Malaria

Malaria 

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Came from the word “mal” “aria” or bad air Still the world’s most important tropical parasitic disease

Epidemiology 

Public health problem in 90 countries (2.4 billion people)

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Worldwide prevalence: 300 – 500 M cases annually

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More than 90%: Subsaharan-Africa – remaining 2/3 are in India, Brazil, Sri Lanka, Afghanistan, Vietnam, and Colombia

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Western Pacific Region : 10 endemic countries – – – – – –

Cambodia Lao People’s Democratic Republic Papua New Guinea Republic of Korea Vanatu

China Malaysia Philippines Solomon Islands Vietnam

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Malaria continues to be a major global health problem

– over 40% of the world's population (> 2400 million people) are exposed to varying degrees of malaria risk in some 100 countries

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with modern rapid means of travel large numbers of people from nonmalarious areas are being exposed to infection which may only seriously affect them after they have returned home. Management of severe malaria A practical handbook 2nd edition WHO Geneva 2000

Epidemiology in the Philippines  

65/78 provinces are endemic 11.3 M Filipinos at risk ( 14.8%) – Farmers, indigenous cultural groups, miners, forest product gatherers, and soldiers

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Ranks as one of the ten leading causes of morbidity in the country Highly endemic province: – Palawan, Kalinga Apayao, Ifugao, and Agusan del Sur

Summary of Reported 2002 Malaria Data: Philippines Indicator Population at risk for malaria Confirmed malaria cases Incidence rate per 1000 population P. falciparum cases Malaria deaths Probable malaria cases Severe malaria cases Proportion of risk population protected by ITNs (insecticide-treated nets)

2002 Data 6 458 708 37 005 0.5 22 831 71 19 489 1 103 8% (2001)

Malarial species Species

older designation

newer designation

falciparum

malignant tertian

falciparum malaria

vivax

benign tertian

vivax malaria

ovale

ovale tertian

ovale malaria

malariae

quartan

quartan

Causal Agents:  

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Blood parasites of the genus Plasmodium.  approximately 156 named species of Plasmodium which infect various species of vertebrates.  Four are known to infect humans: – – – –

P. falciparum P. vivax P. ovale  and P. malariae.

>90% of human cases

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In the Philippines more than 70% is caused by P. falciparum – Less than 30% by P. vivax – Less than 1% by P. malariae

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P. ovale – reported in Palawan in the 1960s Peak transmission: beginning and at the end of the rainy season

Malarial species Differences between the species include:  blood-stage morphology  minor life cycle variations – P. vivax and P. ovale exhibit the hypnozoite stage and can cause true relapses – trophozoite- and schizont-infected erythrocytes of P. falciparum sequester in the microvasculature and are not found in the peripheral circulation  host erythrocyte preference – P. vivax and P. ovale prefer reticulocytes (immature erythrocytes) – P. malariae prefers senescent erythrocytes – P. falciparum exhibits no preference  disease and clinical manifestation

Malarial species Key Morphological Differences Between Human Plasmodium Species in Blood Smears

falciparum o numerous rings o smaller rings o no trophozoit es or schizonts o crescentshaped gametocyt es

vivax

ovale

malaria e o enlarged o similar to o compac erythroc P. vivax t o compact yte parasit o Schüffne trophozoi e o merozoi r's dots te o 'ameboi o fewer tes in d' merozoit rosette trophozo es in ite schizont o elongate d erythrocy

Vector

Anopheles Mosquito

Vector 

Philippines: – Anopheles minimus var. flavirostris Night biter  Prefers to breed in slow, flowing, partly shaded streams that abound in foothill areas  Occasionally, they utilize new habitats such as irrigation ditches, rice fields, pools and wells  Horizontal flight : 1 – 2 km 

Vector 

Philippines: – Anopheles litoralis 

In coastal areas of Mindanao, particularly Sulu

– Anopheles maculates Coexists with A. flavirostris in the portions of streams exposed to sunlight  Appear to be responsible for malaria transmission in high altitudes 

– Anopheles mangyanus Has the same breeding habitats and seasonal prevalence as A. flavirostris  Prefers habitat located in forest fringes 

Larvae of Anopheles gambiae, the major malaria vector in Africa •can breed in very diverse habitats •three habitats are shown from left to right: tire tracks, rice fields, and irrigation water

Other modes of transmission of Malaria  Blood transfusion from infected donors  Contaminated needles and syringes  Congenital

Life cycle 

Asexual cycle: occurs in humans – Schizogony: leads to formation of merozoites – Gametogony : leads to formation of the gametocytes

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Sexual cycle : occurs in the mosquitoes – Sporogony: leads to the formation of sporozoites

Life Cycle

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Some merozoites of P. vivax and P. ovale re-invade the liver cells forming hypnozoites  these dormant exoerythrocytic forms may remain quiet for years Reactivation of the hypnozoite forms lead to relapse – Cold, fatigue, trauma. Pregnancy, infections, other illnesses may precipitate reactivation

Pathogenesis 

Pathological processes are the result of the erythrocytic stage

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Once merozoites invade the erythrocytes cells reduce deformability

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In the course of invasion, electron dense submembranous structures appear and enlarge and become “knobs”.

– KNOBS : important in cytoadhesion  They contain several proteins such as rosettins, riffins, histidine-rich protein and the P. falciparum erythrocyte membrane protein (PfEMP-1) - - which is the most adhesive of the knobs

Pathogenesis 

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Infected erythrocytes also undergo membrane transport mechanisms Hemoglobin is digested forming hematin, and variant strain-specific neoantigens are expressed Soluble antigens of P. falciparum are potent inducers of pro-inflammatory cytokines  stimulates release of TNF or cachexin which causes of malarial fever – Result of the release of cytokines at the time of Schizont rupture : fever, febrile paroxysms, headache, various aches and pains

Pathogenesis 

Altered red cell surface membranes + host’s immunological response to the parasite antigens  pathologic changes  alteration in regional blood flow and in the vascular endothelium, altered biochemistry, anemia, and tissue and organ hypoxia

Clinical manifestations 

Prepatent period: the interval of time from sporozoite injection to detection of parasites in blood – 11 days to 4 weeks – P.falciparum : 11-14days – P.vivax : 11 – 15 days – P. ovale – 14 – 26 days – P. malariae: 3 to 4 weeks

Clinical manifestations 

Incubation period: The time between sporozoite injection and the appearance of clinical symptoms – Typically 8 to 40 days depending on the species ( 9 days to 3 years) P. falciparum: 8-15days  P. ovale 11-16 days 

P. vivax 12-20 days P. malariae 18-40days

– Depends on parasite strain, dose of sporozoites inoculated, immune status of the host, malaria chemoprophylaxis history

Clinical manifestations 

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There are no absolute diagnostic clinical features except for the regular paroxysms of fever with asymptomatic intervals Prodromal symptoms: feeling of weakness and exhaustion, a desire to stretch and yawn, aching bones, limbs, loss of appetite, nausea and vomiting, a sense of chilliness

Clinical manifestations 

3 stages of classical malaria paroxysms: total duration of a typical attack  8 to 12 hours – COLD STAGE: starts with sudden inappropriate feeling of coldness and apprehension  violent teeth shattering and shaking of the whole body Intense peripheral vasoconstriction despite increased core temperature  These rigors last 15 to 60 minutes 

Clinical manifestations 

HOT STAGE: – Flush phase – Patient becomes hot and manifests with headache, palpitations, tachypnea, epigastric discomfort, thirst, nausea and vomiting; confused and delirious; skin is flushed and hot – Temp. 40C – 41C – 2 – 6 hours

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SWEATING STAGE: – Defervescence or diaphoresis ensues with profuse sweating – Temp lowers within the next 2-4 hours and symptoms diminish

Malaria paroxysms 

These paroxysms will exhibit periodicities of 48 hours for P. vivax, P. ovale, and P. falciparum, and a 72-hour periodicity for P. malariae.

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Initially the periodicity of these paroxyms may be irregular as the broods of merozoites from different exoerythrocytic schizonts synchronize. – This is especially true in P. falciparum which may not exhibit distinct paroxysms, but exhibit a continuous fever, daily attacks or irregular attacks (eg., 36-48 hour periodicity).

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Patients may also exhibit splenomegaly, hepatomegaly (slight jaundice), and hemolytic anemia during the period in which the malaria paroxysms occur.

Malignant tertian

Benign tertian

Quartan

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Recrudescence: renewal of parasitemia and/or clinical features arising from persistent undetectable asexual parasitemia in the absence of an exoerythrocytic cycle

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Relapse: renewed asexual parasitemia following a period in which the blood contains no detectable parasites – Occur with P.vivax and P. ovale are due to reactivation of hypnozoites in the liver

Recurrent infections in malaria are of 3 types:  Relapse: occur as a result of delayed maturation of the dormant liver stages  Recrudescence: occurs when parasitemia caused by the same parasite responsible for initial infection recurs after clearance or a significant reduction in the initial parasitemia

– Occurs most commonly with P. falciparum because of drug resistance

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Reinfection: with diff parasites, as well as infection with more than one type, occurs in areas with a high intensity of transmission

Feign: Textbook of Pediatric Infectious Diseases 5th edition

Classical signs and symptoms Triad of :  ANEMIA  FEVER AND CHILLS  SPLENOMEGALY

Complications Cerebral Malaria: complication of severe P. falciparum malaria  a diffuse encephalopathy with loss of consciousness – – – 

consciousness ranges from stupor to coma onset can be gradual or rapid unresponsive to pain, visual, and verbal stimuli

associated with sequestration in cerebral microvasculature

Complications 

Other signs of severe malaria – Severe anemia – Thrombocytopenia – Renal failure – Pulmonary edema – Hypoglycemia – Circulatory collapse/shock

Diagnosis Microscopic identification of the malarial parasites in thick and thin blood smears stained with Giemsa or Wright’s stain : gold standard

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Quantitative Buffy Coat (QBC)

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Obtain smears every 6 to 8 hrs uses a specially prepared capillary tube coated with acridine orange; only screens presence of malarial parasites

Rapid malaria diagnostic tests (RDTs)

Prognostic indicators Clinical indicators of poor prognosis         

Age under 3 years Deep coma Witnessed or reported convulsions Absent corneal reflexes Decerebrate/decorticate rigidity or opisthotonos Clinical signs of organ dysfunction (e.g. renal failure, pulmonary edema) Respiratory distress (acidosis) Circulatory collapse Papilledema and/or retinal edema

Prognostic indicators Laboratory parameters of poor prognosis   

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Hyperparasitaemia (>250 000/µl or >5%) Peripheral schizotemia (Peripheral blood polymorphonuclear leukocytosis (>12 000/µl) Mature pigmented parasites (>20% of parasites) Peripheral blood polymorphonuclear leukocytes with visible malaria pigment (>5%) Packed cell volume less than 15% Haemoglobin concentration less than 5 g/dl Blood glucose less than 2.2 mmol/l (<40 mg/dl)

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Blood urea more than 60 mg/dl Serum creatinine more than 265 µmol/l (>3.0 mg/dl) High CSF lactic acid (>6 mmol/l) and low CSF glucose Raised venous lactic acid (>5 mmol/l) More than 3-fold elevation of serum enzymes (aminotransferases) Increased plasma 5'-nucleotidase Low antithrombin III levels Very high plasma concentrations of tumour necrosis factor (TNF)

Laboratory Diagnosis : THICK AND THIN BLOOD SMEARS 

Thick films: place a drop of blood in the middle of a clean microscope slide and with the corner of a second slide spread the drop until it is about 10-15mm in diameter. The thickness should be such that it is just possible to see news print through it.

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Thin films are made in the standard manner. Allow the films to dry, do not leave on the bench in a laboratory which is not fly proofed, otherwise the film will be eaten.

Microscopic findings

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Ring: early developmental stage of the asexual erythrocytic parasite; the ring is a young trophozoite. – the term is derived from the morphologic appearance of this stage, which includes chromatin (red), cytoplasm (blue), often arranged in a ring shape around a central vacuole; Trophozoite: next developmental stage – has lost its "ring" appearance, and has begun to accumulate pigment (colored yellow to black). Schizont: late developmental stage – has begun its division into merozoites, and thus is characterized by the presence of multiple contiguous chromatin dots (to be distinguished from multiple chromatin dots from multiple infections, which tend not to be contiguous). Gametocyte: sexual erythrocytic stage

Diagnostic points:  Red Cells are not enlarged.  Rings appear fine and delicate and there may be several in one cell.  Some rings may have two chromatin dots.  Presence of marginal or applique forms.  It is unusual to see developing forms in peripheral blood films.  Gametocytes have a characteristic crescent shape appearance. However, they do not usually appear in the blood for the first four weeks of infection.  Maurer's dots may be present.

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P. falciparum Growing trophozoite showing Maurer's cleft

Diagnostic points: Red cells containing parasites are usually enlarged.  Schuffner's dots are frequently present in the red cells as shown above.  The mature ring forms tend to be large and coarse.  Developing forms are frequently present.

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Schuffner’s dots P. vivax

Diagnostic points :-   Ring forms may have a squarish appearance.  Band forms are a characteristic of this species.  Mature schizonts may have a typical daisy head appearance with up to ten merozoites.  Red cells are not enlarged.  Chromatin dot may be on the inner surface of the ring.

Diagnostic points : Red cells enlarged.  Comet forms common (top right)  Rings large and coarse.  Schuffner's dots, when present, may be prominent.  Mature schizonts similar to those of P. malariae but larger and more coarse.

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In oval malaria caused by Plasmodium ovale, the red cells infected by oval-shaped trophozoites reveal Schuffner's spots. The red cells with ring form become oval in shape. Oval malaria is seen mostly in the subsaharan Africa.

Blood stages malarial parasites

Blood Smears 

Fig.1.normal red cell 218:trophozoit es (Fig.2-10 ring-stage trophozoites) 19-26: schizonts (fig26 ruptured schizont) 27, 28: mature macrogameto cytes (female) 29, 30:

Plasmodium falciparum: Blood Stage Parasites: Thick Blood Smears

malariae: Blood Stage Parasites: Thin Blood Smears fig. 1: Normal red cell 2-5: young trophozoites (rings) 613:trophozoites 14-22: schizonts 23: developing gametocyte 24:macrogamet ocyte (female) 25: microgametocyt e

Plasmodium malariae Blood Stage Parasite Thick Blood Smears

blood stage parasites: Thin Blood Smears Fig. 1: Normal red cell 2-5:young trophozoites (Rings) 6-15: trophozoites 16-23: schizonts 24: macrogametocy tes (female) 25: microgametocyt e

parasites:

thin blood smears  Fig.1: Normal red cell 2-6:young trophozoites (ring stage parasites) 7-18: trophozoites 19-27: schizonts 28-29: macrogametocy te (female) 30: microgametocyt e

Plasmodium falciparum

ction of mosquito showing oöcysts(1) and sporozoites

ection of liver showing a greatly enlarged parenchym ell full of merozoites (see arrow).

on of brain showing blood vessels blocked with develo ciparum parasites (see arrows).

Approach to Diagnosis  

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history of being in endemic area symptoms: fever, chills, headache, malaise, splenomegaly, anemia microscopic demonstration of parasite (blood smear) antigen detection (ParaSight-F, OptiMal)

Treatment  2. 3. 4.

The main uses of antimalarial drugs: Protective (prophylactic) Curative (therapeutic) Preventive

Treatment 

Prophylaxis: used before the infection occurs or before it becomes evident – Aim: preventing either the occurrence of the infection or any of its symptoms – Blood schizonticides

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Curative or therapeutic : refers to action on the established infection which uses blood schizonticidal drugs for the treatment of the acute attack and in the case of relapsing malaria, radical treatment of the dormant liver forms

Treatment 

Prevention of transmission: – means deterrence of mosquitoes with the use of gametocytocidal drugs to attack the gametocytes in the blood of the human host. – Also means interruption of the development of the sporogonic phase in the mosquito when it feeds on the blood of an infected person who has been given appropriate sporonticidal drugs

Treatment Drug Class

Examples

Fast-acting blood schizontocide

choloroquine (+other 4-aminoquinolines), quinine, quinidine, mefloquine, halofantrine, antifolates (pyrimethamine,

Slow-acting blood schizontocide

Blood + mild tissue schizontocide

proquanil,sulfadoxine,dapsone), artemisinin (quinhaosu) doxycyclinederivatives (+ other tetracycline antibiotics) proquanil, pyrimethamine, tetracyclines

Treatment Drug class

Example

Tissue schizontocide (antirelapsing)

primaquine

Gametocidal

primaquine, artemisinin derivatives, 4aminoquinolines (limited?)

Combinations

Fansidar (pyrimethamine+sulfadoxine), Maloprim (pyrimethamine + dapsone), Malarone (atovaquone + proquanil)

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Drug resistance is defined by a treatment failure and can be graded into different levels depending on the timing of the recrudescence following treatment (Figure)

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Traditionally these levels of drug resistance have been defined as: – Sensitive (no recrudescence) – RI (delayed recrudescence) – RII (early recrudescence) – RIII (minimal or no anti-parasite

RI  

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Mildest form of resistance Characterized by initial clearance of the parasites but recrudescence occurs within a month after the start of treatment Classified as early: clearance occurs for the first 48 hours and recrudescence takes place within the first 14 days after start of treatment Late : clearance within the first 48 hours and recrudescence occurs within the 14th to 28th day

RII  Shows initial reduction in parasitemia after treatment but there is failure to clear the blood of asexual parasites and soon after, increase of parasitemia occurs RIII  Severest form of resistance  Parasitemia either show no significant change with treatment or will increase

Treatment 

A modified protocol based on clinical outcome was introduced by WHO in 1996. – In this protocol the level of resistance is expressed as adequate clinical response (ACR), late treatment failure (LTF), or early treatment failure (ETF) as defined by the following:

Treatment 

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ACR, absence of parasitemia (irrespective of fever) or absence of clinical symptoms (irrespective of parasitemia) on day 14 of follow-up LTF, reappearance of symptoms in the presence of parasitemia during days 414 of follow-up ETF, persistence of clinical symptoms in the presence of parasitemia during the first 3 days of follow-up

Prevention and Control reduce human-mosquito contact  impregnated bednets  repellents, protective clothing  screens, house spraying reduce vector  environmental modification  larvicides/insecticides  biological control reduce parasite reservoir  case detection and treatment  chemoprophylaxis

Drug prophylaxis Drug resistance

Prophylactic drug

Breakthrough drug

None

Chloroquine

Chloroquine

Doxycycline

Pyrimethamin e and sulfadoxine Pyrimethamin e& sulfadoxine

Chloroquine plus Doxycycline pyrimethamin or Mefloquine Quinine SO4 e-sulfadoxine tablet plus tetracycline

Prophylaxis 

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Taken during the duration of the stay and continued until 4 weeks after the last possible exposure to infection Chloroquine – for areas where malaria is exclusively due to P. vivax and where ther is low risk of chloroquineresistant P. falciparum Mefloquine, doxycycline or atovaquone/proguanil – areas where levels of resistance to chloroquine are high

Massive increase in spleen size in hyperreactive splenomegaly due to malaria.

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Nephrotic syndrome secondary to chronic infection with Plasmodium malariae. Notice the swollen face and ascites.

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Plasmodium falciparum. In cerebral malaria, numerous petechiae appear in the brain.