Other Complications

Jaundice and Hepatic Dysfunction

Jaundice is common in falciparum malaria. Most often it is caused by hemolysis and accordingly there is elevation of unconjugated bilirubin levels. Hemolysis can also elevate levels of aspartate aminotransferase (SGOT). These findings alone therefore do not imply severe hepatic dysfunction in malaria. The mild elevation in serum bilirubin level usually returns to normal within 3-5 days of effective antimalarial treatment. It does not warrant any special dietary restrictions nor does it require any treatment by ‘traditional methods’ (ayurveda etc.).

[pullquote]Remember! Malaria is the most common cause for jaundice in a malarious area[/pullquote]

However, hepatic dysfunction may also be seen in cases of severe falciparum malaria. Such patients have conjugated hyperbilirubinemia, marked elevations of aspartate aminotransferase and alanine aminotransferase and prolongation of prothrombin time. Massive hemolysis, disseminated intravascular coagulation and hepatic dysfunction may all contribute to this picture. A term ‘malarial hepatitis’ has been used to describe this entity but is not well accepted. Clinical signs of liver failure are never due to malaria and in such cases, other associated hepatic diseases, like viral hepatitis, should be considered.

See Pathology

Investigations: Serum bilirubin and serum transaminases should be done in all cases of falciparum malaria who have icterus and pallor and who are sick and require admission. Prothrombin time and serum protein estimation may be also be needed.

Treatment: [See Treatment of Severe P. falciparum malaria]

In most patients, the bilirubin and enzyme levels return to normal within days of antimalarial treatment. No other specific treatment is needed.


Shahnaz Shah, Liaquat Ali, Rukhsana Abdul Sattar, Tariq Aziz, Tahir Ansari, Jamal Ara. Malarial Hepatopathy in Falciparum Malaria. Journal of the College of Physicians and Surgeons Pakistan 2009;19 (6):367-370.
Full Text Available at http://www.cpsp.edu.pk/jcpsp/archive/Jun2009/10.pdf


Hypoglycemia is one of the tricky complications of falciparum malaria and may often go unnoticed, adding to the morbidity and mortality. Hypoglycemia in malaria may be asymptomatic. On the other, many of the clinical manifestations of hypoglycemia are caused by malaria itself or by some of its other complications. Therefore, hypoglycemia, which is easily treatable, may be missed. Added to this, hypoglycemia can occur repeatedly and hence continuous monitoring of blood glucose levels is needed.

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 quinine. More than one of these factors may be at play in a given patient.

It occurs commonly in the following three situations:

  • Severe falciparum infection, especially in young children.
  • Pregnancy with falciparum malaria.
  • Treatment with quinine (or quinidine), as a result of drug induced hyperinsulinemia.

In pregnancy, hypoglycemia may develop even without severe falciparum infection or treatment with quinine. Patients may have sweating, anxiety, feeling of coldness, breathlessness, confusion, dilation of pupils, laboured and noisy breathing, tachycardia, convulsions and if protracted, coma. It may be easily confused with cerebral malaria. Hypoglycemia can cause fetal bradycardia and fetal distress. Treatment with 25-50% dextrose injection results in a dramatic recovery and prognosis in these patients is generally good.

In cases of severe falciparum infection, it is usually associated with severe anemia, jaundice, hyperparasitemia and there may be lactic acidosis. In such cases, mortality tends to be high. The usual symptoms and signs of hypoglycemia may be absent or may be indistinguishable from that of malaria itself. Sweating is inconstant, pupils may be normal, breathing may be cyclical or stertorous and deep and there may be decerebrate posturing. There is alteration in the level of consciousness and convulsions can occur. Administration of 25-50% dextrose results in an improvement in the respiration and level of consciousness.

Hypoglycemia tends to be recurrent and this calls for regular monitoring of blood glucose in all patients who have had hypoglycemia or who are at risk for developing hypoglycemia.


[See Treatment of Severe P. falciparum malaria] Administration of 25-50% dextrose 100 ml, (1 ml/kg for children), intravenously followed by a continuous infusion of 5-10% dextrose. It is better to presume hypoglycemia in all cases of falciparum malaria presenting with altered sensorium, convulsions and coma and treat them with dextrose, after collecting blood for glucose estimation.

Regular monitoring of blood glucose, once in 4-6 hours.

In cases of hypoglycemia due to quinine induced hyperinsulinemia, the drug may have to be stopped. Continuous infusion of 5-10% dextrose is helpful, specially since drug induced hypoglycemia can be recurrent and protracted. In severe cases, drugs that inhibit pancreatic insulin secretion, like octreotide, may be needed (50 microgram or higher, twice or thrice a day, subcutaneously).

Algid Malaria

Algid malaria or hypotension due to peripheral circulatory failure may develop suddenly in severe malaria or it may be the presenting feature in some cases of malaria, with a systolic blood pressure less than 80 mmHg (10.7 kPa) in the supine position [less than 50 mmHg (6.67 kPa) in children], a cold, clammy, cyanotic skin, constricted peripheral veins and rapid feeble pulse. In some countries this clinical picture is often associated with a complicating Gram-negative septicemia and possible sites of associated infection should be sought in such patients, e.g. lung, urinary tract (especially if there is an indwelling catheter), meninges (meningitis), intravenous injection sites, intravenous lines etc.[1] Severe hypotension can also develop suddenly in patients with pulmonary edema, metabolic acidosis, sepsis, and/or massive hemorrhage due to splenic rupture or from the gastrointestinal tract.[1,2] Postural hypotension may be secondary to autonomic dysfunction.[2]

Most patients with shock exhibit a low peripheral vascular resistance and elevated cardiac output. Cardiac pump function appears remarkably well preserved despite intense sequestration of parasitized erythrocytes in the microvasculature of the myocardium.[1] The cardiac index may be elevated with low peripheral vascular resistance and low to normal ventricular filling pressures. Hypovolumia (due to reduced fluid intake, high grade fever, sweating, vomiting and diarrhoea) also may contribute to the reduced pressures. There may be reduction in visceral perfusion. Septicemia, metabolic acidosis and hypoxia may result in a drop in cardiac index.

Gram negative septicemia has been blamed as an important cause of hypotension in some cases of falciparum infection. Gram negative organisms have been frequently cultured from the blood of patients with cerebral malaria. Septicemia is restricted to patients with severe falciparum infection and it may be due to reduced immunity, secondary infections from the gut, indwelling catheters and intravenous lines and infections in the lung, urinary tract, meninges, etc.
Management: [See Treatment of Severe P. falciparum malaria]

  • Hypovolumia and dehydration is common and often goes unnoticed. If untreated, it can cause oliguria and even acute renal failure. Control of temperature by antipyretics plus tepid sponging and careful management of vomiting and/or diarrhoea are important in all cases of malaria. Dehydration should be managed with intravenous saline or Ringer’s lactate. If the patient has associated anemia, blood transfusion can be given. The central venous pressure should be maintained at 0-5 cm of H2O and if needed, Dopamine infusion can be started. However, fluid overload should be avoided at all costs, especially in pregnant women. Anti-emetics can be used to control vomiting. Metaclopramide is known to cause extrapyramidal signs, particularly in children. In such cases, promethazine or other centrally acting anti-emetics can be tried.
  • Blood and urine culture should be done. Soon after collection of the specimen for culture, broad-spectrum antibiotics should be started. Third generation cephalosporins or Benzyl penicillin with Gentamicin can be used.[1]

Other Cardiovascular Problems:

Cardiac arrhythmias: Cardiac arrhythmias are very rarely observed in severe falciparum malaria. It could be due to myocardial ischaemia caused by sequestration of red cells in the coronary circulation or due to the adverse effects of drugs like quinine, quinidine and mefloquine.

Exacerbation of pre-existing cardiac failure: Malaria may prove fatal for patients with pre-existing cardiac failure due to valvular stenosis or myocardial disease. High grade fever, parasitemia, fluid overload can all contribute to the problem. In all such cases, measures should be taken to bring down the temperature rapidly with anti-pyretics and tepid sponging. Potentially cardiotoxic drugs like quinine, mefloquine and halofantrine should be avoided.

Bleeding and coagulation abnormalities are seen in less than 5% of patients with severe falciparum malaria. It can be due to thrombocytopenia and/or disseminated intravascular coagulation.

Mature parasitised red cells and cytokines activate the coagulation cascade. Accelerated cogulation cascade, consumpton of antithrombin III, increased concentration of FDP and increased splenic clearance of platelets contribute to the coagulopathy and thrombocytopenia in malaria. Hypofibrinogenemia due to DIC occurs in 5% of patients.

Thrombocytopenia is commonly seen in severe falciparum malaria. It is presumed to be due to increased consumption of the platelets in the periphery, may be in the spleen. Bone marrow shows appropriate megakaryocyte response. However, bleeding due to thrombocytopenia is very rare in malaria. Corticosteroids are not indicated. However, if thrombocytopenia is severe, platelet transfusion may be considered. Generally, the platelet count returns to normal with the completion of antimalarial chemotherapy.

Disseminated intravascular coagulation is seen in less than 5% of patients with severe falciparum malaria. It tends to be more common in patients with cerebral malaria, pregnancy and secondary bacterial infections. D.I.C. in turn may aggravate the other complications of malaria like cerebral malaria, renal failure, pulmonary oedema and anemia (due to bleeding). Since it is rare, routine use of drugs like heparin may cause more harm than good and should be avoided. Prolonged prothrombin and partial thromboplastin time suggests the possibility of D.I.C. which can be confirmed by measuring plasma concentrations of fibrinogen and fibrin degradation products. D.I.C. in malaria has to be differentiated from that caused by many other conditions like heat stroke, viral haemorrhagic fevers, snake bites, immune complex disorders and shock. Treatment involves administration of fresh whole blood or fresh frozen plasma and injection of Vitamin K 10 mg intravenously. If there is fear of fluid overload, then exchange transfusion with fresh blood can be tried. Drugs that may cause gastrointestinal bleeding (aspirin, other NSAIDs and steroids) are better avoided in patients with severe malaria.


  1. Management of Severe Malaria: A practical handbook. Second edition. World Health Organization. Geneva, 2000. Available at http://apps.who.int/malaria/docs/hbsm.pdf
  2. Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria. Critical Care 2003;7:315-323 Available at http://ccforum.com/content/7/4/315
  3. World Health Organization: Severe and complicated malaria. Trans R Soc Trop Med Hyg 1990;84(suppl 2):S1-S65.
  4. World Health Organization: Severe falciparum malaria. Trans R Soc Trop Med Hyg 2000;94(suppl 1):S1-S90.


Hemoglobinuria due to massive intravascular hemolysis can occur in falciparum malaria. It is usually seen in non-immune or semi-immune individuals. Immune individuals who have lost their immunity due to stay in a non-malarious area may also develop the complication if they happen to get malaria on their return to malarious area.

The intravascular hemolysis can be due to non-immune destruction of parasitized red cells in case of high parasitemia or due to immune mediated destruction of parasitized as well as non-parasitized red cells. The changes in the red cell antigen structure brought about by the parasitic invasion stimulate the production of antibodies against the red cell. This triggers the immune mediated red cell lysis. Sensitivity to quinine may play a role in some patients who have been treated with quinine earlier, but now it seems to be rare. Patients with deficiency of glucose 6-phosphate dehydrogenase enzyme may develop hemolysis when treated with oxidant drugs like primaquine.

The hemolysis can occur so rapidly that the hemoglobin may drop significantly within a few hours and it may recur periodically at intervals of hours or days. Patient presents with head ache, nausea, vomiting and severe pain in the loins and prostration. Fever up to 39.40C with a rigor is also seen. Urine is dark red to almost black. Patient may have tender hepatosplenomegaly. The urine becomes darker and the output slowly drops. Renal failure and peripheral circulatory failure are the usual causes of death in these patients.

The increased release of hemoglobin into the circulation results in hemoglobinuria and the urine appears dark brown or black (‘Black water fever’). Due to hemoglobinemia, the hemoglobin estimation may be unreliable. Similarly the parasite count may not represent the actual parasite load. There is methemoglobinuria and heavy albuminuria. Renal function gets affected and the urea and creatinine levels rise. There is increase in the levels of unconjugated and conjugated bilirubin as well. Hepatic failure can occur in severely ill patients and is of grave prognosis.

Treatment: Treatment is directed towards anemia and renal failure.

Transfusion of whole blood or packed cells should be started if the hemoglobin level is less than 5g%.

Renal failure can be treated conservatively by careful fluid-electrolyte management and use of diuretics like furoscemide. Dialysis must be considered in patients who do not respond to conservative treatment.

Antimalarial therapy

In cases with hemolysis following primaquine therapy, Glucose 6 phosphate dehydrogenase assay should be done and the drug should be stopped.

See Bruneel F, Gachot B, Wolff M, Régnier B, Danis M. Resurgence of Blackwater Fever in Long-Term European Expatriates in Africa: Report of 21 Cases and Review. Clinical Infectious Diseases 2001;32:1133–1140. Full text available at http://www.journals.uchicago.edu/doi/full/10.1086/319743

Bleeding and Coagulation Disorders

Bleeding and coagulation abnormalities are seen in less than 5% of patients with severe falciparum malaria. It can be due to thrombocytopenia and/or disseminated intravascular coagulation.

Mature parasitised red cells and cytokines activate the coagulation cascade. Accelerated cogulation cascade, consumpton of antithrombin III, increased concentration of FDP and increased splenic clearance of platelets contribute to the coagulopathy and thrombocytopenia in malaria. Hypofibrinogenemia due to DIC occurs in 5% of patients.

Thrombocytopenia is commonly seen in severe falciparum malaria. It is presumed to be due to increased consumption of the platelets in the periphery, may be in the spleen. Bone marrow shows appropriate megakaryocyte response. However, bleeding due to thrombocytopenia is very rare in malaria. Corticosteroids are not indicated. However, if thrombocytopenia is severe, platelet transfusion may be considered. Generally, the platelet count returns to normal with the completion of antimalarial chemotherapy.

Disseminated intravascular coagulation is seen in less than 5% of patients with severe falciparum malaria. It tends to be more common in patients with cerebral malaria, pregnancy and secondary bacterial infections. D.I.C. in turn may aggravate the other complications of malaria like cerebral malaria, renal failure, pulmonary oedema and anemia (due to bleeding). Since it is rare, routine use of drugs like heparin may cause more harm than good and should be avoided. Prolonged prothrombin and partial thromboplastin time suggests the possibility of D.I.C. which can be confirmed by measuring plasma concentrations of fibrinogen and fibrin degradation products. D.I.C. in malaria has to be differentiated from that caused by many other conditions like heat stroke, viral haemorrhagic fevers, snake bites, immune complex disorders and shock. Treatment involves administration of fresh whole blood or fresh frozen plasma and injection of Vitamin K 10 mg intravenously. If there is fear of fluid overload, then exchange transfusion with fresh blood can be tried. Drugs that may cause gastrointestinal bleeding (aspirin, other NSAIDs and steroids) are better avoided in patients with severe malaria.


In P. falciparum infection, the parasite density can be very high, particularly in non-immune individuals. High parasite count above 5% is considered as hyperparasitemia and is a form of severe falciparum malaria. The parasite count can go up to 50% or 500000/m l. High parasitemia and presence of schizonts of P. falciparum in the peripheral blood are associated with a higher mortality. Partially immune children, however can tolerate high parasitemia (20-30%) without clinical symptoms.

Patients with hyperparasitemia may not have any specific clinical features and therefore it is very important to do a peripheral smear examination for parasite count in all cases of falciparum malaria. Some patients may have significant anemia, jaundice, prostration etc.

Management: Patients with hyperparasitemia should be treated with parenteral antimalarials, even if they can take oral medications. Artemisinin derivatives may be especially useful in these patients. The parasite count should be monitored once every 12 hours to assess the response to therapy. Adequate hydration should be maintained.

If the parasite count is above 10%, exchange transfusion may be beneficial. It can reduce the parasitemia more rapidly than chemotherapy alone and in addition could remove harmful metabolites, toxins, cytokines and other mediators and may also restore normal red cell mass, platelets, clotting factors, albumin and other depleted substances. However, the procedure carries its own risks of electrolyte disturbances, hypocalcemia, cardiovascular problems, blood-borne infections and infection of the intravenous line. There are also reports of ARDS developing with this procedure. However, the procedure may still be tried in patients who are severely ill, not responding adequately to antimalarial therapy and who have a parasite count of >10%. Newer drugs like artemisinin which clear parasitemia rapidly may obviate the need for exchange transfusion.


High body temperature above 105°F (40.5°C) is common in falciparum malaria. Hyperpyrexia is more common in children and may be associated with convulsions, delirium and coma. Temperature above 42°C may cause permanent severe neurological sequelae. In pregnant women, high temperature can result in fetal distress or fetal loss.

Treatment involves administration of antipyretics like paracetamol (15 mg/kg body weight), tepid sponging and fanning.

Fluid and Electrolyte Problems

Malaria is often associated with abnormalities of fluid, electrolytes and acid-base balance. These can occur in anybody, but are more common in severe falciparum malaria, extremes of age, and in patients with high degree of fever and vomiting/diarrhoea.

Patients with severe falciparum malaria often have signs of dehydration (thirst, dry tongue, reduced ocular tension and reduced skin turgor) and hypovolumia (low central venous pressure, postural hypotension, oliguria with high urinary specific gravity). Mild hyponatremia (S. Sodium 125-135 mmol/L) is common. Severe, symptomatic hyponatremia, however, is rare.

Metabolic acidosis may develop in severely ill patients with shock, hypoglycemia, hyperparasitemia or renal failure. Lactic acidosis is common in such patients and carries a high mortality.

Management of fluid balance is of utmost importance in severe falciparum malaria. While untreated dehydration and hypovolumia can result in hypoperfusion of kidneys, brain and other vital organs, thereby aggravating the complications, enthusiastic over-hydration can precipitate pulmonary oedema. Therefore, fluid balance should be managed carefully and meticulously.

Assess the status of hydration- moisture on the tongue, ocular tension, skin turgor, temperature of extremities, blood pressure and postural changes in blood pressure, peripheral venous filling and jugular venous pressure, urine output, urine specific gravity (>1.015 indicates dehydration), urinary sodium (

Serum electrolytes, blood urea and serum creatinine should be done in all these cases. If acidosis is suspected, arterial blood gases and blood pH should also be done.


Re-hydration- Isotonic saline should be used for correcting dehydration and hyponatremia. Generally 3000 ml of saline may be required in the first 24 hours. Hypokalemia in malaria rarely requires treatment .

Lactic Acidosis

Metabolic acidosis can be due to renal dysfunction and/or lactic acidosis (which should be suspected if the anion gap exceeds 10-12 meq/L). Attempt should be made to correct acidemia only if the arterial pH is less than 7.20. Sodium bicarbonate can be added to isotonic saline infusion for this purpose. However, sodium bicarbonate itself may contribute to pulmonary oedema by increasing the sodium load. THAM and dichloroacetate are other alternatives.

It is also important to improve oxygenation of blood. A clear airway should be ensured. Concentration of oxygen in the inspired air should be increased by administering oxygen through facemasks or nasal prongs. If necessary, mechanical ventilation should be done.

Metabolic acidosis (predominantly lactic acidosis) has been now recognized as a principal pathophysiological feature of severe manifestations of P. falciparum malaria like cerebral malaria and severe anemia. It is the single most important determinant of survival and can lead to respiratory distress syndrome. Lactic acidosis has been identified as an important cause of death in severe malaria.

Lactic acidosis in severe malaria has been attributed to several causes:

  • Increased production of lactic acid by parasites (through direct stimulation by cytokines)
  • 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.

Mean venous blood lactate concentrations have been found to be almost twice as high in fatal cases as in survivors and to correlate with levels of tumour necrosis factor and interleukin 1-alpha. The lactate concentrations fell rapidly in survivors but fell only slightly, or rose, in fatal cases. Sustained hyperlactataemia has been found to be the best overall prognostic indicator of outcome.


  • Maintenance of airway patency and oxygen delivery; intubate if the patient is unconscious, in severe shock, or otherwise unstable
  • Establish an intravenous (IV) line; replace adequate intravascular fluid volume if the patient has tachycardia, hypotension, or other signs of poor tissue perfusion like poor capillary refill.
  • Monitor for cardiac dysrhythmias.

The use of sodium bicarbonate is controversial and generally should be avoided


  1. Miller LH, Baruch DI, Marsh K et al. The pathogenic basis of malaria. Nature 2002;415:673-9
  2. Krishna S, Waller DW, ter Kuile F et al. Lactic acidosis and hypoglycaemia in children with severe malaria: pathophysiological and prognostic significance. Trans R Soc Trop Med Hyg. 1994 Jan-Feb;88(1):67-73.

Secondary Infections

Patients diagnosed with malaria can suffer from other bacterial or protozoal diseases as either super-infections or co-infections. These infections can be severe and sometimes even life-threatening. These associated infections are more common in patients with P. falciparum malaria (with or without complications), elderly, pregnant women and immunocompromised patients. Further, in most parts of the world where malaria is rampant, so many other infectious diseases are also prevalent, sometimes resulting in co-infection rather than super-infection.

Malarial infection has depressant effect on the immune system. Acute malarial parasitemia has a profound immuno suppressant effect, probably through the activation of suppressor T cells. In an malaria endemic area, young children may suffer from severe infections (viral like measles or bacterial) due to this immunosuppression.

In addition, complicated falciparum malaria can be a predisposing factor for certain specific infections. For example, patients with cerebral malaria, altered consciousness or generalised seizures can develop aspiration bronchopneumonia; patients with indwelling catheters may develop urinary tract infection; patients with prolonged coma may develop decubitus ulcers that may get infected; infection can also occur through the sites of intravenous cannulation. Patients with malaria, in addition, can also have other infections that are prevalent in the community e.g., pneumonia, bacillary dysentery, amebiasis, typhoid, tuberculosis etc. Gram negative septicemia can occur without any evident focus and may also lead to Gram negative shock.

Manifestations of secondary infections and of malaria can overlap. Fever, cough, diarrhoea and dysentery can be seen in malaria, making the identification of the secondary infections rather difficult.

Persistence of fever even after 48-72 hours of antimalarial treatment and reduction in parasitemia should raise the possibility of secondary infections. One should not change the antimalarial therapy or add newer antimalarial drugs (considering resistance) in these cases , instead should look for these secondary infections.

Presence of tachypnoea, productive sputum, lateral chest pain related to breathing, bronchial breath sounds, crackles would suggest the possibility of a pneumonia and a chest x ray should be done.

Neck stiffness and other signs of meningeal irritation would suggest meningitis. A CT scan and lumbar puncture for CSF examination should be considered.

In places where tuberculosis is common, malaria may bring the patient to the doctor and underlying tuberculosis can create confusion if undiagnosed. Tubercular meningitis can masquerade as cerebral malaria if the patient gets malaria as a co-infection.

Total and differential count, urine analysis and culture, stool examination and culture, blood culture, chest X ray, Widal test etc. should be done as required.

Neutrophilic leukocytosis in the absence of severe falciparum malaria may indicate bacterial infection. Mild albuminuria and pyuria may be seen in malaria with high fever, however significant changes may indicate urinary infection. Stool examination may confirm bacillary or amebic colitis. Widal test may show positive titres up to 1:320 dilution even in malaria. Positive titre for both S. typhi and S. parathyphi A or S. paratyphi B usually indicates anamnestic reaction. A diagnostic titre of more than 1:640, however, confirms enteric fever.

All cases of secondary infection should be treated with appropriate antibiotics. In case of septicemic shock, a third generation cephalosporin with or without an aminoglycoside should be used.

Pre-existing Clinical Conditions

Cardiovascular Disease | Anemia | Kidney Disease | Liver Disease | Central Nervous System Disorders | Diabetes Mellitus | Myasthenia Gravis | Malaria and anaesthesia |Dermatitis | Pregnancy | HIV/AIDS

Malaria can exacerbate/complicate pre-existing clinical conditions, adding to its morbidity and mortality. In this regard, the following points should be kept in mind:

  1. Patients with these conditions should be managed energetically to avoid any potential problems.
  2. Even P. vivax (or other milder types) can lead to deterioration in the condition, even causing death.
  3. Since P. vivax and other milder types generally do not cause any complications or death by themselves, one should be careful in filling up the death certificates in these patients. In these cases, malaria can at the most be sited as a contributory cause and not as a primary cause.
  4. Pre-existing problems may influence treatment of malaria, especially the choice of antimalarials.

Pre-existing cardiovascular disease: Patients with severe valvular obstruction, compromised ventricular function and other conditions of cardiac decompensation may land in trouble on contracting malaria. In severe falciparum malaria, the myocardial function is remarkably maintained and most patients have an elevated cardiac index, with low systemic vascular resistance and low to normal right and left sided filling pressures. However in patients with decompensated heart, the high grade fever, tachycardia, hypoxemia, metabolic acidosis etc. associated with malaria may add to the existing cardiac decompensation.

Case report: A 43 year old bank executive, known case of severe aortic stenosis and claiming to be asymptomatic and not on any treatment, presented with high grade fever with chills of 3 days duration and repeated vomiting. On examination he had a temperature of 103.40F, heart rate of 120/min, blood pressure of 100/60 and dry tongue, his cardiac examination revealed harsh systolic murmur in the aortic area and chest was clear. His blood smear was positive for P. vivax malaria. He was first treated with anti emetics, tepid sponging and antipyretics and after half an hour, chloroquine was administered. His vomiting continued and he was unable to take orally and his blood pressure dropped to 90 mm systolic. He was started on normal saline infusion that was given carefully in view of his aortic stenosis. After 40 minutes of the infusion, he developed mild cough and breathlessness and there were creps in the bases of lungs . The infusion was immediately stopped (by then about 75 ml had flowed in) and Inj. Fruscemide 20 mg was given intravenously. After 5 hours, his fever settled down and he started feeling better. Antimalarials, antipyretics and anti-emetics were continued. Next morning echocardiography was done and it confirmed the diagnosis of severe aortic stenosis. That afternoon he again had fever of 1020F and was treated with tepid sponging and antipyretics. By 8 p.m., his temperature was 99.80F and as he was talking to his wife he complained of chest discomfort and suddenly he collapsed. He was immediately shifted to the Intensive care unit and the monitor showed ventricular fibrillation. He was immediately defibrillated and put on advanced life support system. He died after 3 days.

Anti malarials in cardiovascular disease: Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with known cardiac illness.

Chloroquine: Oral chloroquine is safe in therapeutic or prophylactic doses. If the therapeutic dose or a high dose are administered too rapidly by parenteral route, it can cause significant cardiotoxicity. Hypotension, vasodilation, myocardial suppression, ECG abnormalities and cardiac arrest can occur. Treatment includes mechanical ventilation, adrenaline and diazepam. Concomitant use of chloroquine with amiodarone should be avoided.

Quinine: At therapeutic doses, quinine is relatively safe. Rapid intravenous administration may cause hypotension. Acute overdosage can cause fatal dysrhythmias such as sinus arrest, junctional rhythms, A-V block, ventricular tachycardia and fibrillation. Quinine may delay the absorption and elevate the plasma levels of cardiac glycosides like digoxin. Quinine should not be used concomitantly with amiodarone. Concomitant use with astemizole and terfenadine can also increase the risk of ventricular arrhythmias.

Mefloquine: Mefloquine should be used with extreme caution in patients suffering from cardiac conduction diseases. Mefloquine has been shown to cause asymptomatic sinus bradycardia and other conduction abnormalities e.g. prolongation of the QT interval. Patients who are on either a beta-blocker or calcium channel blocker are at particular risk if there are signs of sinus bradycardia and/or atrioventricular block. Cardiac arrest has been reported in a patient receiving a single prophylactic dose of mefloquine while concomitantly taking propranolol. There appears to be no interaction between ACE inhibitors and mefloquine*.

Halofantrine: Halofantrine prolongs QT interval in a concentration dependent manner and it can result in ventricular arrhythmias and even death. It is therefore contraindicated in patients with prolonged QT interval and with drugs known to cause prolongation of QT interval.

Pre-existing anemia: Anemia is a common problem in developing countries of Africa and Asia and it is commonly due to helminthiasis and malnutrition. Malaria is also common in these areas. Both vivax and falciparum malaria can exacerbate the anemia, specially causing problems in pregnancy and in children. Also, blood transfusion for anemia may transmit malaria. See anemia in P. falciparum malaria

Pre-existing renal disease: Severe falciparum malaria can compromise renal blood flow by sequestration and obstruction to the microcirculation, by hemolysis, by dehydration and hypovolumia, by acidosis etc. Any of this could prove detrimental to patients with pre-existing renal disease. Acute intrinsic renal impairment occurs during apparently ‘uncomplicated’ falciparum malaria in children.

Malaria has been reported in renal transplant recipients. Malaria should be considered in the differential diagnosis of fever in transplant recipients who have received organs or blood products from an area of endemic malaria.

The dose of quinine needs modification in renal failure whenever S. creatinine is > 3mg%.

Chloroquine increases plasma cyclosporin concentration and may increase the risk of toxicity.

Pre-existing liver disease: Patients with hepatocellular failure due to cirrhosis etc. may deteriorate if they contract malaria.

A case of malaria in a recipient of orthotopic liver transplantation has been reported. The patient was found to have Plasmodium ovale malaria during evaluation of a severe febrile illness. The infection was traced to a platelet transfusion and responded to treatment with chloroquine. Risk factors associated with the development of malaria infection are identifiable and should be reviewed from the recipient and donor when possible. Routes of infection in the liver transplant patient would include blood products, the organ itself, and resurgence of latent infection. (Post-transfusion acquired malaria complicating orthotopic liver transplantation. Talabiska DG, Komar MJ, Wytock DH, Rubin RA: Am J Gastroenterol 1996 Feb 91:2 376-9)

None of the antimalarial drugs have any direct hepatotoxic effect. However, chloroquine is not advisable in patients with severe hepatic insufficiency.

Pre-existing C.N.S. Disease: Malaria and anti malarial drugs may pose problems in patients with pre-existing C.N.S. disorders like dementia, epilepsy etc.

Severe P. falciparum infection, dehydration, hyponatremia, high grade fever can lead to deterioration of patients having pre-existing dementia.

Elderly patients and patients with dementia contracting malaria may be prone for secondary infections like aspiration bronchopneumonia

Chloroquine, quinine and mefloquine can cause neuropsychiatric side effects. Chloroquine and mefloquine are better avoided in patients with significant neuropsychiatric disorders.

Epilepsy: There are some reports of chloroquine causing convulsions even in previously healthy patients. Mefloquine is contraindicated in patients with a history of convulsions. Several case reports of first-time seizures in patients taking mefloquine in prophylactic doses have been reported. There have also been reports of mefloquine reducing the half-life and lowering the blood levels of sodium valproate. This may be due to mefloquine accelerating the hepatic metabolism of sodium valproate, because they are both metabolized by the same hepatic enzyme system*.

Doxycyline does not affect epilepsy, but may interact with some of the anti-convulsants. Carbamazepine, phenytoin and barbiturates may shorten the half-life of doxycycline by up to 50% and lower mean serum levels by liver enzyme induction, thus possibly compromising its therapeutic efficacy. The degree to which the levels are affected is not clear. In theory, this means that the usual recommended prophylactic dose of 100mg daily could be taken more frequently, probably twice daily. However an exact recommendation cannot be made because there is limited experience with an increased incidence of side-effects. Therefore epileptic patients not taking carbamazepine, phenytoin and barbiturates can safely use doxycycline as malarial prophylaxis. Patients taking the above drugs must by aware of the fact that the normal dose of doxycycline may not provide adequate protection and increasing the dose may result in an increased incidence of side-effects*.

Diabetes Mellitus: Severe P. falciparum malaria can cause hypoglycemia and this fact should be borne n mind in diabetics receiving insulin and/or oral hypoglycemic agents. Suitable dosage adjustments may be needed.

Quinine has stimulatory effects on the pancreatic beta cells and is known to cause severe hypoglycemia. Thereby it may potentiate the effects of sulfonylureas.

In normal patients and in normal doses chloroquine does not appear to cause increased pancreatic secretion of insulin and has no effect on plasma glucose concentrations. Some studies suggest that in non-insulin-dependent diabetes mellitus chloroquine may improve glucose tolerance, possibly by decreased metabolic degradation of insulin rather than increased pancreatic secretion*.

There is very limited evidence that doxcycline occasionally increases the hypoglycemic effects of insulin and sulphonylureas. Although there is no need to avoid concomitant use, patients must be aware of signs of hypoglycemia and, if needed, the dose of hypoglycemic agent should by adjusted*.

It is unknown whether mefloquine interacts with oral antidiabetic agents. Treatment doses of mefloquine have caused hypoglycemia especially in children and pregnant women, but mefloquine apparently does not stimulate the release of insulin. Patients should be made aware of the possibility and should be able to reduce the hypoglycemic dose if necessary*.

The impact of the above on the control of diabetes is unknown; it is therefore suggested that blood glucose be monitored even more closely and that medication adjustments are made as required*.

Myasthenia Gravis: Quinine decreases the excitability of the motor end-plate region so that response to repetitive nerve stimulation and to acetyl choline are reduced. Quinine may produce alarming respiratory distress and dysphagia in patients with myasthenia gravis.

Chloroquine also may increase the symptoms of myasthenia gravis and reduce the effect of neostigmine and pyridostigmine.

Antimalarials and anaesthesia: Quinine enhances the effect of neuromuscular blocking agents and opposes the actions of acetyl choline esterase inhibitors.

Tetracycline also can produce neuromuscular blockade.

Chloroquine also has interactions with the neuromuscular blocking agents.

This may have implications in anaesthesia and post operative recovery where these drugs are routinely used.

Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all the three can cause dermatitis

* The Journal of MODERN PHARMACY, Volume 5 no. 3, 1998 and Malaria Update 1997, a publication by the staff of the Medicines Information Centre, Cape Town, S.A.

Tropical Splenomegaly Syndrome

Tropical Splenomegaly Syndrome or Big Spleen Disease, also known as Hyper-reactive malarial splenomegaly is massive enlargement of the spleen resulting from abnormal immune response to repeated attacks of malaria. It is seen among residents of endemic areas of malaria and it is not species specific. It occurs mainly in tropical Africa, but also in parts of Vietnam, New Guinea, India, Sri Lanka, Thailand, Indonesia, South America and the Middle East. It must be differentiated from splenomegaly associated with acquisition of immunity in endemic and hyperendemic areas.

Tropical Splenomegaly Syndrome is characterised by massive splenomegaly, hepatomegaly, marked elevations in levels of serum Ig M and malaria antibody. Hepatic sinusoidal lymphocytosis is also seen. In about 10% of African patients, it may be associated with peripheral lymphocytosis (B cells).

The interaction of repeated malarial infection and unknown host factors results in the production of cytotoxic Ig M antisuppressor lymphocyte (CD8+) antibodies. This causes inhibition of suppressor T cells, which normally regulate IgM production. This leads to uninhibited B cell production of IgM and the formation of cryoglobulins (IgM aggregates and immune complexes). The need to clear these macromolecular aggregates stimulates the reticuloendothelial system, resulting in hyperplasia. This causes the progressive and massive enlargement of the spleen and hepatomegaly.

The spleen is massively enlarged. It shows dilated sinusoids lined with reticulum cells showing marked erythrophagocytosis and lymphocytic infiltration of the pulp. Liver exhibits sinusoidal dilatation, infiltration with lymphocytes and hyperplasia of the Kupffer’s cells with phagocytosis of cellular debris and red cells.

Most patients present during adult life. Patients present with dragging pain in the upper abdomen, or sometimes may even complain of a palpable mass. Some may experience recurrent sharp pains in the upper abdomen, probably due to perisplenitis or splenic infarcts. Some patients may have weight loss and cachexia. On examination, there is massive splenomegaly and hepatomegaly.

The peripheral smear shows normocytic normochromic anemia with increased reticulocyte count. Leukopenia and thrombocytopenia may also be seen due to hypersplenism. Malarial parasites are not found in the peripheral blood. There is increase in the serum levels of polyclonal IgM with cryoglobulinemia, reduced C3 and the rheumatoid factor may be positive.

The condition should be differentiated from other causes of splenomegaly in the tropics- Kala-Azar, Schistosomiasis, post-necrotic cirrhosis, thalassemia, leukemia, lymphoma, myelofibrosis, non-tropical idiopathic splenomegaly, Felty’s syndrome etc. In patients with splenic lymphoma, more than 30% of circulating lymphocytes are villous and they can be differentiated from hairy-cell leukemia by their lack of CD25, CD11C and tartrate-resistant acid phosphate markers. Increased levels of IgM and antimalarial antibody, hepatic sinusoidal lymphocytosis on liver biopsy and response to antimalarial therapy (improvement in clinical condition as well as reduction in IgM and malarial antibody titre within three months of continuous antimalarial treatment) favour a diagnosis of tropical splenomegaly syndrome.

The disease generally runs a benign course. However, sometimes it may be associated with severe anemia, leading to congestive cardiac failure. These patients are also more prone for secondary bacterial infections of the skin and respiratory tract and have an increased mortality. Portal hypertension does not develop and the condition is reversible with antimalarial treatment. Some patients in Ghana were found to develop splenic lymphoma with hairy lymphocytes.

The treatment of tropical splenomegaly syndrome involves administration of antimalarial prophylaxis for prolonged periods of time. This removes the antigenic stimulus provided by repeated malarial infection and allows the immune system to return to normal. The choice of antimalarial depends on the local sensitivity pattern. Chloroquine weekly or proguanil daily have been found to be useful. These drugs may have to be continued for long periods, possibly for life. Severe anemia may require blood transfusion. Splenectomy may do more harm than good and it may be beneficial in only patients with splenic lymphoma. Splenic irradiation or antimitotic therapy are not beneficial and may be even dangerous.

 ©malariasite.com ©BS Kakkilaya | Last Updated: Mar 11, 2015

One Comment:

  1. Dr. Ashok Balajirao Bulbule

    Kindly tell exactly whether chloroquine should be given or not in a patient having Vivax malaria with mild to moderate jaundice.

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