malaria

Malaria

EPIDEMIOLOGY — Approximately 200 to 300 million cases of malaria occur each year and 1 to 2 million deaths occur annually most death occur due to P. falciparum and occur among children less than 5 years old in sub-Saharan Africa  , P. vivax is most prevalent in Central America, the Middle East, Southeast Asia, South America, and India.
The risk of malaria transmission in endemic countries is increased in rural areas and varies seasonally in many locations; transmission is highest at the end of the rainy season. Humans are the only important malarial reservoir.

TRANSMISSION — Malaria transmission is predominantly via the bite of a female Anopheles sp. mosquito, which occurs mainly between dusk and dawn. Other potential mechanisms for transmission include: congenitally acquired disease occur rarely,  but stillbirth from infected mothers is more frequent .malaria also be transmitted by injection or blood transfusion, sharing of contaminated needles, and organ transplantation  .
Incubation period : approximately 7-14 days for p. falciparum , 8-14 days for p. vivax & p.ovale & 7-30 days for p. malariae
With infection by blood transfusion , incubation periods depend on the number of parasite infused & are usually short .suboptimal drug suppression , such as from prophylaxis , may result in prolonged incubation period .
 
LIFE CYCLE — Human infection by all four Plasmodia spp. occurs by transmission of sporozoites via a bite from an infected anopheline mosquito. The sporozoites travel from the salivary glands of the mosquito through the bloodstream of the host to the liver. In the liver, they invade hepatocytes and divide many 1000-fold until mature tissue schizonts, each containing thousands of daughter merozoites, are formed. This exoerythrocytic stage is asymptomatic.
 The liver schizonts rupture after 6 to 16 days and release thousands of merozoites into the bloodstream, where they interact with specific erythrocyte membrane proteins and invade red blood cells . this erythrocytic stage.
Within red cells, the merozoites mature successively from ring forms to trophozoites to mature red cell schizonts (asexual forms) over 48 (P. vivax, P. ovale, P. falciparum) or 72 (P. malariae) hours. Finally, new daughter merozoites are released from the erythrocytes and can infect new red cells.

A few merozoites differentiate into male or female gametocytes (sexual forms) which cause no symptoms but which can circulate in the bloodstream until they are ingested by a blood-feeding anopheline mosquito. These sexual forms complete their life cycle within the midgut of the Anopheles mosquito, and the sporozoites that form then migrate to the salivary glands of the mosquito from where they can reinfect humans .

With mosquito-transmitted P. vivax and P. ovale infections, some parasites remain dormant in the liver as hypnozoites and can cause late relapse by reactivating after many months. By contrast, for vivax and ovale  infections derived from merozoite-contaminated blood, residual hepatic hypnozoites are not present and are not sources of potential relapse that would necessitate therapy with primaquine. For both P. falciparum and P. malariae infections, hypnozoite parasites do not develop in the liver and hence are not causes of later potential relapse.

PATHOGENESIS — All four malaria parasite species digest red cell proteins and hemoglobin. The parasites also alter the red cell membrane, making it less deformable and resulting in hemolysis  and accelerated splenic clearance, which ultimately causes anemia.
other causes of anaemia include :
Release of proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, is stimulated by red cell lysis, and TNF-alpha suppresses hematopoiesis , which also contributes to the anemia.
 The liver and spleen enlarge over time; the latter may become massively enlarged  . Thrombocytopenia is caused by increased splenic sequestration and decreased platelet survival time (ie,hypersplenism),
 depletion of folate store is also cause of anaemia .
The parasites derive energy from anaerobic glycolysis of glucose to lactic acid, which can cause hypoglycemia and lactic acidosis. 
*Microvascular disease and sequestration — As falciparum parasites mature within red blood cells, they induce the formation of sticky knobs on the surface of erythrocytes  . These knobs bind to receptors on endothelial cells in capillaries and venules causing sequestration of red cells within these small vessels, which results in obstruction to blood flow.
 individuals living in endemic areas may develop partial immunity to disease following repeated infections. These individuals are referred to as being "semi-immune". Following a bite by an infected mosquito, they will still develop parasitemia, but the severity of symptoms is typically limited. Most blake Africans show natural resistance to infection with p. vivex , which is associated with the absence of Duffy factors of their erythrocyte . persons with sickle cell trait have relatively low parasitemia when infected with p.falciparum , and therefore are relatively protected from sever disease . 
clinical manifistations:
1-The signs and symptoms of malaria are varied, but virtually all nonimmune individuals will experience fever (Fever develops with the release of merozoites from ruptured, infected red cells.) . so that febrile paroxysms can typically occur every other day for P. vivax, P. ovale, and P. falciparum and every third day for P. malariae 
Other frequent symptoms include: chills, sweats, headache, myalgias, fatigue, nausea, abdominal pain, vomiting, diarrhea and cough . Anemia, thrombocytopenia, splenomegaly, hepatomegaly and jaundice can develop, and splenic rupture can occasionally occur. Lymphadenopathy is rare. The diagnosis of malaria should be considered in any febrile individual who has traveled to or resided in a malarious region, even if briefly or only in transit.

P. falciparum — P. falciparum can invade red cells of all ages, thereby enabling high levels of parasitemia to develop, occasionally involving more than 50 percent of red cells. The risk of severe disease is highest among nonimmune individuals, children less than five years old, and pregnant women.

Cerebral malaria — Cerebral malaria usually presents as an impaired state of consciousness and/or seizures, and can result in coma and death. The degree of central nervous system (CNS) dysfunction involves a combination of factors including parasite virulence, host immune response, and the time between symptom onset and the initiation of therapy

Cerebral malaria is universally fatal if untreated, and even with treatment, 20 percent of adults and 15 percent of children die . In addition, up to 10 to 12 percent of patients who survive cerebral malaria have persistent neurologic abnormalities when discharged from the hospital

Risk factors for cerebral malaria include age (children , older patients , pregnancy, poor nutritional status, HIV infection, host genetic susceptibility, transmission intensity, and history of splenectomy ) .

Other complications — A number of extracerebral complications can be seen in patients with P. falciparum infection. 
*Renal failure — Severe, usually oliguric renal failure  , Large amounts of hemoglobin and malarial pigments may be present in the urine secondary to intravascular hemolysis, producing what is known as "blackwater fever."

Plasmodium vivax and P. ovale — Both P. vivax and P. ovale infect only young red blood cells (reticulocytes), thereby limiting parasitemia levels to one to two percent. Anemia due to hemolysis does occur, but there is no peripheral sequestration of parasitized red blood cells and no complications from microvascular changes. Thrombocytopenia is considered less common than in patients with P. falciparum.

hypnozoites (dormant liver forms) are produced. Thus, late relapses of both P. vivax and P. ovale can occur from mosquito-transmitted
but not blood-derived infections

Plasmodium malariae — Low grade infections with P. malariae can persist for greater than 40 years  . The parasites preferentially invade mature erythrocytes resulting in low parasitemia levels (<1 to 2 percent) and mild symptoms only. An acute illness is rare in normal hosts. No hypnozoites are produced, and therefore there is no latent hepatic form.
DIAGNOSIS :
*Light microscopy — The conventional method for diagnosing malaria is light microscopy of a Giemsa-stained thick and/or thin blood smear. Because of the cyclical nature of the parasitemia, smears should be taken every 6 to 12 hours for 48 hours before the diagnosis of malaria is ruled out, The thick smear is used in diagnosing malaria& counting the number of parasites and WBC on a thick smear (Parasite density estimation)
 and the thin smear allows examination of the morphologic features of both the parasites and the host red blood cells, which is helpful for species identification also allows quantification of the percentage of parasitized red cells. Other methods of diagnosis are :

*Fluorescent microscopy — for detecting malaria parasite in peripheral blood specimens . this technique take advantage of the fact that the parasitized red cell are less dense than un parasitized red cell.
*Antigen detection: recent study  by testing for specific parasite antigens
*Polymerase chain reaction ( PCR ) : is the most aensitive method available , but is aspecialized assay not generally available in diagnostic lab   

Methods of control of malaria :
I- community based measures :
1-Encourage sanitary improvement : that result in permanent elimination  mosquito breeding habitats
Methods to eliminate unusable impounded water ( filling in & draining )
Increased the speed that water flows in natural & artificial channels.
2- use of residual insecticide against adult anophiline vectors in area where it tend to rest & feed indoors, the sole application of residual insecticides on the inside walls of dwelling may not necessarily result in permanent malaria control & it ineffective where the vector has developed resistance to these insecticides or the vectors do not enter houses .
  3- other important considerations of an integrated control plan should include :
a- access to health car services for daily DX & prompt RX .
b- monitoring of human population movement patterns ( migration & circulation )
c- massive public information measures directed to those exposed to risk .
d- prompt & effective RX of acute & chronic cases  .
e- blood donors should be questioned for a history of malaria or a history of travel to , or residence in malarias area 
II- personal protective measures :
1- measures to reduce the risk of mosquito bites include :
a- avoid going out between dusk & dawn when anopheline mosquitoes commonly bite.
b- apply insect repellent to exposed skin .
c- stay in a well- constructed & well- maintained building in the most developed part of town.
d- use screens over doors & windows or close windows & doors at night.
e-use of mosquito net over the bed .
f- use ant- mosquito sprays or insecticide dispensers.
 
2- people who are or will be exposed to mosquitoes in malarious areas should be given the following information :
a- the risk of malaria infection varies among countries & within different areas of each country . 
b- malaria can kill if RX is delay.
c- symptoms of malaria may be mild , malaria should be suspected if , 1 week after entry into a transmission area , an individual suffers any fever, malaise , with or without headache , backache , muscular aching &/or weakness, vomiting , diarrhea  & cough . prompt medical advice must be sought .

3- pregnant woman & parents of young children should be advice of the following:
a- pregnant women & young children when exposed & infected are highly susceptible to development of severe & complicated malaria. malaria in  pregnant women increases the risk of maternal death, miscarriage, still birth & neonatal death.
b- a malarias area should not be visited unless absolutely necessary
c- using measures to protect against mostqito bite
d- chloroquine (5mg/kg/week) & proguanil (3mg/kg/day) should be taken for prophalaxis. In areas with chloroqine resistence P. falciparium, chloroquin & proguinal should be taken during the 1st 3 months of pregnancy, mefloquine prophalaxis (5mg/kg/week) may be considered, start from 4 month of pregnancy
e- doxycycline prophalaxis should not be taken
f- medical help should be sought immediately if malaria is suscepected, emergency "stand by" treatment should be taken
g- malaria prophylaxis for  young children. Chloroquine (5mg/kg/week) plus proguanil (3mg/kg/day)
h- mefloquine prophalaxis (5mg/kg/week) may be taken by women of childbearing age, but pregnancy should be avoided for 3 months after stopping the drug
i- doxycycline prophylaxis may be taken by women of childbearing age but pregnancy should be avoided for about 1 week after stopping the drug .

4- stand by treatment: the most important factors that determine the survival of patient with P. falciparium are early diagnosis & immediate treatment, that self treatment is a temporary measure & medical advice is still to be sought as soon as possible.
5- prophalaxis: non- immune individual who will be exposed to mosquitos bite should be benefit from the use of suppressive drugs for chemoprophaxis:
for suppressive malaria drug therapy for travlerres :  chloroquine are recommended  & those who will be exposed to chloroquine resistence, P. falciparum infection, mefloquine alone (5mg/kg/week) is recommended. Suppressive drug should be continued weekly, starting 1-2 week before travel & continued weekly during travel  & for 4 weeks after the return to non-malarious area. For those who are unable to take mefloquine , doxycycline alone, 100 mg once dially is an alternative regim. It should not be given to pregnant women & children less than 8 years old. Doxycyline prophalaxis can being 1-2 days prior to traveler to malarious area & should be continuo daily during traveler & for 4 weeks after leaving malarious area.

In areas of chloroquine resistence to both P vivax alternative prophalaxis regiem for adult. This regiem consist of primequine only at 0.5 mg/kg/day begening on the 1st day of exposure & continue for 1 week after leaving the risk area italso eliminate intrahepatic parasite, , so that clinical relapses of vivax or ovale malaria does not  occur.
 
B- Control of patient, contact & the immediate environmenmt:
- obligatory case report to local health authority.
- isolation for hospitalized patient, blood precaution.
- investigations of contact & source of infection: determine history of previous infection or of possible exposure.
a- oral administration of 25 mg of chloroquine per kg over 3 days period
b- for emergency treatment of adult with severe or complicated infection or for people unable to take oral medication, quinine dihydrochloride is taken by infusion.
c- for P falciparum infection acquired in area where chloroquine resistence are present, administer quinine 30mg/kg/day for 3-7 days in Iraq we give fansidar as single dose (3 tablet ).
d- for P vivax infection, mefloquine should be used for RX (15 mg/kg in a single dose).
C- epidemic measures: determine the nature & the extent of the epidemic situation. Intensify case detection & control measures against adult & larval stages vectors, eliminate breeding places, treat acute case, use personal protection & suppressive drug. Mass treatment may be considered.