Tropical illnesses (including Hemoglobinopathies & Malaria)

DR MUHAMMAD ALI SHO PAEDS

Tropical diseases
Tropical diseases are diseases that are prevalent in or unique to tropical and subtropical regions. The diseases are less prevalent in temperate climates, due to the occurrence of a cold season, which controls the insect population by forcing hibernation. Insects such as mosquitoes and flies are by far the most common disease carrier.

World map with the intertropical zone highlighted in red

Chagas Disease
(also called American trypanosomiasis) is a parasitic disease which occurs in the Americas, particularly in South America. Pathogenic agent is a flagellate protozoan named Trypanosoma cruzi, which is transmitted mostly by blood-sucking assassin bugs (Reduviid bug). other methods of transmission are possible, such as ingestion of food contaminated with parasites, blood transfusion and fetal transmission. Between 16 and 18 million people are currently infected

Dengue
Dengue fever, also known as breakbone fever, is caused by the dengue virus. Symptoms include fever headache muscle and joint pains a characteristic skin rash that is similar to measles In a small proportion of cases ----life-threatening dengue hemorrhagic fever, resulting in bleeding low levels of blood platelets and blood plasma leakage, or into dengue shock syndrome

 Dengue is transmitted by genus Aedes, principally A. aegypti. The virus has four different types; infection with one type usually gives lifelong immunity to that type, but only short-term immunity to the others. Subsequent infection with a different type increases the risk of severe complications. Treatment of acute dengue is supportive, using either oral or intravenous rehydration for mild or moderate disease, and intravenous fluids and blood transfusion for more severe cases.

Helminths
Parasitic worms or helminths are a division of eukaryotic parasites that live inside their host. Parasitic worms are categorized into three groups: cestodes (tapeworms) tapeworm infection nematodes (roundworms) ascariasis, dracunculiasis,
elephantiasis, enterobiasis (pinworm), filariasis, Ancylostomiasis (hookworm) , onchocerciasis, trichuriasis (whipworm)

trematodes (flukes) Schistosomiasis

Leishmaniasis
transmitted by the bite of sand fly. The symptoms of leishmaniasis are skin sores Visceral leishmaniasis the most serious form and potentially fatal if untreated. Cutaneous leishmaniasis the most common form which causes a sore at the bite site, which heals in a few months to a year, leaving an unpleasant looking scar. This form can progress to any of the other three forms. Diffuse cutaneous leishmaniasis this form produces widespread skin lesions which resemble leprosy and is particularly difficult to treat. Mucocutaneous leishmaniasis commences with skin ulcers which spread causing tissue damage, (particularly) to the nose and mouth

Leprosy
or Hansen's disease is a chronic infectious disease caused by Mycobacterium leprae. Leprosy is primarily a granulomatous disease of the peripheral nerves and mucosa of the upper respiratory tract; skin lesions are the primary external symptom. Left untreated, leprosy can be progressive, causing permanent damage to the skin, nerves, limbs, and eyes.

Tuberculosis
Global Emergency Tuberculosis kills 5,000 people a day ! 2.3 million die each year Pulmonary tuberculosis is a disease of respiratory transmission, Patients with the active disease (bacilli) expel them into the air by: coughing, sneezing, shouting, or any other way that will expel bacilli into the air

Risk Factors for TB

Development of disease depends on individual susceptibility HIV increases the risk of getting TB disease 10% Life time risk of TB in HIV negative 10% Annual risk of TB in HIV positive

Diagnosis of TB
Clinical history fever, sweating, Cough (productive),Weight loss, Haemoptysis Signs of fever, pleural rub, crackles Investigations: X ray chest Intradermal PPD Mauntax ZN staning PCR DNA probing

 3 Groups depending upon the degree of effectiveness and potential side effects First Line: (Primary agents)
are the most effective and have lowest toxicity. Isoniazid Rifampin

Second Line:
Less effective and more toxic effects include (in no particular order): p-amino salicylic acid, Streptomycin, Ethambutol, pyrazinamide

Third Line
are least effective and most toxic. Amikacin, Kanamycin, Capreomycin, Viomycin, Kanamycin, Cycloserine

Hemoglobinopathy and Thalassemia

Hemoglobinopathies Globin gene mutations Specific Hemoglobinopathies
Sickle Cell Disease Unstable Hemoglobins (Heinz Body Hemolytic Anemia) Hemoglobins with increased Oxygen Affinity Hemoglobins with Decreased Oxygen Affinity Methemoglobinemias

Thalassemia
Thalassemia Thalassemia

Hemoglobinopathy
Hemoglobinopathy: A genetic defect which results in an abnormal structure of one of the globin chains of the hemoglobin molecule.

Globin Structure: 2 chains 2 chains

Globin Gene Cluster

- Like Genes Short arm of Chromosome 16 - Like Genes Short arm of Chromosome 11

Ontogeny of Hemoglobin
Embryonic Hemoglobin
Hgb Gower 1 ( 2, 2) Hgb Gower 2 ( 2, 2)
Early embryogenesis Yolk sac erythroblasts Major Hemoglobin of Intra-uterine life Adult Hemoglobin

Fetal Hemoglobin
Hgb F ( 2, 2)

Adult Hemoglobin
Hgb A ( 2, 2) Hgb A2 ( 2, 2) Hgb F ( 2, 2) (<1%)

Ontogeny of Hemoglobin
Yolk Sac Liver Spleen Bone Marrow
50

% of Total Globin Synthesis

40 30 20 10 6 18 30 6 18 30 42 54

Post-conceptual Age (weeks)

Birth

Post-Natal Age (weeks)

Hemoglobinopathy
Type of Mutation Single amino acid substitution
Hgb S, Hgb C

Examples of Hemoglobinopathy Chain

Hgb Gphiladelphia

Deletion
Hgb Gun Hill

Chain
Hgb S, Hgb C

Abnormal Hybridization
Hgb Lepore

Chain
Hgb FTexas

Abnormal elongation
Hgb Constant Spring

Chain
Hgb A2Flatbush

Specific Hemoglobinopathies

1. 2. 3. 4. 5.

Sickle cell anemia Unstable hemoglobins Increased Oxygen affinity Decreased oxygen affinity Methemoglobinemia

Sickle Cell Anemia

History Genetic mutation Pathogenesis Distribution Clinical Features

Sickle Cell Anemia

History
First case report written by Dr. James Herrick in 1910, describing a dentistry Student from Walter Noel .

Linus

Pauling first described different electrophoretic mobility of Hgb S compared to Hgb A

Sickle Cell Anemia

Genetic Mutation

Single point mutation on the gene at position 6, resulting in a valine instead of glutamine For comparison, Hgb C a mutation at the same spot, leads to A lysine instead of glutamine

Sickle Cell Anemia

Pathogenesis
The substitution of a valine for a glutamine results in decreased solubility of deoxy-Hgb S compared to Hgb A. When deoxygenated, Hgb S tetramers form polymers which associated into bundles. These precipitate in the red cell

Sickle Cell Anemia

Pathogenesis
Consequences of sickled hemoglobin: Sickling in red cells Loss of red blood cell deformability Hemolysis of red blood cells Vaso-occlusion of small vessels End organ damage

Sickle Cell Anemia

Prevalence
Prevalence of the sickle cell trait in African Americans is 8 to 10% Prevalence of the sickle cell trait In Western African countries is as high as 25 to 30% Heterozygous Advantage: Positive evolutionary pressure because the heterozygous state confers some resistance to falciparum malaria.

Sickle Cell Anemia

Clinical Features
Autosomal Recessive Disease Hgb AS (sickle cell trait) is A asymptomatic B Four principle genotypes of sickle cell disease: C D
Genotype Homozygous sickle cell disease Sickle cell-hemoglobin C disease Sickle cell-beta+thalassemia Sickle cell-beta0thalassemia Abbreviated Form SS disease

SC disease

S beta+-thalassemia

S beta0-thalassemia

Sickle Cell Anemia

Clinical Features Consequences of Hemolysis
1. 2. 3. 4.

Anemia Jaundice Gallstones Aplastic Crisis

Peripheral blood smear with sickle cells

Bone marrow biopsy in aplastic crisis

Jaundice

Sickle Cell Anemia

Clinical Features
Consequences of Vaso-Occlusion: Painful crisis Stroke Acute Chest syndrome Dactylitis Splenic infarction Renal Disease Early Death

Hemoglobinopathies
Unstable Hemoglobins/Heinz Body Hemolytic Anemias Definition: hemoglobins with reduced solubility or higher susceptibility to oxidation of amino acid residues within the individual globin chains. Rare, but > 100 unique unstable hemoglobins have been identified. Most are associated with minimal clinical manifestations Both and globin variants can cause this disorder but > 75% of them are

Hemoglobinopathies
Unstable Hemoglobins/Heinz Body Hemolytic Anemias Heinz body formation: Destabilizing of the normal heme and globin linkage. Heme released form usual linkage, binds non-specifically to globin subunits. Heme/globin subunits precipitate as Heinz bodies Heinz bodies interact with red cell membrane. Abnormal red cells trapped in splenic microcirculation and destroyed

Hemoglobinopathies
Unstable Hemoglobins/Heinz Body Hemolytic Anemias
Diagnosis: Evidence of accelerated red cell destruction


Examples: 43 Phe Val HgbTorino 28 Leu GLN Hgbst. Louis 63 His Arg HgbZrich 91-95 Deletion HgbGun Hill

  

Chronic or intermittent hemolytic anemia Jaundice Gallstones splenomegally

Hemoglobinopathies
Hemoglobins with Increased Oxygen Affinity Caused by mutations in hemoglobin which alter the interaction of heme with oxygen. Shift of the oxygen dissociation curve to the left. Patients present with erythrocytosis but rarely need treatment.

Example: Hgb Kempsey (

99Asp Asn).

Hemoglobinopathies
Hemoglobins with Decreased Oxygen Affinity
Mutations which cause hemoglobin to bind oxygen less well and shift the oxygen dissociation curve to the right. Hemoglobin delivers higher than normal oxygen to the peripheral tissues. Because tissue O2 delivery is more efficient than normal, normal oxygen requirements can be met by a lower than normal hematocrit (anemia). The amount of desaturated hemoglobin in the periphery is greater than normal and patients may appear cyanotic. Example: Hgb Kansas

Cyanosis

Methhemoglobinemias Acquired hemoglobinopathy Methemoglobin is HbA where iron exists in ferric rather than normal ferrous form Ferric form- unable to bind with oxygen, so O2 carrying capacity of arterial blood decreased Shifts oxyhemoglobin dissociation curve to left Normal concentration < 1%, due to methhemoglobin reductase enzyme .Congenital absence predisposes in patients receiving nitrate containing compounds Diagnosis: Hypoxic patient with cyanosis,normal Pao2 Pulse oximetry decrease in Spo2 with normal Pao2

Symptoms of: Lethargy,dizziness,headache Characteristic muddy appearance of freshly drawn blood Diagnostic test of choice methemoglobinemia content Treatment Methylene blue 1mg/kg IV over 5 mins,dose can be repeated every 60 mins if cyanosis persists

SULFHEMOGLOBINEMIA

Rare cause of cyanosis,drug induced, oxidation of iron in Hb occurs due to drugs Nitrate containing compounds,metoclopramide therapy can cause Sulfhemoglobin cannot carry oxygen. High concentration tolerated due to shift of oxyhemoglobin dissociation curve to right. DIAGNOSIS: Decrease in Spo2 values despite normal PaO2 Clinical cyanosis Bluish tinge of freshly drawn blood

TREATMENT

No pharmacological treatment available Only means to remove sulfhemoglobin is eventual destruction of affected RBCs.

CARBOXYHEMOGLOBIN

Acquired hemoglobinopathy due to carbon-monoxide poisoning CO has 200 times higher affinity for Hb than oxygen, it can displace oxygen and diminish oxygen delivery. Manifests as : dyspnea, headache, nausea, vomiting emotional lability, confusion, impaired judgement Cherry red colour of skin ,mucous membrane Masks development of cyanosis associated with poor oxygen delivery to tissues

Management:

100% oxygen via a tight fitting mask until CO levels decrease < 10% and symptoms resolve Hyperbaric oxygen: in comatose patient with CO level >40%. And in patients with CO levels > 25% who had seizures.

HEMOGLOBIN C AND E

HbC a beta-chain variant Common in West Africa HbE, beta-hemoglobinopathy is common in South East Asia Mild hemolytic anaemia Mild to moderate splenomegaly Can combine with other mutations and produce symptoms of sickle cell disease and thalassemia.

Thalassemia
Inherited anemia characterized by a decrease in synthesis of one or more of the globin chains. The defect may affect the
chains chains chains chains Combination of , , chains Never and chains

The clinical syndromes arise from a combination of

Inadequate production of hemoglobin Unbalanced accumulation of globin chains

and

Thalassemia
The gene is duplicated: 2 genes per chromosome, therefore 4 genes in a normal adult. The gene is single therefore the normal adult will have two genes

and

globin gene clusters

Chromosomes 11 and 16

Thalassemia
Four possible 1. thalassemia syndromes:

-thalassemia-2 trait (silent carrier): One of the four globin gene loci fails to function. 2. -thalssemia-1 trait ( Thal trait): Two of the four -globin gene loci fails to functions. 3. Hgb H disease: Three of the four -globin gene loci fails to functions. 4. Barts Hydops Fetalis: Four of the four -globin gene loci fails to functions.

Thalassemia
Syndrome Silent Carrier Alpha thalassemia trait Hb H Disease Hydrops fetalis # alpha genes deleted 1 2 3 4 Newborn Hb Barts ( 4) % 1-2 3-10 25 80-100 Clinical Picture

Silent Mild hypochromic, microcytic anemia Hb H ( 4) mild hemolytic anemia Death in utero or shortly after birth

Thalassemia
Thalassemia Trait:
Two of four genes mutated Clinically silent Mild anemia Microcytosis

Peripheral Blood Smears

Thalassemia
Hemoglobin H Disease:
Three of four genes mutated High to globin synthetic ratio Formation of Hgb H ( 4) Clinical features
Microcytic Anemia Splenomegally Jaundice Iron overload

Peripheral Blood Smear: stained With brilliant cresyl blue, showing Precipitated Hgb H

Thalassemia
Barts Hydrops Fetalis:
All four genes mutated Presence of Barts Hgb ( 4) Common in South East Asia due to the mutation (--SEA), which is the cis deletion of two genes. Embryonic Hgb (Hgb Gower 1 ( 2, 2)) is present but fetal Hgb (HgB F ( 2, 2)) is not made. Most babies die in utero of severe anemia and resulting heart failure

Thalassemia
Types of mutations:
Each chromosome 11 codes for 1 gene, therefore the normal adult has two genes. Many types of mutation can occur in the gene:
Promoters and enhancers of transcription  Transcription  RNA splicing  Integrity of the coding sequence  Polyadenylation  Post transcriptional modification


Different ethnic groups have different beta mutations

Thalassemia Major
Thalassemia Major Severe anemia Homozygous or doubly heterozygous: two seriously impaired globin genes Presents early in life Results in: Retarded growth Multiple organ dysfunction Premature death

Thalassemia Major

Thalassemia Major

Marked bony changes from bone marrow proliferation

Thalassemia Major

Massive splenomegally from extramedullary hematopoiesis

Thalassemia Major

Bone marrow hyper expansion gives the classic hair on end appearance on X-ray of the skull

Thalassemia Major

Basophilic Stipling

Target cells and microcytosis

Thalassemia Major
Treatment: Chronic blood transfusion Treatment of iron overload (chelation therapy) Treatment of complications of iron overload Endocrinopathy Heart disease Liver disease Osteoporosis

Thalassemia Intermedia
Various genetic interactions produce the Thalassemia intermedia phenotype Beta+ rather than beta0 mutation Increased gamma chains available Decreased alpha chains because of coinheritance of alpha deletion Somewhat milder phenotype with a broad range of clinical severity. May be transfusion independent. Ineffective erythropoiesis is due to excess free alpha chains that precipitate intracellularly

Thalassemia Minor
Thalassemia Minor Minor biological defects Typically of little consequence clinically May never be diagnosed

Mild anemia Microcytosis

Diagnosis of Hemoglobinopathies and Thalassemia

Important Laboratory Tests:
CBC: Anemia, microcytosis (thalassemia) Blood Smear: Sickle cells, target cells Hemoglobin Electrophoresis Quantitation of Hgb F, Hgb A2, Hgb Barts

Diagnosis of Hemoglobinopathies and thalassemia

Hemoglobin Electrophoresis: Electrophoresis is a means of separating hemoglobins. It depends on the migration of the hemoglobin molecules dissolved in a buffer on, or in, a supporting medium when an electric current is passed through them.

Diagnosis of Hemoglobinopathies and Thalassemia: Hemoglobin Electropheresis

Quantitation of Hemoglobin is important for detecting thalassemia: These are the normal amount of Hgb A, Hgb A2, and Hgb F in adults and children.

Diagnosis of Hemoglobinopathies and Thalassemia: Hemoglobin Electropheresis

Thalassemia patients will have elevated Hgb F and often Hgb A2. thalassemia can be very difficult to detect because all normal forms of Hgb are decreased proportionately.

I n t r o d u c t i o n 1

Malaria
Malaria is a major public health problem in warm climates especially in developing countries. It is a leading cause of disease and death among children under five years, pregnant women and non-immune travellers/immigrants.
Children under 5 are the major at risk group in malarious regions. Inset: An Anopheles mosquito taking a blood meal

What is malaria ?
Malaria is a disease caused by the protozoan parasites of the genus Plasmodium. The 4 species that commonly infect man are:

Species
P. falciparum

Major features
 The most important species as it is responsible for 50% of all malaria cases worldwide and nearly all morbidity and mortality from severe malaria  Found in the tropics & sub-tropics  The malaria parasite with the widest geographical distribution  Seen in tropical and sub-tropical areas but rare in Africa  Estimated to cause 43% of all malaria cases in the world

P. vivax

P. ovale

 This species is relatively rarely encountered

 Primarily seen in tropical Africa, especially, the west coast, but has been reported in South America and Asia

P. malariae

 Responsible for only 7% of malaria cases

 Occurs mainly in sub-tropical climates

The burden of malaria

The direct burden of malaria morbidity and mortality Every year, there are about 500 million clinical attacks of malaria. Of these, 23 million are severe and about 1 million people die (about 3000 deaths every day). Malaria in pregnancy accounts for about 25% of cases of severe maternal anaemia and 10-20% of low birthweight. Low birthweight due to malaria accounts for about 5-10% of neonatal and infants deaths. The indirect burden of malaria Human development: Impaired intellectual development, developmental abnormalities (especially following cerebral malaria), lost school attendance and productivity at work Economics: Malaria retards economic development in the developing world. The cost of a single bout of malaria is equivalent to over 10 working days in Africa. The cost of treatment is between $US0.08 and $US5.30, depending on the type of drugs prescribed as required by the local pattern of drug resistance.

Geographical Distribution of Malaria

Although previously widespread, today malaria is confined mainly to Africa, Asia and Latin America. About 40% of the worlds population is at risk of malaria. It is endemic in 91 countries, with small pockets of transmission occurring in a further 8 countries.

Malaria is transmitted by the female anopheles mosquito. Factors which affect mosquito ecology, such as temperature and rainfall, are key determinants of malaria transmission. Mosquitoes breed in hot, humid areas and below altitudes of 2000 meters. Development of the malaria parasite occurs optimally between 25-30oC and stops below 16oC. Indigenous malaria has been recorded as far as 64oN and 32oS. Malaria has actually increased in sub-Saharan Africa in recent years. The major factor has been the spread of drug-resistant parasites. Other important factors include the persistence of poverty, HIV/AIDS, mosquito resistance to insecticides, weak health services, conflict and population migration.

How is malaria transmitted?

Malaria parasites are transmitted from one person to another by the bite of a female anopheles mosquito. The female mosquito bites during dusk and dawn and needs a blood meal to feed her eggs. Male mosquitoes do not transmit malaria as they feed on plant juices and not blood. There are about 380 species of anopheles mosquito but only about 60 are able to transmit malaria. Like all mosquitoes, anopheles breed in water - hence accumulation of water favours the spread of the disease.
Female Anopheles mosquito taking a blood meal Source:http://phil.cdc.gov/phil/quicksearch.asp

How does infection develop ?

Plasmodium infects the human and insect host alternatively and several phases of the parasite life cycle are described. During feeding, saliva from the mosquito is injected into the human blood stream. If the mosquito is carrying malaria, the saliva contains primitive stages of malaria parasites called sporozoites. Hepatic, tissue or pre-erythrocytic phase: Sporozoites invade and develop in liver cells. The infected hepatocyte ruptures to release merozoites. Erythrocytic phase: Merozoites then invade red blood cells. The red cells lyse and this causes bouts of fever and the other symptoms of the disease. This cycle repeats as merozoites invade other red cells. Sexual phase: Sexual forms of the parasites develop and are ingested when another female anopheles mosquito feeds. These develop into sporozoites in the gut of the insect host and travel to its salivary glands. Then the cycle starts again The life cycle of the malaria parasite is shown on the next slide

The Malaria Parasite Life Cycle

Infection S porozoites

Click on the diagram to explore different areas of the life cycle

Liver M erozoites

A sexual cycle

Transm ission to m osqu ito G a m etocytes

The Malaria Parasite Life Cycle

1. Transmission Female anopheles mosquito bites and releases sporozoites into the blood stream. These circulate for about 30 mins and then invade the liver.
Infection S porozoites

Liver M erozoites

A sexual cycle

Transm ission to m osqu ito G a m etocytes

The Malaria Parasite Life Cycle

2. Pre-erythrocytic phase
Infection S porozoites

Also called the tissue or hepatic phase Takes place in hepatocytes. The sporozoites mature into schizonts which rupture to release merozoites. Duration of this phase depends on the species. In P. vivax and P. ovale, the schizont may also differentiate into hypnozoites. These are dormant forms of the parasite which may remain in the liver for several months or years and cause relapse in the human host.

Liver M erozoites

A sexual cycle

Transm ission to m osqu ito G a m etocytes

The Malaria Parasite Life Cycle

Infection S porozoites

Liver

Transm ission to m osqu ito

3a. Asexual phase (Erythrocytic schizogony) M erozoites A sexual Merozoites invade red blood cells. Here cycle they grow and mature into trophozoites which appear as ring forms. The trophozoites develop into schizonts. The infected red blood cells then rupture to release numerous merozoites from the G a m etocytes schizont to infect other red cells. Merozoite release results in fever, chills, rigours and other symptoms of malaria infection.

The Malaria Parasite Life Cycle

Infection S porozoites

Liver M erozoites

3b. Sexual phase

Transm ission Some merozoites differentiate into male to m osqu ito and female gametocytes, the forms of Plasmodia infective to mosquitoes. These are taken up by a mosquito during another blood meal. These fuse to form an ookinette in the gut lumen of the mosquito. The ookinette invades the stomach wall to form the oocyst. This in turn develops and releases sporozoites which migrate to the salivary gland of the mosquito. This mosquito then goes on to infect another human host.

A sexual cycle

G a m etocytes

Severity of disease and host factors

In addition to parasite factors, several host factors determine the outcome of exposure to malaria: Naturally-acquired immunity. People who are constantly exposed to malaria gradually acquire immunity, firstly against clinical disease and later against parasite infection. Clinical manifestations of malaria are most severe in the non-immune. In holoendemic areas, these are children aged <5 years and pregnant women (especially primagravidae). People of any age from areas that are free from malaria, or have limited malaria transmission, are at risk when they are exposed to malaria. Red cell and haemoglobin variants. Well known examples of inherited factors that protect against malaria are Haemoglobin S carrier state, the thalassaemias and Glucose-6-phosphate dehydrogenase (G6PD) deficiency. Malaria provides the best known example whereby an environmental factor (malaria) has selected human genes because of their survival advantage. Foetal haemoglobin (HbF): High levels of HbF occur in neonates, and in some people with inherited haemoglobin variants, protect against severe forms of P. falciparum malaria. Duffy blood group: P. vivax requires the Duffy blood receptor to enter red blood cells. Therefore, people who do not carry the Duffy blood group are resistant to this malaria species. This explains the rarity of P. vivax in Africa, as most Africans are Duffy blood group negative.

The clinical course of P. falciparum

Following a bite by an infected mosquito, many people do not develop any signs of infection. If infection does progress, the outcome is one of three depending on the host and parasite factors enumerated in the previous slides:

Asymptomatic parasitaemia (clinical immunity) B. Acute, uncomplicated malaria C. Severe malaria

A.

A. Asymptomatic parasitaemia
This is usually seen in older children and adults who have acquired natural immunity to clinical disease as a consequence of living in areas with high malaria endemicity. There are malaria parasites in the peripheral blood but no symptoms. These individuals may be important reservoirs for disease transmission. Some individuals may even develop anti-parasite immunity so that they do not develop parasitaemia following infection.

B. Simple, uncomplicated malaria

This can occur at any age but it is more likely to be seen in individuals with some degree of immunity to malaria. The affected person, though ill, does not manifest life-threatening disease. Fever is the most constant symptom of malaria. It may occur in paroxysms when lysis of red cells releases merozoites resulting in fever, chills and rigors (uncontrollable shivering).

Children with malaria waiting to be seen at a malaria clinic in the south western part of Nigeria. Identifying children with severe malaria, and giving them prompt treatment, is a major challenge when large numbers attend clinics.

The periodicity of malaria fever

Erythrocytic schizogony is the time taken for trophozoites to mature into merozoites before release when the cell ruptures. It is shortest in P. falciparum (36 hours), intermediate in P. vivax and P. ovale (48 hours) and longest in P. malariae (76 hours). Typical paroxysms thus occur every 2nd day or more frequently in P. falciparum (sub-tertian malaria) 3rd day in P. vivax and P. ovale (tertian malaria) 4th day in P. malariae infections, (quartan malaria) Note how the frequency of spikes of fever differ according to the Plasmodium species. In practice, spikes of fever in P. falciparum, occur irregularly - probably because of the presence of parasites at various stages of development.

Other features of simple, uncomplicated malaria include:

o o o o o Vomiting Diarrhoea more commonly seen in young children and, when vomiting also occurs, may be misdiagnosed as viral gastroenteritis Convulsions commonly seen in young children. Malaria is the leading cause of convulsions with fever in African children. Pallor resulting mainly from the lysis of red blood cells. Malaria also reduces the synthesis of red blood cells in the bone marrow. Jaundice mainly due to haemolysis.

Malaria is a multisystem disease. Other common clinical features are: o Anorexia o Cough o Headache o Malaise o Muscle aches o Splenomegaly o Tender hepatomegaly

These clinical features occur in mild malaria. However, the infection requires urgent diagnosis and management to prevent progression to severe disease.

C. Severe and complicated malaria

Nearly all severe disease and the estimated >1 million deaths from malaria are due to P. falciparum. Although severe malaria is both preventable and treatable, it is frequently a fatal disease. The following are 8 important severe manifestations of malaria:
Click on each severe manifestation for details

1. 2. 3. 4.

Cerebral malaria Severe malaria anaemia Hypoglycaemia Metabolic acidosis

5. Acute renal failure 6. Pulmonary oedema 7. Circulatory collapse, shock or algid malaria 8. Blackwater fever

Note: It is common for an individual patient to have more than one severe manifestation of malaria!

Summary of differences in the clinical features of severe malaria in adults and children
Frequency of occurrence
Clinical Manifestation Similar in adults and children Prostration Circulatory collapse More common in children Cerebral malaria Severe anaemia Multiple convulsions Metabolic acidosis Hypoglycaemia More common in adults Jaundice Pulmonary oedema Haemoglobinuria Abnormal bleeding Renal failure Children +++ + +++ +++ +++ +++ ++ + +/+/+/+/Adults +++ + ++ + + + +/+++ ++ + + +

Diagnosis
Malaria is a multisystem disease. It presents with a wide variety of non-specific clinical features: there are no pathognomonic symptoms or signs. Many patients have fever, general aches and pains and malaise and are initially misdiagnosed as having flu. P. falciparum malaria can be rapidly progressive and fatal. Prompt diagnosis saves lives and relies on astute clinical assessment: A good history Residence or a recent visit (in the preceding 3 months) to a malaria endemic area History of fever (may be paroxysmal in nature) Recognise significance of non-specific clinical features such as vomiting, diarrhoea, headache, malaise Physical examination Identify signs consistent with malaria: fever, pallor, jaundice, splenomegaly Exclude other possible causes of fever (e.g. signs of viral and bacterial infections)

The diagnosis of malaria should be considered in any unwell person who has been in a malarious area recently

Investigations
Blood Film Examination Thick and thin blood films (or smears) have remained the gold standard for the diagnosis of malaria. The films are stained and examined by microscopy. Thick blood film - Used for detecting malaria: a larger volume of blood is examined allowing detection of even low levels of parasitaemia. Also used for determining parasite density and monitoring the response to treatment. Me Show Thin blood film Gives more information about the parasite morphology and, therefore, is used to identify the particular infecting species of Plasmodium.Show Me

Thick blood film

A drop of blood is spread over a small area. When dry, the slide is stained with Fields or Giemsa stains. The red cells lyse leaving behind the parasites. Used to detect parasites, even if parasitaemia is low Less useful for speciation

Thin blood film

A small drop of blood is spread across a microscope slide, fixed in methanol and stained with Giemsa stain. The microscopist finds the area of the film where red cells are lying next to each other. The fine details of the parasites can be examined to determine the species. Used for speciation Does not detect low parasitaemia

Appearance of P. falciparum in thin blood films

Ring forms or trophozoites; many red cells infected some with more than one parasite

Gametocytes (sexual stages); After a blood meal, these forms will develop in the mosquito gut

http://phil.cdc.gov/phil/quicksearch.asp

Other methods of diagnosis of malaria

These are not routinely used in clinical practice. They include : a) Antigen capture kits. Uses a dipstick and a finger prick blood sample. Rapid test - results are available in 10-15 minutes. Expensive and sensitivity drops with decreasing parasitaemia. PCR based techniques. Detects DNA or mRNA sequences specific to Plasmodium. Sensitivity and specificity high but test is expensive, takes several hours and requires technical expertise. Fluorescent techniques. Relatively low specificity and sensitivity. Cannot identify the parasite species. Expensive and requires skilled personnel. Serologic tests. Based on immunofluorescence detection of antibodies against Plasmodium species. Useful for epidemiologic and not diagnostic purposes.

b)

c)

d)

Malaria in pregnancy
More than 45 million women (30 million in Africa) become pregnant in malaria endemic areas each year. Common adverse effects of malaria in pregnancy include: Maternal anaemia Stillbirths Premature delivery and intrauterine growth retardation result in the delivery of low birth weight infants The WHO now recommends intermittent preventive treatment (IPT): the administration of anti-malarial drugs (e.g. sulphadoxine-pyrimethamine) during antenatal care whether or not women show symptoms. IPT has been shown to substantially reduce the risk of maternal anaemia in the mother and low birth weight in the newborn. Previously, chemoprophylaxis (e.g. with chloroquine) was recommended for all women living in malaria endemic areas.

Source: http://phil.cdc.gov/phil/quicksearch.asp

1. Cerebral malaria - clinical

The most well-known severe manifestation of malaria Defined as: unarousable coma persisting for more than one hour with asexual forms of P. falciparum in the peripheral blood other common causes of encephalopathy excluded* Occurs most commonly in young children although non-immune adults are also at risk Cerebral malaria can rapidly progress to death, even with appropriate treatment. Case fatality is between 20-30%. In survivors, resolution of coma usually occurs within 1-2 days in children and within 2-4 days in adults but may be complicated by neurological sequelae in ~5% adults and >10% of children.

A 4 year old boy who was deeply comatose and had persistent deviation of the eyes

The illness may start with drowsiness and confusion and then progress to coma. The loss of consciousness is often preceded by repeated convulsions. Retinal haemorrhages may be seen on fundoscopy. * None of the clinical features are pathognomonic, malaria parasitaemia is common in people living in endemic areas and coma may complicate many illnesses. Therefore, a clinical diagnosis of cerebral malaria is made only after other common causes of coma (e.g. meningitis) have been excluded.

Cerebral malaria pathophysiology

The exact pathogenesis of cerebral malaria is not well understood. It is believed to result from sequestration of parasitised red cells in the small blood vessels in the brain. The consequences of this include: reduced cerebral blood flow cerebral hypoxia release of cytokines which in turn induce the release of nitrous oxide, a known depressor of consciousness

A young girl with cerebral malaria. Note the abnormal, decerebrate posturing

Sequestration of parasitised red cells in different tissues probably underlies most severe manifestations of malaria

A 3 year old boy with impaired consciousness, grimacing and marked extensor posturing of the arms

2. Severe malaria anaemia

Defined as a haematocrit of <15% or haemoglobin concentration <5 g/dl. Occurs commonly in young children and pregnant women. Anaemia in malaria results from a combination of factors: Destruction of parasitised red blood cells Destruction of unparasitised red cells by complement-mediated lysis Bone marrow suppression by cytokines produced by malaria parasites Haemolysis induced by medications in individuals with glucose-6-phosphate dehydrogenase deficiency Many patients require urgent transfusion. The condition may be rapidly fatal when blood transfusion is delayed.

Marked pallor in an African child with severe anaemia due to P. falciparum infection

3. Hypoglycaemia
Blood sugar <2.5 mmol/L Increases the risk of mortality and sequelae in children with cerebral malaria; may present with convulsions or a deterioration in level of consciousness. Results from a combination of factors: reduced glycogen stores because of reduced food intake increased metabolism due to fever and repeated convulsions glucose consumption by malaria parasites cytokine or quinine-stimulated hyperinsulinaemia

4. Metabolic acidosis
Lactic acidosis is a major contributor and probably results from tissue anoxia and anaerobic glycolysis Presents with deep, rapid respirations (as in diabetic ketoacidosis)

5. Acute renal failure

occurs almost exclusively in adults and older children in areas of unstable malaria affected patients are usually oliguric (urinary output <400 ml/day) or anuric (<50 ml/day) serum creatinine levels are elevated

6. Acute pulmonary oedema

This is a grave and usually fatal manifestation of severe falciparum malaria and occurs mainly in adults. Hyperparasitaemia, renal failure and pregnancy are recognised predisposing factors and the condition is commonly associated with hypoglycaemia and metabolic acidosis.
Acute pulmonary oedema, developing shortly after delivery in a woman with severe P. falciparum malaria

7. Circulatory collapse, shock, algid malaria

Features of circulatory collapse (cold/clammy skin, hypotension, peripheral cyanosis, weak/thready pulses) may be seen in patients with severe P. falciparum malaria.

Algid malaria is characterised by hypotension, vomiting, diarrhoea, rapid respiration and oliguria. This condition is associated with a poor prognosis.

8. Haemoglobinuria or Blackwater Fever Typical, dark urine of haemoglobinuria on This results from massive intravascular
haemolysis. The condition presents with severe pallor, jaundice and passage of dark urine due to haemoglobinuria. It may be associated with acute renal failure.
day 0 which has cleared by day 3

A 3 year old boy with severe anaemia (Hb 3.3 g/dl) and dark urine (shown in the container)

THANK YOU