MALARIA

DR.WIHIB G,INTERNAL MEDICINE RESIDENT

A vector-borne infectious disease caused by protozoan parasites. It is widespread in tropical and subtropical regions

At risk for malaria: 40% of the world’s population

more than 500 million are ill of malaria yearly

If treated in the early stages, malaria can be cured.

“HIV, malaria and TB are among

the most important infectious agents in the world. There are no vaccines against them, and all have the same property of establishing chronic infection without an effective immune response.”

Plasmodium falciparum - most common and deadly type of malaria infection - can lead to cerebral malariaP.vivax - most common- causes relapse if treatment was not completed.

P.malaria

P.ovale.

Female Anopheles are:

Anthropophilic : from humans Zoophilic : from animals Endophagic : prefer to bite indoors Exophagic : prefer outdoor biting

PATHOPHYSIOLOGY:Liver StageHuman infection is initiated when sporozoites are injected with the saliva during mosquito feeding. The sporozoites enter the circulatory system and within 30-60 minutes will invade a liver cell.

Host cell entry, as in all apicomplexa, is facilitated by the apical organelles. After invading the hepatocyte, the parasite undergoes an asexual replication. This replicative stage is often called exoerythrocytic (or pre-erythrocytic) schizogony.

In P. vivax and P. ovale some of the sporozoites do not immediately undergo asexual replication, but enter a dormant phase known as the hypnozoite. This hypnozoite can reactivate and undergo schizogony at a later time resulting in a relapse.

Blood Stage. Merozoites released from the infected liver cells invade erythrocytes. The merozoites recognize specific proteins on the surface of the erythrocyte and actively invade the cell in a manner similar to other apicomplexan parasites.

After entering the erythrocyte the parasite undergoes a trophic period followed by an asexual replication. The young trophozoite is often called a ring form due to its morphology in Geimsa-stained blood smears. As the parasite increases in size this 'ring' morphology disappears and it is called a trophozoite.

During the trophic period the parasite ingests the host cell cytoplasm and breaks down the hemoglobin into amino acids. A by-product of the hemoglobin digestion is the malaria pigment, or hemozoinhemozoin. These golden-brown to black granules have been long recognized as a distinctive feature of blood-stage parasites.

Nuclear division marks the end of the trophozoite stage and the beginning of the schizont stage. Erythrocytic schizogongy consists of 3-5 rounds (depending on species) of nuclear replication followed by a budding process. Late stage schizonts in which the individual merozoites become discernable are called segmenters.

The host erythrocyte ruptures and releases the merozoites. These merozoites invade new erythrocytes and initiate another round of schizogony. The blood-stage parasites within a host usually undergo a synchronous schizogony.

Sexual Stage. As an alternative to schizogony some of the parasites will undergo a sexual cycle and terminally differentiate into either micro- or macrogametocytes. Gametocytes do not cause pathology in the human host and will disappear from the circulation if not taken up by a mosquito.

Gametogenesis, or the formation of micro- and macrogametes, is induced when the gametocytes are ingested by a mosquito. After ingestion by the mosquito, the microgametocyte undergoes three rounds of nuclear replication. The macrogametocytes mature into macrogametes

The highly mobile microgametes will seek out and fuse with a macrogamete. Within 12-24 hours the resulting zygote develops into an ookinete. The ookinete is a motile invasive stage which will transverse both the peritrophic matrix and the midgut epithelium of the mosquito.

Sporogony After reaching the extracellular space between the epithelial cells and the basal lamina, the ookinete develops into an oocyst. The oocysts undergo an asexual replication, called sporogony, which culminates in the production of several thousand sporozoites.

This generally takes 10-28 days depending on species and temperature.Upon maturation the oocyst ruptures and releases the sporozoites which cross the basal lamina into the hemocoel (body cavity) of the mosquito.

Signs & symptoms:

The pathology and clinical manifestations associated with malaria are almost exclusively due to the asexual erythrocytic stage parasites. Tissue schizonts and gametocytes cause little, if any, pathology..

Plasmodium infection causes an acute febrile illness which is most notable for its periodic fever paroxysms occuring at either 48 or 72 hour intervals. The severity of the attack depends on the Plasmodium species as well as other circumstances

Sometimes the incubation periods can be prolonged for several months in P. vivax, P. ovale, and P. malariae. All four species can exhibit non-specific prodromal symptoms a few days before the first febrile attack. These prodromal symptoms are generally described as 'flu-like' and include: headache, slight fever, muscle pain, anorexia and nausea. The symptoms tend to correlate with increasing numbers of parasites.

In contrast to the other three species, P. falciparum can produce serious disease with mortal consequences. This increased morbidity and mortality is due in part to the high parasitemias associated with P. falciparum infections. These potentially high parasitemias are due in part to the large number of merozoitesmerozoites produced and the ability of P. falciparum to invade all erythrocytes.

Other Physical symptoms:

Fever: Fever can be very high from the first day. Temperatures of 40°C and higher are often observed. Fever is usually continuous or irregular. Classic periodicity may be established after some days.

Hepatomegaly: The liver may be slightly tender.Splenomegaly: Splenomegaly takes many days, especially in the first attack in non immune children. In children from an endemic area, huge splenomegaly sometimes occurs.Anemia: Prolonged malaria can cause anemia, and malarial anemia causes significant mortality.

Jaundice: With heavy parasitemia and large-scale destruction of erythrocytes, mild jaundice may occur. This jaundice subsides with the treatment of malaria.

Dehydration: High fever, poor oral intake, and vomiting all contribute to dehydration.

Black water feverMassive intravascular hemolysisDue to P. falciprumSevere acute hemolytic anemiaRBC=1-2*106 /mlHemoglobinuruia Increase bilirubinAcute tubcular necrosis & Hb casts

Examine blood under microscope

Golden test

chest x-ray: helpful if respiratory symptoms are presentCT scan: to evaluate evidence of cerebral edemaedema or hemorrhage

Dipstick test •not as effective when parasite levels are below 100 parasites/mL of bloodBlood examination:•Thick and thin blood filmPCR: •determine the species of plasmodium

◦ Other tests:◦ CBC:LukopeniaThrombocytobeniaEsinophiliamonocytosis

◦ Quntitative buffy coat techniqe◦ Urinalysis◦ Increase ESR

Management Treatment (based on WHO recommendations)Rx of uncomplicated P.falciparumRx of sever malariaRx of P.vivax, P.ovale, P.malariaePrevention

Definitions Uncomplicated malaria: symptomatic malaria withoutwithout signs of vital organ dysfunction.

Definitions Complicated malaria:

◦ ClinicalClinical features:◦ Prostration.◦ Impaired consciousness.◦ Respiratory distress.◦ Convulsions.◦ Circulatory collapse.◦ Pulmonary edema.◦ Jaundice.◦ Abnormal bleeding.

◦ Laboratory test:◦ Sever anemia.◦ Hypoglycemia.◦ Acidosis.◦ Renal impairment.◦ Hyperlactemia.◦ Hyperparasitemia=

HARMS

Morepparasites

Treatment Combination therapy: is the use of 2 or more blood schizontocidal drugs with different modes of action.

Rx of uncomplicated P.falciparum Artemisinis combination are the best.

◦ MOA: ◦ production of free radicals that kill the parasite. ◦ Active against all human malaria parasites.◦ Does notnot affect the hepatic stage.

◦ Artesunate 100 mg + amodiaquine 270 mg BID for 3 days.

◦ Artemether + lumefantrine (Riamet®): 4 tabs/12h for 6 doses.

Rx of sever malariaAtresunate 2.4 mg/kg IV or IM given on admission then after 12h and 24h, then once daily.i.e 12hr 12hr 24hrFluid therapy for rehydration.Blood transfusion: usually used in children, because anemia is sever (Hb < 5 g/dl)

Rx of P.vivax, P.ovale, P.malariae Chloroquine For radical cure of P.vivax and P.ovale:

◦Primaquine 15 mg daily for 14 days.◦ It destroys the hypnozoite phase in the liver.

◦ It may cause hemolysis with G6PD deficient patients.

Prevention Avoid mosquito bites:◦Wearing long sleeves, trousers.◦Nets.◦Repellent creams or sprays.

Prevention Chemoprophylaxis:

◦ Should be given 1 week before traveling, and continued 4 weeks after leaving.

◦ Depends on the area of travel (ie. Chloroquine resistance or not)

Area Antimalarial Chloroquine resistance high Mefloquine

(or doxycycline or malarone)Chloroquine resistance

moderateChloroquine + proguanil

Chloroquine sensitive Chloroqunie Or proguanil

Complication of malaria

Malaria is probably the only infection that can be treated in just three days, yet that kills millions every year . Malaria may become a medical emergency by rapidly progressing to complications and death. Early diagnosis & proper management can prevent serious complication.Most complications have similar pathogenesis .

Predisposing factors for complications

(1.) Extremes of age. (2.) Pregnancy, especially in primigravidae and in 2nd half of pregnancy.

(3.) Immunosuppressed - patients on steroids, anti- cancer drugs, immunosuppressant drugs.

(4.) Immunocompromised - patients with advanced tuberculosis and cancers.

(5.) Splenectomy. (6.) Lack of previous exposure to malaria (non-immune) or lapsedlapsed immunity

(7.) Pre-existing organ failure.

Complications of P. falciparum malaria

◦ Cerebral malaria ( coma )◦ Convulsions◦ Hyperpyrexia◦ Severe anemia ◦ Metabolic (Lactic) Acidosis ◦ jaundice◦ renal failure ◦ Pulmonary odema & ARDS ◦ hypoglycemia ◦ Hypotention & shock ◦ Bleeding & clotting disorder ◦ haemoglobinuria◦ hyperparasitemia ◦ Associated infection

Complications of P. vivax / P. malariae

◦ Rupture of spleen ◦ Hepatic dysfunction ◦ Thrombocytopenia ◦ Severe anemia ◦ malarial nephropathy

Cerebral malaria For a diagnosis of cerebral malaria, the following criteria should be met:(i.) Deep, unarousable coma: Motor response to noxious stimuli is non-localising or absent.(ii.) Exclusion of other encephalopathies.(iii.) Confirmation of P. falciparum infection all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria.

HAS HH Causes of neurological manifestations in malaria:

◦High-grade fever ◦Antimalarial drugs ◦Hypoglycemia ◦Hyponatremia ◦Severe anaemia

Management of cerebral malaria : manage airway Phenobarbitone IM, 10-15 mg/kg body weight should be given y to prevent convulsions Antimalarial treatment: (see the dose)

Metabolic (Lactic) AcidosisIncreased production of lactic acid by parasites Decreased clearance by the liver Most importantly the combined effects of several factors that reduce oxygen delivery to tissues Marked reductions in the deformability of uninfected RBCs may

compromise blood flow through tissues Dehydrated and hypovolemia can exacerbates microvascular

obstruction by reducing perfusion pressure Destruction of RBCs and anemia further compromises oxygen

delivery

Acute Pulmonary Odema: It is a fatal complication of severe falciparum malaria with more than 50% mortality .In a few patients it could be due to fluid overload increased permeability of pulmonary capillaries. Sequestration of red cells and clogging of pulmonary microcirculation and disseminated intravascular coagulation DICmore common in patients with hyperparasitemia, renal failure and pregnancy .

Shock : Hypotension in malaria could be due to

many reasons: ◦ Dehydration due to high-grade fever, excessive

sweating and inadequate fluid intake. ◦ Dehydration due to vomiting and/or diarrhoea. ◦ Pulmonary oedema. ◦ Metabolic acidosis. ◦ Associated Gram negative septicemia. ◦ Massive gastrointestinal haemorrhage

Renal Failure : Renal dysfunction in falciparum malaria can be due to many factors:

◦Renal failure in malaria is caused by renal cortical vasoconstriction and resultant hypoperfusion, sequestration and resultant acute tubular necrosis due to microvascular obstruction and due to massive intravascular hemolysis in blackwater fever .

Anemia : In falciparum malaria, anemia can develop rapidly due to profound hemolysis The degree of anemia correlates with parasitemia and schizontemia More serious in children and pregnant .Bleeding disorder :

◦ Thrombocytopenia ◦ Disseminated intravascular coagulation DICDIC

Hypoglycemia: Hypoglycemia in malaria may be asymptomatic Therefore, hypoglycemia, which is easily treatable, may be missed Causes:

◦ 1. Increased consumption of glucose by the host and the growing parasites.

◦ 2. Failure of hepatic gluconeogenesis and glycogenolysis as a result of impaired liver function and acidemia and hyperinsulinemia

◦ 3. Stimulation of pancreatic insulin secretion by drugs like quininequinine. More than one of these factors may be at play in a given patient

Rupture of spleen: It is moremore common in vivaxvivax malaria than falciparum malaria occur in up to 0.7% of the patients Rupture occurs in acute, rapid, hyperplastic enlargement of spleen Patients present with abdominal pain, fever, tachycardia, prostration and rapidly developing anemia and hypotension. Ultra sound evaluation of abdomen and paracentesis of the abdomen can confirm the diagnosis Treatment includes replacement of fluid and blood, laparotomy and splenectomy

Complication due to medication

Vomiting Dizziness Itching ( chloroquine ) Abdominal pain Convulsion ( chloroquine , quinine, meflequine ) Coma ( chloroquine , quinine) Hypoglycemia ( quinine) Anemia , jaudice ,Haemoglobinuria ( primaquine in pt with G6PD deficiency )

Fever HAJ by

ICC

HCC

Thank you!