Malaria

Dr. Sudhir Dev Dept. G.P and Emergency Medicine

BPKIHS

The word “malaria” comes from the

Italian mala aria, meaning “bad air.” When the term was coined, it was commonly believed that malaria was caused by breathing in bad air.

What does Malaria mean?

Malaria is a mosquito-borne parasitic disease

caused by genus Plasmodium, affecting over 100 countries of the tropical and subtropical regions of the world.

Around 400-900 million people are affected At least 2.7 million deaths annually. It is one of the major public health concerns

Overview

Around 300-500 million clinical cases of malaria are

reported every year, of which more than a million die of severe and complicated cases of malaria.

Malaria is known to kill one child every 30 sec, 3000 children per day under the age of 5 years.

Malaria ranks third among the major infectious diseases in causing deaths after pneumococcal acute respiratory infections and tuberculosis, and accounts for approximately 2.6% of the total disease burden of the world.

Epidemiology

It mainly occurs throughout tropical regions 515 million clinical cases per year An estimated 655,000 people died from malaria

in 2010 with two-thirds of these occurring in sub-Saharan

Africa especially amongst children and pregnant women the incidence of malaria was greatly reduced

between 1950 and 1960 but since 1970 there has been resurgence.

Epidemiology (cont.)

Who is at Risk?

Most people who get malaria are travelers or people who live in an area with malaria transmission.

Young children and pregnant women.

Poor people that live in rural areas who lack knowledge, money and the access to health care.

Malaria is caused by species of Plasmodium. The genus Plasmodium contains over 200 species

at least 11 species infect humans. Most important are: Plasmodium falciparum Plasmodium malariae Plasmodium ovale Plasmodium vivax Plasmodium knowlesi

Plasmodium parasites are highly specific with female Anopheles mosquitoes

Causative Agent

Female mosquitos of genus Anopheles are

primary hosts and transmission vectors. There are approximately 460 recognized

species Over 100 can transmit human malaria Only 30–40 commonly transmit parasites of

the genus Plasmodium Anopheles gambiae is one of the best

known which transmits Plasmodium falciparum

Vector

Only female mosquitoes feed on blood

while the males feed on plant nectar and do not transmit the disease.

The females of Anopheles genus prefer to feed at night

They start searching for a meal at dusk and continue throughout the night until they take a meal

Vector (cont.)

Life Cycle

Inside the vector (sexual reproduction): Young female mosquitoes ingest the malaria parasite

by taking a blood meal from an infected human carrier The ingested gametocytes will differentiate into

male and female gametes and then unite to form a zygote (ookinete) in the mosquito’s gut

The resulting ookinete penetrates the gut lining to form an oocyst in the gut wall

The oocyst ruptures to release sporozoites that migrate in the mosquito’s body to the salivary glands and are ready to infect new human hosts

Life Cycle & Pathogenesis

Inside humans: Malaria develops via two phases:

Exoerythrocytic: involves infection of liver Erythrocytic phase: involves infection of RBC

(erythrocytes)

Life Cycle & Pathogenesis

A mosquito infects a person by taking a blood meal. First, sporozoites enter the bloodstream, and migrate

to the liver. They infect liver cells (hepatocytes), where they multiply into merozoites, rupture the liver cells, and escape back into the bloodstream. (Exoerythrocytic phase)

Then, the merozoites infect red blood cells, where they develop into ring forms, trophozoites and schizonts which in turn produce further merozoites. (Erythrocytic phase)

Sexual forms (gametocytes) are also produced, which, if taken up by a mosquito, will infect the insect and continue the life cycle.

Life Cycle & Pathogenesis

Relationship between life cycle of parasite and clinical features of malaria

Cycle/ Feature P. Vivax, P. Ovale P. Malariae P. Falciparum

Pre- Patent Period (minimum Incubation)

8- 25 days 15- 30 days 8-25 days

Asexual Cycle 48 hrs synchronous 72 hrs synchronous

< 48 hrs synchronous

Periodicity of Fever

Tertian Quartan Aperiodic

Exo Erythrocytic cycle

Persistent as hypnozoites

Pre- Erythrocytic only

Pre- Erythrocytic only

Delayed onset Common Rare Rare

Relapses Common upto 2 yrs

Recrudescence many yrs later

Recrudescence upto 1year

P. Falciparum: It is the most dangerous of the malarias Onset is insidious, with malaise, headache and

vomiting… commonly mistaken for influenza The fever has no particular pattern. Jaundice is common due to hemolysis & hepatic

dysfunction. Hemoglobinuria (blackwater fever), a darkening of the urine seen with severe RBC hemolysis

There is hepatosplenomegaly Anemia develops rapidly

Clinical Features

P. falciparum complications: Cerebral Malaria: the most grave complication, causing either confusion or coma

without localizing signs. Cerebral malaria develops when parasitized red blood cells (PRBCs) adhere to the cerebral microvasculature, causing blockage of the blood's pathway .  This blockage stops blood flow, leading to a shortage of oxygen and nutrients those areas of the brain.  Complications of cerebral malaria include: Convulsions Hypoglycemia Acute pulmonary edema Acure renal failure (Blackwater fever ) Metabolic acidosis Aspiration pneumonia Severe anemia Coagulopathy/Spontaneous bleeding

These severe manifestations may occur in travelers without immunity or in young children who live in endemic areas.

Clinical Features

Hypoglycemia :The aetiology is incompletely understood and is likely to be multifactorial. Depletion of glucose stores due to starvation, parasite utilisation of glucose, impairment of gluconeogenesis have been implicated . Hyperinsulinaemia, secondary to quinine therapy may cause hypoglycemia.

Convulsions: Cerebral hypoxia associated with cerebral malaria, fever, hypoglycaemia, other metabolic disturbances such as lactic acidosis and antimalarial drugs.

Pulmonary Edema: Such cases may be due to increased permeability of pulmonary capillaries. Sequestration of red cells and obstruction of pulmonary microcirculation and disseminated intravascular coagulation may also play their role.

Coagulopathy: May be due to thrombocytopnea. This abnormality is seen in less than 5% of malaria.(Specially Falciparum )

P. vivax & P. Ovale: In many cases the illness starts with several days

of continued fever before the development of classical bouts of fever on alternate days. Fever starts with a rigor. The patient feels cold and the temperature rises to about 40 C. After an hour hot or flush phase begins. It lasts several hours and gives way to profuse perspiration and a gradual fall in temperature. The cycle is repeated 48 hours later.

Anemia develops slowly

Clinical Features

P. malariae infection This is usually associated with mild symptoms

and bouts of fever every third day. Parasitemia may persist for many years with the occasional recurrence of fever, or without producing any symptoms.

Clinical Features

The characteristic, text-book picture of malarial illness

is not commonly seen. It includes three stages viz. Cold stage, Hot stage and Sweating stage. The febrile episode starts with shaking chills, usually at mid-day, and this lasts from 15 minutes to 1 hour (the cold stage), followed by high grade fever, even reaching above 1060 F, which lasts 2 to 6 hours (the hot stage). This is followed by profuse sweating and the fever gradually subsides over 2-4 hours. These typical features are seen after the infection gets established for about a week.

Typical Features

In vivax malaria, this typical pattern of fever

recurs once every 48 hours and this is called as Benign Tertian malaria. Similar pattern may be seen in ovale malaria too (Ovale tertian malaria). In falciparum infection (Malignant tertian malaria), this pattern may not be seen often and the paroxysms tend to be more frequent (Sub-tertian). In P. malariae infection, the relapses occur once every 72 hours and it is called Quartan malaria.

Typical Features

Typical Features

Temperature observations over four days, showing typical fever patterns in malaria infection by different Plasmodium species.

Atypical Features

In an endemic area, malaria often presents with atypical manifestations

Atypical features are more common in the following situations:

Falciparum malaria Early infection Patients at extremes of age Patients who are immune-compromised (extremes of age,

malnourished, AIDS, tuberculosis, cancers, on immunosuppressive therapy etc.)

Patients on chemoprophylaxis for malaria Patients who have had recurrent attacks of malaria Patients with end stage organ failure Last but not the least, pregnancy.

Atypical Features

Atypical Fever Headache, Bodyache and Joint pain Dizziness, Vertigo Altered Mental Status Cough, Chest pain Jaundice , Pallor, Puffiness of face Abdominal pain, diarrhoea Hepatospleenomegaly

This list is not exhaustive and malaria may present in many other ways. In all the above listed situations, patients may not have associated fever, thus confusing the picture. In some, fever may follow these symptoms. Therefore, one should not wait for the typical symptoms of malaria to get a blood test done; it is always better to do a smear whenever reasonable doubt exists.

Classification: Malaria is divided into severe and uncomplicated by the World Health

Organization (WHO). Severe malaria is diagnosed when any of the following criteria are present, otherwise it is considered uncomplicated.

Decreased consciousness Significant weakness such that the person is unable to walk Inability to feed Two or more convulsions Low blood pressure (less than 70 mmHg in adults or

50 mmHg in children) Breathing problems Circulatory shock Kidney failure or hemoglobin in the urine Bleeding problems, or hemoglobin less than 5 g/dl Pulmonary edema Low blood glucose (less than 2.2 mmol/l / 40 mg/dl) Acidosis or lactate levels of greater than 5 mmol/l A parasite level in the blood of greater than 2%

P. falciparum-infected erythrocytes sequester in

blood vessels, creating blockages.

Infected erythrocytes also “stick to endothelium, platelets, and other erythrocytes”

Rosetting -- cohesion of erythrocytes

Leads to immune evasion because of lack of circulation through the spleen.

Aids in the progression of the severity of malaria

Causes of severe malaria

In patients with suspected malaria, obtaining a

history of recent or remote travel to an endemic area is critical. Asking explicitly if they traveled to a tropical area at anytime in their life may enhance recall. Maintain a high index of suspicion for malaria in any patient exhibiting any malarial symptoms and having a history of travel to endemic areas.

Also determine the patient's immune status, age, and pregnancy status; allergies or other medical conditions that he or she may have; and medications that he or she may be using.

Approach to Patient with Malaria.

In returning travelers from endemic areas,

malaria is suggested by the triad of thrombocytopenia, elevated lactate dehydrogenase (LDH) levels, and atypical lymphocytes. These findings should prompt obtaining malarial smears.

In general, blood cultures should be drawn in a febrile patient. Patients from tropical areas may have more than 1 infection; maintaining a high suspicion for additional infections should be considered when patients do not respond to antimalarials.

Diagnostic Workup

Detects circulating

malaria antigens in whole blood.

15 minute test The only FDA cleared

rapid malaria test.

Rapid Test for  Malaria with Kits( Optimal)

P. falciparum Sensitivity: 99.7% Specificity: 94.2%*P. vivax Sensitivity: 93.5% Specificity: 99.8%

The test targets the histidine-rich protein II (HRPII)

antigen specific to P. falciparum and a pan-malarial antigen (aldolase), common to all four malaria species capable of infecting humans - P. falciparum, P. vivax, P. ovale, and P. malariae.

It is intended to aid in the rapid diagnosis of human malaria infections and to aid in the differential diagnosis of Plasmodium falciparum infections from other less virulent malarial infections. Negative results must be confirmed by thin / thick smear microscopy.

How the test works?

• Giemsa thick/thin smears (GOLD STANDARD )• Density of parasitemia (>3% = inpatient)• Fluorescent microscopy (QBC: Quantitative Buffy

Coat (QBC) Test• PCR (POLYMERASE CHAIN REACTION )

• (~100% sensitive/specific , but expensive/technical)• Other Basic investigation like CBC, CXR, ECG,

Electrolytes, LFT, RFT , CT , USG could be done to rule out other complication.

Other Investigation For Diagnosing Malaria

Medications (will be mentioned in treatment) Vector control Mosquito nets and bedclothes Immunity (natural & vaccines) Education

Prevention

Efforts to eradicate malaria by eliminating

mosquitoes have been successful in some areas. Malaria was once common in the United States and southern Europe, but vector control programs, in conjunction with the monitoring and treatment of infected humans, eliminated it from those regions.

Malaria was eliminated from most parts of the USA in the early 20th century by use of the pesticide DDT.

Vector Control

Mosquito nets help keep mosquitoes away from

people and greatly reduce the infection and transmission of malaria. The nets are not a perfect barrier and they are often treated with an insecticide designed to kill the mosquito before it has time to search for a way past the net. Insecticide-treated nets (ITNs) are estimated to be twice as effective as untreated nets and offer greater than 70% protection compared with no net. Since the Anopheles mosquitoes feed at night, the preferred method is to hang a large "bed net" above the center of a bed such that it drapes down and covers the bed completely.

Mosquito nets

Natural immunity occurs, but only in response to repeated

infection with multiple strains of malaria. A completely effective vaccine is not yet available for

malaria, although several vaccines are under development. SPf66 was tested extensively in endemic areas in the

1990s, but clinical trials showed it to be insufficiently effective.

Other vaccine candidates, targeting the blood-stage of the parasite's life cycle, have also been insufficient on their own.

Several potential vaccines targeting the pre-erythrocytic stage are being developed.

Immunity

First proposed in 1960s, still nothing fully effective

Difficulties include :

Intracellular parasites Polymorphism and clonal variation Parasite induced immunosuppression Antigenic variation Evaluation and trials difficult to interpret High level of parasite mutation

Vaccines

Education in recognizing the symptoms of malaria

has reduced the number of cases in some areas of the developing world by as much as 20%.

Recognizing the disease in the early stages can also stop the disease from becoming a killer.

Education can also inform people to cover over areas of stagnant, still water which are ideal breeding grounds for the parasite and mosquito, thus cutting down the risk of the transmission between people.

This is most put in practice in urban areas where there are large centers of population in a confined space and transmission would be most likely in these areas.

Education

When properly treated, a patient with malaria can

expect a complete recovery. The treatment of malaria depends on the severity of the disease; whether patients can take oral drugs or must be admitted depends on the assessment and the experience of the clinician.

Uncomplicated malaria is treated with oral drugs. The most effective strategy for P. falciparum infection recommended by WHO is the use of artemisinins in combination with other antimalarials artemisinin-combination therapy, ACT, to avoid the development of drug resistance against artemisinin-based therapies.

Treatment

Severe malaria requires the parenteral administration

of antimalarial drugs. Until recently the most used treatment for severe malaria was quinine but artesunate has been shown to be superior to quinine in both children and adults. Treatment of severe malaria also involves supportive measures.

Infection with P. vivax, P. ovale or P. malariae is usually treated on an outpatient basis. Treatment of P. vivax requires both treatment of blood stages (with chloroquine or ACT(artemisinin based Combination) as well as clearance of liver forms with primaquine.

Treatment

Casual prophylaxis (cause of infection): On pre

erythrocytic phase. Proguanil, Primaquine Suppressive cure: on blood schizontocidal

Rapidly acting: Chloroquine, quinine, artemisinin derivatives, mefloquine

Slow acting: suphadoxine, pyrimethamine, doxycycline

Radical cure: On latent tissue forms ie exoerythrocytic stage hypnozoites: Primaquine

Prevent transmission to Anopheles mosquito: gameticidal. Primaquine, artemisinins

Clinical classification of anti malarial drugs

Treatment of Uncomplicated Malaria

Cholroquine sensitive strains of pl. vivax, malariae, ovale – chloroquine 600mg base(10 mg base/kg) stat followed by 300mg base (5 mg/kg at 12, 24 and 36 hrs).

Radical treatment for vivax and ovale infection – Primaquine 15 mg daily for 14 days to eradicate hepatic hypnozoites and prevent relapse.

In mild-to-moderate G6PD deficiency, primaquine 0.75 mg base/kg body weight given once a week for 8 weeks.

In severe G6PD deficiency, primaquine is contraindicated and should not be used.

Glucose-6-phosphate dehydrogenase (G6PD)

Treatment of Uncomplicated Malaria

In areas with chloroquine resistant P. vivax, artemisinin-based combination therapies are recommended for the treatment of the same.

At least a 14-day course of primaquine is required for the radical treatment of P. vivax.

Uncomplicated falciparum malaria

Artemisinin- based combination therapy [ACT] Artesunate100mg BD(4mg/kg/day for 3 days) – sulphadoxine 1500 mg (25mg/kg)+ pyrimethamine 75 mg(1.25mg/kg) single dose

Quinine 600mg 3 times a day for 7 days followed by suphadoxine 1.5g combined with pyrimethamine 75 mg (3 tabs of fansidar)

Who 2010 guidelinesArtemisinin-based combination therapies should be used in preference to sulfadoxinepyrimethamine(SP)+amodiaquine (AQ) for the treatment of uncomplicated P. falciparum malaria.ACTs should include at least 3 days of treatment with an artemisinin derivative.Dihydroartemisinin+piperaquine (DHA+PPQ) is an option for the first-line treatment of uncomplicated P. falciparum malaria worldwide.

Who 2010 guidelines cont.....

Non immune patients on malaria treatment should have daily parasite count performed until negative thick films indicate clearance of parasites

If level of parasitemia does not fall below 25% of the admission value in 48 hrs or if parasitemia has not cleared by 7 days, drug resistance is likely and regimen should be changedIn multidrug resistant P. falciparum malaria

Artemether+lumifantrine or Artesunate+mefloquine should be used.

.

Severe Falciparum malaria

Specific therapy:Artesunate iv or im( 2.4mg/kg stat followed by 2.4 mg/kg at 12 &

24 hrs and then daily for 7 days) + Tab doxycycline 100 mg od x 7 days

Quinine dihydrochloride( 20mg/kg infused over 4 hrs followed by 10 mg/kg over 4 hrs every 8 hrs)

(Doxycycline is contraindicated in pregnant women and children under 8

years of age; instead, clindamycin 10 mg/kg bw 12 hourly for 7 days should

be used).

Patients receiving artemisinin derivatives should get full course of oral ACT.

However, ACT containing mefloquine should be avoided in cerebral malaria due to

neuropsychiatric complications.

Special Precautions

Intensicve nursing care quinine if injected rapidly can cause hypotension so

administered carefully by rate limiting infusion. All patients with iv quinine should get a continuous infusion of 5-10% dextrose

Acute renal failure or severe metabolic acidosis – hemofiltration and hemodialysis

If unconscious, blood glucose measured every 4-6 hrs, & if <40 mg/dl, iv dextrose should be started

Hematocrit measured every 6 hrs, if <20% then whole blood or packed cells infused slowlySpontaneous bleeding- fresh blood and IV vitamin KConvulsions – IV or rectal benzodiazepines.

Special risk groups

PregnancyFirst trimester:

Quinine plus clindamycin to be given for 7 days (artesunate plus clindamycin for 7 days is indicated if this treatment fails)

An ACT is indicated only if this is the only treatment immediately available, or if treatment with 7-day quinine plus clindamycin fails or uncertainty of compliance with a 7-day treatment.

Second and third trimesterACTs known to be effective in the region or artesunate plus clindamycin to be given for 7 days,

or Quinine plus clindamycin to be given for 7 days.

Special risk groups

Lactating women: Should receive standard antimalarial treatment (including ACTs) except for dapsone, primaquine and tetracyclines.

Infants and young children: ACTs are first-line treatment in infants and young children with attention to accurate dosing and ensuring the administered dose is retained

Antimalarial tablets

Adult prophylactic dose

Regimen

Chloroquine resistance high

Mefloquine 250mg weekly Started 2-3 weeks before travel and continued until 4 weeks after

or Doxycycline 100mg daily Started 1 week before and continued until 4 weeks after travel

Or Malarone 1 tablet daily From 1-2 days before travel until 1 week after return

Chloroquine resistance absent

Chloroquine 300mg base weekly

Started 1 week before & continued until 4 weeks after traveland proguanil 100-200mg daily

Chemoprophylaxis

Misdiagnosis

Over-diagnosisObsession with malaria

and forgetting the OTHER causes of fever

In an endemic area, there may be a tendency to diagnose all cases of fever as malaria, forgetting to even consider other causes. Whereas presumptive treatment with chloroquine in cases of fever is well accepted, sometimes, doctors may go beyond that and indulge in presumptive treatment with newer drugs, (reserved for multi drug resistance falciparum malaria), even if the MP test is repeatedly negative. Most often such cases turn out to be non-malarial fevers. Therefore, DO NOT FORGET THE OTHER CAUSES OF FEVER.

Under-diagnosisForgetting malaria

1. Malaria may not be considered as a possibility in places where it is not common-history of travel to malarious area should be elicited.2. It may not be considered in patients on chemoprophylaxis for malaria. Chemoprophylaxis does not offer 100% protection and malaria should be therefore looked for in these patients.3. Malaria can always co-exist with other infections in an endemic area. Therefore, it should be considered even in patients with other obvious infections causing fever.

Common Mistakes

Common Mistakes

Misreport

False positive

Artifacts may be read as malarial parasites on peripheral smear as well as QBC test. Dirty slides, contaminated stains, inexperienced microscopist, recycled QBC tubes may be the causes.

False negative

Malarial parasites may be missed and the test reported as negative. Inadequate smear, dirty stains, contaminated/deteriorated stains, wrong buffer pH, inexperienced technician, incomplete examination of the slide, storage of blood in anticoagulant before preparing the smear etc. may contribute to this problem.

Mis-judgement of severity

Panic reaction to P. falciparum malaria is common among patients and not uncommon among doctors, resulting in over-reaction to the situation and over-treatment. Mild anemia, mild icterus, headache etc. are common in falciparum malaria and need not necessarily imply severe malaria. Such patients need not be treated with parenteral or second line antimalarial drugs. Also it should not be forgotten that some of the manifestations could be due to fever, drugs etc., and not necessarily due to severe malaria.

P. falciparum malaria can cause dramatic complications and therefore one should be always looking for them. Patients who are at increased risk for development of complications should be ideally admitted for observation. Any indication of complication should be properly managed. Neglecting the signs like high fever, prostration, significant pallor and jaundice, dehydration etc. may prove costly. Hypoglycemia may be easily missed.

Common Mistakes

MismanagementOver-treatment (1.) Use of parenteral antimalarials when not needed can

cause unnecessary hardship to patient. (2.) Using 2nd line antimalarials when not indicated- this only adds to the cost of therapy and to the adverse effects. It also depletes our stock of reserve antimalarial drugs and exposes them to the risk of development of resistance. (3.) Using 2-3 antimalarial drugs concurrently (4.) Higher dose and longer duration: Antimalarial drugs do not offer better efficacy at higher dose, this only adds to the adverse effects. (5.) Failure to switch to oral therapy: Unnecessary continuation of parenteral therapy may increase the adverse effects and also cost of therapy. (6.) Rapid intravenous infusions of chloroquine and quinine may be fatal. (7.) Over-hydration and fluid overload: Enthusiastic administration of fluid and/or blood may precipitate acute pulmonary oedema. (8.) Unnecessary endotracheal intubation in comatose patients who can be managed with conservative measures. (9.) Use of potentially dangerous ancillary therapies: Corticosteroids, anti-inflammatory agents, dextran, heparin, adrenaline, prostacycline etc. should be avoided

Common Mistakes

Under-treatment (1.) Delay in starting treatment: Delay in initiating treatment in a case of severe malaria may prove costly. In such cases, if the suspicion of malaria is high, treatment should be started even without waiting for the report or even if the initial report is negative. Also non-availability of a particular dug should not delay the initiation of therapy. (2.) Withholding antimalarial drug for fear of toxicity etc. (3.) Inadequate dosage: Dose should always be calculated as per the body weight of the patient. Inadequate dose may not be effective. (4.) Miscalculation of the dose due to base-salt confusion. (5.) Failure to identify the need for parenteral therapy in severe malaria and to identify therapeutic priorities in severe malaria (6.) Oral therapy in severe malaria (7.) Stopping antimalarial therapy for minor side effects is unjustified. Always weigh the benefits and risks. (8.) Failure to control convulsions (9.) Failure to recognize and treat severe anemia (10.) Delay in starting mechanical ventilation in patients with ARDS, metabolic acidosis etc. (11.) Delay in starting dialysis in cases of renal failure (12.) Delay in considering obstetrical intervention.

Thank You!