Severe Complicated Malaria

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Severe & Complicated Malaria Severe & Complicated Malaria 1 Prepared by: Dr. Rajsi D. Buch Dr. Ankur V. Tiwari

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“Now World is in hands of DOCTORS” O OBJECTIVES 1. Introduction 03 2 . Review 04 3 . Case : Description & discussion Case 1 31 34 Case 2 36 38 Case 3 39 42 Case 4 44 46 Case 5 48 51 Case 6 52 54 4 . Summary 56 5 . Acknowledgement 57 6 . Bibliograohy 58 ”’’ 2

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Definition of SEVERE MALARIA by the working group of World Health Organisation (WHO)‏ One or more of the following major criteria + the presence of asexual parasitaemia defines severe malaria. Major criteria: 1. Cerebral malaria (unrousable coma not attributable to any other causes). 2. Severe anaemia (haematocirt < 15% or haemoglobin < 5 g/dl). 3. Acute renal failure (urine output < 400 ml/ 24 hours in adults, or <12 ml/Kg/24 hours in children, failing to improve after rehydration; & s.creatinine >265μmol/l i.e. >3 mg/dl). 4

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4. Pulmonary oedema or Adult Respiratory Distress Syndrome (ARDS) 5. Hypoglycaemia (whole blood glucose < 2.2 mmol i.e., <40 mg/dl). 6. Circulatory collapse, shock, hypotension (systolic blood pressure < 50 mm Hg in children aged 1-5 years or < 70mm Hg in adults), with cold, clammy extremities. 7. Spontaneous Bleeding/Disseminated Intravascular Coagulation(DIC). 8. Repeated generalised convulsions (more than two episodes in 24 hours). 9. Acidaemia (arterial pH < 7.25) or Acidosis (plasma bicarbonate < 15 mmol/1). 10. Macroscopic haemoglobinuria. 5

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Minor criteria [newly added in 2000] 1. Impaired Conciousness. 2. Hyperparasitaemia (> 5% of RBCs are parasitised). 3. Hyperpyrexia (rectal temperature > 400°C). 4. Jaundice (Serum bilirubin > 50 mol/1 or > 3 mg/dl.). 5. Severe prostration. 6

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Others: 1. Fluid and electrolyte imbalance. 2. Vomiting of oral drugs. 3. Complicating or associated infections. 4. Other indicators of poor prognosis:- → leucocytosis → high CSF lactate and low CSF glucose → raised aminotransferases → low antithrombin III levels → peripheral schizontaemia → papilloedema / retinal oedema 7

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Summary of differences in the clinical features of severe malaria in adults and children Frequency of occurrence 8

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1. Cerebral malaria - clinical The most well-known severe manifestation of malaria Defined as: -unarousable coma persisting for more than one hour -with asexual forms of P. falciparum in the peripheral blood -other common causes of encephalopathy excluded* * None of the clinical features are pathognomonic, malaria parasitaemia is common in people living in endemic areas and coma may complicate many illnesses. Therefore, a clinical diagnosis of cerebral malaria is made only after other common causes of coma (e.g. meningitis) have been excluded. 9

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• Occurs most commonly in young children although non- immune adults are also at risk • Cerebral malaria can rapidly progress to death, even with appropriate treatment. Case fatality is between 20-30%. • In survivors, resolution of coma usually occurs within 1-2 days in children and within 2-4 days in adults but may be complicated by neurological sequelae in ~5% adults and >10% of children. The illness may start with drowsiness and confusion and then progress to coma. The loss of consciousness is often preceded by repeated convulsions. Retinal haemorrhages may be seen on fundoscopy. 10

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Cerebral malaria - pathophysiology The exact pathogenesis of cerebral malaria is not well understood. It is believed to result from sequestration of parasitised red cells in the small blood vessels in the brain. The consequences of this include: reduced cerebral blood flow cerebral hypoxia release of cytokines which in turn induce the release of nitrous oxide, a known depressor of consciousness. A young girl with cerebral malaria. Note the abnormal, decerebrate posturing Sequestration of parasitised red cells in different tissues probably underlies most severe manifestations of malaria A 3 year old boy with impaired consciousness, grimacing and marked extensor posturing of the arms 11

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2. Severe anaemia Defined as: - A haematocrit of <15% or -Haemoglobin concentration <5 g/dl. Occurs commonly in young children and pregnant women. Pathology Marked pallor in an African child with severe anaemia due to P. falciparum infection Bone marrow: Dyserythropoietic changes are prominent. Macrophages contain pigment and erythrophagocytosis may be seen. Iron is usually in plenty. Platelets & WBCs are usually normal. 12

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Spleen : Often dark from malarial pigment, enlarged, soft and friable. There is reticular hyperplasia. Recurrent malaria is associated with hard, fibrous splenic enlargement. Pathogenesis 1. Obligatory destruction of RBCs containing parasites at merogony. 2. Accelerated destruction of non-parasitised RBCs, parallels disease severity. 3. Bone marrow dysfunctions – reticulocyte count is low in acute phase. 4. Lowered threshold for splenic clearance of abnormal erythrocytes. Red blood cell survival is decreased. 5. Decreased concentrations of IL-10 and increased concentration of TNF alpha. 13

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Haptoglobin is a marker of haemolysis. Haptoglobinaemia may be considered as a useful indicator of falciparum malaria. Many patients require urgent transfusion. The condition may be rapidly fatal when blood transfusion is delayed. Blood Transfusion 14

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3. Acute Renal Failure The kidneys are often slightly swollen. Tubular abnormalities consistent with acute tubular necrosis (ATN) are seen. Sequestration in glomerular capillaries, mesangial endothelial cell proliferation, and immunoglobulin deposits may be seen. Cortical necrosis never occurs. When there is fulminant presentation of ARF with oliguria, there is high incidence of hepatic dysfunction (jaundice and bleeding tendency), metabolic acidosis, and pulmonary edema. 15

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Blood pressure is usually normal. Mild proteinuria may be there but urinary sediments are unremarkable. In subacute presentation with oligura/polyuria, serum creatinine rises over a period of days producing uraemic complications requiring dialysis or there is a gradual resolution. In survivors, urine flow resumes in 4 days. Creatinine returns to normal in 7 days. In certain studies, 30% of ARF was due to malaria. Renal failure may be associated with haemoglobinuria (Black water fever). Nephrotic syndrome can occur with P. falciparum. 16

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4. Acute pulmonary oedema This is a grave and usually fatal manifestation of severe falciparum malaria and occurs mainly in adults. Hyperparasitaemia, renal failure and pregnancy are recognised predisposing factors and the condition is commonly associated with hypoglycaemia and metabolic acidosis. Pulmonary edema results from increase in pulmonary vascular permeability which is not reflected in other vascular beds Cause of increased permeability is not known. Acute pulmonary oedema, developing shortly after delivery in a woman with severe P. falciparum malaria 17

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Pulmonary oedema/ARDS can develop at any time in falciparum malaria, even after several days of antimalarial treatment, and even in otherwise uncomplicated vivax malaria. It is particularly common in pregnant women, but rare in children. It may be difficult to distinguish from aspiration pneumonia. Heart sounds, pulmonary capillary wedge pressure (PCWP), and central venous pressure (CVP) are usually normal. The chest X-ray shows increased interstitial shadowing. 18

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5. Hypoglycaemia Blood sugar <2.5 mmol/L Increases the risk of mortality (40%) and sequelae in children with cerebral malaria; may present with convulsions or a deterioration in level of consciousness. Results from a combination of factors: 1. Increased peripheral requirement of glucose consequent upon anaerobic glycolysis. 2. Increased metabolic demands of febrile illness. 3. Obligatory demand of parasites. 19

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4. Failure of hepatic gluconeogenesis and glycogenolysis (parasites consume upto 70 times as much glucose as uninfected cells ). 5. Quinine stimulated insulin secretion from pancreatic beta cells. Hyperinsulinaemia is balanced by decreased tissue sensitivity. Hypoglycaemia contributes to nervous system dysfunction. ‘Malaria induced hypoglycaemia’ is often present at admission and response to glucose is unimpressive, while ‘quinine induced hypoglycaemia’ usually develops 24 hours after treatment, and response to glucose administration is dramatic. 20

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6. Circulatory collapse, shock, “algid malaria” Systolic BP < 50 mmHg in children and < 80 mmHg in adults defines hypotension/shock. Patient with severe malaria can develop sudden hypotension & become shocked. This is “Algid Malaria” The patient can have cold, clammy, cyanotic skin, peripheral vasoconstriction, and rapid feeble pulse with core/skin temperature difference of ≥ 10° C. 21

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In some cases there is septicaemia. In the majority, blood cultures are negative. Hypotension usually responds to saline infusions and ionotropes, but these therapeutic measures could provoke pulmonary oedema. The overall mortality is high. Circulatory collapse can also be seen in patients with pulmonary oedema, metabolic acidosis, GI haemorrhage, and ruptured spleen. Dehydration and hypovolaemia could also contribute to hypotension/ shock. 22

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7. Spontaneous Bleeding Coagulopathy & thrombocytopenia Severe haemorrhage is seen in 5% of severe malaria. There is accelerated coagulation cascade activity with accelerated fibrinogen turnover, consumption of antithrombin III, and increased concentration of fibrinogen degradation products (FDP). RBCs containing parasites and released cytokines are procoagulant. Prothrombin time (PT) and Activated partial prothrombin time(ApTT) are prolonged. Thrombocytopenia is caused by increased splenic clearance. Platelet turnover is increased. Role of platelet bound antibody is controversial. 23

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The patient may develop bleeding gums, epistaxis, petechiae, subconjunctival haemorrhages. Significant bleeding, malena, and haemetemesis occurs in < 10% cases. This is more common in non-immune individuals in the temperate zone Epistaxis 24

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8. Repeated Generalised Convulsions 25 ≥ 2 convulsions in 24 hours

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ECG & EEG recordings of patient having Repeated Generalised Convulsions 26

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9. Metabolic Acidosis This may result form renal failure, but more commonly there is a primary lactic acidosis (Type B). Arterial, venous, capillary, and CSF concentration of lactate increases in proportion to the severity. Lactic acidosis results from : 1. Anaerobic glycolysis due to microvascular obstruction. 2. Failure of hepatic and renal lactate clearance. 3. Production of lactate by the parasite. Lactate levels rise after generalised convulsions. Hyperventilation (Kussmaul breathing) with a clear chest on auscultation suggests metabolic acidosis 27

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Venous lactate concentration at 4 hours after admission to hospital is the BEST PROGNOSTIC INDICATOR in severe malaria. pH compared with pH chart pH strips & urine sample Blood sample in vacutaineers 28

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10. Haemoglobinuria or “Blackwater Fever” This results from massive intravascular haemolysis. The condition presents with severe pallor, jaundice and passage of dark urine due to haemoglobinuria. It may be associated with acute renal failure. A 3 year old boy with severe anaemia Typical dark urine of (Hb 3.3 g/dl) and dark urine Haemoglobinuria on (shown in the container) Day 0 & cleared by Day3 29

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Malaria in pregnancy More than 45 million women become pregnant in malaria endemic areas each year. Common adverse effects of malaria in pregnancy : Maternal anaemia Stillbirths Premature delivery and Intra-Uterine Growth Retardation (IUGR) result in the delivery of Low Birth weight (LBW) infants The WHO now recommends Intermittent Preventive Treatment (IPT): the administration of anti-malarial drugs (e.g.sulphadoxine-pyrimethamine) during antenatal care whether or not women show symptoms. IPT has been shown to substantially reduce the risk of maternal anaemia in the mother and low birth weight in the newborn. Previously, chemoprophylaxis (e.g. With chloroquine) was recommended for all women living in malaria endemic areas. 30

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Case 1 Description: A 30 year old male was admitted to Dhiraj General Hospital with chief complaint of -Abdominal pain in para-umbilical region since 4 days -High grade fever with chills since 3 days -loss of appetite since 2 days -Constipation since 2 days On elaborating history of present illness, he told that pain was dull aching & aggravated by movements. Also fever showed step-ladder pattern with peak at afternoon. Fever was accompanied with chills & no rigors. He gave past history of heavy alcohol intake since many years. 31

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Examination (at the time of addmission) revealed: significant pallor, high-grade fever, temp 102°F, mild icterus. Tenderness present over umbilical & right hypochondriac region with Liver enlarged about 2 fingers & guarding present. No h/o nausea & vomitting. Investigation: P/S- P.faciparum + P.vivax Haematology- Microcytic Hypochromic Anemia Hb- 7.2gm/dl Thrombocytopenia Raised Prothombin Time(PT), 17 sec Urine- pale yellow Liver Function Tests(LFT)- altered S.bilirubin-elevated, Alkaline Phosphatase(ALP)-244 32

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Diagnosis: Severe Malaria Malaria with mild Jaundice, Severe Anemia, Thrombocytopenia Ring forms or trophozoites; many red cells infected – some with more than one parasite 33

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Discussion: It is clearly evident from the history, examination & investigations that pt. is suffering from malaria. It is diagnosed to be P.falciparum & P.vivax both. He is also suffering from mild Jaundice, severe malaria & Thrombocytopenia. Jaundice would have been precipitated due to hepatic dysfunction as a result of superinfection of malaria alongwith chronic Alcoholic Liver Disease (ALD). The condition is being worsened as a result of superseded Severe Anemia & Thrombocytopenia due to hemolysis of RBCs & platelets because of impaired liver functon and sequestration of parasitised blood cells. 34

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He has shown good response to the line of treatment. He’s been supplemented with Quinine & Primaquine therapy for radical treatment of malaria. Also antibacterial cover has been provided with Amoebicide. Besides these health management provided comprised of Blood Transfusion on 5th day, vit.B12, folic acid & iron supplementation. As a result of above management pt. recovered by 8th day & his symptoms subsided. 35

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Case 2 Description: a 34 year old primigravida at 22 weeks of gestation was transferred to hospital with fever (temp-39.8°c), right abdominal discomfort, nausea, vomiting and rapidly worsening hemolytic anaemia, severe thrombocytopenia and raised concentration of aspartate(AST) & alanine(ALT). 3 days earlier, she had been admited to a local hospital with similar symptoms. At that time Hb% was 8.8gm%, WBC - 6700cumm, platelets – 95 Thousand, AST- 64 IU/L, ALT- 44 IU/L. Abdominal USG was normal and no signs of foetal distress detected. 36

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On admision, the patient complained only of fatigue and physical examination revealed vague abdominal tenderness. BP was 120/62mmHg, Pulse-110 bpm, temp- 37.4°C. On day 3 after admision, CRP was high (210mg/l, normal <10mg/l), prothrombin time – 17s (prolonged). Blood cultures remained sterile. Trophozoites of P.falciparum in P/S 37

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Discussion: The combination of haemolysis, high concntrations of AST and ALT, and low platelet count suggested HELLP (haemolysis,elevated liver enzyme and low platelets) syndrome. Her blood smear was also taken. The smear was positive for P.falciparum and the initial parasite count was 20%(corresponding to 570000 parasites per µL of blood). Treatment with quinine was started immediately. After 24 hrs, exchange blood transfusion was started with rapid reduction of parasite density and eventually complete recovery of the patient. Treatment with 1 wk of clindamycin was given. In about 4 months the patient gave birth to a healthy daughter. 38

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Case 3 Description: A 12 year old child presented with high fever for 5days followed by a sudden development of severe jaundice and drowsiness. She was well before 5 days. Then she started with high fever for which the local doctor treated her. The details of her treatment were not available. Within two days of development of jaundice and drowsiness, she was hospitalised for the same. There was no history of anorexia, nausea or vomiting, nor was there a history of clay coloured stools or high coloured urine. On direct questioning there was oliguria, though the parents attributed it to poor intake over last 2 days due to drowsiness. No significant past or family history. 39

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Physical Examination Well built and properly nourished. Temp- 102 F Pulse- 160 / min RR – 35/min BP – 90/55 mmHg Markedly Pale. Deep Icterus. Mild edema feet. Raised JVP. No ecchymosis or purpura. Liver 7cm +, firm, tender, hepatojuguler reflux present. Liver span 10cm. No ascites. Spleen 4cm+, firm. No engorged abdominal veins. CVS- Soft systolic functional murmur. CNS- Drowsy No localising signs. 40

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Investigations Hb- 4gm% WBC- 10000/cumm P 60 L 32 E 5 M 3 Platelets- 75000/cumm Peripheral smear shows trophozoites of P.falciparum. Parasitic index 5% Serum Bilirubin – 38mg% Direct 28mg% ALT- 180u/dL Serum ammonia normal. Blood sugar normal. Prothrombin time(PT) normal. Serum proteins normal. Blood urea – 120mg% Serum creatinin- 3.5mg% Serum electrolytes normal. Trophozoites of P.falciparum 41

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Discussion: It is evident in the history that, Jaundice in this child has appeared after 5 days of high fever. Hence it is likely that primary illness which has caused high fever, led to a secondary hepatic involvement coming on after a few days or it is a complication of drugs taken for primary illness. Febrile illnesses with subsequent liver involvement include typhoid fever, malaria & leptospirosis. On examination, though a deeply jaundiced child with hepatic failure can bleed & therefore present with significant pallor, such bleeding is obvious and has not been reported in this child. Therefore sudden developement of severe pallor, severe enough to push the child into cardiac failure, along with jaundice, suggests acute hemolysis. However, even in acute hemolysis, jaundice is rarely severe; the severity of the illness favours the possibility of falciparum malaria. 42

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Investigations suggest that the child has a multisystem involvement affecting the liver primarily, but also the brain and the kidney besides causing severe hemolysis. Drowsiness is not due to hepatic encephalopathy in view of the normal serum ammonia, blood glucose & prothrombin time, but may have resulted from cerebrovascular sludging due to malaria. Renal failure could also be a result of a similar pathology in the renal vasculature. Even though there is a hemolysis, the predominant bilirubin in falciparum malaria is direct bilirubin due to involvement of liver cells. The patient was treated with IV quinine & supportive therapy including packed cell transfusion. The serum bilirubin came down to 12mg% within the next 2 days, drowsiness improved and so also the urine output. The child made a complete recovery within next 5 days. Ref: Dr. Umesh Buch, Paediatrician 43

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Case 4 Description: One year old, 8.5 kg male child was hospitalized in a critically ill state with history of fever, breathlessness and excessive crying for two days. Child was in gasping state, had severe anaemia, congestive cardiac failure and moderate hepatosplenomegaly. Anterior fontanelle and neurological examination were within normal limits. Investigation revealed: Hb% - 4gm%, TLC - 6000/cumm, Peripheral blood film(PBF) – dimorphic blood picture with severe hypochromia, microcytosis, hypersegmented neutrophils and ring forms of plasmodium vivax. Platelet count was – 48000/ Liver and Renal function tests were normal. 44

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On the third day of hospitalization, child developed upper GI bleed, deterioration of sensorium and seizures followed by generalized hypertonia. Repeated PBF showed numerous gametocytes of P.vivax with severe thrombocytopenia(Platelet count going down to less than 20000). CSF findings were suggestive of Intracranial bleed. Optimal malaria antigen test was positive for P.vivax and negative for P.falciparum. CT scan head showed massive intracerebral bleed in right fronto-parietal region with communicating hydrocephalus 45

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Discussion: This case provides sufficient evidence that plasmodium vivax infection was complicated with cerebral manifestations in association with profound thrombocytopenia and massive intracranial bleed which latter on led to hydrocephalus. The child was treated with chloroquine,blood transfusions, diuretics, digitalis & antibiotics for aspiration pneumonia. 46

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Child was given platelet transfusions, steroids and anti- convulsants for recurrent seizures. In view of persistent parasitemia child was treated with iv quinine dihydrochloride for 10 days followed by primaquine for 5 days. Patient became afebrile but developed symptomatic hydrocephalus which required shunt surgery latter on. 47

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Case 5 Description: Four year old male child presented with history of fever, blood stained stools, vomiting for four days and altered sensorium with recurrent seizures for one day. Child was in shock and coma, was initially provisionally diagnosed and managed on the lines of shigellosis with encephalopathy. Investigations revealed: Hb-7.2gm%, TLC-10000/ Peripheral blood film revealed normocytic blood picture with moderate hypochromia, platelets were adequate and no hemoparasite detected. Urine examination, CSF and blood biochemistry was within normal limits. 48

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Child was treated with iv fluids, antibiotics, anticonvulsants and blood transfusions. He remained Febrile and persisted in encephalopathy after 2 weeks of antibiotics. OptiMAL malaria antigen test (delayed because of financial reasons) was positive for Plasmodium vivax and negative for Plasmodium falciparum. Fundus examination was normal. CTscan head revealed mild hydrocephalus. IV Quinine dihydrochloride was given then for 10 days followed by a single dose of Fansidar (sulfamethazone+ pyrimethamine) after which fever settled and sensorium improved. However, behavioural changes and headache persisted which necessitated acetazolamide. 49

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The features and course of illness suggested cerebral complications of Plasmodium vivax malaria. At follow up after 4 weeks child had improved in behaviour and headache had resolved. P.vivax in brain sample of person with cerebral manifestations 50

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Discussion: The second case had presented with gastrointestinal manifestations in the form of desentry, encephalopathy and hydrocephalus which improved on follow up without surgical intervention. Though the peripheral blood film did not show any haemoparasite, the OptiMal malaria antigen test was positive. This test detects the presence of plasmodium lactate dehydrogenase (pLDH); an enzyme produced both by the sexual and asexual forms of parasite. The presence of pLDH is revealed using monoclonal antibodies directed against isoforms of enzyme. 51

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Case 6 Description: A 40 yr old man, presented with high-grade fever, chills, malaise and headache of 3 day duration. The patient’s peripheral blood revealed a total leucocyte count of, with 52.2% neutrophils, 31.2% lymphocytes, 15.2% monocytes and 1.52% basophils. The platelets count was 3.54 lacs. The peripheral blood smear was exained after 2 hrs, which revealed a heavy parasitemia consisting of the ring forms, gamatocytes and ameboid trophozoites of P.vivax. In addition several filamentous microgametes were seen outside the erythrocytes. 52

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The finding was correlated with literature and confirmed to be Exflagellated microgametes of P.vivax. The patient showed good response to Chloroquine and primaquine therapy. Exflagellated microgametes of P.vivax 53

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Discussion: The patient received chloroquine and primaquine therapy. Three days later, a post-therapy follow up peripheral blood examination revealed a complete response to treatment with the absence of parasite. This is one of the rare cases of the presence of Exflagellated microgametes in human peripheral blood. Literature in standard medical textbooks mention that trophozoites, schizonts ad gametocytes of the malarial parasite are typically found in human blood and are useful for diagnosing and typing malarial infection. 54

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The remaining forms, like exflagellated microgametes, ookinetes and oocysts are found in the mosquitoes and are not expected to appear in the human blood. This is the first case to be reported of its kind from India, a country with many endemic areas for malarial infection ! 55

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56 Summary Malaria though one of the simplest diseases is one of the most life threating disease. This is due to malaria getting complicated with several ailments. Most of the complicated malaria is due to P.falciparum infection but some of them might also be due to P.vivax or both. We saw that how severe malaria can precipitate the complications of health. Presence of these complications is more severe in previously diseased & even more disastrous in Pregnancy. As seen in these cases Cerebral Malaria & Severe anemia, Thrombocytopenia & Jaundice are the most prevalent & life endangering complications. Quick, timely & adequate management can completely cure the patient

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57 Acknowledgement Our work, “Severe & Complicated Malaria” is dedicated to our families, who have been always encouraging us to take initiatives & do newer things; providing a strong support to us & enabling us to Aspire, Organise & Execute them. We salute u all, Mr. Vipin Tiwari Mr. Durgesh Buch Mrs. Vibha Tiwari Mrs. Dipti Buch Ms. Ruchi Tiwari Ms. Mansi Buch, Also we are thankful to our friends who have been always there for us & helped us to get going even when it was tough, Dr. Mansi, Dr. Shail, Dr. Hardik & Dr. Ridhima. Last but not least we want to thank our guides, Dr. Umesh Buch, Paediatrician Dr. JD Lakhani, Physician & HOD Medicine dept.

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58 BIBLIOGRAPHY 1. Association of Physicians of India (API) 2. Harrison’s Textbook of Medicine 3. Journal, Indian Academy of Medicine 4. Journal, Infectious Diseases 5. 6.

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A doctor whose breath smells has no right to medical opinion. ~ Martin H. Fischer A doctor must work eighteen hours a day and seven days a week. If you cannot console yourself to this, get out of the profession. ~ Martin H. Fischer Every disease is a physician. ~ Irish Proverb When you are called to a sick man, be sure you know what the matter is - if you do not know, nature can do a great deal better than you can guess. ~ Nicholas de Belleville Drugs are not always necessary. Belief in recovery always is. ~ Norman Cousins “Quotes” Thank You !