MALARIA

Case Management

Dr. Biruk Samson

Assistant Professor of Internal Medicine
Armed Forces Comprehensive Specialized Hospital
April 11, 2023
Adama
Outline

• Introduction

• Epidemiology

• Etiology

• Life cycle

• Clinical Manifestations

• Diagnosis

• Treatment

• Treatment in special groups

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Introduction

• Malaria is a protozoan disease transmitted by the bite of

infected Anopheles mosquitoes

• Malaria is an overwhelming problem in tropical

developing countries, accounting for up to 500 million
febrile illnesses and several million deaths annually

• It is estimated that up to 40% of the world’s population is

at risk for acquiring malaria.
• In sub-Saharan Africa, most severe cases and deaths
occur in children younger than 5 years old and in
pregnant women
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• The most important of the parasitic disease of humans-107 countries, 3 billion people,
1-3 million deaths/yrly

• Eliminated from few countries but resurged in many parts of the tropics

• Post WWII, in 1955 the WHO launched its campaign to eradicate the disease
• This goal soon proved overly optimistic, and the campaign were discontinued in 1967
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Intro…
•HCWs are expected to make an accurate diagnosis of malaria based on microscopic exam
of patient blood and multi-species RDT rather than relying on clinical assessment alone.

•Nurses at health facilities must provide optimal nursing care for hospitalized patients.

•Laboratory technicians should undertake microscopic investigation to identify species of

malaria and density of parasite.

•Ensuring prompt and effective Rx of cases with uncomplicated malaria within 24hrs
after Sx onset will prevent most cases from progressing to severe and fatal illness.
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• According to the latest world malaria report in 2020:

• there were 229 million cases of malaria in 2019 with estimated malaria death
of 409,000 in 2019

• The WHO African Region, with an estimated 215 million cases in

2019, accounted for about 94% of cases

• In 2019, in 33 moderate to high transmission countries in the WHO

African Region,
• there were an estimated 33 million pregnancies, of which 35% (12 million)
were exposed to malaria infection during pregnancy
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Malaria Burden in Ethiopia

• Malaria has been a major public health problem in Ethiopia and has been consistently
reported as one of the leading causes of morbidity and mortality

• P. falciparum and P. vivax are the two dominant parasite species causing malaria in
Ethiopia, with relative frequencies of about 60% and 40%, respectively

• P. falciparum is the dominant parasite species in malaria epidemic situations

• this species causes severe and complicated manifestations and almost all malaria deaths.
• has a remarkable biological diversity including an ability to develop resistance rapidly
 Epidemiology: Ethiopia
• Malaria is one of the leading public health
problems in Ethiopia

• 75% of the country is malarious

(<2000m), with about 68% of the
population (50 million) at risk

• Major impediment to socio-economic

development, coincides with major
planting and harvesting season
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Transmission of Malaria in ETHIOPIA

• Bimodal type of transmission:

• Major: Sep – Dec following the main rainy season from Jun to Aug.

• Minor: Apr–May following a short rainy season from Feb to Mar.

• Major epidemics occur every 5-8 years, focal outbreaks are common.

• Distribution varies from place to place depending on climate and altitude.

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Malaria In Ethiopia Is Unstable:

Stable Malaria Unstable Malaria

• Intense, Constant, frequent, year-round infection

• Seasonal

• High immunity
• Lack of immunity
• Epidemic uncommon
• Epidemic common
• Children & pregnant women more affected.

• All age groups affected

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ETIOLOGY & PATHOGENESIS

5 species of the genus plasmodium cause nearly all
•Major Malaria Vectors malarial infections in humans

• An. arabiensis (common in ethiopia) • P. falciparum--- predominates in Africa

• An. funestus
• P. vivax--- more common in Central America
• An. phareonsis(common in ethiopia)
• P. malariae--- is found in sub-Saharan Africa,
• An. nili
• P. ovale--- relatively unusual outside of Africa
• P. Knowlesi

Almost all deaths are caused by P.f.

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Pathogenesis
• Man – Intermediate host.

• Mosquito – Definitive host

• Sporozoites are infective forms

• Present in the salivary gland of female anopheles mosquito

• After bite of infected mosquito sporozoites are introduced into blood circulation

• Human infection begins when a female anopheline mosquito inoculates sporozoites from its salivary

gland during a blood meal

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• Sporozoites are carried via bloodstream to the liver, they invade hepatic parenchymal cells
(becomes hepatic Schizonts) and begin a period of asexual reproduction

• The swollen infected liver cells eventually burst, discharging motile merozoites into the
bloodstream

• After entry into the bloodstream, merozoites rapidly invade RBCs and become trophozoites
and multiply 6to20 fold every 48 h(P. knowlesi, 24 h; P. malariae,72 h)

• In P. vivax and P. ovale infections, a proportion of the intrahepatic forms remain inert for a period
ranging from 3 weeks to ≥1 year before reproduction begins
• These dormant forms, or hypnozoites, are the cause of the relapses that characterize infection with these
two species

• When the parasites reach densities of ~50/μL of blood the symptomatic stage of the infection
begins

• By the end of the intra erythrocytic life cycle, the parasite has consumed two-thirds of the
RBC’s hemoglobin and has grown to occupy most of the cell

• The disease in human beings is caused:

• By the direct effects of the asexual parasite—(RBC invasion and destruction) and
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Life cycle of malaria

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Characteristics of Plasmodium Species Infecting Humans
Characteristic P. falciparum P. vivax P. ovale P. malariae
Duration of intrahepatic phase(days) 5.5 8 9 15

Number of merozoites released per 30,000 10,000 15,000 15,000

infected hepatocyte
Duration of erythrocytic cycle 48 48 50 72
(hours)
Red cell preference Younger cells (but Reticulocytes and Reticulocytes Older cells
can invade cells of cells up to 2 weeks
all ages) old

Pigment color Black Yellow- Dark brown Brown-black

brown
Morphology Usually only ring Irregularly shaped Infected RBCs Band or rectangular
forms Banana - large rings & enlarged & oval forms of trophozoites
shaped gametocytes trophozoit enlarged with tufted ends; common
erythrocytes Schuffner’s dots
Schuffner’s dots
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Pathophysiology
• Cerebral Malaria

• Intense sequestration of parasites in the cerebral microvasculature, often accompanied by

• Ring hemorrhages,
• Perivascular leukocyte infiltrates, and
• Immunohistochemical evidence for endothelial cell activation

• Hypoglycemia

• Impaired hepatic gluconeogenesis, decreased oral intake

• Increased consumption of glucose by hypermetabolic peripheral tissues.
• Large amounts of glucose consumed by intra-erythrocytic parasites.

• Anemia:microcytic or normocytic hypochromic

• Mechanical destruction of parasitized RBCs

• Reduced erythropoiesis in the bone marrow
• Lysis and phagocytosis of uninfected RBCs splenomegally
• Consumption of more than 70% of haemoglobin in RBCs by the parasite.
• Failure of the liver to convert liberated iron
• In a small number of patients with malignant tertian malaria there is autoimmune destruction of RBCs
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• Pulmonary Edema & Respiratory distress

• Iatrogenic fluid overload and acute renal failure

• Sequestration of infected erythrocytes in the lungs is thought to initiate regional production of

inflammatory cytokines that increase capillary

• Metabolic Acidosis

• Principally caused by reduced delivery of oxygen to tissues, from the combined effects of

• Anemia (decreased oxygen-carrying capacity),

• Sequestration (microvascular obstruction), and

• Hypovolemia
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Genetic Resistance

• There are certain people, who are resistant to malaria infection,

• 1.Duffy antigen blood group negative (esp. for vivax).

• 2.Sickle cell traits.

• 3.Thalassemia.

• 4.Glucose-6-phosphate-dehydrogenase deficiency.
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Clinical features
• Malaria is a very common cause of fever in
tropical countries

• Febrile paroxysm:
• It comprises of 3 successive stages; cold stage, hot
stage, sweating stage

• It generally begins in the early afternoon

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• The periodicity of the attack varies with the species: of the infecting parasite.

1. In P. vivax is 48 hrs (benign tertian)

2. In P. ovale is 48 hrs (ovale tertian)

3. In P. malariae 72 hrs (quatrain).

4. In P. falciparum typical tertian is not usual, so it is called malignant tertian (cold stage is less pronounced

and the fever stage is more prolonged and intensified )

• Malaria Febrile paroxysms follow the completion of erythrocytic schizogony

• when the mature schizont ruptures releasing merozoites, malarial pigment and other parasitic debris.
• Macrophages engulf these and release endogenous pyrogens leading to pyrexia
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Non-specific symptoms
 Headache
 Abdominal Discomfort
 Fatigue
 Muscle Aches
 Chills And Rigor
 Arthralgia And Myalgia
 Diarrhea
 Nausea, vomiting, and orthostatic hypotension

 Splenomegaly, hepatomegaly, jaundice

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MANIFESTATIONS OF SEVERE MALERIA

Major sign manifestation
Unarousable coma/cerebral Failure to localize or respond appropriately to noxious stimuli;
malaria coma persisting for >30 min after generalized convulsion

Acidemia /acidosis Arterial pH of <7.25 or plasma bicarbonate level of <15 mmol/L;

venous lactate level of >5 mmol/L;
manifests as labored deep breathing, often termed “respiratory distress”

Severe normochromic, Hematocrit of <15% or hemoglobin level of <50 g/L (<5 g/dL) with
normocytic anemia parasitemia <10,000/μL

Renal failure Serum or plasma creatinine level of >265 μmol/L(>3 mg/dL);

urine output (24 h) of <400 mL in adults or <12 mL/kg in children;
no improvement with rehydration

Pulmonary edema/ARDS Noncardiogenic pulmonary edema,

Often aggravated by over hydration
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Hypoglycemia Plasma glucose level of <2.2 mmol/L (<40 mg/dL)
Hypotension/shock Cont’dSystolic BP of <80 mmHg in adults core/skin temperature difference of >10°C
Capillary refill >2 s

Bleeding/DIC Significant bleeding and hemorrhage from the gums, nose, and gastrointestinal tract and/or
evidence of disseminated intravascular coagulation

Convulsions More than two generalized seizures in 24 h; signs of continued seizure activity,
sometimes subtle (e.g., tonic-clonic eye movements without limb or face movement)

others
Hemoglobinuria Macroscopic black, brown, or red urine
Extreme weakness Prostration; inability to sit unaided
Hyperparasitemia Parasitemia level of >5% in nonimmune patients
(>10% in any patient)
Jaundice Serum bilirubin level of >3 mg/dL
if combined with a parasite density of 100,000/μL or other evidence of vital-organ dysfunction
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Relative Incidence of Severe Complications of falciparum malaria

Complication Non pregnant Pregnant Children

Adults Women
Anemia + ++ +++

Convulsions + + +++

Hypoglycemia + +++ +++

Jaundice +++ +++ +

Renal failure +++ +++ _

Pulmonary edema ++ +++ +

Note: –, rare; +, infrequent; ++, frequent; +++, very frequent

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CHRONIC COMPLICATIONS OF MALARIA

• Malarial nephropathy(Quartan nephropathy):- P.malariae

• Hyper reactive malarial splenomegaly syndrome

• BURKITT’S LYMPHOMA AND EPSTEIN-BARR VIRUS INFECTION

• Chronic anemia .

• Failure to thrive.
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Diagnosis of Malaria

• Light microscopy of Giemsa-stained peripheral blood smear

• RDT

• PCR

****Malaria is not a clinical diagnosis****

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Diagnosis
Clinical Diagnosis : Is by taking reliable history of the illness and performing a complete
physical examination.

• Clinical diagnosis of malaria is made when:

• A patient from malaria endemic area has fever or history of fever in the last 48 hours or

• A patient from nonmalaria endemic area has fever or history of fever in the last 48 hours and has a history of
travel to malaria-endemic areas within the last 30 days.

• *Making the diagnosis of malaria on clinical features alone is not recommended, as this often has low specificity and
increases the chances of the patient being misdiagnosed

• NB: When examining a malaria suspect case

• Look for other causes of fever
• (e.g. typhoid fever, relapsing fever, acute respiratory tract infections, meningitis, schistosomiasis, VL)

• Malaria should still be considered, even if the individual has another obvious cause for the fever
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Dx Contd..
Parasitological Diagnosis

•Microscopic diagnosis and RDTs are the methods employed for confirmation of malaria etiology.

•Light microscopy using thick blood films can be very sensitive, detecting as few as 5 parasites/pl of blood.

•Thin blood film stained with Giemsa can identify malaria parasite species and has a sensitivity of 20 parasites/pl.

•Parasite load is determined by quantifying the number of malaria parasites per microliter of blood on thick blood film.

•Multispecies RDTs capable of detecting both P. falciparum and P. vivax, are enhancing malaria diagnosis by species at the
periphery and reducing the need for empiric treatment and wastage of drugs.

•Patients who test negative by malaria RDT or microscopy DO NOT need antimalarial medications.
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Peripheral Blood Smear

• The definitive diagnosis of malaria rests on the demonstration of asexual forms of the
parasite in stained peripheral-blood smears

• Thick and thin blood smears should be prepared and examined by experienced personnel
immediately to confirm the diagnosis and identify the species of infecting parasite
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• Thick smears
• Concentrate red cell layers approximately 40-fold and are used to screen a
relatively large amount of blood for the presence of parasites.

• Because red cells are lysed in the process of staining in the thick smear
technique, parasites are visualized outside red cells

• Thin Smear: are used to determine:

• The Plasmodium species

• The presence of intraleukocytic pigment (a poor prognostic sign) or

• Other blood pathogens (e.g., filaria, Borrelia recurrentis).

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RDT
• Rapid, simple, sensitive, and specific antibody-based diagnostic stick or
card tests

• Detect P. falciparum–specific histidine-rich protein 2 (PfHRP2), lactate

dehydrogenase, or aldolase antigens in finger-prick blood samples

May remain positive for several weeks after acute infection

Do not quantify parasitemia

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Polymerase chain reaction (PCR)

• More sensitive than microscopy or RDT for detecting malaria parasites and defining
malarial species

• Used in reference centers in endemic areas

• Nucleic acid tests (eg, PCR) are typically used as a gold standard in efficacy studies
for antimalarial drugs, vaccines, and evaluation of other diagnostic agents
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Treatment Approach
•Rx of malaria should be based upon a parasitologicaly confirmed Dx whenever situations
permits

•Pregnancy by itself is not sign of severity of malaria

•When there is a negative laboratory result by RDT or microscopy for malaria

•No malaria medications should be provided,
•Search for other causes of AFI should continue

•The first dose should be given under direct supervision of the health worker.

•AL (Coartum) should preferably be taken with food or fluids.

• A fatty meal or milk improves absorption of the AL.

•If vomiting occurs within half an hour after the patient swallows the drug, the dose should be
repeated
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Contd..
• Take detailed history (including travel history of the suspected case)

• Do thorough Physical examination and clinically assess for other causes of fever

• Confirm Parasitological testing (RDT Vs Microscopy)

• Look for danger signs in the patient

• Other laboratory investigations to aid diagnosis and to rule out other medical conditions
resembling malaria

* Uncomplicated Malaria Vs Complicated Malaria

·
Treatment: Uncomplicated falciparum Malaria

• WHO recommends that artemisinin-based combination therapies (ACTs) be used for the
treatment of uncomplicated P. falciparum malaria

• Five ACT regimens are currently recommended by the WHO

Artemether-lumefantrine

Artesunate-mefloquine

Dihydroartemisinin-piperaquine

Artesunate-sulfadoxine-Pyrimethamine

Artesunate-amodiaquine
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• Artemisinin derivatives: have faster parasite elimination and broader

efficacy across the parasite life cycle

• Dihydroartemisinin
• Artesunate and
• Artemether...

• Quinine
• Schizonticidal for all, gametocytocidal for p.v and p.m but not p.f
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Management of uncomplicated malaria

P. falciparum positive by multi–species RDT or Microscopy:

• AL (Coartum) and single dose primaquine is the recommended first-line drug.

• AL tablets are given according to body weight in six doses over three days
• Treat infants weighing < 5 kg with uncomplicated malaria with AL per body weight target dose

• The first dose should be given under direct supervision of the health worker.
• AL should preferably be taken with food or fluids.
• A fatty meal or milk improves absorption of the drug.

• If vomiting occurs within half an hour swallowing the drug, the dose should be repeated
and should be provided with a replacement dose to ensure completion of treatment
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P. V and other malaria species other than P. falciparum by RDT or microscopy:

• The first line drug of choice is chloroquine plus 14 days primaquine radical cure.

• A tablet of 250 mg CQ phosphate (“salt”) is the same as chloroquine 150 mg base.

• The ideal chloroquine dose is:

• 10 mg base/kg po (Day 1), 10 mg base/kg po at 24 hrs (Day 2), and 5mg base/kg po at 48 hrs (Day 3)

• Primaquine is given at a dose of 0.25mg/kg per day for 14 days

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Positive for P. falciparum and P. vivax (mixed infection):

• The recommended first-line treatment for mixed infection is AL and Primaquine

(Microscopy Vs Multi species RDT )

• NB: do not treat confirmed mixed infection with both AL and chloroquine.

Multi-species RDT negative for malaria:

• If the result of the multi-species RDT is negative for all malaria species, malaria is
unlikely. Other causes of fever should be investigated.
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Alteranate treatment for uncomplicated malaria

• AL maybe used to treat P. vivax infection when chloroquine is not available

• If AL is not available for P. falciparum or mixed malaria infections, use oral quinine.

• If both chloroquine and AL are not available for P. vivax infection, use oral quinine.
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Supportive treatment
• If patients with axillary temperature record of ≥37.5o C , treat with antipyretics

• Paracetamol (acetaminophen) 15 mg/ kg every 4 hours is widely used; it is safe and well tolerated, given
orally or as a suppository

• Provide supportive therapy

Referral

• It is important that all patients be assessed for the presence of danger signs

• If a patient presents with danger signs or found to have any of the danger signs, they require URGENT
medical attention and should be referred to a higher-level facility as soon as possible.
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Clinical Danger Signs • Any patient presenting with any of the danger signs, should be referred to the next higher-
level health facility as soon as possible.
• Children < 6 yrs should be given pre-referral RX

Pre-referral treatment:
• The conscious patient:
• single dose of rectal artesunate (10mg/kg)
• Do not use rectal artesunate in older children and adults.
• Patients older than six years should be referred immediately to higher health facility for
further investigation and management ·
• If high fever is present, give paracetamol
• Encourage fluid intake during the transfer; continue breastfeeding in young infants; ·
• The unconscious patient:
• Ensure the airway is not blocked ·
• Show family members how to position the patient on side
• Give rectal artesunate as a pre-referral treatment
• give paracetamol suppositories for high fever
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Treatment Failure
• Failure of antimalarial drug to resolve fever and/or parasitemia.

• For clinical purpose, consider treatment failure in a patient tested positive for malaria who was treated for malaria

in the past 28 days.

• Treatment failures may result from:

 Drug Resistance,

 Poor Adherence Or Inadequate Drug Exposure (I.E. From Under-dosing, Vomiting Or Unusual Pharmacokinetic

Properties In That Individual),

 Drug Interaction,

 Misdiagnosis Or

 Substandard Medicines.

• Monitoring treatment failure is very important because it can signal the appearance of anti-malarial drug resistance
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• The majority of treatment failures occur after two weeks of initial treatment.

• Rx failures can result from either recrudescence (Treatment Failure) or Re-Infection.

• This distinction can only be made through parasite genotyping by PCR

Management of treatment failure:

• After a full history, clinical assessment and laboratory examination:

 If a cause for treatment failure is identified (e.g. anti-malarial drug is vomited), such cause must be addressed and
treatment reinstituted with the first-line anti-malarial drug;

 If a P. F or P. V-infected patient returns with fever or Hx of fever between days 4 to 28 of treatment,

 A microscopic blood examination should be made (Note: do not use RDTs).
 If parasites are detected, the treatment should be changed to the second-line drug, i.e. quinine tablets;

 In patients who are suspected to have Rx failure after 28 days, the first-line anti-malarial drug should be used;
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Cont’d
• Second-line treatments for recrudescence following first-line therapy,

• A different ACT regimen may be given

• Another alternative is a 7-day course of either Artesunate or Quinine plus

(tetracycline, doxycycline, or clindamycin)

Poor adherence

Not used in pregnant and Children< 8yrs

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Management of Severe Malaria

• Severe malaria needs URGENT medical attention.
• A delay in diagnosis and treatment can lead to unnecessary death of the patient.
• Referral to a general or specialized hospital may be required in some patients.

• Diagnosis of severe malaria ·

• Taking a reliable history (including travel history); AND ·
• Complete physical examination (ophthalmoscopy if available); AND ·
• Parasitological testing (use of microscopy); AND ·
• Other laboratory investigations to aid diagnosis and rule out other infections resembling malaria.

• P. falciparum malaria is commonest cause of severe Malaria

• Occasionally, P. vivax infection can also cause severe malaria illness,
• but the treatment and management is the same
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Lab Tests for Severe Malaria

• Microscopy is used for initial confirmation of diagnosis and for follow-up

• Monitoring of the level of parasitemia linked to the clinical evolution of the patient.
• In non-immune individuals, high numbers of parasites (>4% parasite density or >200,000 parasites per ul of blood) is
generally associated with severe disease.
• If clinical features strongly suggest severe P. falciparum malaria, treatment maybe started, even though results are not
yet confirmed.

• Other essential laboratory tests (where available) to aid management of the severe malaria
patient and differential diagnosis

• Parasitological test (microscopy) ·

• Blood glucose level ·
• Hemoglobin (Hb) estimation or packed cell volume (hematocrit) ·
• Lumbar puncture ·
• White blood count
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First line treatment for severe malaria

• IV or IM artesunate (preferred) OR ·

• IM artemether (alternate) OR ·

• IV quinine infusion (if artesunate or artemether is not available); OR ·

• IM quinine (if artesunate is not available)

• Once the patient with severe malaria regains consciousness and tolerates oral therapy,
• A full course of oral AL therapy should be started to complete the treatment for P. falciparum cases

• If AL is contraindicated, continue treatment with quinine tablets.

• Additionally, a single dose primaquine will be added for P. falciparum cases.

• A full course of oral chloroquine and a 14-day primaquine should be given for P. vivax cases.
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General management of the patient with severe malaria

• Start immediate resuscitation measures.

• A = airway: B = breathing: C = circulation:

• After initial resuscitation, assess and record the GCS or Blantyre score

• Establish an IV line, Take blood while establishing an IV line for lab Ix

• Correct hypoglycaemia

• Re-check blood glucose every 2-4 hours during the course of treatment, particularly in the

pregnant or comatose patient because hypoglycemia can recur even after an IV bolus of glucose.

• Assess the patient’s fluid requirements

• Control Fever, Control Seizure

• Need for transfusion, NGT feeding and Urinary catheter

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Management of Malaria in Special Groups

Pregnant women

• Malaria in pregnancy is associated with premature labor, low birth weight, anemia, and risk of development of severe malaria

• Pregnant women with symptomatic acute malaria are a high-risk group and must promptly receive effective anti-malaria
treatment.

• The 1st-line treatment for P. F infection in pregnant women in the 1st trimester of pregnancy is PO quinine

• AL is indicated in first trimester pregnancy only if this is the only treatment available for P.F

• If pregnant women have P. F or mixed infection in their second or third trimester, they will be treated with AL.

• Pregnant women with only P. vivax will be treated with chloroquine in all trimesters

• Treatment for severe malaria in pregnant women is Artesunate Injection or alternatively Artemether IM during the second and third trimester or

alternatively quinine infusion if both are unavailable.

• Primaquine is contraindicated in all trimester of pregnancy and lactating mothers during the first 6 months

• Mefloquine as prophylaxis is contraindicated during 1 st TM pregnancy

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Children <5kg body weight

• AL is recommended in children below 5 kg of body weight with uncomplicated P.F

• Chloroquine is a safe drug that can be used in all children with only P. vivax infection

HIV
• Treatment of malaria is similar in HIV-infected and HIV-uninfected patients.

• There is limited information regarding drug interaction between anti-malarial and

anti-retroviral drugs.

• Pharmacovigilance is recommended to document observed interactions.

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Thank You