MJ, Campos Herrero MI, et al. Exogenous reinfection with tuberculosis on a European island with a
moderate incidence of disease. Am J Respir Crit Care Med. 2001;163(pt 1):717-720.
20. Sola C, Devallois A, Horgen L, et al. Tuberculosis in the Caribbean: using spacer oligonucleotide typing
to understand strain origin and transmission. Emerg Infect Dis. 1999;5:404-414.
ISI
| PUBMED
21. Small PM, Shaffer RW, Hopewell PC, et al. Exogenous reinfection with multidrug resistant Mycobacterium
tuberculosis in patients with advanced HIV infection. N Engl J Med. 1993;328:1137-1144.
FREE FULL TEXT
22. Horn DL, Hewlett D, Haas WH, et al. Superinfection with rifampin-isoniazid-streptomycin-ethambutol (RISE)–resistant
tuberculosis in three patients with AIDS: confirmation by polymerase chain
reaction fingerprinting. Ann Intern Med. 1994;121:115-116.
FREE FULL TEXT
23. Turett GS, Fazal BA, Justman JE, Alland D, Duncalf RM, Telzak EE. Exogenous reinfection with multidrug resistant Mycobacterium
tuberculosis. Clin Infect Dis. 1997;24:513-514.
ISI
| PUBMED
24. Wilson SM, Goss S, Drobniewski F. Evaluation of strategies for molecular fingerprinting for use in routine
work of a Mycobacterium reference unit. J Clin Microbiol. 1998;36:3385-3388.
FREE FULL TEXT
25. Sola C, Horgen L, Maisetti J, Devallois A, Seng Goh K, Rastogi N. Spoligotyping followed by double repetitive element PCR as rapid alternative
to IS6110 fingerprinting for epidemiological studies
of tuberculosis. J Clin Microbiol. 1998;36:1122-1124.
FREE FULL TEXT
26. Zumárraga MJ, Martín C, Samper S, et al. Usefulness of spoligotyping in molecular epidemiology of Mycobacterium bovis–related infections in South America. J Clin Microbiol. 1999;37:296-303.
FREE FULL TEXT
27. Yang ZH, Ijaz K, Bates JH, Eisenach KD, Cave MD. Spoligotyping and polymorphic GC-rich repetitive sequence fingerprinting
of Mycobacterium tuberculosis strains having few
copies of IS6110. J Clin Microbiol. 2000;38:3572-3576.
FREE FULL TEXT
28. Kamerbeek J, Schouls L, Kolk A, et al. Simultaneous detection and strain differentiation of Mycobacterium tuberculosis for diagnosis and epidemiology. J Clin Microbiol. 1997;35:907-914.
ABSTRACT
29. Das S, Paramasivan CN, Lowrie DB, Prabhakar R, Narayanan PR. IS6110 restriction fragment length polymorphism
typing of clinical isolates of Mycobacterium tuberculosis from patients with pulmonary tuberculosis in Madras, south India. Tuber Lung Dis. 1995;76:550-554.
FULL TEXT
|
ISI
| PUBMED
30. Gillespie SH, Dickens A, McHugh TD. False molecular clusters due to nonrandom association of IS6110 with Mycobacterium tuberculosis. J Clin Microbiol. 2000;38:2081-2086.
FREE FULL TEXT
31. Van Soolingen D, de Haas PEW, Hermans PW, Groenen PM, van Embden JD. Comparison of various repetitive DNA elements as genetic markers for
strain differentiation and epidemiology of Mycobacterium
tuberculosis. J Clin Microbiol. 1993;31:1987-1995.
FREE FULL TEXT
32. Stead WW, Bates JH. Recurrent tuberculosis due to exogenous reinfection. N Engl J Med. 2000;342:1050-1051.
FREE FULL TEXT
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Garcia de Viedma et al.
J. Clin. Microbiol. 2004;42:3415-3418.
ABSTRACT
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