A meta-analysis of the diagnostic performance of the direct agglutination test and rK39 dipstick for visceral leishmaniasis
BMJ 2006; 333 doi: https://doi.org/10.1136/bmj.38917.503056.7C (Published 05 October 2006) Cite this as: BMJ 2006;333:723
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Localized mass screening of serological (e.g.rK39 anigen test) should be done in areas where Kalazar (visceral leishminiasis) is endemic , e.g. Bihar in India and Bangala Desh and Nepal as according to a study 43.9% of the asymptomatic seropositive contacts of kalazar patients developed kala-azar within the first 3 months, and a cumulative total of 69% developed kala-azar within 1 year (1).
Asymptomatic cases can become symtomatic when coupled with HIV/ AIDS. Further, co-infected patients can serve as human reservoirs, harbouring numerous parasites in their blood and becoming a source of infection for the insect vector (2). Therefore in endemic areas, do mass screening with rK39 and treat apprehending fulll-blown cases and possible reservoirs.
References:
1: Singh S, Kumari V, Singh N. Predicting kala-azar disease manifestations in
asymptomatic patients with latent Leishmania donovani infection by detection of
antibody against recombinant K39 antigen. Clin Diagn Lab Immunol. 2002
May;9(3):568-72. Erratum in: Clin Diagn Lab Immunol. 2004 Nov;11(6):1199.
2. http://www.who.int/leishmaniasis/burden/hiv_coinfection/burden_hiv_coinf...
Competing interests: No competing interests
Dear Colleague,
We thank you for your interesting comments. We agree that studies
that include healthy individuals as controls inflate the specificity of
diagnostic tests under evaluation. This is the reason why we performed
separate meta-analyses of the diagnostic performance of the DAT and the
rK39 dipsticks in various control groups and underlined the results of
studies conducted in patients with clinically suspected visceral
leishmaniasis (VL).
Following your letter, the results of the DAT and the rK39 dipstick
in patients with diseases other than VL have been revised and are
available on request. More extensive data is available for the DAT than
the rK39 dipstick. Positive results appear to be more common in infections
caused by closely related organisms such as Trypanosoma cruzi (2% with DAT
and 18% with rK39 dipstick) or Trypanosoma brucei spp (18% with DAT and
20% with rK39 dipstick) and are thus likely to be true false positive
results. Positive results observed with diseases such as malaria (2% with
DAT and 7% with rK39 dipstick) or bacterial infections (7% with DAT and
10% with rK39 dipstick) may also be false positive results, in particular
if these patients come from a VL endemic area, thus carrying a significant
risk to have been infected with Leishmania donovani sl in the past.
However, as it is common for these diseases to occur concomitantly with
VL, a subset of these patients were possibly suffering of VL unrecognised
by the test(s) of reference used during the study. In this situation, the
positive test result would thus be a true positive result.
Competing interests:
None declared
Competing interests: No competing interests
The specificity of the direct agglutinin test (DAT) and the rK39
dipstick tests vary depending on how many healthy individuals were present
in the different papers’ control groups [1]. If a test is to be used
alone for screening asymptomatic patients, then it is valid to include
apparently healthy patients when assessing ‘specificity’. However, if a
test is to be used for screening patients who already have symptoms e.g.
fever or weight loss, then it is not appropriate to calculate
‘specificities’ based on apparently healthy subjects. The inclusion of
healthy patients in a study to assess diagnostic tests may falsely inflate
the ‘specificity’ and thus the ‘likelihood ratio’.
The DAT and the rK39 dipstick tests were positive in as many as 9.4
to 17.4% of symptomatic patients without leishmaniasis. It would be
helpful for diagnostic purposes to know how frequently each of these other
conditions (e.g. malaria, TB, or a self-limiting illnesses) produced
positive DAT or rK39 results. These other conditions would thus be the
‘differential diagnoses’ of the positive DAT and rK39 dipstick test
results. It would also be helpful to know how often each of these
‘differential diagnoses’ occurred in patients with positive results.
It is important to recognise that two different approaches can be
used when assessing diagnostic tests. One is the ‘screening’ approach,
which uses Bayes theorem to calculate the probability of one diagnosis in
a population by using the indices of sensitivity and specificity. The
other approach involves considering differential diagnoses suggested by a
diagnostic lead [2]. This ‘diagnostic lead’ approach does not use
‘specificities’ at all but instead uses the frequency of occurrence of
findings in each differential diagnosis (their ‘sensitivities’) and also
the frequency of each differential diagnosis in those with a diagnostic
lead.
References
1. Chappuis F, Rijal S, Soto A, Menten J, Boelaert M. A meta-
analysis of the diagnostic performance of the direct agglutination test
and rK39 dipstick for visceral leishmaniasis. BMJ 2006; 333:723, 723-6.
2. Llewelyn H, Ang H A, Lewis K, Al-Abdullah A. The Oxford Handbook
of Clinical Diagnosis, Oxford University Press, 2006.
Competing interests:
None declared
Competing interests: No competing interests
Dear colleagues,
We thank you for the valuable comments. We agree that the rK39
dipstick needs to be evaluated for the diagnosis of visceral leishmaniasis
in Leishmania infantum endemic areas. Only one of the thirteen studies
included in our meta-analysis was conducted in a L. infantum endemic
country.
The 100% specificity found in your study should not be compared with
the 90.6% specificity reported in our meta-analysis as this result comes
from the analysis of the 4 studies that prospectively included patients
with clinical suspicion of visceral leishmaniasis. As the controls
included in your study were patients with other diseases coming from a non
-endemic area, this most likely lead to an overestimation of the
specificity. Actually, your results match well the 97.1% specificity found
in our meta-analysis of the 7 studies that included patients with cross-
reacting diseases as controls (table 1).
The rK39 dipstick had a relatively low sensitivity in your study
(82.4%) but we must emphasize that because of the low number (17) of cases
of visceral leishmaniasis that were included, the margins of the 95%
confidence interval are very wide (59.0 – 93.8%).
This is indeed of interest that your study was conducted in infants
and young children, the main target of L. infantum-induced visceral
leishmaniasis in Iran. As the results of the dipstick diagnostic
performance was not stratified by age in any of the studies included in
the meta-analysis, we could not proceed with the analysis of age sub-
groups.
Sincerely yours
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir
Regarding your valuable article, I would like to draw your attention to
the article entitled: “Evaluation of rK39 strip test for the diagnosis of
visceral leishmaniasis in infants” that is a report from Iran and has
published in Eastern Mediterranean Health Journal Vol 12 No 3/4, 2006.
Comparing the results of your met-analysis with our report, there are some
interesting points that can be considered:
-In the article, we reported 100% specificity for the test that differs
from yours, which is 90.6%. But the sensitivity of the test in our report
was 82.4%.
-It is also worth mentioning that we considered the disorders such as TB,
Toxoplasmosis, Lupus, and Malaria that can cause false positive results.
-Your mata-analysis considered mainly the articles that had been studied
the adults, while our report have focused on infants.
- Our report is one of the unique reports considering the L.infantum as a
cause of Kala-Azar while most other articles have studied other species.
We agree with you that using rK39 is a suitable test for the diagnosis of
visceral leishmaniasis. Besides we propose that this test is a very
reliable to use in those developing countries where there is no access to
laboratory facilities.
Sincerely yours
A alborzi MD
Competing interests:
None declared
Competing interests: No competing interests
Giving the drug to asymptomatic cases of Kala-zar can be dicey though diagnostic performance and affordability of the rK39 dipstick are very good
So far the strategy with Kala-zar is that treat all symptomatics after confirmation with rk39 rapid diagnostic test besides vector control. Our contention is that since asymptomatic patients can become symptomatic later and can also become reservoirs of infection, so do mass screening with rapid and easy test rk39 and treat all positives with miltefosine ( a new orally bioavailable drug) as discussed in the rapid response published on 11th April, 2015(1).
We further thought that If the sensitivity and specificity of the test is high and logistics is not an issue, the strategy can be contemplated.. The sensitivity and specificity of rk39 are very high and cost is pretty low. One can read in the paper2. Another hitch that has cropped up while musing over earlier response which we would like to share with others as well, is that miltefosine (the oral drug available) is not cheap and resistance can develop in case of non-compliant and irregular treatment which has to be supervised strictly.
References:
1. http://www.bmj.com/content/333/7571/723/rr..
2. BMJ 2006;333:723
Competing interests: No competing interests