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 Guidelines for
the treatment of malaria
 G uidelines for the t reatment of malar ia

WHO Library Cataloguing-in-Publication Data

Guidelines for the treatment of malaria/World Health Organization.

Running title: WHO guidelines for the treatment of malaria.

1. Malaria – drug therapy. 2. Malaria – diagnosis. 3. Antimalarials – administration

and dosage. 4. Drug therapy, Combination. 5. Guidelines. I. Title. II. Title: WHO
guidelines for the treatment of malaria.

ISBN 92 4 154694 8 (NLM classification: WC 770)

ISBN 978 92 4 154694 2 WHO/HTM/MAL/2006.1108

© World Health Organization, 2006

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,
World Health Organization, 20, avenue Appia, 1211 Geneva 27, Switzerland (tel. +41 22 791 3264;
fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or
translate WHO publications – whether for sale or for noncommercial distribution – should be
addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]).
The designations employed and the presentation of the material in this publication do not imply
the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the
delimitation of its frontiers or boundaries.
The mention of specific companies or of certain manufacturers’ products does not imply that they
are endorsed or recommended by the World Health Organization in preference to others of a similar
nature that are not mentioned. Errors and omissions excepted, the names of proprietary products
are distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information
contained in this publication. However, the published material is being distributed without warranty
of any kind, either express or implied. The responsibility for the interpretation and use of the material
lies with the reader. In no event shall the World Health Organization be liable for damages arising
from its use. The named authors alone are responsible for the views expressed in this publication.

For technical information, please contact:

Dr P. Olumese
Global Malaria Programme
World Health Organization
20, avenue Appia – CH-1211 Geneva 27
Tel. +41 22 791 4424
Fax +41 22 791 4824
E-mail: [email protected]

Printed in Switzerland
Design: B. Duret – Cover: T. Cailler

ii
 Contents

Glossary v

Abbreviations viii

1. Introduction 1
1.1 Background 1
1.2 Objectives and target audience 2
1.3 Methods used in developing the guidelines and recommendations 3

2. The clinical disease 5

3. Treatment objectives 7
3.1 Uncomplicated malaria 7
3.2 Severe malaria 7

4. Diagnosis of malaria 8
4.1 Clinical diagnosis 8
4.2 Parasitological diagnosis 9
4.3 Where malaria transmission is low–moderate and/or unstable 10
4.4 In stable high-transmission settings 10
4.5 Malaria parasite species identification 11
4.6 In epidemics and complex emergencies 11

5. Resistance to antimalarial medicines 12

5.1 Impact of resistance 12
5.2 Global distribution of resistance 12
5.3 Assessing resistance 13

6. Antimalarial treatment policy 14

6.1 Assessment of in vivo therapeutic efficacy 14
6.2 Criteria for antimalarial treatment policy change 15

7. Treatment of uncomplicated P. falciparum malaria 16

7.1 Assessment 16
7.2 Antimalarial combination therapy 16
7.3 The choice of artemisinin based combination therapy options 20
7.4 Practical aspects of treatment with recommended ACTs 23
7.5 Incorrect approaches to treatment 26
7.6 Additional aspects of clinical management 27
7.7 Operational issues in treatment management 29
7.8 Management of treatment failures 31
7.9 Treatment in specific populations and situations 32
7.10 Coexisting morbidities 38

iii
 G uidelines for the t reatment of malar ia

8. Treatment of severe falciparum malaria 41

8.1 Definition 41
8.2 Treatment objectives 41
8.3 Clinical assessment 42
8.4 Specific antimalarial treatment 42
8.5 Practical aspects of treatment 47
8.6 Follow-on treatment 48
8.7 Pre-referral treatment options 49
8.8 Adjunctive treatment 51
8.9 Continuing supportive care 53
8.10 Additional aspects of clinical management 54
8.11 Treatment during pregnancy 58
8.12 Management in epidemic situations 59
8.13 Hyperparasitaemia 60

9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae 62

9.1 Diagnosis 62
9.2 Susceptibility of P. vivax, P. ovale and P. malariae to antimalarials 63
9.3 Treatment of uncomplicated vivax malaria 63
9.4 Treatment of severe vivax malaria 66
9.5 Treatment of malaria caused by P. ovale and P. malariae 66
9.6 Monitoring therapeutic efficacy for vivax malaria 66

10. Mixed malaria infections 68

11. Complex emergencies and epidemics 69

11.1 Diagnosis 69
11.2 Use of rapid diagnostic tests in epidemic situations 69
11.3 Management of uncomplicated malaria in epidemics 70
11.4 Areas prone to mixed falciparum/vivax malaria epidemics 70
11.5 Use of gametocytocidal drugs to reduce transmission 71
11.6 Anti-relapse therapy in vivax malaria epidemics 71
11.7 Mass treatment 71

Annexes
Annex 1. The guidelines development process 77
Annex 2. Adaptation of WHO malaria treatment guidelines for use
in countries 83
Annex 3. Pharmacology of antimalarial drugs 87
Annex 4. Antimalarials and malaria transmission 133
Annex 5. Malaria diagnosis 147
Annex 6. Resistance to antimalarials 155
Annex 7. Uncomplicated P. falciparum malaria 185
Annex 8. Malaria treatment and HIV/AIDS 198
Annex 9. Treatment of severe P. falciparum malaria 207
Annex 10. Treatment of P. vivax, P. ovale and P. malariae infections 225
Index 240
iv
 Glossar y

GLOSSARY
Artemisinin-based combination therapy (ACT). A combination of artemisinin
or one if its derivatives with an antimalarial or antimalarials of a different class.

Asexual cycle. The life-cycle of the malaria parasite in host red blood cells (intra-
erythrocytic development) from merozoite invasion to schizont rupture
(merozoite → ring stage → trophozoite → schizont → merozoites). Duration
approximately 48 h in Plasmodium falciparum, P. ovale and P. vivax; 72 h in
P. malariae.

Asexual parasitaemia. The presence in host red blood cells of asexual para-
sites. The level of asexual parasitaemia can be expressed in several different
ways: the percentage of infected red blood cells, the number of infected cells
per unit volume of blood, the number of parasites seen in one microscopic field
in a high-power examination of a thick blood film, or the number of parasites
seen per 200–1000 white blood cells in a high-power examination of a thick
blood film.

Cerebral malaria. Severe falciparum malaria with coma (Glasgow coma scale
<11, Blantyre coma scale <3). Malaria with coma persisting for >30 min after
a seizure is considered to be cerebral malaria.

Combination treatment (CT). A combination of two or more different classes

of antimalarial medicines with unrelated mechanisms of action.

Cure. Elimination of the symptoms and asexual blood stages of the malaria
parasite that caused the patient or carer to seek treatment.

Drug resistance. Reduced susceptibility of the causal agent to a drug. WHO

defines resistance to antimalarials as the ability of a parasite strain to survive
and/or multiply despite the administration and absorption of a medicine given
in doses equal to – or higher than – those usually recommended but within
the tolerance of the subject, with the caveat that the form of the drug active
against the parasite must be able to gain access to the parasite or the infected
red blood cell for the duration of the time necessary for its normal action.
Resistance to antimalarials arises because of the selection of parasites with
genetic mutations or gene amplifications that confer reduced susceptibility.

Gametocytes. Sexual stages of malaria parasites present in the host red

blood cells, which are infective to the anopheline mosquito.

v
 G uidelines for the t reatment of malar ia

Hypnozoites. Persistent liver stages of P. vivax and P. ovale malaria that

remain dormant in host hepatocytes for a fixed interval (3–45 weeks) before
maturing to hepatic schizonts. These then burst and release merozoites,
which infect red blood cells. Hypnozoites are the source of relapses.

Malaria pigment (haemozoin). A dark brown granular pigment formed by

malaria parasites as a by-product of haemoglobin catabolism. The pigment is
evident in mature trophozoites and schizonts.

Merozoites. Parasites released into the host bloodstream when a hepatic or

erythrocytic schizont bursts. These then invade the red blood cells.

Monotherapy. Antimalarial treatment with a single medicine (either a single

active compound or a synergistic combination of two compounds with related
mechanism of action).

Plasmodium. A genus of protozoan vertebrate blood parasites that includes

the causal agents of malaria. Plasmodium falciparum, P. malariae, P. ovale and
P. vivax cause malaria in humans.

Pre-erythrocytic development. The life-cycle of the malaria parasite when it

first enters the host. Following inoculation into a human by the female
anopheline mosquito, sporozoites invade parenchyma cells in the host liver
and multiply within the hepatocytes for 5–12 days, forming hepatic schizonts.
These then burst liberating merozoites into the bloodstream, which subse-
quently invade red blood cells.

Radical cure. In P. vivax and P. ovale infections only, this comprises cure as
defined above plus prevention of relapses.

Rapid diagnostic test (RDT). An antigen-based stick, cassette or card test for
malaria in which a coloured line indicates that plasmodial antigens have
been detected.

Recrudescence. The recurrence of asexual parasitaemia after treatment of the

infection with the same infection that caused the original illness (in endemic
areas now defined by molecular genotyping). This results from incomplete
clearance of parasitaemia by treatment and is therefore different to a relapse
in P. vivax and P. ovale infections.

Recurrence. The recurrence of asexual parasitaemia following treatment. This

can be caused by a recrudescence, a relapse (in P. vivax and P. ovale infections
only) or a new infection.

vi
 Glossar y

Relapse. The recurrence of asexual parasitaemia in P. vivax and P. ovale

malaria deriving from persisting liver stages. Relapse occurs when the blood
stage infection has been eliminated but hypnozoites persist in the liver and
mature to form hepatic schizonts. After a variable interval of weeks (tropical
strains) or months (temperate strains) the hepatic schizonts burst and liberate
merozoites into the bloodstream.

Ring stage. Young usually ring-shaped intra-erythrocytic malaria parasites,

before malaria pigment is evident under microscopy.

Schizonts. Mature malaria parasites in host liver cells (hepatic schizonts) or

red blood cells (erythrocytic schizonts) that are undergoing nuclear division.
This process is called schizogony.

Selection pressure. Resistance to antimalarials emerges and spreads because

of the selective survival advantage that resistant parasites have in the presence
of antimalarials that they are resistant to. Selection pressure describes the
intensity and magnitude of the selection process; the greater the proportion
of parasites in a given parasite population exposed to concentrations of an
antimalarial that allow proliferation of resistant, but not sensitive parasites,
the greater is the selection pressure.

Severe anaemia. Haemoglobin concentration of <5 g/100 ml.

Severe falciparum malaria. Acute falciparum malaria with signs of severity

and/or evidence of vital organ dysfunction.

Sporozoites. Motile malaria parasites that are infective to humans, inoculated

by a feeding female anopheline mosquito. The sporozoites invade hepatocytes.

Transmission intensity. The intensity of malaria transmission measured by the

frequency with which people living in an area are bitten by anopheline
mosquitoes carrying sporozoites. This is often expressed as the annual
entomological inoculation rate (EIR), which is the number of inoculations of
malaria parasites received by one person in one year.

Trophozoites. Stage of development of the malaria parasites within host red

blood cells from the ring stage and before nuclear division. Mature trophozoites
contain visible malaria pigment.

Uncomplicated malaria. Symptomatic infection with malaria parasitaemia

without signs of severity and/or evidence of vital organ dysfunction.

vii
 G uidelines for the t reatment of malar ia

ABBREVIATIONS
ACT artemisinin-based combination therapy
AL artemether-lumefantrine combination
AQ amodiaquine
AS artesunate
AS+AQ artesunate + amodiaquine combination
AS+MQ artesunate + mefloquine combination
AS+SP artesunate + sulfadoxine-pyrimethamine combination
CI confidence interval
CQ chloroquine
EIR entomological inoculation rate
HIV/AIDS human immunodeficiency virus/
acquired immunodeficiency syndrome
HRP2 histidine-rich protein 2
IC50 concentration providing 50% inhibition
MIC minimum inhibitory concentration
MQ mefloquine
OR odds ratio
PCR polymerase chain reaction
pLDH parasite-lactate dehydrogenase
RCT randomized controlled trial
RDT rapid diagnostic test
RR relative risk
SP sulfadoxine–pyrimethamine
WHO World Health Organization
WMD weighted mean difference

viii
 1. Introduction

1. INTRODUCTION
1.1 Background
Malaria is an important cause of death and illness in children and adults in
tropical countries. Mortality, currently estimated at over a million people per
year, has risen in recent years, probably due to increasing resistance to
antimalarial medicines. Malaria control requires an integrated approach
comprising prevention including vector control and treatment with effective
antimalarials. The affordable and widely available antimalarial chloroquine that
was in the past a mainstay of malaria control is now ineffective in most
falciparum malaria endemic areas, and resistance to sulfadoxine–pyrimethamine
is increasing rapidly. The discovery and development of the artemisinin
derivatives in China, and their evaluation in South-East Asia and other regions,
have provided a new class of highly effective antimalarials, and have already
transformed the chemotherapy of malaria in South-East Asia. Artemisinin-based
combination therapies (ACTs) are now generally considered as the best current
treatment for uncomplicated falciparum malaria.
These treatment guidelines recommend antimalarials for which there is
adequate evidence of efficacy and safety now, and which are unlikely to be
affected by resistance in the near future. Much of the world’s symptomatic
malaria is treated in peripheral health centres or remote villages, where
facilities are limited. The aim is therefore to provide simple and straightforward
treatment recommendations based on sound evidence that can be applied
effectively in most settings.
These guidelines are based on a review of current evidence and are developed
in accordance with WHO’s standard methodology. Clinical evidence has been
assessed in an objective way using standard methods. The number of anti-
malarial drug trials published has doubled in the past seven years, so these
guidelines have a firmer evidence base than previous treatment recommen-
dations. Inevitably, information gaps remain, however, and so the guidelines
will remain under regular review and will be updated as new evidence becomes
available. There are also difficulties when comparing results from different areas,
as levels of drug resistance and background immunity vary. Where transmission
levels and, consequently, immunity are high, the malaria symptoms are self-
limiting in many patients, in particular in adults, so that drugs that are only
partially effective may appear still to work well in many cases, misleading
patients and doctors alike. But in the same location, the young child who lacks
immunity to illness caused by P. falciparum may die if ineffective drugs are given.

1
 G uidelines for the t reatment of malar ia

The treatment recommendations given in these guidelines aim for effective

treatment for the most vulnerable and therefore take all the relevant factors into
account. These factors include laboratory measures, such as tests for in vitro
antimalarial susceptibility and validated molecular markers of resistance, the
pharmacokinetic and pharmacodynamic properties of the different antimalarials,
and clinical trial results. Cost is a factor that has been taken into consideration
in antimalarial treatment policy and practices. However, there are increasing
international subsidies for antimalarials. Efficacy (both now and in the future)
and safety have therefore taken precedence when making the recommendations.
The malaria treatment guidelines given below are brief; for those who wish to
study the evidence base in more detail, a series of annexes is provided.

1.2 Objectives and target audience

1.2.1 Objectives
The purpose of this document is to provide comprehensible, global, evidence-
based guidelines to help formulate policies and protocols for the treatment
of malaria. Information is presented on the treatment of:
• uncomplicated malaria, including disease in special groups (young children,
pregnant women, people who are HIV-positive, travellers from non-malaria
endemic regions) and in epidemics and complex emergency situations;
• severe malaria.
The guidelines do not deal with preventive uses of antimalarials, such as
intermittent preventive treatment or chemoprophylaxis.

1.2.2 Target audience

The guidelines are aimed primarily at policy-makers in ministries of health.
The following groups should also find them useful:
• public health and policy specialists working in hospitals, ministries, non-
governmental organizations and primary health care services;
• health professionals (doctors, nurses and paramedical officers).
The guidelines provide a framework for the development of specific and more
detailed treatment protocols that take into account national and local malaria
drug resistance patterns and health service capacity (see Annex 2). They are not
intended to provide a comprehensive clinical management guide for the
treatment of malaria. However, where there are controversies about specific
clinical practices, and evidence is currently available to provide information to
guide decision-making about these practices, that information has been included.

2
 1. Introduction

1.3 Methods used in developing the guidelines and

recommendations
These guidelines have been developed in accordance with the WHO Guidelines
for Guidelines Development.1 In order to ensure that the guidelines are based
on the best current evidence, WHO commissioned two academic centres to
identify, compile and critically review published and unpublished studies of
antimalarial treatments. The collated evidence was then reviewed by the
Technical Guidelines Development Group made up of a broad spectrum of
experts on malaria, malaria control programmes, and treatment guidelines
methodology. A large number of external reviewers with a wide range of
expertise were also involved in developing the guidelines.

1.3.1 Evidence considered

In assessing the available information on treatment options, four main types
of information were considered, and should also be considered by countries
seeking to adapt the guidelines.2 Wherever possible, systematic reviews of
randomized trials that directly compare two or more treatment alternatives in
large populations were identified and used as the basis for recommendations.
It is clear that such evidence does not exist for all options, but recommendations
on these options still need to be made. Other information including studies
measuring cure rates but not directly comparing treatments, pharmacological
assessments and surveillance data about resistance patterns have therefore
also been considered.
In relation to malaria, as with other diseases, systematic reviews are not the
sole basis for decision-making: the large differences in transmission intensity,
and thus baseline immunity, in treatment populations and in resistance
patterns all have major effects on treatment responses. Any statistical analysis
that combines the results of individual studies has to take due account of these
factors and be interpreted accordingly. However, such analyses do not obviate
the need for a systematic and comprehensive review of all available trials before
reaching decisions about treatment recommendations.
Treatments for malaria, like those for many infectious diseases, must be
considered from the perspective of community or public health benefits and
harms as well as from that of the patient. In some instances, therefore, the
recommendations provided here are based on public health considerations as
well as the potential individual benefits.

1
The process is described in detail in Annex 1.
2
A guide to assist country adaptation of these guidelines is provided in Annex 2. 3
 G uidelines for the t reatment of malar ia

Cost-effectiveness studies have not been included in the information considered

by the Technical Guidelines Development Group at this stage for two reasons:
there are very few completed, generalizable cost-effectiveness studies that
relate to the main treatment options being considered and the price of the
antimalarials concerned is extremely fluid, rendering such studies unreliable.
However, as relevant information becomes available, it will be considered for
inclusion in future editions of the guidelines.

1.3.2 Presentation of evidence

For clarity, these guidelines have adopted a simple descriptive approach;
this may be revised in future editions. They are presented as a central
unreferenced main document containing the recommendations. Summaries
of the recommendations are given in boxes. Symbols for the evidence used
as the basis of each recommendation (in order of level of evidence) are:
S formal systematic reviews, such as a Cochrane Review, including more
than one randomized controlled trial;
T comparative trials without formal systematic review;
O observational studies (e.g. surveillance or pharmacological data);
E expert opinion/consensus.
In addition, for each policy or treatment question leading to a recommendation,
a brief summary of evidence is provided in a separate evidence box. Full
reviews of the evidence and references are provided in annexes. If pharmaco-
kinetics studies have been included as part of the deliberations, this is noted
in the main document.3

3 Details of the pharmacology of antimalarials are provided in Annex 3.

4
 2. The c linic al disease

2. THE CLINICAL DISEASE

Malaria is caused by infection of red blood cells with protozoan parasites of
the genus Plasmodium. The parasites are inoculated into the human host by
a feeding female anopheline mosquito. The four Plasmodium species that infect
humans are P. falciparum, P. vivax, P. ovale and P. malariae. Occasional
infections with monkey malaria parasites, such as P. knowlesi, also occur.
The first symptoms of malaria are nonspecific and similar to the symptoms of
a minor systemic viral illness. They comprise: headache, lassitude, fatigue,
abdominal discomfort and muscle and joint aches, followed by fever, chills,
perspiration, anorexia, vomiting and worsening malaise. This is the typical
picture of uncomplicated malaria. Residents of endemic areas are often
familiar with this combination of symptoms, and frequently self-diagnose.
Malaria is therefore frequently overdiagnosed on the basis of symptoms
alone. Infection with P. vivax and P. ovale, more than with other species, can
be associated with well-defined malarial paroxysms, in which fever spikes, chills
and rigors occur at regular intervals. At this stage, with no evidence of vital
organ dysfunction, the case-fatality rate is low (circa 0.1% for P. falciparum
infections – the other human malarias are rarely fatal) provided prompt and
effective treatment is given. But if ineffective drugs are given or treatment is
delayed in falciparum malaria, the parasite burden continues to increase and
severe malaria may ensue. A patient may progress from having minor symptoms
to having severe disease within a few hours. This usually manifests with one
or more of the following: coma (cerebral malaria), metabolic acidosis, severe
anaemia, hypoglycaemia and, in adults, acute renal failure or acute pulmonary
oedema. By this stage, mortality in people receiving treatment has risen to
15–20%. If untreated, severe malaria is almost always fatal.
The nature of the clinical disease depends very much on the pattern and
intensity of malaria transmission in the area of residence, which determines
the degree of protective immunity acquired and, in turn, the clinical disease
profile. Where malaria transmission is “stable” – meaning where populations
are continuously exposed to a fairly constant rate of malarial inoculations –
and if the inoculation rates are high – entomological inoculation rate (EIR)
>10/year –, then partial immunity to the clinical disease and to its severe
manifestations is acquired early in childhood. In such situations, which prevail
in much of sub-Saharan Africa and parts of Oceania, the acute clinical disease
described above is almost always confined to young children who suffer high
parasite densities and acute clinical disease. If untreated, this can progress
very rapidly to severe malaria. In stable and high-transmission areas, adoles-
cents and adults are partially immune and rarely suffer clinical disease,

5
 G uidelines for the t reatment of malar ia

although they continue to harbour low blood-parasite densities. Immunity is

reduced in pregnancy, and can be lost when individuals move out of the
transmission zone.
In areas of unstable malaria, the situation prevailing in much of Asia and
Latin America and the remaining parts of the world where malaria is endemic,
the rates of inoculation fluctuate greatly over seasons and years. EIRs are
usually <5/year and often <1/year. This retards the acquisition of immunity
and results in people of all ages, adults and children alike, suffering acute
clinical malaria, with a high risk of progression to severe malaria if untreated.
Epidemics may occur in areas of unstable malaria when inoculation rates
increase rapidly. Epidemics manifest as a very high incidence of malaria in all
age groups and can overwhelm health services. Severe malaria is common if
effective treatment is not made widely available.
Thus in areas of high transmission, it is children who are at risk of severe malaria
and death, whereas in areas of low or unstable transmission, all age groups
are at risk.

6
 3 . Tre a t m e n t o b j e c t i v e s

3. TREATMENT OBJECTIVES

3.1 Uncomplicated malaria

The objective of treating uncomplicated malaria is to cure the infection. This
is important as it will help prevent progression to severe disease and prevent
additional morbidity associated with treatment failure. Cure of the infection
means eradication from the body of the infection that caused the illness. In
treatment evaluations in all settings, emerging evidence indicates that it is
necessary to follow patients for long enough to document cure (see section
6.1). In assessing drug efficacy in high-transmission settings, temporary
suppression of infection for 14 days is not considered sufficient by the group.
The public health goal of treatment is to reduce transmission of the infection
to others, i.e. to reduce the infectious reservoir.4
A secondary but equally important objective of treatment is to prevent the
emergence and spread of resistance to antimalarials. Tolerability, the adverse
effect profile and the speed of therapeutic response are also important
considerations.

3.2 Severe malaria

The primary objective of antimalarial treatment in severe malaria is to prevent
death. Prevention of recrudescence and avoidance of minor adverse effects are
secondary. In treating cerebral malaria, prevention of neurological deficit is also
an important objective. In the treatment of severe malaria in pregnancy,
saving the life of the mother is the primary objective.

4 Further information on antimalarials and malaria transmission is provided in Annex 4.

7
 G uidelines for the t reatment of malar ia

4. DIAGNOSIS OF MALARIA
Prompt and accurate diagnosis of malaria is part of effective disease manage-
ment and will, if implemented effectively, help to reduce unnecessary use of
antimalarials.5 High sensitivity of malaria diagnosis is important in all settings,
in particular for the most vulnerable population groups, such as young
children, in which the disease can be rapidly fatal. High specificity can reduce
unnecessary treatment with antimalarials and improve differential diagnosis
of febrile illness.
The diagnosis of malaria is based on clinical criteria (clinical diagnosis)
supplemented by the detection of parasites in the blood (parasitological or
confirmatory diagnosis). Clinical diagnosis alone has very low specificity and
in many areas parasitological diagnosis is not currently available. The decision
to provide antimalarial treatment in these settings must be based on the
prior probability of the illness being malaria. One needs to weigh the risk of
withholding antimalarial treatment from a patient with malaria against the risk
associated with antimalarial treatment when given to a patient who does not
have malaria.

4.1 Clinical diagnosis

The signs and symptoms of malaria are nonspecific. Malaria is clinically
diagnosed mostly on the basis of fever or history of fever. The following WHO
recommendations are still considered valid for clinical diagnosis.6
• In general, in settings where the risk of malaria is low, clinical diagnosis
of uncomplicated malaria should be based on the degree of exposure to
malaria and a history of fever in the previous 3 days with no features of other
severe diseases.
• In settings where the risk of malaria is high, clinical diagnosis should be
based on a history of fever in the previous 24 h and/or the presence of
anaemia, for which pallor of the palms appears to be the most reliable sign
in young children.
The WHO/UNICEF strategy for Integrated Management of Childhood Illness
(IMCI)7 has also developed practical algorithms for management of the sick
child presenting with fever where there are no facilities for laboratory diagnosis.

5 Further information on the diagnosis of malaria is provided in Annex 5.

6
WHO Expert Committee on Malaria. Twentieth report. Geneva, World Health Organization, 2000
(WHO Technical Report Series, No. 892).
7 IMCI information package, 1999. Geneva, World Health Organization, 1999 (document WHO/CHS/
8 CAH/98.1).
 4. Diagnosis of malar ia

4.2 Parasitological diagnosis

The introduction of ACTs has increased the urgency of improving the specificity
of malaria diagnosis. The relatively high cost of these drugs makes waste
through unnecessary treatment of patients without parasitaemia unsustainable.
In addition to cost savings, parasitological diagnosis has the following
advantages:
• improved patient care in parasite-positive patients owing to greater certainty
that the patient has malaria;
• identification of parasite-negative patients in whom another diagnosis
must be sought;
• prevention of unnecessary exposure to antimalarials, thereby reducing
side-effects, drug interactions and selection pressure;
• improved health information;
• confirmation of treatment failures.
The two methods in use for parasitological diagnosis are light microscopy and
rapid diagnostic tests (RDTs). Light microscopy has the advantage of low cost
and high sensitivity and specificity when used by well-trained staff. RDTs for
detection of parasite antigen are generally more expensive, but the prices of
some of these products have recently decreased to an extent that makes
their deployment cost-effective in some settings. Their sensitivity and specificity
are variable, and their vulnerability to high temperatures and humidity is an
important constraint. Despite these concerns, RDTs make it possible to expand the
use of confirmatory diagnosis. Deployment of these tests, as with microscopy,
must be accompanied by quality assurance. Practical experience and
operational evidence from large-scale implementation are limited and,
therefore, their introduction should be carefully monitored and evaluated.
The results of parasitological diagnosis should be available within a short time
(less than 2 h) of the patient presenting. If this is not possible, the patient must
be treated on the basis of a clinical diagnosis.

4.2.1 The choice between RDTs and microscopy

The choice between RDTs and microscopy depends on local circumstances,
including the skills available, the usefulness of microscopy for other diseases
found in the area, and the case-load. Where the case-load of fever patients is
high, microscopy is likely to be less expensive than RDTs. Microscopy has
further advantages in that it can be used for speciation and quantification of
parasites, and identification of other causes of fever. However, most malaria
patients are treated outside the health services, for example, in the community,

9
 G uidelines for the t reatment of malar ia

in the home or by private providers; microscopy is generally not feasible in such

circumstances, but RDTs may be.
The following conclusions and recommendations are based on evidence summa-
rized by recent WHO consultations, especially the Technical Consultation on the
Role of Parasitological Diagnosis in Malaria Case Management in Areas of High
Transmission, held in Geneva from 25 to 26 October 2004 (report in preparation).

4.3 Where malaria transmission is low to moderate

and/or unstable
Parasitological confirmation of the diagnosis of malaria is recommended.
This should be provided by microscopy or, where not available, RDTs. Low to
moderate transmission settings8 include many urban areas in Africa, and the
low transmission season in areas with seasonal malaria.
In settings where malaria incidence is very low, parasitological diagnosis for
all fever cases may lead to considerable expenditure to detect only a few
patients who are actually suffering from malaria. In such settings, health
workers should be trained to identify, through the history, patients that have
been exposed to malaria risk before they conduct a parasitological test.

4.4 In stable high-transmission settings

Malaria is usually the most common cause of fever in children under 5 years
of age in these areas. Antimalarial treatment should therefore be given to
children with fever (>37.5 oC) or a history of fever and no other obvious cause.
Malaria is the most likely cause of their illness and there is as yet no evidence
to show that the benefits of parasitological diagnosis in this highly vulnerable
group outweigh the risks of not treating false negatives. In children of 5 years
of age and above, malaria becomes progressively less likely as a cause of fever,
as immunity is acquired. In these older children and in adults, malaria diagnosis
should be based on a parasitological confirmation. Parasitological diagnosis
should be promoted in pregnant women, to improve the differential diagnosis
of fever and to reduce unnecessary use of antimalarials in pregnancy. Parasito-
logical diagnosis is also particularly important in settings with a high prevalence
of HIV/AIDS because of the high incidence of febrile disease that is not
malaria in HIV-infected patients.

8
Transmission intensity is conventionally expressed in terms of EIR (see section 2). There is as yet no
consensus on criteria for determining the thresholds between high, and low to moderate transmission
settings. Suggested criteria include: the proportion of all children under 5 years of age with patent
parasitaemia, and the incidence of individuals with the spleen palpable below the umbilicus in
10 children aged 2–9 years. The IMCI guidelines recommend that areas in which fewer than 5% of young
children with fever have malaria parasitaemia should be considered as low-transmission settings.
 4. Diagnosis of malar ia

4.5 Malaria parasite species identification

In areas where two or more species of malaria parasites are common, only a
parasitological method will permit a species diagnosis. Where mono-infection
with P. vivax is common and microscopy is not available, it is recommended
that a combination RDT which contains a pan-malarial antigen is used. Alternatively,
RDTs specific for falciparum malaria may be used, and treatment for vivax
malaria given only to cases with a negative test result but a high clinical
suspicion of malaria. Where P. vivax, P.malariae or P.ovale occur almost always
as a co-infection with P. falciparum, an RDT detecting P. falciparum alone is
sufficient. Anti-relapse treatment with primaquine should only be given to cases
with confirmed diagnosis of vivax malaria.

4.6 In epidemics and complex emergencies

In epidemic and complex emergency situations, facilities for parasitological
diagnosis may be unavailable or inadequate to cope with the case-load. In such
circumstances, it is impractical and unnecessary to demonstrate parasites
before treatment in all cases of fever. However, there is a role for parasitological
diagnosis even in these situations (see section 11.1).

Summary of recommendations on parasitological diagnosis

LEVEL OF
RECOMMENDATIONS
EVIDENCE
In areas of low to moderate transmission, prompt parasitological E
confirmation of the diagnosis is recommended before treatment is
started. This should be achieved through microscopy or, where not
available, RDTs.
In areas of high stable malaria transmission, the prior probability of E
fever in a child being caused by malaria is high. Children under 5 years
of age should therefore be treated on the basis of a clinical diagnosis
of malaria. In older children and adults including in pregnant women,
a parasitological diagnosis is recommended before treatment is
started.
In all suspected cases of severe malaria, a parasitological confirmation E
of the diagnosis of malaria is recommended. In the absence of or a
delay in obtaining parasitological diagnosis, patients should be
treated for severe malaria on clinical grounds.

11
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