MALARIA

Akshat Jain

Malaria - History

Alphonse Laveran

Sir Ronald Ross

Giovanni Grassi

On August 20th, 1897, Ronald Ross, a British officer in the Indian Medical Indian Medical ServiceService, was the first to demonstrate that malaria parasites could be transmitted from infected patients to mosquitoes.

13 yr. old M admitted from ER with fever for last 11 days of T max 105.8F Fever was associated with chills and headache.

Used to feel warm in the night time .

Patient also had occasional diarrhea and 3 episodes of vomiting at the onset of illness, but resolved.

Was taken to another ED one week back was diagnosed with A.G.E. and discharged.

No photophobia, no neck pain or stiffness,

No dizziness or altered senses, No tinnitus, no ear complains, no sore throat .

Immunizations up to date Travel - went to Guinea 2 yrs back.

No illness during or after arrival to USA.

Family hx - none significant, no sickle cell trait or disease in family

PMH - none significant, except intermittent asthma

Meds -Albuterol

PSH -none

Physical Exam : General: Marked Pallor , alert, active, well-hydrated, in no acute distress

Small LN’s palpated Left & Right inguinal Skin: no skin disorders noted

Eyes: Extra-ocular structures normal bilaterally.

Ears: normal

Nose: normal Throat/Mouth: normal Neck: supple, FROM

Chest: normal Lungs: lungs clear to auscultation and percussion

Heart: Grade1 early systolic Flow murmur d/t fever Abdomen: RUQ tenderness

Back: normal

Extremities: normal

Genitalia: normal

Neuro: AAOX3,NEURO age appropriate Intact, No meningeal signs ,Normal fundus

Labs:

CBC -- 4.5>13.0/40.0<68 ,N 71.5 L 23.2 no bandsMCV 69 MCH 22.4 MCHC 32.5 RDW 13.9

Repeat CBC -- 8.26>14.3/40.1<78 ,N76.7 L11.6 no bandsMCV 68.4 MCH 24.4 MCHC 35.7 RDW 13.9Retic 1.13 ESR 6

BMP 133/3.6/96/23.5 BUN 10, Cr 1, Glc 100, ca8.7

Amylase 24, lipase 105LFT 23/32/185 T bili1.74/0.33 Alb 3.3

UA: trace ketones, blood Pr 100 urobilinogen 4

Smear for Thick and Thin film sent d/t high Clinical Suspicion.

Labs:

Blood parasite Thin Smear:4% RBC’s infected with parasite.

Sent to New York city department of health for Identification of sub species.

(Severe Parasitemia is >5% of parasite load on PBF)

A French army surgeon stationed in Constantine, Algeria, was the first to notice parasites in the blood of a patient suffering from malaria IN 1880.

Laveran was awarded the Nobel Prize in 1907

Malaria – Geographic distribution

Malaria – Vectors

Anopheles balabacensis

A. freeborni

A. gambiae

A. stephensi

Serious problem in Africa One in every five (20%) childhood

deaths is due to the effects of the disease.

An African child has on average between 1.6 and 5.4 episodes of malaria fever each year.

And every 30 seconds a child dies from malaria.

Disease Burden-United States

Approximately 1300 cases are diagnosed every year

Most of them acquired outside the country. Only about 1% of patients acquire the infection in the United States.

Over half the cases are acquired in Africa. Usually fewer than 10 deaths are reported in the United States annually.

Malaria – Red blood cell invasion

The Panama Canal (1905-1910)

The construction of the Panama Canal was made possible only after yellow fever and malaria were controlled in the area.

26,000 employees . Of these, over 21,000 were hospitalized for malaria at some time during their work .

Clinical Presentation- The Classic picture of malaria, with periodic

fever, shivering, and sweating, is not observed.

Malaria can mimic any febrile illness and should be suspected in any febrile child who has recently been in a malarious area.

Older children may manifest the classic periodicity of fever with chills and shivering.

Clinical Presentation- After release from the RBC Children

then become restless, drowsy, apathetic, and anorexic.

Older children may report aching body, headache, and nausea.

SYMPTOMSFeverFever - usually continuous and may

be very high (40°C) from the first day.

Many children have only flulike respiratory symptoms at presentation, with mild cough and cold.

SYMPTOMS Vomiting is very common in children

with malaria and may make oral therapy ineffective. Mild diarrhea is often observed, with dark green mucoid stools .

SYMPTOMS Seizures are common and may occur at

the onset of the disease, even before high fever has set in.

Differentiating postictal impairment of consciousness from cerebral malaria is often difficult.

Features in kids in Endemic region- Children living in an area where malaria

is endemic have repeated frequent infections and develop and maintain partial immunity.

These children often develop only a low-grade fever, tiredness, restlessness. anemia, poor appetite, and malaise.

NEONATES Parasitemia in neonates within 7 days of

birth implies transplacental transmission.

This congenital malaria is usually associated with placental parasitemia, which sometimes persists even after persists even after adequate treatment with antimalarial adequate treatment with antimalarial drugsdrugs.

Babies have fever, are irritable, refuse feeds, and often develop anemia, jaundice, and hepatosplenomegaly.

RECRUDESCENCE OR RELAPSE

Both recrudescent and relapsing infections manifest as return of disease after its apparent cessation.

Recrudescence occurs most often within days or weeks; relapse occurs within weeks or months.

In recrudescence, parasites remain in the bloodstream undetected due to ineffective treatment or host immunological response. In relapse, new hypnozoites are released from liver cells causing another parasitemia.

Understanding Relapse  

P. falciparum is the usual cause of recrudescent infections, although P. malariae can remain dormant for years; P. vivax and P. ovale may cause relapse months after the primary blood stage infection is cured, as these species have hypnozoite forms.

P vivax malaria may relapse for up to 3 years ,ovale for 1-1.5 years.

Although P falciparum can recrudesce for up to 1 year.

P malariae may continue to cause clinical malarial attacks even 20 years after the original infection.

Clinical Pearl ….

Only the sporozoites (introduced by the mosquitoes themselves) can penetrate the liver cells.

Thus, if malaria is acquired by blood transfusion or transplacentally, no infection of the liver occurs and relapses do not occur.

“Roman fever”

Malaria may have contributed to the decline of the Roman Empire and was so pervasive in Rome that it was known as the “ROMAN FEVER”

Physical Signs- Fever can be very high from the first day. Temperatures

of 40°C and higher are often observed. Classic periodicity may be established after some days.

The liver may be slightly tender. Splenomegaly takes many days.

Prolonged malaria can cause anemia, and malarial anemia causes significant mortality.

Mild jaundice may occur. This jaundice subsides with the treatment of malaria.

Striking contrast between the palm of a Kenyan child with anaemia, and that of his

mother.

DIFFERENTIAL DIAGNOSIS

COMPLICATIONS Cerebral malaria Hypoglycemia Acidosis Renal Impairment Noncardiogenic pulmonary edema Hematologic abnormalities Liver dysfunction Concomitant infection

Cerebral malaria An encephalopathyAn encephalopathy that presents with impaired

consciousness, delirium, and/or seizures. Focal neurologic signs are unusual. The onset may be gradual or sudden following

a convulsion.

Mean opening pressure is about 16 cm of CSF . Slightly elevated total protein level and cell count . CSF glucose concentration glucose concentration below 3.4 mmol/L (61 mg/dL) is

the best discriminator of cerebral malaria from presumed viral encephalitis.

Retinal hemorrhages Retinal hemorrhages may be observed in 30 to 40 percent of cases.

Dysconjugate (asymmetric) gaze in a comatose Gambian child with cerebral malaria. Convulsions, which are often prolonged and

multiple, complicate over 60% of cases.

Renal Impairment  & Blackwater Fever Common among adults with severe

falciparum malaria.

It is relatively rare among children.

Large amounts of hemoglobin and malarial pigments may be present in the urine secondary to intravascular hemolysis.

Manifests as very dark urine following several attacks of falciparum malaria

Noncardiogenic pulmonary edema

With severe falciparum malaria , even Vivax.

This complication may develop even after several days of antimalarial therapy, and can be aggravated by overly vigorous administration of intravenous fluid.

Spanish Jesuit missionaries in South America learned of a medicinal bark from indigenous Indian tribes.

With this bark, the Countess of Chinchón, the wife of the Viceroy of Peru, was cured of her fever .

The tree was named Cinchona after the countess .

Malaria and Sickle cell anemia

Work Up Thick and thin films Thick and thin films (staining with Giemsa) remain the

cornerstone and gold standard for diagnosis , quantification and detection of the type of the sub species.

Serological tests provide confirmation of past malaria in patients and are valuable for epidemiological studies .

-Indirect fluorescent antibody test (IFAT), -Indirect hem agglutination antibody (IHA) test, -Enzyme-linked immunosorbent assay (ELISA) -DNA and RNA probes and polymerase chain reaction (PCR)

All these tests produce positive results several days after malaria parasites appear in the blood ,do not help in the diagnosis of the acute infection .

PvPm

Pf

Po

Immunofluorescent antibody

Malaria PCR

Dipstick tests - Dipstick tests based on the detection of P

falciparum histidine -rich protein-2 (PfHRP-2) ,does not detect the other 3 species.

For Vivax and Falciparum -Dipstick tests based on parasite lactate dehydrogenase are now available.

These tests have high sensitivity and specificity, require no special equipment or training, and produce results rapidly.

However, they remain positive for a week or more after the treatment and cure, and, in this situation, can yield false-positive results.

In the Susruta, a Sanskrit (Indian) medical treatise, the symptoms of malarial fever were described and attributed to the bites of certain insects >2000 yrs back.

In China, during the second centurysecond century BCE, the Qinghao plant (Artemisia annua L) was described in the medical treatise , Centuries later in 1970 , the plant was re studied and brought forth was the discovery of Artemisenin.

Malaria - Treatment

Artemisinin

TREATMENT - Blood schizonticides are the first-line

drugs for the treatment of malaria

Chloroquine (Aralen)

This drug is effective against the erythrocytic forms of the parasite .

The drug of choice for P vivax, P malariae, and P ovale malaria, against which it is gametocidal as well.

It is not effective against hypnozoites. It is very effective against sensitive strains of P falciparum.

However, P falciparum resistance to chloroquine is now widespread .

Quinine (Quinamm)

A blood schizonticidal drug and still the DOC for severe and complicated malaria in most parts of the world.

It is gametocidal for P vivax and P malariae, but not for P falciparum.

Pyrimethamine-sulfadoxine (Fansidar)

Antifolate drug combination that is a slow-acting blood schizonticide, effective in some cases of chloroquine-resistant P falciparum malaria, especially those acquired in Africa.

Primaquine The only drug in clinical use that destroys hypnozoites of

both P vivax and P ovale, and so is used for the radical cure of the relapsing malarias.

It is also gametocidal against all 4 species of human plasmodia and is used to render patients noninfectious.

Primaquine has a very weak effect against erythrocytic forms of P vivax and cannot be used to terminate an acute attack.

It has no activity against erythrocytic forms of P falciparum

Not to be used until erythrocytic forms have been destroyed by another drug.

Halofantrine (Halfan)

A rapid-acting drug against erythrocytic forms of malaria.

Primarily used for treatment of acute attacks of malaria caused by multidrug-resistant P falciparum.

Mefloquine (Lariam)

It is useful for the treatment of multidrug-resistant P falciparum infections.

It is effective against blood schizonts but has no activity against hypnozoites and gametocytes.

Long half-life makes it suitable for use as a prophylactic med.

Qinghaosu-Qinghaosu- Effective against erythrocytic forms of all 4 human plasmodia, but is used for multidrug-resistant P falciparum malaria

Artesunate (Lotio Artesan) – --Fastest acting drug against blood forms of the

malaria parasite --So the IV form is especially valuable in the

management of severe and complicated malaria.

Artemether (Artenam) --It has no action on hepatic forms or

gametocytes. --Very short elimination half-life, requiring follow-

up treatment with mefloquine or treatment for at least 7 days.

Atovaquone/proguanil (Malarone)

Treatment and prophylaxis of malaria. Atovaquone has significant parasiticidal activity.

PO use only, and so can be used only for uncomplicated malaria .

INNATE PROTECTION HbSS, TRAIT – SICKLE

Trait - is 90 percent protective against severe and complicated malaria (cerebral malaria and severe anemia) and 60 percent protective against clinical malaria leading to hospital admission .

Disease - Prevalence of P. falciparum parasitemia was lower among children with SCD than children without it. Although controversial.

INNATE PROTECTION HbC- 29 and 93 percent reduction in risk of clinical malaria

in Hb C heterozygotes (HbAC) and homozygotes (HbCC), respectively

Neonatal RBC -growth of P. falciparum is diminished in red cells containing fetal hemoglobin

Thalessemia -Both alpha thalassemia and, to a lesser degree, beta thalassemia are protective against malarial infection.

HbE- a mutation of the beta globin chain, associated with reduced expression -"Hb E triangleHb E triangle" where the frontiers of Cambodia, Laos, and Thailand converge

People of West African origin who do not have the DuffyDuffy blood group are not susceptible to P vivax malaria

Regimens — Chemoprophylaxis

MALARONE

Atovaquone-proguanil is administered daily beginning two days prior to exposure, during exposure, and for one week following exposure

Mefloquine —  Effective for prevention of malaria due

to chloroquine -sensitive and chloroquine-resistant P. falciparum, as well as the other malaria species that cause human malaria.

Efficacy 91 percent .

Doxycycline Has activity against chloroquine-sensitive

and chloroquine-resistant P. falciparum, as well as the other malaria species.

Comparative trials have demonstrated equivalent efficacy of doxycycline with mefloquine

Doxycycline is administered daily beginning one to two days prior to exposure, daily during exposure, and daily for four weeks following exposure

Chloroquine — Chloroquine may be

used for prophylaxis for individuals traveling to malarious areas without chloroquine resistance .

Chloroquine is administered once once weekly weekly starting one week prior to exposure, once weekly while in the malaria endemic area, and then once weekly for four weeks following exposure.

Primaquine —  

Primaquine may be used either as presumptive anti-relapse therapy (PART) or as primary prophylaxis.

Primary prophylaxis is appropriate for travelers to regions where the principal endemic species is P. vivax (such as Mexico and Central America)

Primaquine is administered daily beginning one to two days prior to exposure, once daily during exposure, and daily for seven days following exposure

Pregnant travelers —

Risk of stillbirth, spontaneous abortion, and other adverse pregnancy outcomes is increased in the setting of malaria, and pregnant travelers should be advised to defer travel defer travel until after delivery whenever feasible .

Pregnant travelers Regions where chloroquine-sensitive

malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis with chloroquine .

Mefloquine is also acceptable

Pregnant travelers Regions where chloroquine-resistant

malaria is present, mosquito avoidance measures should be used in conjunction with chemoprophylaxis using mefloquine .

Limited data suggest that mefloquine may be safely administered during the second safely administered during the second and third trimestersand third trimesters, and can probably also be administered during the first trimester .

Contraindicated in Pregnancy Atovaquone-proguanil- this agent

should be avoided in pregnancy.

Doxycycline-- dysplasia and inhibition of bone growth and dental discoloration.

Primaquine should not be administered during pregnancy given the potential possibility for fetal G6PD deficiency.

Treatment –P.A.R.T. Primaquine-for travelers to regions

where there is substantial risk of P. vivax or P. ovale transmission

Following departure from an endemic area, primaquine should be administered for 14 days

VACCINES

RTS,S/AS01 (Pre –erythrocytic recombinant) started Pivotal Phase III evaluation in May 2009- the vaccine gave 7 out of 8 volunteers challenged with P. falciparum protective immunity .

Thank You !!

COURTESY –