Malaria Treatment Updates and Guidelines

Module 1


Learning Objectives

To orient practitioners to the background of malaria including historical aspects of the
disease, epidemiology, current scenario, etiopathogenesis of malaria and latest
treatment guidelines
To review the pathophysiology of malaria with special emphasis on the malaria life
cycle with regard to the immune system
To revise essential clinical features and management goals of malaria in the light of
the latest recommendations of WHO and the National Vector Borne Disease Control
Programme, Government of India
To serve as a refresher for practitioners in relation to current guidelines for diagnosis
of different types of malaria
To acquaint professionals with the challenges of drug resistant malaria which are
frequently seen in clinical practice

Contents:
1. Introduction
Cause of Malaria
Epidemiological Terms
History
Current Situation
Treatment Objectives
2. Pathophysiology
Life cycle of malaria parasite
Immune Response
3. Clinical Presentation
Difference between adult and paediatric malaria
Difference between P. Vivax and P.Falciparum malaria
Important Points for Complications of P. Falciparum
4. Diagnosis
Parasitological diagnosis
5. Antimalarial treatment policy
Resistance to antimalarial medicines
Global impact of drug resistance
Criteria for antimalarial treatment policy change
Therapeutic efficacy threshold for changing treatment policy

1) Introduction

Malaria is a parasitic disease caused by different species of plasmodium which spends part of
its life in mosquitoes and part of it in humans (1). It can manifest as a serious clinical
condition and remains one of the major public health problems in India (2). The cause,
history, current situation and treatment objectives are described ahead.

1.1 Cause of Malaria
The causative organism for malaria is a single-celled parasite belonging to the genus
Plasmodium. Several different types of Plasmodium occur in nature. They result in malaria
not only in humans but also in animals and birds. Humans can be infected commonly by four
species of Plasmodium. Each of these has distinctive microscopic features and is
characterized by somewhat distinct pattern of symptoms. A single individual can be infected
by more than one species co-existing in the same area. Out of the various types of species,
Plasmodium falciparum is the most lethal and is responsible for a majority of deaths due to
malaria. The infection can develop suddenly resulting in many life-threatening complications.
However it is mostly curable with immediate and effective treatment. Plasmodium vivax is
the most widespread species geographically and produces symptoms which are less severe.
Relapses, however, can take place for up to 3 years, and chronic disease has lasting adverse
effects. Plasmodium malariae infections produce typical malaria symptoms and can persist
for very long periods in the blood, sometimes for decades, without ever producing symptoms.
A person with asymptomatic Plasmodium malariae, can however infect others, either through
mosquito bites or blood donation. Plasmodium ovale is uncommon with the potential to cause
relapses (3).

In India, malaria epidemiology is complex as a result of diversity and distribution of nine
different anopheline vectors which transmit three Plasmodial species: P. vivax, P. Falciparum
and P. malariae. Anopheles culicifacies is found widely and is the main vector of rural
malaria and An. stephensi is the main urban vector (2).

1.2 Epidemiological Terms
There are several measures related to malaria. However the most commonly used terms
which one should be familiar with are the following.

ABER or Annual Blood Examination Rate. calculated as (number of slides
examined/population) x 100. WHO recommendation for malarious areas is that the
number of slides examined per month should equal at least 1% of the population (4).
API or Annual Parasite Index calculated as (confirmed cases during 1
year/population under surveillance) x 1000 (4).
SPR or Slide Positivity Rate calculated as (No. of blood smears found positive for
malaria parasite/No. of blood smears examined) X 100 (5).
Sporozoite is the infective stage of the malaria parasite that is passed to the human
host from the salivary glands of the mosquito. Sporozoites infect liver cells,
disappearing from bloodstream within 30 minutes (4).
Sporozoite rate is the percentage of female anopheline mosquitoes of a particular
species that bear sporozoites in their salivary glands. Expressed as a percentage (4).

Table 1: Geographical areas classified by intensity of transmission (based upon percent of

children, age 29, with enlarged spleens and malaria parasitemia)

Sl.
No.
Category Transmission Immunity Epidemic
potential
Spleen and
parasite rates
1) Holoendemic Intense High No Over 75%
2) Hyperendemic Regular, often
seasonal
Varied No 50-75%
3) Mesoendemic Regular at
lower level
Varied Yes, in those with
little immunity
10-50%
4) Hypoendemic Limited Little or
nil
Yes, involving all
age groups
<10%

Source: Adapted from OCW, Johns Hopkins University, Epidemiology and Control of
Malaria (6)

1.3 History

World
Malaria is a historical disease. It was mentioned by the Greeks and described in detail by the
Father of Medicine Hippocrates. In ancient Rome, just like in other temperate climates,
malaria was more likely to be seen around marshes and swamps. People blamed the illness in
these places on rot and decay that resulted in foul air. Hence, the name derived from the
Italian, mal aria, or bad air. The real cause of malaria was discovered by the French
scientist Alphonse Laveran in 1880 (3). On 4th July 1898, Dr. Ronald Ross, a British military
doctor and malaria researcher working in India made a startling discovery. After years of
trying to find out how plasmodium parasite was transmitted from mosquitoes to humans, he
discovered that the mosquitos bite was responsible for transmission of this often lethal
disease (7). The discovery that malaria transmission resulted from mosquitoes lead to several
ambitious public health interventions aimed at eliminating malaria. These measures were
aimed at both larval stages and insect adult stages. In some places, draining waterlogged
areas and changing land use resulted in partial success with regard to eliminating mosquitoes.
Control measures rapidly improved with the introduction of DDT for mosquitoes and
chloroquine for the treatment of malaria; both of which were found to be highly effective. By
the mid-1950s WHO began a big global campaign aimed at eliminating malaria. At the
beginning, the programme was a huge success leading to the total eradication of malaria for
600 million and a dramatic reduction in infections for 300 million others. Soon however
financial and administrative problems arose. To make matters worse there were an increasing
number of Anopheles mosquito strains which were developing resistance to DDT as well as
other insecticides. The environmental consequences of DDT were also being recognized.
Meanwhile the malarial parasite became resistant to the antimalarial drug chloroquine.
Infection rates from 1970 to the turn of the century had increased in several places. To tackle
this alarming resurgence, the public health strategy adopted was to ensure that prevention
methods were carefully selected and best suited for a particular area. In addition to medicines
and insecticides, the strategies included reducing water logging, mosquito nets and repellants
amongst other measures Increasingly the emphasis has been on surveillance, developing
newer drugs, prevention of transmission by the mosquito and the development of a vaccine
(3).

India
In 1947, when India became independent, there were approximately 75 million malaria cases
in a population of 330 million. During the eradication era in the late 1950s and early 1960s,a
spectacular achievement was witnessed on the malaria eradication front because malaria
cases significantly declined to just 100,000 in 1964. However, reversal was experienced, and
malaria staged a comeback. By 1976, malaria cases had touched the 6.4 million mark. A
continued rise in P. falciparum was witnessed, and its proportion has gradually risen to nearly
50% in the recent past (see figure 1 below) (2).

1.4 Current Situation (2)


Fig 1: Malaria incidence trends in India from 1960 to 2005.
Note Eradication was nearly achieved in 1960s (< 100,000 cases). Resurgence was seen in
the mid-1970s (6.4 million cases) stabilizing to 2 million cases by the 1990s. P.
falciparum proportion has gradually risen to 50% in recent past. The rest is accounted by P.
vivax and a small proportion by P. malariae.
SPR:slide positivity rate; ABER: annual blood examination rate.
Source: Kumar A, Valecha N, Jain T et. al. (2007)
Please seek permission for reproduction

Malara incidence varies across India. The distribution of malaria in different states is as
follows. API in most of the country is < 2, 25 API can be seen in scattered regions, and
places with > 5 API were found in the states of Gujarat, Rajasthan, Karnataka, Goa, Southern
Madhya Pradesh, Jharkhand, Chhattisgarh and Orissa as well as in northeastern states (Figure
2) (2).

Fig. 2. Distribution of malaria incidence in India according to annual parasite incidence in
2004.
Note: Majority of India had < 2 cases per 1,000 population, 25 cases in some scattered
regions, and > 5 cases per 1,000 population where ethnic tribes live and stable malaria
conditions prevail.
Source: Kumar A, Valecha N, Jain T et. al. (2007)
Please seek permission for reproduction

Amongst the states of India, malaria contribution by Orissa is by far the most. Although the
population was around 4% of India, the number of cases was 25% of the 1.52 million annual
malaria cases, approximately 40% of P. falciparum malaria, along with 30% of deaths due to
malaria in India. Similarly, in other states characterized by ethnic tribes residing in forest
areas, meso to hyperendemic exist with 90% or more of the cases being P. falciparum. The
proportion of P. vivax and P. falciparum is different in different parts of India. Mostly Indo-
Gangetic plains, northwestern India , northern hilly states, and southern Tamil Nadu have <
10% P. Falciparum. The rest are P. vivax infections. In remaining places P. Falciparum is
between10% and 30%. (2).

1.5 Treatment Objectives (8)

1.5.1 Uncomplicated Malaria
The objective of treating uncomplicated malaria is to ensure that the cure of the infection
takes place as quickly as possible. Cure means the elimination of illness causing parasites
from the body. Progression to severe disease is prevented, along with greater morbidity
related to treatment failure. In evaluations of treatment, it is imperative to follow patients for
adequate time in order to appropriately assess cures.

The public health aim of treatment is to minimize infection transmission to others, i.e. to
minimize the infectious reservoir as well as preventing emergence and spread of antimalarial
medicines resistance. The adverse effect profile, tolerability of antimalarial medicines and the
pace of therapeutic response are also significant considerations.

1.5.2 Severe malaria
The main objective of antimalarial treatment in the case of severe malaria is the prevention of
death. In cerebral malaria treatment, neurological deficit prevention is also an important
objective. In severe malaria treatment for pregnancy, saving the mothers life is the primary
objective. In all severe malaria cases, prevention of relapses and minor adverse effects
avoidance are secondary objectives.


2) Pathophysiology

2.1 Life cycle of malaria parasite

The life cycle constitutes of two components, the Plasmodium life cycle as well as the vector
feeding cycle. The parasite enters the mosquito along with a blood meal. The mosquito is
infectious 1016 days later, by when the parasite develops into sporozoites. Meanwhile, the
mosquito would have fed many times over. Most infected mosquitoes do not survive to
become infectious. Surviving mosquitoes become infectious and can give many infectious
bites before dying. Human infections start during the mosquito blood meal at the time when
sporozoites enter the skin. Parasites are not seen in the blood upto about 11 days later.
Individuals with P. falciparum infection are not infectious till some of the blood-stage
parasites turn into gametocytes, ultimately maturing some 810 days later. Untreated or
improperly treated infections can go on for 200 days on average and some infections can
even go on for more than a year. Till the blood-stage parasites persist, some gametocytes will
continue to be produced. The number of mosquitoes becoming infectious depends, partially
on the rate at which parasites develop, the longevity of mosquitoes and the number of
mosquitoes biting humans, and (1).



Fig. 3 Various stages of the plasmodium life cycle
Source: OCW, Johns Hopkins University, Epidemiology and Control of Malaria (6)

Please seek permission for reproduction

2.2 Immune Response
There is little evidence for the human immune response to malaria, such as cytokine
characteristics, Plasmodium antigens activating the innate immune system, the most
significant innate immune receptors, and how Plasmodium escapes immune system detection.
The case is similar for the adaptive immune response. Both B and T cells have important
roles in Plasmodium clearance. Plasmodium related immune mediators such as peptides
recognized by B and T cells are however not well characterized. In chronic cases T cells and
B cells are likely to be exhausted and less functional. A recent study depicted that a majority
of patients have functional memory B cells and long lasting antibody titers. Further research
is needed but the evidence available thus far suggests that vaccines targeted at activating B
cells could lead to success. Also, depletion of regulatory T cells dampens the immune
responses in mouse models of malaria and enhances the immune response in relation to
malaria. Thus regulatory T cell activity is suggested as a target for drug modulation (9).

2.2.1 A Vaccine for Malaria (9)
There are several difficulties in developing a broadly effective, viable human vaccine to
malaria.
1) The most vulnerable populations, that is, pregnant women, children and the
immunocompromised might not be able to receive vaccination.
2) Protective immunity owing to vaccination could develop in vulnerable individuals
without any need for booster shots thus resulting in a high cost of the vaccine.
3) Malaria is found along with tuberculosis and HIV infections. Elimination of the
parasite is more laborious with these co-infections.
4) Plasmodium has many life stages. Thus choosing important antigens for vaccine
targeting is difficult.
5) A vaccine should ideally reduce disease for individuals as well as reduce the
transmission rate for the community. Both these goals may not be achieved.
6) An inadequate understanding of the immune response seen in malaria.

Despite all these difficulties, human vaccines development for malaria is ongoing. No
successful blood stage vaccines have been developed, though attenuated Plasmodium
deficient in merozoite essential proteins are promising in relation to mouse models of
malaria. The pre-erythrocytic stage possibly holds more promise for vaccine targeting. It has
been seen that immunization with sporozoites having the potential to target the liver can lead
to the liver stage of development leading to the development of immunological memory.
Here too the attenuated Plasmodium strains could be effective just like the erythrocytic stage.
Additionally, subunit vaccines with immunodominant epitopes could be effective. Most
significantly for relentless progress in vaccine development, it is critical to bridge the
numerous, wide gaps in our comprehension of the immune response to malaria in humans.


3) Clinical Presentation
Malaria manifests as a number of recurrent attacks, or paroxysms, characterized by chills,
followed by fever, and thereafter sweating. Other symptoms could be headache, fatigue,
malaise, muscular pains, nausea, vomiting, and diarrhea. The body temperature rises and the
skin feels hot as well as dry within an hour or two. Thereafter, a profuse sweat begins as the
body temperature falls. The symptoms initially appear about 10 to 16 days after the mosquito
bite. It takes place at the same time as the bursting of infected RBCs. When the bursting

process takes place in several RBCs at the same time, malaria attacks may recur at regular
episodes, every 2 days for P. vivax as well as P. ovale, and every 3 days for P. Malariae (3).

The acute febrile attacks (malaria paroxysms) take place in the blood stage, not the liver stage
or gametocytes. These paroxysms correlate with simultaneous release of pyrogens, High
levels of tumor necrosis factor- relate with paroxysms. In between these episodes the
temperature is not elevated and the patient feels well. P. falciparum however, may be seen as
a continuous fever rather than classic paroxysms. The paroxysms become irregular and less
severe as the disease progresses. Semi-immune individuals may exhibit little, that is, 1-2 days
fever or no symptoms. The manifestations as well as severity depend on species along with
host factors. The latter includes immunity, genetics, general health and nutritional state.
Relapses can take place over months or years along with the development of severe
complications, especially in the case of P. falciparum (10).

The patterns of fever due to different plasmodium species are depicted below.

Fig. 4 Fever patterns for different species of plasmodium
Source: Tulane University, Malaria Life Cycle (10)

All clinically suspected malaria cases should be investigated immediately by microscopy

and/or rapid diagnostic test (RDT). Malaria ought to be suspected in individuals residing in
endemic areas and presenting with symptoms mentioned at the start of this section. In
addition it should also be suspected in patients who have been recent visitors to an endemic
area. Although malaria is known to have signs and symptoms similar to several common
infectious diseases, other causes should be suspected and investigated when the
manifestations mentioned below are seen. (11).

Respiratory infection features such as running nose and cough
Burning micturition and/or lower abdominal pain
Painful swelling of joints
Skin rash/infections
Lymphadenopathy
Ear discharge
Dysentery
Abscess

3.2 Difference between adult and paediatric malaria
Children are less likely to complain of chills, arthralgia/myalgia or headaches but more likely
to present with non-specific symptoms such as fever, malaise, lethargy, and somnolence in
comparison to adults. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain,
and diarrhoea are particularly common. They are also more likely to present with
hepatomegaly and splenomegaly (12). Anemia is likely to be seen in palms in children (13).

3.3 Difference between P. Vivax and P.Falciparum malaria
These are depicted in tabular form below

Table 2: Differences between P. Falciparum and P. Vivax (3,14,15)

Sl. No. P Falciparum P Vivax
1) Peaks at an older age Peaks at a younger age
2) Risk of complications decreases relatively
slowly with age
Risk of complications decreases faster
with age
3) Greater burden of febrile illness for older
children, adolescents and adults
Lesser burden of febrile illness for
older children, adolescents and adults
4) Fever more more often due to parasitemia
above pyrogenic threshold
Fever occurs less often due to
parasitemia below pyrogenic threshold
5) Most secondary infections associated with
fever
Most secondary infections not
associated with fever
6) Affected person does not feel fine between
bouts of fever
Affected person feels fine between
bouts of fever
7) Severe malaria characterized by severe
anaemia, hypovolemia, metabolic acidosis
and cerebral malaria is more common
Severe malaria is less common
8) Cellular and humoral immunity involved Antibodies against P. Vivax protein
primary mechanism
9) Red blood cells at all stages of
development are affected thus can be lethal
Only young RBCs are affected
10) Immunity is less rapidly acquired Immunity is more rapidly acquired

3.4 Important Points for Complications of P. Falciparum (16)

3.4.1 Cerebral Malaria
Common features are as given below
o Psychosis
o Extrapyramidal tremor
o Cranial nerve lesions
o Polyneuropathy
o Mononeiritis multiplex
o Guillain-Barre syndrome
o Focal epilepsy
Steroids do not have an effect on mortality
About 90% become comatose prior to death
Gradual impairment or coma after seizure
Immobile or tossing about
Extensor posturing
Uncommon in adults or non-immunes

3.4.2 Severe Anemia
Decreased production along with increased red cell destruction
As a result of iron deficiency and ineffective erythropoeisis
Rouleaux formation of uninfected erythrocytes accelerates spleen destruction
Associated with secondary bacterial infections
Transfusion is life saving
Degree of anemia corresponds with severity and duration of parasitemia
Parasitemia isnt a predictor of mortality in severe anemia
Treated uncomplicated P. Falciparum malaria decreases hematocrit by one seventh
Severe anemia causes mortality as hemoglobin drops below 5g/dl
Mortality rises with metabolic acidosis and tissue hypoxia
Another infection can result in catabolic metabolism

3.4.3 Tropical Splenomegaly Syndrome
Also known as hyperreactive malarial splenomegaly
Progressive, massive, splenic enlargement
Past medical history comprises of several attacks of malaria or fever
Abdominal distention, vague dragging sensation and sharp abdominal pains
Peritonis suggesting perisplenitis
Cachexia
Lower leg ulcerations
Normocytic normochromic anemia with hemolytic episodes
Very low or undetectable parasitemia
Morality rate is high if untreated
Death as a result of overwhelming skin or pulmonary infections
Gross splenomegaly
Elevated IgM (polyclonal)
Clinical and immunological response to anti-malarial prophylaxis

3.4.4 Placental Malaria (Malaria during pregnancy)

In areas of stable malaria transmission
Maternal death, abortion, stillbirth, premature delivery and low birthweight are
common complications

In areas of unstable malaria transmission
Clinical symptoms as well as parasitemia is higher in primigravida
Low birth weight
Non-immunes
o Higher mortality
o Progressive anemia
o Quinine induced hypoglycemia
Pulmonary edema
o May develop at any stage of disease
o First clinical signs are increased respiratory rate, dyspnea and crepitations
o Acute Respiratory Distress Syndrome with normal right heart pressures
o Chest X ray shows bronchopneumonia
o Metabolic acidosis

4) Diagnosis

The early diagnosis of malaria and accompanying treatment is critical to the management of
malaria. It ensures the following (11).
Complete cure
Prevention of deaths
Interruption of transmission
Minimizing risk of selection and spread of drug resistant parasites
Prevention of progression of uncomplicated malaria to severe disease

Clinical diagnosis has been described in the previous section in terms of the clinical
presentation. The parasitological diagnosis is described in the next section.

4.1 Parasitological diagnosis
Changing malaria epidemiology and Arteminisin-based Combination Therapy (ACT)
introduction have increased the urgent need for improving malaria diagnosis specificity.

Parasitological diagnosis has the following advantages (8):
improved patient care in parasite-positive patients;
identification of parasite-negative patients in whom another diagnosis must be sought;
prevention of unnecessary use of antimalarials
reducing frequency of adverse effects, especially in those who do not need the medicines,
and drug pressure selecting for resistant parasites;
improved malaria case detection and reporting;
confirmation of treatment failures

The 2009 Guidelines for Diagnosis and Treatment of Malaria in India describes the two
primary methods of diagnosis as follows (11)

4.1.1 Microscopy (see slides for difference between P. Falciparum and Vivax)
The gold standard for confirmation is by microscopy of thick and thin stained blood smears.

The advantages of microscopy are:
High sensitivity. Malarial parasites can be detected at low densities.
Parasite load can be quantified.
It is possible to distinguish the various species of malaria parasite and their different stages.

4.1.2 Rapid Diagnostic Test (RDT)
The basis of Rapid Diagnostic Tests is circulating parasite antigens detection. Several types
of RDTs are found. Some can only detect P. falciparum, whereas others can also detect other
parasite species. The latter kits are costly and temperature sensitive. Presently, the National
Vector Borne Disease Control Programme (NVBDCP) supplies kits for RDT detection of P.
falciparum at places where microscopy is not possible in 24 hours of sample collection.

RDTs are produced by several different companies. There may be differences in contents and
the way in which the test is done. Instructions should be followed carefully going by the
users manual. Results ought to be read at the specified period. The clinician or technician
performing the test is responsible for ensuring that the expiry date of the kit has not passed
and has been transported as well as stored under recommended conditions. Failure to ensure
these criteria can result in false/negative results.


Fig 5. P. Falciparum thick film
Source: OCW, Johns Hopkins University, Diagnosis and Clinical Complications of Malaria
(16)
Please seek permission for reproduction

Fig 6. P.Vivax thick film
Source: OCW, Johns Hopkins University, Epidemiology and Control of Malaria (16)
Please seek permission for reproduction

Table 3: Distinguishing Blood Film Characteristics (16)
Feature P. Falciparum P. Vivax
Red cell size Normal Large
Merozoites in schizont

Up to 32 Up to 16

Rings

Fine, delicate double chromatin dots
and appliqu (patchy) forms
Large, irregular

RBC cytoplasm

Maurers dots

Schuffners dots

Gametocytes

Sickle or banana shape

Round

Special

Trophozoite and schizonts rare

Amoeboid trophozoites


Note: Explanation of terms (17)
Merozoite: A daughter cell formed by asexual development in the life cycle of malaria
parasites. Liver-stage and blood-stage malaria parasites develop into schizonts which contain
many merozoites. When the schizonts are mature, they (and their host cells!) rupture; the
merozoites are released and infect red blood cells.
Schizont: A developmental form of the malaria parasite that contains many merozoites.
Schizonts are seen in the liver-stage and blood-stage parasites.

Trophozoite: A developmental form during the blood stage of malaria parasites. After
merozoites have invaded the red blood cell, they develop into trophozoites (sometimes, early
trophozoites are called "rings" or "ring stage parasites"); trophozoites develop into schizonts.

4.1.3 WHO Guidelines (8)

Choice between microscopy and rapid diagnostic tests (RDTs)
The choice depends on local circumstances, including patient case-load, skills available,
malaria epidemiology and possible microscopy use for diagnosing other diseases. Where the
case-load of patients with fever is high, microscopy is possibly cheaper than RDTs, but may
be less feasible from an operational point of view. Microscopy is also advantageous in that it
can be used for speciation as well as quantification of parasites along with assessing the
response to antimalarial treatment. Microscopy maybe used for identification of other fever
causes as well. However, a major limitation of light microscopy is the need for well-trained,
skilled staff as well as an energy source to power the microscope in most cases.

In several areas, malaria patients receive treatment outside formal health services, e.g. in the
home, in the community or by private providers. Microscopy is generally not feasible for
such situations, but RDTs may be possible. Although RDTs for parasite antigen detection are
generally more costly, their use maybe much more cost effective in many such settings. The
specificities and sensitivities of RDTs are variable, and their vulnerability to humidity and
high temperatures is an important aspect. Despite these concerns, RDTs have the potential to
expand the use for confirmatory diagnosis. Practical experience as well as operational
evidence of best practices with regard to large-scale implementation, though limited, should
be the driver for wide-scale use with respect to RDTs at the programmatic level.

In severe malaria diagnosis, microscopy is the preferred option. It ensures the diagnosis of
malaria and is also useful in assessing other vital parameters in a severely sick patient. In
cases where an RDT is used for malaria confirmation, this allows for a rapid start of
antimalarial treatment. Microscopic examination is recommended however for enhancing
overall patient management.

Where malaria transmission is low-to-moderate and/or unstable
Parasitological confirmation of malaria diagnosis is strongly recommended. This should be
done by high quality microscopy or, where this is not available, by RDTs. In places where
malaria incidence is very low, diagnosis of the parasite in all fever cases can lead to
considerable cost for detecting just a few patients actually suffering from malaria. In such
settings, health workers ought to be trained for identifying patients that could have been
exposed to malaria (e.g. travel in a malaria endemic area recently, or ineffective preventive
measures) and have symptoms that could be attributable to malaria before conducting a
parasitological test.

So far there is no consensus on criteria in relation to determining thresholds between high-
and low-to-moderate settings of transmission. Suggested criteria include: proportion of
children under 5 years of age with overt parasitaemia, and the incidence of spleen palpable
below the umbilicus in 29 years aged children. The Integrated Management of Childhood
Illnesses (IMCI) guidelines recommend that areas with fewer than 5% of young children with
fever having malaria parasitaemia ought to be considered low-transmission settings.

In stable high-transmission settings

Parasitological confirmation of malaria diagnosis provided by high-quality microscopy or,
where not available, by RDTs is suggested for all suspected malaria cases. In these places,
slide positivity rate for febrile children under age five years is more than 5%. Parasitological
confirmation is recommended. It improves differential diagnosis for fever. It also improves
case management for fever and reduces unnecessary antimalarial medicines use. Antimalarial
treatment on the basis of malaria clinical suspicion of malaria should be considered only in
situations where parasitological diagnosis cannot be accessed. This consideration is very
important particularly in vulnerable groups (e.g. suspected severe malaria cases, children
under five years, pregnant women and in places with a high HIV/AIDS prevalence where
patients have fever or a fever history and no other obvious cause for the fever is present) in
whom the disease could rapidly become fatal.

Malaria parasite species identification
In places where more than two malaria parasites species are common, only the parasitological
method permits diagnosis of the species. Where mono-infection with P. vivax is common and
microscopy is unavailable, combinant RDT is recommended containing a pan-malarial
antigen. Where P. vivax, P. ovale , P. malariae occur as a co-infection with P. falciparum,
RDT detecting P. falciparum alone could be sufficient; non-falciparum malaria treatment is
given only for cases with a negative test result where no other obvious illness cause is
present. Anti-relapse treatment with primaquine ought to be given for cases with confirmed
diagnosis of P. ovale or P. vivax malaria in the absence of contraindications like glucose-6-
phosphate dehydrogenase (G6PD) deficiency.

In epidemics and complex emergencies
In epidemic and complex emergencies, facilities for parasitological diagnosis could be
unavailable or inadequate for coping with the case-load. In such cases, it may be unnecessary
and impractical for demonstration of parasites before treatment in all cases of fever.

Summary of recommendations on parasitological diagnosis
Prompt parasitological confirmation by microscopy, or RDTs, is recommended in all
patients suspected of malaria before treatment is started.
Treatment solely on the basis of clinical suspicion should only be considered when
parasitological diagnosis is not accessible.

5) Antimalarial treatment policy

5.1 Resistance to antimalarial medicines (18)
Chloroquine has been the primary treatment of malaria for decades. This cost effective and
safe medicine has become ineffective for falciparum malaria treatment in many parts of the
globe as a result of development of resistance by the parasite. In India, chloroquine resistance
was seen for the first time in 1973 in Assam in 1973 followed by reports from Gujarat,
Orissa, North Eastern states and Madhya Pradesh. Also, the drug is not gametocytocidal in
relation to P. Falciparum. Thus it cannot block transmission and also cannot prevent relapses
in P. vivax. The second line drug sulphadoxine-pyrimethamine is effective but resistance can
develop very fast. It is not effective for vivax malaria treatment thus is not a good choice for
the management of clinically diagnosed cases in places where falciparum and vivax co-exist.
Quinine is effective, however it is reserved for complicated malaria treatment. It leads to
several side effects and when used oral or parenterally needs monitoring apart from a long
duration of treatment if used alone. Mefloquine, although effective for treating multidrug

resistant falciparum malaria, is characterized by a prolonged duration of action making it

vulnerable for resistance development. Cross resistance between mefloquine and quinine is
also reported. Artemisinin group of drugs are very effective but due to short duration of
action, relapses are common. Dose schedules are empirical, safety during pregnancy is still
questionable and neurological side effects are of concern. Primaquine, for gametocytocidal
action in relation to P. falciparum and P. vivax antirelapse activity is contraindicated for
pregnancy and infants. There is no alternative therapy available as of now. Presently, WHO
recommends ACT use which is considered to be highly effective. The use presents new
avenues for preventing drug resistance. Another major development in the recent past is the
decreased sensitivity of P. vivax to chloroquine. This is the drug of choice in complicated
malaria as well as multi-organ dysfunction.

Following action is necessary to tackle this problem.
Complete treatment preferably after diagnosis confirmation
Use of ACT for P. falciparum treatment
Constitution of task force at the country level for monitoring and systematic drug resistance
studies
Inter-country collaboration for resistance monitoring along international borders as well as
convergence in antimalarial drug policy in these aspects for resistance management.
Creation of an institutional and researchers network working on monitoring of drug
resistance of current antimalarials.
Monitoring of chloroquine resistance in P. vivax. This should be viewed as an emergency
and steps ought to be taken to prolong chloroquine use in malaria viax treatment.
Antimalarial drug policies should also closely address operational aspects linked with
chemotherapy such as diagnosis, quality of surveillance, compliance as well as health-
seeking behaviour of communities affected by malaria.
Chemoprophylaxis policy for tourists ought to be formulated with periodic review.

5.2 Global impact of drug resistance

This is summarized in the table below

Table 4 Global impact of drug resistance (19)
Disease burden o Increasing chloroquine resistance in Africa led to more hospital admissions.
o Increasing mortality trends at community level
o Ineffective treatment leads to anaemia and low birth weight.
o Renders health of adults and children with P. falciparum or P. vivax more fragile
o Implicated in malaria epidemics
o Associated with increased transmission

Economic cost o Increased the worldwide price of disease control, including the price of new drug
development
o Therarapeutic failure requires visit to health facility for further evaluation,
resulting in working days loss for adults, school absence for children and
increased cost for the health system.

Changes to
distribution of
malaria species
o The proportion of malaria due to P. falciparum has changed.
o An increase with regard to P. vivax.resistance to antimalarial drugs

Access to
high-quality
treatment
o Ineffective treatment in public sector owing to resistance could result in greater
reliance of patients on unregulated private sector, which could lead to a greater use
of monotherapies or standard and counterfeit medicines thus increasing the risk of
drug resistance.

5.3 Criteria for antimalarial treatment policy change (8)
The therapeutic efficacy of current antimalarial medicines is the primary determinant of
antimalarial treatment policy. Other significant determinants include: varying patterns of
morbidity and mortality for malaria; provider and consumer dissatisfaction with the current
policy; as well as the availability of alternative medicines, approaches and strategies.
Therapeutic efficacy monitoring involves assessment of both clinical and parasitological
treatment outcomes over at least 28 days after the start of adequate treatment in order to
monitor reappearance of blood parasites. Reappearance of same genotype indicates decreased
parasite sensitivity to the drug being used for treatment.
Antimalarial treatment assessment should be the foundation of parasitological cure rates. The
time of post-treatment follow-up is determined by the elimination half-life of the antimalarial
treatment under evaluation. The present recommended time of follow-up is atleast 28 days for
all antimalarial medicines, whereas it is extended for greater periods of time depending on
elimination half-life, that is, 42 days for combinations with piperaquine and mefloquine.
When possible, antimalarial blood or plasma levels should also be assessed in prospective
assessments in order to distinguish drug resistance from treatment failures as a result of
inadequate drug exposure.
In high-transmission settings re-infection is probable, but malaria cure (i.e. prevention of
relapse) is vital; it benefits the patient, by reducing anaemia, as well as the community by
decreasing the parasite reservoir and emergence and spread of resistance. Slow elimination of
antimalarials provide further benefit of suppressing malaria that is newly acquired during this
time in which there is still some residual antimalarial drug levels persisting in the body. On
the other hand, residual drug levels also provide a selection pressure for resistance.

In these treatment recommendations, antimalalarial curative efficacy takes precedence over
the provision of a prophylaxis period.

5.4 Therapeutic efficacy threshold for changing treatment policy (8)
A different antimalarial medicine is recommended in the national treatment policy for malaria
and should be initiated if total treatment failure proportion is 10%, assessed through
therapeutic efficacy in vivo monitoring. The choice of new and/or alternative antimalarial
medicine for use at the community level within the context of national treatment guidelines,
ought to be based on a mean cure rate of > 95%, assessed in clinical trials.

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