CORRESPONDENCE
1 Ewer K, Deeks J, Alvarez L, et al.
Comparison of T-cell-based assay with
tuberculin skin test for diagnosis of
Mycobacterium tuberculosis infection in a
school tuberculosis outbreak. Lancet 2003;
361: 1168–73.
2 Wood PR, Jones SL. BOVIGAM™: an in
vitro cellular diagnostic test for bovine
tuberculosis. Tuberculosis 2001; 81: 147–55.
3 Buddle BM, Ryan TJ, Pollock JM,
Andersen P, de Lisle GW. Use of ESAT-6 in
the interferon-
test for diagnosis of bovine
tuberculosis following skin testing.
Vet Microbiol 2001; 80: 37–46.
4 Vordermeier HM, Chambers MA,
Cockle PJ, et al. Correlation of ESAT-6
specific gamma interferon production with
pathology in cattle following Mycobacterium
bovine BCG vaccination against experimental
bovine tuberculosis. Infect Immun 2002; 70:
3026–32.
5 Mazurek GH, LoBue PA, Daley CL, et al.
Comparison of a whole-blood interferon-

assay with tuberculin skin testing for
detecting latent Mycobacterium tuberculosis
infection. JAMA 2001; 286: 1740–47.
Sir—The test described by Katie Ewer
and colleagues1 has great potential as
an alternative to the tuberculin test.
But, what is really needed is a test able
to detect active tuberculosis in
children. Little emphasis is placed on
the management of childhood
tuberculosis in national tuberculosis
control programmes that incorporate
the WHO DOT (directly observed
therapy) strategy; too much importance
is given to sputum-smear positivity.
Diagnosis on the basis of positive
sputum smears is rarely possible in
children, because they produce little
sputum.
Simple, quick, and fairly inexpensive
tests with high sensitivity and
specificity are needed for the diagnosis
of childhood tuberculosis. I draw your
readers’ attention to two such tests.
The glutaraldehyde test is based on
the observation that whole blood from
patients with tuberculosis contains
more than the usual amount of
fibrinogen and, after mixing with an
equal volume of 1·25% glutaraldehyde,
coagulates within 10 min.2 When 2·5%
glutaraldehyde was used, Larsson and
colleagues3 observed a sensitivity of
89% and a specificity of 95%, and
Leon and colleagues4 noted 93%
sensitivity and 97% specificity with a
positive predictive value of 97·2% and
a negative predictive value of 93% in
children.
The second test involves the use of
hypertonic saline (3%) to induce
sputum production, which enhances
the bacteriological confirmation of
pulmonary tuberculosis in children.5
These tests, when used in
conjunction with a clinical
examination, can help to diagnose
pulmonary tuberculosis in children.
They will be particularly useful in
2082
For personal use. Only reproduce with permission from The Lancet Publishing Group.
developing countries, where costly
investigations are impractical.
Satish Agadi
Department of Paediatrics, Karnataka Institute
of Medical Sciences, Vidyanagar,
Hubli 580022, India
(e-mail: agadisatish@hotmail.com)
1 Ewer K, Deeks J, Alvarez L, et al.
Comparison of T-cell-based assay with
tuberculin skin test for diagnosis of
Mycobacterium tuberculosis infection in a
school tuberculosis outbreak. Lancet 2003;
361: 1168–73.
2 WHO. WHO tuberculosis diagnostic
workshop: product development
guidelines—Cleveland, Ohio, July 27, 1997.
http://www.who.int/tdr/publications/publicat
ions/pdf/TB%20Workshop%201997.pdf
(accessed May 15, 2003).
3 Larsson S, Shrestha MP, Pokhrel BM,
Upadhyay MP, Shrestha KB. The
glutaraldehyde test as a rapid screening
method for pulmonary tuberculosis: a
preliminary report. Ann Trop Med Parasitol
1990; 84: 111–17.
4 Leon B-RV, Go OC, Rivera CR. Validity of
2·5% and 2·0% glutaraldehyde test in the
diagnosis of pulmonary tuberculosis in
children. Chest 2002; 122 (suppl 4): S131.
5 Zar HJ, Tannenbaum E, Apolles P, Roux P,
Hanslo D, Hussey G. Sputum induction for
the diagnosis of pulmonary tuberculosis in
infants and young children in an urban
setting in South Africa. Arch Dis Child 2000;
82: 305–08.
Sir—Katie Ewer and colleagues1
suggest that an ELISPOT test based
on ESAT-6 and peptides from CFP-10
could improve tuberculosis control.
Screening of contacts is undertaken to
detect and prevent new cases of
tuberculosis. Ewer and co-workers
mention that there were 69 secondary
cases of tuberculosis, nine of whom
were culture-positive, seven with an
identical strain. Were these cases of
tuberculosis positive for the new test?
Studies from the same group2 and
others3 have suggested that patients
with tuberculosis produce less
interferon
in response to ESAT-6
than contacts.
The gold standard for assessment of
latent tuberculosis infection is the later
development of disease, which is
estimated as a 10% lifetime risk for
those with a positive tuberculin skin
test or 1·68% at 2 years or longer in
those who do not receive preventive
treatment.4 If the ELISPOT test were
used to focus preventive treatment,
then 31 participants in the study would
have been spared chemoprophylaxis,
but a further 27 would have needed
treatment. The new test is therefore
not better than tuberculin skin testing,
unless some of the 27 with a positive
ELISPOT but negative tuberculin skin
test develop tuberculosis. Furthermore,
80% of healthy residents of Mumbai,
India have a positive ELISPOT, and
preventive treatment cannot possibly
THE LANCET • Vol 361 • June 14, 2003 • www.thelancet.com
be given to such a large section of the
population.5
To improve tuberculosis control, a
test that can identify those contacts
who will develop infectious
tuberculosis or at least limit the
unnecessary use of preventive
treatment is needed. The ELISPOT
test as described does not fulfil such
criteria.
Graham H Bothamley
North East London TB Network, Homerton
University Hospital, London E9 6SR, UK
(e-mail: graham.bothamley@homerton.nhs.uk)
1 Ewer K, Deeks J, Alvarez L, et al.
Comparison of T-cell-based assay with
tuberculin skin test for diagnosis of
Mycobacterium tuberculosis infection in a
school tuberculosis outbreak. Lancet 2003;
361: 1168–73.
2 Pathan AA, Wilkinson KA, Klenerman P,
et al. Direct ex vivo analysis of antigen-
specific IFN-
-secreting CD4 T cells in
Mycobacterium tuberculosis-infected
individuals: associations with clinical disease
state and effect of treatment. J Immunol
2001; 167: 5217–25.
3 Vekemans J, Lienhardt C, Sillah JS, et al.
Tuberculosis contacts but not patients have
higher gamma interferon responses to
ESAT-6 than do community controls in
The Gambia. Infect Immun 2001; 69:
6554–57.
4 Smieja MJ, Marchetti CA, Cook DJ,
Smaill FM. Isoniazid for preventing
tuberculosis in non-HIV infected persons.
Evidence-Based Med 1999; July/August: 122.
5 Lalvani A, Nagvenkar P, Udwadia Z, et al.
Enumeration of T cells specific for RD1-
encoded antigen suggests a high prevalence
of latent Mycobacterium tuberculosis infection
in healthy urban Indians. J Infect Dis 2001;
183: 469–77.
Authors’ reply
Sir—We recognise P Wood and
colleagues’ veterinary research on
diagnosis of tuberculosis in cattle, and
their valuable contribution to bovine
health. We are aware of the whole-
blood interferon-
ELISA test, which
we cited. We do not doubt its usefulness
in cattle, but since it has significant
cross-reactivity with previous BCG
vaccination, we are unsure about its
clinical usefulness in diagnosis of latent
tuberculosis infection in BCG-
vaccinated populations, such as in the
UK and most of the world.
Wood and Jones may be unfamiliar
with the ELISPOT technique,
since it is not especially labour
intensive, depends on no sophis-
ticated equipment, and is robust.
Only a centrifuge, an incubator, and a
microscope are needed, and our
collaborations with colleagues
in resource-poor countries—India,
Zimbabwe, South Africa, Zambia,
and Turkey—have enrolled more than
2000 participants without technical
difficulties.