Rapid diagnostic tests compared with malaria microscopy for guiding outpatient treatment of febrile illness in Tanzania: randomised trial
BMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39073.496829.AE (Published 22 February 2007) Cite this as: BMJ 2007;334:403
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Sir,
Over diagnosis of malaria has been identified as one of the
contributory factors which may make delivery of Artemisinin combination
treatments (ACT) unsustainable in Africa.(1)
The paper by Reyburn et al is timely and answered a very relevant
question in the on going debate about the sustainability of widespread
introduction of ACTs in sub-saharan Africa.
Intervention with rapid diagnostic tests (RDT) did not lead to an
improvement in clinician decision making and reduction in over-diagnosis
of malaria.
This is a significant finding which argues against promoting RDTs(
added cost implication) as the only means of preventing wastage of ACTs
if deployed widely in sub-saharan Africa, highlighting the need for a
change in prescribing behavior by health workers and the recognition of
alternative treatable diagnoses as key issues for success.
Delivery of ACTs is likely to depend on international subsidy.(1)
However it is unclear if this subsidy will extend to ACTs bought in the
informal retail sector (shops) where a substantial proportion of the
population purchase antimalarials.(2-4)
Guiding treatment of malaria in these informal settings is likely to be
the bigger challenge.
However, changing practice in hospitals is a very vital first step.
In theory, pairing delivery of ACTs with rapid diagnostic tests (RDT)
for malaria may reduce over diagnosis of malaria and improve the cost
effectiveness of the delivery of ACT in Africa by ensuring that only
patients with a positive test get antimalarials.
This strategy may also be useful in drug shops where diagnosis of
malaria is by clinical symptoms alone. However, studies have shown that a
significant proportion of shop bought antimalarials are purchased on
behalf of others, this negates the opportunity to use the RDT to guide
treatment in these settings.(2-4)
Formal health services without facilities for microscopic diagnosis
of malaria appear to be the best setting for the RDT/ACT combination
strategy.
Strategies to safely and cost effectively deploy ACTs in the informal
retail sector in Africa need to be devised and studied.
References
(1)Reyburn H, Mbakilwa H, Mwangi R et al. Rapid diagnostic tests
compared with malaria microscopy for guiding outpatient treatment of
febrile illness in Tanzania: randomised trial. BMJ.2007 Feb 24;334
(2)Patrick Kachur S, Schulden J et al. Prevalence of malaria
parasitaemia among clients seeking treatment for fever or malaria at drug
stores in rural Tanzania.Trop Med Int Health. 2006 Apr;11(4):441-51.
(3)Afolabi BM, Brieger WR, Salako LA. Management of childhood febrile
illness prior to clinic attendance in urban Nigeria. J Health Popul Nutr.
2004 Mar;22(1):46-51.
(4)Nshakira N, Kristensen M, Ssali F et al. Appropriate treatment of
malaria? Use of antimalarial drugs for children's fevers in district
medical units, drug shops and homes in eastern Uganda.Trop Med Int
Health,7(4):309-16. 2002.
Competing interests:
None declared
Competing interests: No competing interests
The last issue of BMJ focuses on the critical issue of the clinical
management of malaria in endemic countries (1,2). With a group of
researchers from Europe and Burkina Faso we just concluded a randomised
trial on malaria diagnosis and management both in the dry and the rainy
season (NCT00317590). Febrile patients were randomised either to be
managed clinically, or after a rapid diagnostic test (RDT) for malaria
(Paracheck®). Data are currently analysed, and will be published after a
full report has been submitted to the Ministry of Health of Burkina Faso.
Preliminary results for the dry season show no difference in malaria
management between the two groups: clinical officers don’t appear to take
into account test results. On the other hand there is a significant
decrease in “double diagnosis” (i.e., malaria plus a second diagnosis) in
patients submitted to the test. Since test-negative patients are anyhow
suspect for another diagnosis, even if they are treated as malaria, the
explanation for this overall drop in double diagnosis can only be that a
patient with a positive RDT is taken as a confirmed malaria case, without
considering another possibly life threatening condition. In a highly
endemic zone a positive RTD does not automatically mean that malaria is
the true cause of fever: these tests are very sensitive and may detect low
to very low parasitaemias without any clinical significance. Consequently,
there could be a risk of under treatment of other causes of fever, with a
potential harm to the patient.
In conclusion, as Reyburn and Coll. correctly affirm, the problem of
malaria diagnosis and management is complex and unlikely to be solved by
any magic bullet. We believe that this is a research issue of high
priority.
1.Hugh Reyburn, Hilda Mbakilwa, Rose Mwangi, Ombeni Mwerinde, Raimos
Olomi, Chris Drakeley, Christopher J M Whitty. Rapid diagnostic tests
compared with malaria microscopy for guiding outpatient treatment of
febrile illness in Tanzania: randomised trial. BMJ 2007;334:375-376
2.Talisuna A O and Meya D N. Diagnosis and treatment of malaria. BMJ
2007;334:403
Competing interests:
None declared
Competing interests: No competing interests
We welcome the paper of Reyburn et al[1] that addresses a hot topic
in malaria case management in endemic areas: should the clinician rely on
the malaria test to give antimalarials or not? Reyburn’s findings that
about half of the febrile patients were given antimalarials in spite of a
negative test, and this irrespective of the technique used [Rapid
Diagnostic Test (RDT), microscopy] and of the level of endemicity, is
definitely worrying. It shows clearly that clinicians do not think in
terms of pre- or post-test probabilities to decide on treatment. The
authors conclude soundly that the issue to address now is to find out how
to change clinicians’ behaviour, i.e. how to stop them over-prescribing
antimalarial drugs.
We believe that part of the problem is due to ambiguous messages
provided by malaria experts and national guidelines on how to take action
on the result of a malaria test. The diagnostic performance of RDTs is not
any more an issue: meta-analyses have shown the performance to be
excellent and consistently reliable[2]; RDTs based on HRP-2 detection have
even proved to be more sensitive than microscopy in malaria endemic
areas[3]. Despite the strength of this evidence, a rationale argument is
clearly not strong enough to convince clinicians. Hence, training needs to
focus on the other reasons that lead them to prescribe antimalarials in
case of a negative RDT. Undoubtedly, an important one is the ambiguity of
national malaria control programme guidelines on the management of
suspected malaria in children under 5 years. In Tanzania, the
recommendation is: perform microscopy/RDT for malaria -> Negative ->
No signs and symptoms of severe disease -> Under five years: treat as
uncomplicated malaria; look for other condition[4]. Similar inconsistency
is found in the Ugandan guidelines.
It is pretty unusual in medical history to recommend a laboratory
test and in the same sentence to propose not to take into account the
result… Even Reyburn et al state that ‘…in areas of very high malaria
transmission, withholding antimalarial drugs from children under 5 with
febrile illness is potentially hazardous even in the face of negative test
results…’[1]. A case management strategy should not be based on extremely
rare events, such as a true malaria episode with a negative test in semi-
immune populations (because of sequestration etc.), in other terms based
on fears (putting children at risk of severe malaria if not treated as
soon as they get fever). Evidence is now provided that the safety issue is
not where malaria experts think. Indeed the same authors and others have
shown that more patients are dying of non-malarial causes of fever that
are missed because of sticking to the diagnosis of malaria than of severe
malaria[5;6]. The risk of missing a true malaria case in the event of a
negative test, and the resulting consequences has been recently evaluated
thoroughly in Uganda[7]. In this study, febrile children were not given
antimalarials when the microscopy was negative (rate of malaria test
positivity: 32%). Only 2 malaria cases out of 2359 febrile episodes were
missed; both consulted the next day because of persisting fever and were
treated for uncomplicated malaria based on a new test that was positive.
In parallel, 464 non-malaria causes of fever in need of antibiotic
treatment were identified[7].
Hence, the assertion that feverish children under five years should
be treated with antimalarials irrespective of the test result, because the
disease has a more rapid course, is inadequate. Indeed it is the clinical
assessment to identify early enough danger signs that is crucial, but the
performance of the test, and hence the trust we can have in its result, is
the same in all age groups. Teaching material and guidelines should not be
based on beliefs and fears but updated using most recent evidence. There
is an urgent need to give a uniform and unambiguous message for
uncomplicated febrile illness: positive malaria test -> Malaria;
negative malaria test -> NO malaria. This is where we are in 2007…
References
1. Reyburn H, Mbakilwa H, Mwangi R, Mwerinde O, Olomi R, Drakeley C
et al. Rapid diagnostic tests compared with malaria microscopy for guiding
outpatient treatment of febrile illness in Tanzania: randomised trial. BMJ
2007.
2. Marx A, Pewsner D, Egger M, Nuesch R, Bucher HC, Genton B et al.
Meta-analysis: accuracy of rapid tests for malaria in travelers returning
from endemic areas. Ann.Intern.Med. 2005;142:836-46.
3. Ochola LB, Vounatsou P, Smith T, Mabaso ML, Newton CR. The
reliability of diagnostic techniques in the diagnosis and management of
malaria in the absence of a gold standard. Lancet Infect.Dis. 2006;6:582-
8.
4. National Malaria Control Programme MoH, Tanzania. National
guidelines for malaria diagnosis and treatment 2006.
5. Makani J, Matuja W, Liyombo E, Snow RW, Marsh K, Warrell DA.
Admission diagnosis of cerebral malaria in adults in an endemic area of
Tanzania: implications and clinical description. QJM. 2003;96:355-62.
6. Reyburn H, Mbatia R, Drakeley C, Carneiro I, Mwakasungula E,
Mwerinde O et al. Overdiagnosis of malaria in patients with severe febrile
illness in Tanzania: a prospective study. BMJ 2004;329:1212.
7. Njama-Meya D, Clark TD, Nzarubara B, Staedke S, Kamya MR, Dorsey
G. Treatment of malaria restricted to laboratory confirmed cases: a
prospective cohort study in Ugandan children. Malar.J. 2007;6:7.
Competing interests:
None declared
Competing interests: No competing interests
We went through the article “Rapid diagnostic tests
compared with malaria microscopy for guiding outpatient treatment of
febrile illness in Tanzania: randomised trial” By
Hugh Reyburn 1*, Hilda Mbakilwa 2, Rose Mwangi 3, Ombeni Mwerinde 3,
Raimos Olomi 4, Chris Drakeley 1, Christopher J M Whitty 1
BMJ, doi:10.1136/bmj.39073.496829.AE (published 26 January 2007)
Malaria remains today one of the major health problems in the tropics
including in India with increased mortality and morbidity. Falciparum
malaria presents with protean manifestations and is associated with
variety of complications and has a high mortality. P. Falciparum, in
contrast to benign malaria P. Vivax may progress to a life threatening
multi-system organ failure & thus possesses serious complications. In
the West Bengal State Of India Malaria must be considered in any patients
presenting with high fever unless proved otherwise as many areas of the state are highly endemic. Although the first
symptoms usually begin in 10 days to 4 weeks after transmission by an
infected mosquito, in children and often in adults particularly in
Plasmodium falciparum infection the symptoms begin with non specific flu-like symptoms that include malaise, vomiting and even with diarrhea. We
in our institute IPGMER, Kolkata, West Bengal, at first look for the
parasite in thin and thick Blood smear with Romansky stain. Many times
though we miss trophozoites of Plasmodium falciparum malaria in blood
slides and often may confuse with artifacts stain deposits, so we perform
Rapid Test by Pf Rapid antigen assay. This test is very sensitive and
specific for Histidine protein of P. Falciparum species. The Diagnosis of
Malaria, particularly the P. Falciparum, must be prompt.
Failure to expedite appropriate referral may lead to development of life
threatening complications like in severe malaria. Thick and thin blood
films processed in EDTA sample by local hematological laboratory are the
main stay of diagnosis. Generally 3 (three) blood films at height of
temperature are required to exclude malaria. But they require a laboratory
to prepare a good smear, good stain, good microscopy with light and
expert Technician on identification of malaria parasites & or
qualified clinical pathologist, which are not usually found in suburbs
of greater Kolkata even, or in subdivision or in villages of West Bengal.
This Rapid Antigen Assay for PF is very easy to perform and interpret
even in the field and even by a technician and is very sensitive. Unless the Report of
Malaria comes negative, we give the patients a dose of chloroquine
immediate after collecting blood for malaria in all fever cases as the
standard protocol in our institute.
Malaria is still a big problem in India, including in one of its province
West Bengal. West Bengal, one of the eastern provinces in India, has an
area of 88752 sq. kilometer, having twenty( 20) districts towns, 40782
villages and 375 towns. It has 8.2 cores population and density of
population is 903 per Sq kilometer. Percentage of population in urban set up
up is 28% and rest (72%) in rural set up. Highest density of population are
in Kolkata (24718) followed by in Haora (2913), South 24 Parganas (2182),
North-24 Parganas(1173). Percentage of Population in below poverty line [considering World Bank 1991 criteria Us$<_108 i.e="i.e" _47="_47" indian="indian" rupees="rupees" per-day="per-day" per-capita="per-capita" income="income" is="is" _="_" _16="_16" in="in" urban="urban" and="and" _32="_32" rural="rural" set="set" up="up" p="p"/> In West Bengal a statistical analysis on malaria shows that in in
1991 numbers of slide positive cases were 40452, of which P. Falciparum
cases were 7913 and death was only in 13 cases. Since 1991 to 2004, there
was a steady rise of incidence of malaria cases, Pf cases and death due to
P falciparum. In 2004 Number of slide positive cases of malaria was
2,21,617 cases, when Pf cases was 60,643 having Pf%27.4 and death due to
P. falciparum was 190. The SPR% in 1985 was 2.9; it rose to a peak of 7.9
in 1991, fell in 2001 to 4.3 and further rose to 5.7 in 2004. The Pf% in
West Bengal in 1985 was 23.3, rose to a peak of 32 in 1999, fell in 2000 to
22.3 and further rosed to 32.9 in 2004. The highest incidence of Pf cases
was found in Kolkata urban/semiurban then in Jalpaiguri areas, followed by
Kolkata municipal corporation areas then in Bankura, Hoara, Birbhum
districts of West Bengal respectively. But highest incidence of death in
2004 was noted in Jalpaiguri (88), Kolkata (19) Pashim Mednapur districts
in-spite of insecticide spray under National Malaria Control Program in
West Bengal2.
In view of global distribution of cholorquine resistance WHO has already
disapproved of the use of chloroquine for treatment of severe malaria in
general and where chloroquine sensitivity is not known3. For treatment of
P. Falciparum (severe or uncomplicated) the physician does not want to take
any risk and in tertiary institute the physician uses either Artesunate [available in trade name as “Falcigo” of Cadila as 60 mg vial injectable
form in standard recommended doses of 120mg Iv or im on day 1 followed by 60
mg Iv or im in next 4-6 days]. This is also practice in our Institute. One
vial of 60 mg cost around Indian currency Rs 170/= as such total costs for
drugs only is 1100/= in Indian Rupees. The drug is safe except occasional
abdominal pain vomiting and prolongation of Q-T interval and first degree
heart block in very rare cases. Otherwise the treatment is done with
Quinine di-hydrochloride injection [available in the market in 2ml vial
cost Rs 14/=] This injection is given initially 20 mg/kg iV infusion over
4 hours, then 8 hours after the loading dose in adults. A maintenance dose
of 10 mg/kg over 4 hours is then given. This maintenance dose is repeated
every 8 hourly for adults. The side effect may be atrial fibrillation,
heart block. Resistance to Quninine is not known in West Bengal yet. Use of
both these drugs requires hospitalization of patients in either a private
or in nursing home or in public set up hospital where the IV infusion
arrangement to give the loading dose, maintenance dose and ECG monitoring
is possible. However these are not possible in the rural set up or in semi
urban set up [ in home set up also] where 72% population of West Bengal
live.
Therapeutic efficacy study with chloroquine and with sulfa doxine-pyrimethamine were conducted in falciparum malaria according to standard
WHO protocol in Orrisa, North Eastern states of India and across the
international boarders of the country by ICMR3. The analysis of data
showed good efficacy of chloroquine and of sulfadoxine pyrimethamine in
Keonjhar town and in Podmapur of Orrisa state. However high failure rate
up to 50% were observed in Birsa and in Kaurmunda of Sundergarh with sulfa
doxine pyrimethamine. Moreover there is fear of Steven- Jhonsons syndrome
with this drug. In Assam State of India, failure rate of 34% and 30% was
observed in Sonapur
(Kamrup district) and Kathitali (Nawgao district) respectively with
chloroquine. However efficacy of the drug was found good in Boko. The
efficacy of Choloroquine was also evaluated in Indo-Nepal boarder in
Darjeeling district of West Bengal. Cumulative failure rate was 66% and
33% respectively in Sukna & in Naxal Bari Block PHC. But therapeutic
efficacy of chloroquine in P. Vivax is 100% in Goutam Buddha Nagar of UP, in
Mumbai, Chennie & in Kolkata.
References
1)Miram. K. Laufer, Philip. C Thesing and Nicole. D. Eddington et al
Return of choloroquine anti-malarial efficacy in Malwai: New Eng. J. Med
Nov9, 1959-1966;2006
2)Health on March 2004-2005 of state Bureue of Health intelligence,
directorate of Health Services, government of West Bengal, India, Pages
3,6,9,127-133, 282-83;2006
3)Annual Report 2003-2004 of Indian council of Medical Research, New Delhi
published by Director General ICMR ,2005 Page 30
Authors:
1) Professor Pranab kumar Bhattacharya MD (cal)
Professor of Pathology
Ex- incharge of 24 hours Ronald Ross Malaria Clinic
Incharge of Unit III, Incharge of Cytogenetics, Incharge of Blood
Bank
Institute of Post Graduate Medical Education Research, 244A AJC Bose Road, Kolkata- 700020, India
2) Mr. Rupak Bhattacharya Bsc (Cal) MSC(JU)
Purbapalli, Po- Sodepur Dist 24 parganas (North) Kolkata 700110 West
Bengal, India
3) Mr. Ritwik Bhattacharya B.Com(Cal)
Purbapalli, Po-Sodepur Dist 24 parganas (North) Kolkata 700110 West
Bengal, India
4) Dr. Dipankar Mukherjee MD(Cal) DM ( Cardio)
Assistant Professor
Dept. Of Cardiology & Insititute of Cardiovascular sciences
Institute of post Graduate Medical Education Research, 244A AJC Bose Road, Kolkata- 700020, India
Acknowledgement--Authors are grateful for all help from Miss
Upasana Bhattacharya of mahamayatala Garia, Mr Debasis Mukherjee Bsc(Cal)
of South Habra, North 24 parganas, W.B, and DR. Swapan Pathak, Associate
professor, pathology, IPGMER, Kolkata.
Competing interests:
None declared
Competing interests: No competing interests
Over-reliance on thin and thick blood film for diagnosis and radical treatment in malaria in India
There is an over-reliance on thick and thin smear in diagnosis of
Malaria. And radical treatment is given only on smear positivity. Blood
smear assess for the presence of schizonts, gametocytes, and malarial
pigment in neutrophils and monocytes. Before reporting a negative result,
at least 200 oil immersion visual fields at a magnification of 1000?
should be examined on both thick and thin smears, which has a sensitivity
of 90%. A negative test DOES NOT rule out malaria. Repeated tests may
have to be done in all doubtful cases1,2. Duration of the illness, level
of parasitemia, expertise of the technician (which is questionable in
India because of lack of retraining and supervision or cross-checking) and
the method of examination may all have a bearing on the diagnostic
accuracy of the blood smear test1,2. In absence of radical treatment the
reservoir of Plasmodium vivax cases will expand (though not P. falciparum
as there is no hepatic stage) The level of parasitemia may be expressed
either as a percentage of parasitized erythrocytes or as the number of
parasites per microliter of blood.
In falciparum malaria, parasitized erythrocytes may be sequestered in
tissue capillaries resulting in a falsely low parasite count in the
peripheral blood ('visible' parasitemia)1.
Parasitemia can be decreased by inadequate anti-malaria treatment which is
possible in prsence of large number of quacks. this lead to false negative
result.
Just giving Chloroquine/ SP+AS combination in malaria is not going to
eradicate gamatocytes so chances of relapse always present, i.e.
reservior of infection in the community increases. Another reasons are
false negative reporting and lack of follow up lead to failure of
primaraquine treatment in potential malaria case. Such cases would be
having infection and continue to be reservior of infection and suffering
from relapses. 14 days of treatment of primaquine is essential with
chloroquine/SP+AS. But use of this drug is also questionable in view of
hemolysis in G6PD deficiency states.
Moreover, in absence of active case finding forenightly (large number of
vacant posts of Male Health workers) and indiscriminately using
chloroquine can lead to increase in reservior.
References:
1.http://www.malariasite.com/malaria/DiagnosisOfMalaria.htm
2.White NJ. Malaria. Manson's Tropical Diseases (Edited by: Cook GC, Zumla
AI, Weir J). Philadelphia, PA: WB Saunders 2003;1205-1295
Competing interests: No competing interests