Malaria and HIV/AIDS

Man has known malaria for centuries and AIDS has been around for nearly 6 decades. Malaria has already killed millions and continues to kill nearly 3 million every year. As of 1999, nearly 36 million people around the world are infected with HIV and 5 million have died of AIDS related illness. And in the coming millennium, both the diseases are expected to infect many more and to kill many many more around the world. But the bigger tragedy is that HIV infection is on a dramatic increase in those countries where malaria is already a uncontrollable problem.

Many interesting studies have been conducted on the relationship between these two potentially fatal diseases. Here below you will find a summary of these studies:

Effect of HIV infection on malaria:

With what we know of HIV infection, it is only natural that one expects a far poorer outcome for malaria in HIV infected patients. But on the contrary, the reports available indicate either no effect or even a protective effect against death from complications of falciparum malaria!

  1. Malaria does not occur as an opportunistic infection in patients with HIV infection.3
  2. Incidence of malaria is not more common in HIV infected patients.1,3
  3. The response to antimalarial treatment is identical in HIV infected and non-infected patients.3
  4. Although high levels of malarial parasitemia have been observed in African children with symptomatic HIV infection, these children have been found to be ‘protected’ against cerebral malaria and deaths due to cerebral malaria. This has been attributed to lower levels of Tumor Necrosis Factor in HIV infected children. TNF is reported to have a potentiating effect on the endothelial adherence and clogging of microcirculation by parasitized red cells1. In an animal study using mice, murine AIDS was found to confer protection against the severity of neurological manifestations of experimental cerebral malaria and this protection was higher with longer duration of immunodefeciency. Interleukin 10 from splenic cells was shown to play a crucial role in this protection.2
  5. However, there are also studies that have found no difference in the incidence, clinical features and response to treatment of malaria among the HIV positive and HIV negative groups.3,6
  6. Patients with HIV infection may have a false positive serological test for malaria. Therefore, serological tests for malaria may not be useful as surrogate tests for assessing the travel status of individuals.4

Effect of malaria on HIV infection:

It appears that malaria does more harm to HIV patients and HIV transmission than vice versa. Many studies from the African countries have thrown light on this aspect.

  1. It is common knowledge that in areas where malaria is common, the health workers are assigned the job of conducting active surveillance by screening the population for malaria by peripheral smear examination. It is feared that this practice of collecting peripheral smears on a mass scale can certainly heighten the risk of transmission of HIV infection through needle pricks.5
  2. Also in areas where malaria is common, children and pregnant women often suffer from malaria related anemia and may require transfusion of either whole blood or packed cells. This also increases the risk of transmission of HIV infection as it may not be possible to ascertain the serological status of the donor in areas where HIV is also rampant.6,7,8 Therefore it is important to develop definite guidelines for blood transfusion in areas where anemia (due to malnutrition, helminthiasis, malaria etc.) and HIV infection are prevalent.
  3. Malaria has potent immunosuppressive effects. It has been found that patients with HIV infection who contact malaria tend to deteriorate rapidly into AIDS Realted Complex or AIDS. Malarial infection supposedly accelerates the replication of HI virus.9
  4. Chloroquine, the most commonly used antimalarial has been found to have inhibitory effects on the antiviral activity of Interferons alpha and beta in animal studies. It has also been found that chloroquine enhances viral replication in mice. It may suggest a possible connection between AIDS and malaria infection, since the spread of AIDS has been rapid in parts of tropical Africa that have a high incidence of malaria and chloroquine has been frequently used in the chemotherapy of malaria.10

Malaria and Kaposi’s sarcoma:

In sub-Saharan Africa, Kaposi’s sarcoma is a frequent tumor (endemic Kaposi’s) and it has been blamed on environmental factors. Kaposi’s sarcoma also occurs in association with AIDS (AIDS associated Kaposi’s sarcoma). One study on the association of endemic Kaposi’s sarcoma and transmission of malaria based on the available data from 27 African countries found a significant geographical association between proportional rate of Kaposi’s sarcoma and malaria transmission.11 The following possibilities have been suggested to explain this association:

  1. The immunosuppressive effects of malaria might be an additional cofactor in the pathogenesis of endemic Kaposi’s sarcoma.
  2. Abnormalities of cell-adhesion, observed as blood-flow sludging, have been observed in malaria as well as AIDS associated Kaposi’s sarcoma. This factor might be contributory to the pathogenesis of both AIDS associated and endemic Kaposi’s sarcoma.
  3. Kaposi’s sarcoma may also be an arthropod borne illness in Africa.

Interactions of antimalarial and antiretroviral drugs:12,13,14 Research on interactions between antiretrovirals and antimalarials has been lacking. One study found no interaction between mefloquine and indinavir or nelfinavir. The results of a pharmacokinetic study of mefloquine and ritonavir suggest that mefloquine reduces ritonavir blood levels by at least 30%.


  1. Dayachi F, Kabongo L, Ngoie K. Decreased mortality from malaria in children with symptomatic HIV infection. Int Conf AIDS. 16-21 Jun 1991;2:164
  2. Eckwalanga M et al. Murine AIDS protects mice against experimental cerebral malaria: down regulation by interleukin 10 of a T- helper type 1 CD4+ cell-mediated pathology. Proc Natl Acad Sci USA. 1994 Aug 16;17:8097-101
  3. Muller O, Moser R. The clinical and parasitological presentation of Plasmodium falciparum malaria in Uganda is unaffected by HIV-1 infection. Trans R Soc Trop Med Hyg. 1990 May-Jun;3:336-8.
  4. Chrystie IL, Palmer SJ, Voller A, Banatvala JE. False positive malaria and leishmania serology associated with HIV positivity. Int Conf AIDS. 1993 Jun 6-11;2:763
  5. Risk of transmission of AIDS and other blood-related diseases during routine malaria activities. Bull World Health Organ. 1991;2:242-3
  6. Greenberg AE. Studies of the relationship between Plasmodium falciparum malaria and HIV infection in Africa. Int Conf AIDS. 1989 Jun 4-9:983
  7. Fleming AF. Tropical obstetrics and gynaecology. 1. Anaemia in pregnancy in tropical Africa. Trans R Soc Trop Med Hyg. 1989 Jul-Aug;4:441-8.
  8. Lackritz E, Campbell C, Hightower A, Ruebush T, Were J. Is the cure worse than the disease: anemia, malaria, blood transfusion and child mortality in western Kenya. Int Conf AIDS. 1990 Jun 20;236(1):273
  9. Weinke T, Schere W, Pohle HD. Malaria tropica in HIV infection (German). Klin Wochenschr. 1990 May17; 68(10):533-6
  10. Maheshwari RK et al. Effect of interferon in malaria infection. Immunol Lett. 1990 Aug;1-3:53-7
  11. Baumann S, Geier SA, Noehl MA, Goebel FD. On the epidemiologic association between endemic Kaposi’s sarcoma and malaria. Int Conf AIDS. 1994 Aug; 1:(170):7-12
  13. Schippers EF, Hugen PW, den Hartigh J, et al. No drug-drug interaction between nelfinavir or indinavir and mefloquine in HIV-1-infected patients. AIDS 2000;14:2794-5.
  14. Khaliq Y, Gallicano K, Tisdale C et al. Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. Br J Clin Pharmacol 2001;51:591-600

© ©BS Kakkilaya | Last Updated: Mar 11, 2015

Malaria in Children

Most of the 1-3 million who die each year from malaria are children, mainly in Africa, which is hyperendemic for malaria. In older children, malaria has a similar course as in adults. However, in children below the age of 5 years, particularly infants, the disease tends to be atypical and more severe.

In the first two months of life, children may not contract malaria or the manifestations may be mild with low-grade parasitemia, due to the passive immunity offered by the maternal antibodies.

In endemic and hyperendemic areas, the parasite rate increases with age from 0 to 10% during first three months of life to 80 to 90% by one year of age and the rate persists at a high level during early childhood. The mortality rate is highest during the first two years of life. By school age, a considerable degree of immunity would have developed and asymptomatic parasitemia can be as high as 75% in primary school children. In Africa, on an average about 1 in 20 children die from malaria, and in worst affected areas, even 1 in 5 or 6 die from malaria and its related diseases (e.g., anemia).

In areas of low endemicity, where the immunity is low, severe infection occurs in all age groups including adults. The morbidity and mortality due to malaria in children tends to be very high in these areas.

Malnutrition does not increase susceptibility to severe falciparum malaria. In fact, it has been observed that well-nourished children are more likely to develop severe disease than those with malnutrition. However, when severe malaria does occur, malnourished children have a higher morbidity and mortality.

Hemoglobin types in the newborn and the susceptibility to malaria: It has been observed that congenital malaria and malarial parasitemia in newborns are very rare, in spite of significant maternal parasitemia and sequestration of the parasites in the placenta. The reasons for this are not fully understood. Passive immunity due to maternal antibodies, retarded growth of the parasites in erythrocytes containing Hemoglobin F and resistance for parasite growth in old red cells with HbF may be the causes.

Children with heterozygous sickle cell trait have lower parasite rates and less fatal infections compared to normal children (however, homozygous sickle cell disease does not protect against fatal infection). Thalassemias may also confer some protection, may be due to higher levels of HbF. Glucose 6-phosphate dehydrogenase deficiency has been found to have a protective effect against malaria in some studies.

Severe falciparum malaria in children

Severe falciparum malaria is the commonest cause of death in infants and children in areas endemic and hyperendemic for malaria. Inadequate immunity results in rapid increase in the parasite count and development of complications. Delay in diagnosis and treatment also contributes to the mortality.

Clinical features of severe disease should be given utmost priority. History of travel to malarious area, history of previous antimalarial therapy, history of vomiting, diarrhoea, fluid intake, urine output, convulsions etc. should be obtained from parents. Physical examination should include assessment of hydration and of complications of falciparum malaria. Rectal temperature should be measured in infants and small children. All children should be weighed on admission.

Thick and thin films for malaria, haematocrit and hemoglobin, blood glucose (by finger prick) should be done in all cases. If the report is likely to be delayed, presumptive antimalarial treatment should be started. Parasite count should be done in all positive cases of falciparum malaria and a parasite count of >2% indicates impending problems and >5% should be considered as severe infection. All cases with severe falciparum malaria should be managed as medical emergency.

Cerebral malaria:

CNS manifestations are common in children and they can be due to the following causes:

  1. Severe infection and cerebral malaria.
  2. Severe infection and hypoglycemia.
  3. Hypoglycemia induced by quinine.
  4. Severe anemia.
  5. High grade fever.
  6. Drug induced behavioural changes.

Therefore CNS dysfunction may not always indicate cerebral malaria and it is very important to differentiate between the various causes.

Clinical features of cerebral malaria:

The earliest symptoms of cerebral malaria in children include high-grade fever (37.5-410C) and failure to eat and drink. Vomiting and cough are common.Febrile convulsions are common in children aged 6 months to five years and it may be difficult to differentiate from cerebral malaria. If coma persists more than 30 minutes after a convulsion in a child with falciparum malaria, then cerebral malaria should be suspected. Convulsions can continue after the onset of coma and they are associated with higher morbidity and sequelae.

Some children may have noisy and laboured breathing. Deep breathing due to acidosis may be seen in some. Cold, clammy skin with a core-to-skin temperature difference of >100C may be seen. Some children may have associated shock, with the systolic pressure below 50 mm Hg. Some children may present with extreme opisthotonus (‘bent-like-a-bow’) posture, mimicking either tetanus or meningitis.

Neurological signs include features of symmetrical upper motor neuron and brain stem disturbances including disconjugate gaze, decerebrate and decorticate postures. In children with profound coma, corneal reflex and ‘Doll’s eye’ movements may be absent. Retinal haemorrhages and exudates are rarer than in adults.

In all comatose children, CSF examination must be done to rule out other diseases. CSF examination in cerebral malaria is usually normal; however in some, increase in pressure, protein level and cell-count (mostly lymphocytes, 50cells/ml) may be seen.

Leukocytosis may be present in severe disease and may not necessarily indicate bacterial infection.

Treatment: The management of cerebral malaria in children is same as in adults.

A single intramuscular injection of phenobarbitone sodium, 10-15mg/kg of body weight can be given prophylactically to prevent convulsions in all cases of severe falciparum malaria. When convulsions do occur, they can be controlled immediately with diazepam or paraldehyde.

Bronchopneumonia is a common complication in children with cerebral malaria. Comatose children should be nursed in either lateral or semi-prone position and turned frequently to prevent aspiration as well as bedsores.

With effective antimalarial chemotherapy, children generally regain consciousness in 2-3 days; however, sometimes the coma may last as long as one week despite the reduction in fever and parasitemia. Prolonged coma may necessitate nasogastric feeding. About 10% of children who survive may have neurological sequelae in the form of hemiparesis, cerebellar ataxia, cortical blindness, hypotonia, spasticity or aphasia.

Severe anemia: Anemia is the commonest complication of malaria in children. The rate of development and degree of anemia depend on the severity and duration of parasitemia. In some children, repeated untreated episodes of malaria can result in normocytic anemia. In these cases, bone marrow shows changes of dyserythropoeisis and peripheral blood shows low-grade parasitemia, sometimes with pigmented monocytes. In patients with high parasitemia, anemia may develop rapidly due to hemolysis of the parasitized red cells and this may worsen even after completion of antimalarial therapy. It can present with serious problems in children with pre-existing anaemia.

Children with severe anemia may present with symptoms and signs of cardiac failure- dyspnoea, tachycardia, gallop rhythm, basal crackles, hepatomegaly, raised jugular pressure etc. Severe anemia can also cause confusion, restlessness, retinal haemorrhages and even coma.

Treatment: Furoscemide, 1-2 mg/kg up to a maximum of 20 mg can be given in children with signs of cardiac failure. Children with a hematocrit of less than 15% (Hemoglobin less than 5g%) should be given blood transfusion. 10ml/kg of packed cells or 20 ml/kg of whole blood can be given by slow transfusion. Whenever possible, parents should be encouraged to donate blood to minimize the risk of other blood borne infections. Hemoglobin concentration should ideally be maintained above 7g/dL (hematocrit above 20%).

Renal failure: Renal failure is uncommon in children. A slight increase in urea and creatinine may sometimes occur due to dehydration and it returns to normal with rehydration.

Treatment: In older children with renal dysfunction, the management consists of careful assessment and monitoring, initial conservative management and if needed, dialysis.

Commonest cause of oliguria in children with malaria is dehydration. Such patients have signs of dehydration, lower blood pressure, high urine specific gravity with low urinary sodium, and normal urine microscopy. Such patients should be carefully rehydrated. If the urine output fails to improve to about 4ml/kg in the first eight hours despite adequate rehydration, then furoscemide can be given, starting at 2mg/kg, then doubled at hourly intervals to a maximum of 8mg/kg. If this fails to improve the urine output, injection dopamine can be infused at 2-5mg/kg/min through a central venous catheter or a free flowing peripheral vein. If the child fails to produce more than 4 ml urine/kg body weight at the end of 16 hours, then further fluid load should be withheld. If the conservative measures fail, dialysis should be considered.

Bleeding disorders: Bleeding tendencies with prolonged clotting time, thrombocytopenia and decreased coagulation factors may occur in falciparum malaria. Spontaneous bleeding from various sites, including the upper GI tract may occur.

Pulmonary oedema: Children with cerebral malaria, severe anemia and high parasitemia may develop acute pulmonary oedema. It may also be due to fluid overload. Tachypnoea is the earliest sign of impending pulmonary oedema.

Treatment: Pulmonary oedema is managed with stringent fluid management, propped up position, oxygen inhalation, diuretics and venesection and letting of blood. If needed, patient has to be started on mechanical ventilation with positive end expiratory pressure.

Hypoglycemia: This is also less common in children compared to the adults. It may be associated with lactic acidosis in severe falciparum infections. It may present with convulsions, or impairment in the level of consciousness.

Treatment: Intravenous 50% dextrose, 1 ml/kg, should be given followed by intravenous infusion of 10% dextrose. Recurrent hypoglycemia may occur even during administration of 10% dextrose. Further episodes of drug induced, hyperinsulinemic hypoglycemia can be prevented by administration of somatostatin analogue octreotide. However, it is very expensive.

Fever: In children, high-grade fever itself can cause various problems and hence should be managed energetically. Fanning and tepid sponging should be used regularly. Paracetamol injection can be used in hyperpyrexia.

Antimalarial drugs: In cases of severe falciparum malaria, the child should be admitted. Oral antimalarials should be avoided. Chloroquine or quinine injections should be used, depending on the sensitivity. Chloroquine can be given by intravenous, intramuscular or subcutaneous injections while quinine can be given by intravenous or intramuscular injections. All intravenous infusions should be carefully titrated with infusion pumps.

Dose of antimalarials for severe malaria in children
Drug Dose
Chloroquine Intravenous: 5 mg base/kg diluted with normal saline or 5% dextrose 10 ml/kg, infused over 4 hours. The dose can be repeated every 12 hours to obtain a total dose of 25 mg base/kg. Rapid I.V. bolus may cause fatal hypotension.
Subcutaneous: 2.5 mg/kg, followed by another 2.5 mg/kg after one hour; repeated every 12 hours to attain a dose of 25 mg/kg.
Quinine Intravenous: 24mg salt/kg or 20 mg base/kg in normal saline or 5% dextrose, infused over 4 hours as a bolus, followed by 12 mg salt/kg or 10 mg base/kg infused every eight hours. (Bolus dose should be skipped in children who have already received quinine in the previous two days). Note that the dose is slightly higher in children (24 mg of salt per kg as against 20 mg of salt per kg in adults).
Intramuscular: 10 mg base/kg every eight hours by deep I.M. injections to the anterior thigh.
The total duration of treatment is 7-10 days. In children with protracted severe malaria, the dose of quinine may have to be reduced by one third or one half after the third day until the clinical condition improves, to avoid cumulative toxicity.
Arteether  3mg / kg IM for 3 days
Artemether 3.2mg / kg IM followed by 1.6 mg / kg for 5 days or 9.6 mg/kg max.
Artesunate 2.4 mg/kg at 0, 12, 24, 48 and once a day later, if required
Severe Malaria: Differences between Adults and Children
Clinical manifestation Adults Children
Duration of illness prior to complications 5-7 days 1-2 days
Convulsions Common Very common; can be due to severe infection, hypoglycemia, febrile seizures, severe anemia etc.
Abnormal brain stem reflexes (oculovestibular, oculocervical) Rare More common
C.S.F. pressure Usually normal Variable, often raised
Resolution of coma 2-4 days 1-2 days
Neurological sequelae <5% >10%
Cough Uncommon Common
Anemia Common More common and more severe; may be the presenting feature
Jaundice Common Uncommon
Pre-treatment hypoglycemia Uncommon Common
Pulmonary oedema Common Rare
Renal failure Common Rare
Bleeding/clotting disturbances Up to 10% Rare


© ©BS Kakkilaya | Last Updated: Mar 11, 2015

Malaria and Pregnancy

Malaria in pregnancy is a obstetric, social and medical problem requiring multidisciplinary and multidimensional solution. Pregnant women constitute the main adult risk group for malaria and 80% of deaths due to malaria in Africa occur in pregnant women and children below 5 years. In Africa, perinatal mortality due to malaria is at about 1500/day. In areas where malaria is endemic, 20-40% of all babies born may have a low birth weight. Malaria in pregnancy is a Priority Area in Roll Back Malaria strategy.

Malaria and pregnancy are mutually aggravating conditions. The physiological changes of pregnancy and the pathological changes due to malaria have a synergistic effect on the course of each other, thus making the life difficult for the mother, the child and the treating physician. P. falciparum malaria can run a turbulent and dramatic course in pregnant women. The non- immune, primi gravidae are usually the most affected. In pregnant women the morbidity due to malaria includes anemia, fever illness, hypoglycemia, cerebral malaria, pulmonary edema, puerperal sepsis and mortality can occur from severe malaria and haemorrhage. The problems in the new born include low birth weight, prematurity, IUGR, malaria illness and mortality.

Malaria in Pregnancy : Double Trouble

  • Malaria is more common in pregnancy compared to the general population. Immuno suppression and loss of acquired immunity to malaria could be the causes.
  • In pregnancy, malaria tends to be more atypical in presentation. This could be due to the hormonal, immunological and hematological changes of pregnancy.
  • Due to the hormonal and immunological changes, the parasitemia tends to be 10 times higher and as a result, malaria tends to be more severe in pregnancy compared to the non-pregnant population.
  • Malaria in pregnancy being more severe, also turns out to be more fatal, the mortality being double (13 %) in pregnant compared to the non-pregnant population (6.5%).
  • Some anti malarials are contra indicated in pregnancy and some may cause severe adverse effects. Therefore the treatment may become difficult, particularly in cases of severe P. falciparum malaria.
  • Management of complications of malaria may be difficult due to the various physiological changes of pregnancy. Careful attention has to be paid towards fluid management, temperature control, etc. Also decisions regarding induction of labour may be difficult and complex. Foetal loss, IUGR, and premature labour are common.


The pathophysiology of malaria in pregnancy is greatly due to the altered immunity and availability of a new organ called placenta in pregnancy. A dramatic breakdown of acquired immunity occurs in pregnancy, especially in primigravidae. (Paradoxically, fully effective antimalaria immunity is transferred to the child!) Various hypotheses have been put forth to explain the pathophysiology of malaria in pregnancy.

Hypothesis – 1: Loss of antimalarial immunity is consistent with the general immunosupression of pregnancy viz; reduced lymphoproliferative response, sustained by elevated levels of serum cortisol. This is designed to prevent the fetal rejection but renders the pregnant woman susceptible to infection. However, this does not explain the diminished susceptibility to malaria experienced by multigravid women.

Hypothesis – 2: What is lost is cell mediated immunity, but what is transferred is the passive antibody mediated immunity and therefore the pregnant mother suffers.

Hypothesis – 3: Placenta is a new organ in the primigravidae and allows the parasites to by-pass the existing host immunity or allows placenta specific phenotypes of P. falciparum to multiply. Development of placenta specific immunity may thus explain the decreased susceptibility in multigravidae.

Recently, it has been discovered that multigravid women can form strain-independent antibodies against CSA-specific parasites, and they demonstrate greatly diminished parasite load. The unique susceptibility of primigravids to placental infection can be explained by their immune inexperience with the parasite subpopulation.

Hypothesis – 4: Pregnant women display a bias towards type- 2 cytokines and are therefore susceptible to diseases requiring type 1 responses for protection like TB, malaria, leishmaniasis etc. However, in infected pregnant women a change of balance of the local placental environment from TH2 to TH1 has been observed, consistent with large number of monocytes in infected placenta. IL-10 levels are decreased, while IFN-g, IL-2, and TNF-α levels-hallmarks of a type-1 cytokine response-are elevated. These pro-inflammatory cytokines account for the pathology of maternal malaria: Elevated levels of TNF- α are associated with severe maternal anemia; symptomatology of malaria and localized cytokine elevation contributes to adverse pregnancy outcomes.

Role of Placenta, the NEW ORGAN of pregnancy:

P. falciparum has the unique ability of cytoadhesion and adhesion molecules such as CD36 and intercellular adhesion molecule-1 may be involved in the development of severe malaria in children and non-pregnant adults. Chondroitin sulfate A and hyaluronic acid have been identified as the adhesion molecules for parasite attachment to placental cells. The putative ligand expressed by the parasite is PfCSA-L and it has been found to be antigenically conserved among global cases of maternal malaria, suggesting a unique subpopulation of P. falciparum that do not bind to CD36. The parasites sequester along the surface of the placental membrane, specifically the trophoblastic villi, extravillous trophoblasts, and syncytial bridges. Intervillous spaces are filled with parasites and macrophages, interfering with oxygen and nutrient transport to the foetus. Villous hypertrophy and fibrinoid necrosis of villi (complete or partial) have been observed. All the placental tissues exhibit malarial pigments (with or even without parasites). These changes impede oxygen-nutrient transfer and can cause general hemorrhaging. These changes contribute to the complications experienced by both mother and child.

Pregnancy-malaria and intensity of transmission: Clinical presentation and severity of malaria in pregnancy differ in areas of high transmission and low transmission due to differences in the level of immunity. In high endemic areas, acquired immunity is high, mortality is less common, asymptomatic and incidental parasitemia are not uncommon. Sequestration of MP in the placenta and long standing placental malaria occur and peripheral blood may be negative for MP. Higher parasitemia, particularly in II and III trimester; anemia and altered placental integrity result in less nutritional support leading to LBW, abortion, stillbirth, premature birth and low birth weight, and excess infant mortality/morbidity. These problems are more common in first and second pregnancies as the parasitemia level decreases with increasing number of pregnancy. HIV infection extends this to all pregnancies and makes it worse. The strategy for management of malaria in pregnant population in areas of high transmission include intermittent treatment and use of insecticide treated bednets.

In areas of low transmission, the problems are dramatically different. The risk of malaria infection during pregnancy is greater and can result in maternal death and spontaneous abortion in up to 60% of cases. Low birth weight can occur even in cases of treated malaria; however, silent malaria rather rare. The strategy involves measures to avoid malaria by ITMs/chemoprophylaxis and early diagnosis and prompt treatment of cases.

Table: Comparison of occurrence of complications in areas of high and low transmission

Complication High Transmission Low transmission
Hypoglycemia ++
Severe Anemia +++ +++
Pulmonary oedema ++
ARF ++
Hyperpyrexia + +++
Placental malaria +++ +++
LBW babies +++ +++
Abortions +++
Congenital malaria +++

Clinical features:

Atypical manifestations of malaria are more common in pregnancy, particularly in the 2nd half of pregnancy.

Fever: Patient may have different patterns of fever – from afebrile to continuous fever, low grade to hyper pyrexia. In 2nd half of pregnancy, there may be more frequent paroxysms due to immunosuppression.

Anemia: In developing countries, where malaria is most common, anemia is a common feature of pregnancy. Malnutrition and helminthiasis are the commonest causes of anemia. In such a situation, malaria will compound the problem. Anemia may even be the presenting feature of malaria and therefore all cases of anemia should be tested for MP. Anemia as a presenting feature is more common in partially immune multigravidae living in hyperendemic areas.

Splenomegaly: Enlargement of the spleen may be variable. It may be absent or small in 2nd half of pregnancy. A preexisting enlarged spleen may regress in size in pregnancy.

Complications: Complications tend to be more common and more severe in pregnancy. A patient may present with complications of malaria or they may develop suddenly. Acute pulmonary edema, hypoglycemia and anemia are more common in pregnancy. Jaundice, convulsions, altered sensorium, coma, vomiting / diarrhoea and other complications may be seen.

Complications of malaria in pregnancy:

Anemia: Malaria can cause or aggravate anemia. It could be due to the following causes:

  1. Hemolysis of parasitised red blood cells.
  2. Increased demands of pregnancy.
  3. Profound hemolysis can aggravate folate deficiency.

Anemia due to malaria is more common and severe between 16-29 weeks. It can develop suddenly, in case of severe malaria with high grades of parasitemia. Pre existing iron and folate deficiency can exacerbate the anemia of malaria and vice versa.

Anemia increases perinatal mortality and maternal morbidity and mortality. It also increases the risk of pulmonary oedema. Risk of post-partum haemorrhage is also higher.

Significant anemia (Hemoglobin <7-8 g%) may have to be treated with blood transfusion. In view of the increased fluid volume in pregnancy, it is better to transfuse packed cells than whole blood. Rapid transfusion, particularly whole blood, may cause pulmonary oedema.

Acute pulmonary oedema:

Acute pulmonary oedema is also a more common complication of malaria in pregnancy compared to the non-pregnant population. It may be the presenting feature or can develop suddenly after several days. It is more common in 2nd and 3rd trimesters.

It can develop suddenly in immediate post-partum period due to auto transfusion of placental blood with high proportion of parasitised RBC’s and sudden increase in peripheral vascular resistance after delivery.

It is aggravated by pre existing anemia and hemodynamic changes of pregnancy.

Acute pulmonary oedema carries a very high mortality.


This is another complication of malaria that is peculiarly more common in pregnancy. The following factors contribute to hypoglycemia:

  1. Increased demands of hypercatabolic state and infecting parasites.
  2. Hypoglycemic response to starvation.
  3. Increased response of pancreatic islets to secretory stimuli (like quinine) leads to hyperinsulinemia and hypoglycemia..

Hypoglycemia in these patients can remain asymptomatic and may not be detected. This is because, all the symptoms of hypoglycemia are also caused by malaria viz. tachycardia, sweating, giddiness etc. Some patients may have abnormal behaviour, convulsions, altered sensorium, sudden loss of consciousness etc. These symptoms of hypoglycemia may be easily confused with cerebral malaria. Therefore, in all pregnant women with falciparum malaria, particularly those receiving quinine, blood sugar should be monitored every 4-6 hours. Hypoglycemia can be recurrent and therefore constant monitoring is needed.

In some, it can be associated with lactic acidosis and in such cases mortality is very high. Maternal hypoglycemia can cause fetal distress without any signs.

Immuno suppression:

Immunosuppression in pregnancy poses special problems. It makes malaria more common and more severe. And to add to the woes, malaria itself suppresses immune response.

Hormonal changes of pregnancy, reduced synthesis of immunoglobulins, reduced function of reticulo endothelial system are the causes for immunosuppression in pregnancy. This results in loss of acquired immunity to malaria, making the pregnant more prone for malaria. Malaria is more severe with higher parasitemia. Patient may have more frequent paroxysms of fever and frequent relapses.

Secondary infections (UTI and pneumonias) and algid malaria (septicaemic shock) are more common in pregnancy due to immunosuppression.

Risks for the foetus:

Malaria in pregnancy is detrimental to the foetus. High grades of fever, placental insufficiency, hypoglycemia, anemia and other complications can all adversely affect the foetus. Both P. vivax and P. falciparum malaria can pose problems for the foetus, with the latter being more serious. The prenatal and neonatal mortality may vary from 15 to 70%. In one study, mortality due to P. vivax malaria during pregnancy was 15.7% while that due to P. falciparum was 33%. Spontaneous abortion, pre mature birth, still birth, placental insufficiency and IUGR (temporary / chronic), low birth weight, fetal distress are the different problems observed in the growing foetus. Transplacental spread of the infection to the foetus can result in congenital malaria.

Congenital malaria: Congenital malaria due to transplacental or peripartal infection of the fetus is being increasingly reported in has been reported in 8–33% of pregnancies from both malaria-endemic and nonendemic areas.[9-15] It has been reported following maternal infections with all four species of human plasmodium, althighu most cases are reported following P. falciparum or P. vivax malaria.[5,16,17] In nonendemic countries, P. malariae may cause a disproportionately higher number of congenital malaria cases due to its longer persistence in the host.[16] [Also See]

In endemic areas symptomatic malaria in the neonate is rare, despite a high incidence of maternal parasitemia and placental malaria, as maternally derived IgG and the high proportion of fetal hemoglobin inhibit parasite development.[16,17] In endemic areas a high prevalence of neonatal parasitemia has been reported, with majority of the parasitemic newborns being asymptomatic; however, the mortality was found to be higher in the parasitemic newborns compared with the aparasitemic and in the symptomatic compared with the asymptomatic.[11-15] On the other, infants born to nonimmune mothers with malaria at the time of labour may develop parasitemia and illness in the first few weeks of life. Congenital malaria usually manifests between the second and eighth weeks of life (as early as 1 day or delayed by weeks or months)[10] with symptoms such as fever, anorexia, lethargy, anemia, and hepatosplenomegaly etc. Features suggestive of neonatal sepsis such as irritability, poor feeding, regurgitation, loose stools, jaundice, and occasionally drowsiness, restlessness, and cyanosis, may also be seen. However, complications seen in nonimmune adults have not been reported in congenital malaria.[17]

The diagnosis of congenital malaria can be confirmed by a smear for MP from cord blood or heel prick, anytime within a week after birth (or even later if post-partum, mosquito-borne infection is not likely). Differential diagnoses include Rh. incompatibility, infections with CMV, Herpes, Rubella, Toxoplasmosis, and syphilis.

P. vivax malaria in pregnancy:

There are very few documented studies on P. vivax malaria in pregnancy. It appears to be more common in primigravidae than multigravidae. Parasite densities are similar in pregnant and non-pregnant states. It may be associated with mild anaemia and increased risk of low birth weight and not associated with abortion, stillbirth or a reduction of the duration of pregnancy. Benefit of chemoprophylaxis has not been established.

Management of Malaria in Pregnancy:

Management of malaria in pregnancy involves the following three aspects and equal importance should be attached to all the three.

  1. Treatment of malaria
  2. Management of complications
  3. Management of labour

Treatment of malaria: [See Treatment of Malaria in Pregnancy]

Treatment of malaria in pregnancy should be energetic, anticipatory and careful.


  • Don’t waste any time.
  • It is better to admit all cases of P. falciparum malaria.
  • Assess severity- General condition, pallor, jaundice, BP, temperature, hemoglobin, Parasite count, SGPT, S. bilirubin, S. creatinine, Blood sugar.

Anticipatory: Malaria in pregnancy can cause sudden and dramatic complications. Therefore, one should always be looking for any complications by regular monitoring.

  • Monitor maternal and fetal vital parameters 2 hourly.
  • RBS 4-6 hourly; hemoglobin and parasite count 12 hourly; S. creatinine; S. bilirubin and Intake / Output chart daily.

Careful: The physiologic changes of pregnancy pose special problems in management of malaria. In addition, certain drugs are contra indicated in pregnancy or may cause more severe adverse effects. All these factors should be taken into consideration while treating these patients.

  • Choose drugs according to severity of the disease/ sensitivity pattern in the locality.
  • Avoid drugs that are contra indicated
  • Avoid over / under dosing of drugs
  • Avoid fluid overload / dehydration
  • Maintain adequate intake of calories.

Anti malarials in pregnancy:

All trimesters: Chloroquine; Quinine; Artesunate / Artemether / Arteether

2nd trimester: Mefloquine; Pyrimethamine / sulfadoxine

3rd trimester: Mefloquine; ?Pyrimethamine / sulfadoxine

Contra indicated: Primaquine; Tetracycline; Doxycycline; Halofantrine

Management of complications:

[See Treatment of Severe P. falciparum malaria]

Acute Pulmonary Oedema: Careful fluid management; back rest; oxygen; diuretics; ventilation if needed.

Hypoglycemia: 25-50% Dextrose, 50-100 ml I.V., followed by 10% dextrose continuous infusion. If fluid overload is a problem, then Inj. Glucagon 0.5-1 mg can be given intra muscularly. Blood sugar should be monitored every 4-6 hours for recurrent hypoglycemia.

Anemia: Packed cells should be transfused if hemoglobin is <5g%.

Renal failure: Renal failure could be pre-renal due to unrecognised dehydration or renal due to severe parasitemia. Treatment involves careful fluid management, diuretics, and dialysis if needed.

Septicaemic shock: Secondary bacterial infections like urinary tract infection, pneumonia etc. are more common in pregnancy associated with malaria. Some of these patients may develop septicaemic shock, the so called ‘algid malaria’. Treatment involves administration of 3rd generation cephalosporins, fluid replacement, monitoring of vital parameters and intake and output.

Exchange transfusion: Exchange transfusion is indicated in cases of severe falciparum malaria to reduce the parasite load. Patient’s blood is removed and it is replaced with packed cells. It is especially useful in cases of very high parasitemia (helps in clearing) and impending pulmonary oedema (helps to reduce fluid load).

Management of labour:

Anemia, hypoglycemia, pulmonary oedema, and secondary infections due to malaria in full term pregnancy lead to problems for both the mother and the foetus. Severe falciparum malaria in full term pregnancy carries a very high mortality. Maternal and fetal distress may go unrecognised in these patients. Therefore, careful monitoring of maternal and foetal parameters is extremely important and pregnant women with severe malaria are better managed in an intensive care unit.

Falciparum malaria induces uterine contractions, resulting in premature labour. The frequency and intensity of contractions appear to be related to the height of the fever. Fetal distress is common and often unrecognised. Therefore only monitoring of uterine contractions and fetal heart rate may reveal asymptomatic labour and foetal tachycardia, bradycardia or late deceleration in relation to uterine contractions, indicating fetal distress. All efforts should be made to rapidly bring the temperature under control, by cold sponging, anti pyretics like paracetamol etc.

Careful fluid management is also very important. Dehydration as well as fluid overload should be avoided, because both could be detrimental to the mother and/or the foetus. In cases of very high parasitemia, exchange transfusion may have to be carried out.

If the situation demands, induction of labour may have to be considered. Once the patient is in labour, foetal or maternal distress may indicate the need to shorten the 2ndstage by forceps or vacuum extraction. If needed, even caesarian section must be considered.

Treatment of vivax malaria in pregnancy:

In pregnancy, use of primaquine is contraindicated. Therefore to prevent the relapse of vivax malaria from reactivation of hypnozoites in the liver, suppressive chemoprophylaxis with chloroquine is recommended. Tablet Chloroquine 500 mg weekly should be administered to all such patients until delivery. At that point, a complete treatment with full therapeutic dose of chloroquine and primaquine should be administered.

Vaccine against malaria in pregnancy: Although a general malaria vaccine appears to be a distant possibility, there is much hope for a vaccine against placental malaria. The administration of excessive soluble CSA to pregnant women has proven to drastically reduce parasite adhesion; however, in excess levels, this soluble protein is severely nephrotoxic. Studies have demonstrated that the administration of chondroitinase AC can effectively reduce parasite adhesion by 95%. This preliminary data is being further tested in combination with therapeutic use of monoclonal antibodies to CSA

Also see Chemoprophylaxis

Further Reading:

  1. Ribera JM, Hausmann-Muela S, D’Alessandro U, Grietens KP. Malaria in Pregnancy: What Can the Social Sciences Contribute? PLoS Med 2007;4(4): e92. doi:10.1371/journal.pmed.0040092 Full Text Available at
  2. Bernard J Brabin, Marian Wasame, Ulrika Uddenfeldt-Wort, Stephanie Dellicour, Jenny Hill, Sabine Gies. Monitoring and evaluation of malaria in pregnancy – developing a rational basis for control. Malaria Journal 2008;7(Suppl 1):S6doi:10.1186/1475-2875-7-S1-S6. Full Text Available at
  3. Malaria in pregnancy. WHO. Available at
  4. Malaria in pregnancy. Available at
  5. Meghna Desai, Feiko O ter Kuile, François Nosten, Rose McGready, Kwame Asamoa, Bernard Brabin, Robert D Newman. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis 2007;7:93–104 [See Fulltext]
  6. Ali A. Haghdoost, Neal Alexander, Tom Smith. Maternal malaria during pregnancy and infant mortality rate: critical literature review and a new analytical approach. J Vect Borne Dis June 2007;44:98–104. Available at
  7. Gamble C, Ekwaru JP, ter Kuile FO. Insecticide-treated nets for preventing malaria in pregnancy. Cochrane Database of Systematic Reviews 2006, Issue 2. Art. No.: CD003755. DOI: 10.1002/14651858.CD003755.pub2. Available at
  8. Dr Eve Worrall, Chantal Morel, Shunmay Yeung, Jo Borghi, Jayne Webster, Jenny Hill, Virginia Wiseman, Anne Mills. The economics of malaria in pregnancy—a review of the evidence and research priorities. The Lancet Infectious Diseases February 2007;7(2):156-168. Available at
  9. Neena Valecha, Sunita Bhatia, Sadhna Mehta, Sukla Biswas, Aditya P Dash. Congenital malaria with atypical presentation: A case report from low transmission area in India. Malaria Journal 2007;6:43 Full Text at
  10. Ahmad Hashemzadeh, Farhad Heydarian. Congenital Malaria in a Neonate. Arch Iranian Med 2005;8(3):226–228. Full Text at
  11. Emad S, Saira L, Seema H, Shahina H. Congenital Malaria. Pak J Med Sci. 2008;24(5):765-67.
  12. Clara Menendezab, Alfredo Mayor. Congenital malaria: The least known consequence of malaria in pregnancy. Semin Fetal Neonatal Med June 2007;12(3):207-213
  13. Catherine R. Lesko, Paul M. Arguin, Robert D. Newman. Congenital Malaria in the United States. A Review of Cases From 1966 to 2005. Arch Pediatr Adolesc Med. 2007;161(11):1062-1067.
  14. Sotimehin SA, Runsewe-Abiodun TI, Oladapo OT. Possible risk factors for congenital malaria at a tertiary care hospital in Sagamu, Ogun state, South-West Nigeria. J Trop Ped 2008;54(5):313-320. DOI: 10.1093/tropej/fmn016
  15. Adeola A. Orogade et al. Clinical and laboratory features of congenital malaria in Nigeria. Journal of Pediatric Infectious Diseases. 2008;3(3):181-187
  16. Gitau GM, Eldred JM. Malaria in pregnancy: clinical, therapeutic and prophylactic considerations. The Obstetrician & Gynaecologist. 2005;7:5–11. Full text at
  17. WHO. Severe falciparum malaria. Transaction of Roy Soc Trop Med Hyg 2000; 94(suppl 1):1-90.

 © ©BS Kakkilaya | Last Updated: Mar 11, 2015

Complications in P. vivax Malaria

Plasmodium vivax and P. ovale infections are generally benign and complications leading to significant morbidity and mortality are uncommon.

Although P. vivax malaria is considered to be a benign malaria, it has been increasingly reported to cause various manifestations of severe disease, including thrombocytopaenia, cerebral malaria, and acute renal, hepatic and pulmonary dysfunctions, with some reports of deaths. With increasing reports of drug resistance, this indeed is a cause for concern. The underlying mechanisms of severe manifestations are not well understood. Prompt and effective treatment and case management should be the same as for severe and complicated falciparum malaria.

The clinical symptoms of fever, headache, nausea and vomiting in P. vivax may be incapacitating, particularly for those who are non-immune and suffering the infection for the first time.

Rupture of spleen: Malaria is an important cause for spontaneous rupture of spleen. It is more common in vivax malaria than falciparum malaria and tends to occur in up to 0.7% of the patients.

Rupture occurs in acute, rapid, hyperplastic enlargement of spleen. It is rare in chronic malaria, despite massive enlargement. Rapid enlargement results in increased capsular tension and increased parenchymal friability.  Marked splenomegaly can occur even in low-grade parasitemia (50/ml) and it may persist for weeks or months after effective and complete treatment.

Patients present with abdominal pain, fever, tachycardia, prostration and rapidly developing anemia and hypotension. Some of these manifestations are seen in malaria itself and therefore splenic rupture can be easily missed. A degree of suspicion is required to differentiate the two conditions. Leukocytosis, severe anemia and hypotension are more in favour of splenic rupture. Ultra sound evaluation of abdomen and paracentesis of the abdomen can confirm the diagnosis.

Treatment includes replacement of fluid and blood, laparotomy and splenectomy.

Splenic rupture carries a high mortality of about 80% and this is partly attributed to lack of awareness and missed diagnosis.

Hepatic dysfunction: Hepatomegaly and non-specific hepatitis, with or without jaundice can occur in vivax malaria. Fever, jaundice, tender hepatomegaly, mild elevation in the levels of hepatic enzymes and bilirubin are observed. Liver biopsy in such cases has demonstrated brown malarial pigments in Kupffer’s cells, small to moderate sized granulomatous lesions with mononuclear infiltration and hepatocyte necrosis.

Liver function returns to normal shortly after antimalarial treatment.

Thrombocytopenia: Decrease in platelet counts can occur in vivax malaria, however, it is usually mild and bleeding does not occur.

Severe anemia: P. vivax can cause severe anemia, particularly when it is chronic and recurrent. Very rarely this can be life threatening or even fatal.

CNS manifestations: Changes in behaviour, altered sensorium, seizures, cerebral malaria, cerebellar manifestations and ataxia, hemiparesis,  aphasia, psychosis, acute inflammatory demyelinating polyneuropathy and post-malaria neurologic syndrome causing bilateral facial paralysis have all been reported in P. vivax malaria and some of these cases have had multiorgan involvement.

New paper

  1. Kochar DK, Das A, Kochar SK. Severe Plasmodium vivax malaria: A report on serial cases from Bikaner in Northwestern India. Am. J. Trop. Med. Hyg. 2009;80(2):194-198.
  2. Andrade BB, Reis-Filho A, M Souza-Neto S. Severe Plasmodium vivax malaria exhibits marked inflammatory imbalance. Malaria J 2010;9:13. doi:10.1186/1475-2875-9-13 At
  3. Tilluckdharry CC, Chadee DD, Doon R, Nehall J. A case of vivax malaria presenting with psychosis. West Indian Med J. Mar 1996;45(1):39-40.
  4. Taksande B, Jajoo U, Jajoo M. Cerebellar Malaria: A Rare Manifestation of Plasmodium vivax. The Internet Journal of Neurology. 2007;7(1)
  5. AM Taksande, KY Vilhekar Cerebellar Malaria Due to Plasmodium vivax in a Child. Iranian J Parasitol 2008;3(2):57-59. Full Text at
  6. Thapa R, Ranjan R, Patra VS, Chakrabartty S. Childhood Cerebral Vivax Malaria With Pancytopenia. Journal of Pediatric Hematology/Oncology. February 2009;31(2):116-117. doi: 10.1097/MPH.0b013e318186855a
  7.  Beg MA, Khan R, Baig SM, Gulzar Z, Hussain R, Smego RA Jr,. Cerebral involvement in benign tertian malaria. Am J Trop Med Hyg 2002;67:230–232.
  8. Sachdev HS, Mohan M. Vivax cerebral malaria. J Trop Pediatr 1985;31:213–215.
  9. Rajoo Thapa, Vikram Patra, Ritabrata Kundu. Plasmodium vivax Cerebral Malaria. Indian Pediatrics 2007;44:433-434. Full Text at
  10. Ozen M, Gungor S, Atambay M, Daldal N. Cerebral malaria owing to Plasmodium vivax: case report. Ann J Pediatr 2006;26:141-144
  11. Suman Sarkar, Prithwis Bhattacharya. Cerebral malaria caused by Plasmodium vivax in adult subjects. Indian J Crit Care Med. Oct–Dec 2008;12(4):204–205. doi: 10.4103/0972-5229.45084. Full Text at
  12. Anupkumar R. Anvikar, Dinesh K. Singh, Ruchi Singh, Aditya P. Dash, Neena Valecha. Vivax malaria presenting with cerebral malaria and convulsions. Acta Parasitologica March, 2010;55(1):96-98. DOI 10.2478/s11686-010-0013-7
  13. Mishra VN, Singh D. Cerebral malaria by Plasmodium vivax. J Assoc Physicians India. 1989 Jun;37(6):411.
  14. Parakh, A, Agarwal N, Aggarwal A, Aneja A. Plasmodium vivax malaria in children: uncommon manifestations. Annals of Tropical Paediatrics: International Child Health. December 2009;29(4):253-256.
  15. RK Patial, D Kapoor, JK Mokta. Cerebral dysfunction in vivax malaria: a case report. Ind J Med Scs. 1998;52(4):159-60.
  16. Khurshid Ahmad Abbasi, Shabir Ahmed Shaikh. Comparative study of Cerebral Malaria due to Plasmodium vivax and Falciparum. Pak Paed J Dec 1997;21(4):155-158.
  17. Jeanne R. Poespoprodjo et al. Vivax Malaria: A Major Cause of Morbidity in Early Infancy. Clinical Infectious Diseases 2009;48:1704–1712 Available at

 © ©BS Kakkilaya | Last Updated: Mar 11, 2015

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


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
  2. Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria. Critical Care 2003;7:315-323 Available at
  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

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.

 © ©BS Kakkilaya | Last Updated: Mar 11, 2015


Anemia is a common manifestation of all types of malaria. It is more common and poses more problems in pregnancy and children. In developing countries of the tropics, pre-existing anemia, most commonly due to malnutrition and helminthiasis, compounds the problem.

In falciparum malaria, anemia can develop rapidly due to profound hemolysis. The degree of anemia correlates with parasitemia and schizontemia. It is also associated with high serum bilirubin and creatinine levels. Pregnancy, secondary bacterial infections and bleeding disorders like disseminated intravascular coagulation can aggravate the anemia. Children may have severe anemia even with low parasitemia and in such cases the reticuloendothelial cells exhibit abundant malarial pigments.

Anemia in malaria is multifactorial. The causes include obligatory destruction of red cells at merogony, accelerated destruction of non-parasitised red cells (major contributor in anemia of severe malaria), bone marrow dysfunction that can persist for weeks, shortened red cell survival and increased splenic clearance. Massive gastrointestinal haemorrhage can also contribute to the anemia of malaria.

See Pathology

Patients with anemia can present with tiredness, prostration, breathlessness or even severe left ventricular failure and pulmonary oedema.

In pregnancy, anemia can cause premature labour, still birth and high perinatal and maternal mortality.

Anemia and fever tend to increase the cardiac output and this combination can prove fatal for patients with pre-existing cardiac disease.

A hemoglobin level of less than 7.1g% (4.4 mmol/l) should serve as a warning for impending crisis. Hemoglobin of less than 5g% (3.1 mmol/l) is an indication for transfusion of packed cells.


See Treatment of Severe P. falciparum malaria

If the hematocrit falls below 20%, blood transfusion may be needed. Fresh blood may in addition provide clotting factors. If fluid overload is a problem (e.g. pregnancy), it is preferable to transfuse packed red cells. Transfusion should be carefully monitored and central venous pressure should be assessed to avoid fluid overload and pulmonary oedema. 20 mg of Injection Furoscemide can be given as a diuretic to reduce the circulatory load. Repeated transfusions may be necessary in cases of severe parasitemia and profound hemolysis.

Iron and folic acid supplementation should be given, particularly for pregnant women.

  © ©BS Kakkilaya | Last Updated: Mar 11, 2015



Acute pulmonary edema is a grave and usually fatal complication of severe falciparum malaria with more than 50% mortality. Acute lung injury is defined as the acute onset of bilateral pulmonary infiltrates with an arterial oxygen tension/fractional inspired oxygen ratio of 300 mmHg or less, a pulmonary artery wedge pressure of 18 mmHg or less, and no evidence of left atrial hypertension. ARDS is defined as acute lung injury and an arterial oxygen tension/fractional inspired oxygen ratio of 200 mmHg or less. Volume overload and hypoalbuminemia may aggravate pulmonary capillary leakage. Chest radiograph abnormalities range from confluent nodules to basilar and/or diffuse bilateral pulmonary infiltrates. Noncardiogenic pulmonary edema rarely occurs with P. vivax and P. ovale malaria.[1]

In addition to severe falciparum parasitemia and sequestration, secondary infections, severe anemia, hyperpyrexia, dehydration/fluid overload, metabolic acidosis, hypoxia and disseminated intravascular coagulation can also contribute to the cardiovascular problems in malaria. Although myocardial function is generally well preserved in severe falciparum malaria, malaria can complicate pre-existing cardiac decompensation and may even prove fatal for patients with compromised heart. Cardiac arrhythmias are uncommon.

See pathology

Pathology of Acute Pulmonary Oedema: In a few patients it could be due to fluid overload as a result of enthusiastic fluid therapy. In others it develops even with normal or negative fluid balance. Pulmonary oedema develops later compared to other complications and it may even appear several days after treatment for malaria, when the patient is otherwise improving with a reduction in peripheral parasitemia.

The mechanism of pulmonary oedema is not clearly understood. It has a close resemblance to adult respiratory distress syndrome. While over-hydration may be the cause in some cases of pulmonary oedema, it can also develop in patients with normal capillary wedge pressures. Such cases may be due to increased permeability of pulmonary capillaries. Sequestration of red cells and clogging of pulmonary microcirculation and disseminated intravascular coagulation may also play their role. Pulmonary oedema is more common in patients with hyperparasitemia, renal failure and pregnancy and it is commonly associated with hypoglycemia and metabolic acidosis. It may develop suddenly after delivery, due to fluid overload. Pulmonary oedema may be the terminal event in many cases of fatal falciparum infection.

See pathology

The first sign of impending pulmonary oedema is an increase in the respiratory rate. Tachypnoea may also be the first indicator of aspiration bronchopneumonia and metabolic acidosis and a chest X-ray will help in differentiating these conditions. Then patient develops signs of pulmonary oedema like basal crackles, cyanosis, tachycardia etc. The breathlessness worsens rapidly and the patient may die within a few hours. Hypoxia can cause convulsions and deterioration in the level of sensorium.


See Treatment of Severe P. falciparum malaria

Pulmonary oedema is the most fatal of the complications of falciparum malaria and therefore calls for careful and energetic management.

Fluid overload should be avoided at all costs, especially in pregnant women. The central venous pressure should be maintained between 0-5 cm of H2O by regulating fluid intake and nursing the patient propped up at 450. All intravenous fluids should be stopped immediately and diuretics may have to be administered.

Initial management of pulmonary oedema includes treatment with oxygen, back-rest and diuretics if there is evidence of fluid overload. Inj. Furoscemide 40 mg should be given intravenously and if there is no desired response, the dose can be progressively increased up to 200 mg. Fluid volume can be further reduced by venesection and letting of 250 ml of blood initially. This blood or its packed cells can be re-transfused once the problem settles down. The procedure can be repeated carefully if needed.

If the patient deteriorates with conservative treatment, mechanical ventilation is indicated. Positive end expiratory pressure ventilation may also be needed. Drugs like corticosteroids are not of any proven benefit in the management of these cases.
Overall, pulmonary oedema carries a poor prognosis.


  1. Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria Critical Care 2003;7:315-323 Available at

 © ©BS Kakkilaya | Last Updated: Mar 11, 2015

Renal Failure

Renal impairment is a sensitive prognostic indicator in severe falciparum malaria. Renal failure is more common in adults and rarely, if ever, seen in children. Usually there is a reversible dysfunction, which may progress to acute tubular necrosis and acute renal failure. It carries a high mortality.

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.

  1. Dehydration and hypovolumia can lead to renal hypoperfusion, but this is reversible with adequate rehydration. High-grade fever, profuse sweating, lack of adequate intake, vomiting and diarrhoea contribute to dehydration.
  2. Increase in blood viscosity due to dehydration and hyperparasitemia also results in renal hypoperfusion.
  3. Intravascular hemolysis and clogging of the tubules by the products of hemolysis is another important cause for renal dysfunction. Severe falciparum malaria results in hemolysis of parasitized as well as non-parasitized red cells. Oxidant drugs like primaquine can also contribute to hemolysis in severe falciparum malaria, and particularly in patients with deficiency of Glucose 6-phosphate dehydrogenase enzyme. Although hemoglobin itself is not nephrotoxic, other products of hemolysis can cause acute tubular necrosis, particularly in the presence of dehydration and acidosis.

See Pathology

Renal failure in malaria usually manifests as oliguria with urine output less than 400 ml in 24 hours. However in some cases it may be non-oliguric or polyuric.

Investigations: Blood urea, creatinine, electrolytes, bicarbonate, and urine analysis including urine specific gravity should be done. If the patient is severely ill and anuric, ECG can be done to identify hyperkalemia (tall, pointed T waves; widening of QRS). Hyperventilation with a clear chest indicates metabolic acidosis and in such cases, arterial pH and blood gases should also be estimated. All these parameters should be assessed twice every day in the initial stages of the disease.


See Treatment of Severe P. falciparum malaria
Provided that the patient has not been given diuretics, a specific gravity of more than 1.015 suggests dehydration and such patients may respond to rehydration. Normal saline should be infused until the central venous pressure rises to 5 cm of water. If this fails to improve the urine output, then Inj. Furoscemide can be given. Starting at 40 mg, the dose of furoscemide can be progressively increased at half-hourly intervals. Dopamine infusion at 2-5mg/kg/min can also be tried. If these measures fail to re-establish urine flow, further doses of these drugs as well as intravenous fluids should be withheld.

Dialysis should be considered in all patients who do not respond to this conservative treatment. Anuria after adequate fluid replacement, hyperkalemia, fluid overload, metabolic acidosis and clinical signs of uremia (pericarditis, encephalopathy) are indications for dialysis. The rate of exchange of dialysate should be governed by the improvement in biochemical parameters. High glucose dialysate (hypertonic) can be used to reduce fluid overload, which in addition takes care of hypoglycemia.

Hemodialysis is preferred over peritoneal dialysis for splanchnic blood flow may be reduced in severe malaria and solute clearance may be less across the peritoneum. However, if facilities are not available for hemodialysis, peritoneal dialysis can still be tried. It should be kept in mind that bleeding and secondary infections are high with this procedure in cases of severe malaria. Peritoneal dialysis should be carried out with Tenckhoff catheter inserted under aseptic precautions. Whenever there is suspicion of peritonitis, peritoneal effluent should be examined under Gram’s stain and it should be cultured. Appropriate antibiotics can be started based on the Gram’s stain report.

See Quartan Nephropathy


© ©BS Kakkilaya | Last Updated: Mar 11, 2015

Cerebral Malaria

Cerebral malaria is the most common complication and cause of death in severe P. falciparum infection. In falciparum malaria, 10% of all admissions and 80% of deaths are due to the CNS involvement. On the other hand, CNS manifestations are fairly common in malaria and it could be due to not only severe P. falciparum infection, but also high-grade fever and antimalarial drugs. Therefore, it is extremely important to differentiate between these so as to avoid unnecessary anxiety and improper treatment.

Manifestations of cerebral dysfunction include any degree of impaired consciousness, delirium, abnormal neurological signs, and focal and generalized convulsions. In severe P. falciparum malaria, the neurological dysfunction can manifest suddenly following a generalized seizure or gradually over a period of hours.

Causes of neurological manifestations in malaria:

  • High-grade fever alone can produce impairment of consciousness, febrile convulsions (in children) and psychosis. These manifestations subside with the decrease in the body temperature. Such cases and patients with unimpaired consciousness after seizures tend to have good prognosis.
  • Antimalarial drugs like chloroquine, quinine, mefloquine and halofantrine also can cause altered behaviour, convulsions, hallucinations and even psychosis. Absence of high-grade fever and of falciparum parasitemia may suggest such a possibility.
  • Hypoglycemia, either due to severe malaria or due to drugs like quinine, may also present with similar manifestations. Hypoglycemia is more common in pregnancy. It may be worthwhile considering this possibility in ALL cases and to administer 25-50% dextrose intravenously.
  • Hyponatremia, most often in the elderly and caused by repeated vomiting, is another important cause for neurological manifestations.
  • Severe anaemia and hypoxemia can also cause cerebral dysfunction, particularly in children.
  • There could be other causes for neurological dysfunction in patients with malaria like vascular disease, other neurological infections and diseases. Focal neurological deficits, neck rigidity, photophobia, papilloedema and neurological sequelae are very rare in falciparum malaria and such a picture would therefore suggest these other possibilities.

A strict definition of cerebral malaria has been recommended for sake of clarity and this requires the presence of unarousable coma, exclusion of other encephalopathies and confirmation of P. falciparum infection. This requires the presence of P. falciparum parasitemia and the patient to be unrousable with a Glasgow Coma Scale score of 9 or less, and other causes (e.g. hypoglycemia, bacterial meningitis and viral encephalitis) ruled out. To distinguish cerebral malaria from transient postictal coma, unconsciousness should persist for at least 30 min after a convulsion. The deeper the coma, the worse is the prognosis. If necessary, a lumbar puncture should be performed to rule out bacterial meningitis. However, all patients with P. falciparum malaria with neurological manifestations of any degree should be treated as cases of cerebral malaria.[1]

Pathophysiology: Cerebral malaria is the most important complication of falciparum malaria. However, its pathophysiology is not completely understood. The basic underlying defect seems to be clogging of the cerebral micocirculation by the parasitized red cells. These cells develop knobs on their surface and develop increased cytoadherent properties, as a result of which they tend to adhere to the endothelium of capillaries and venules. This results in sequestration of the parasites in these deeper blood vessels. Also, rosetting of the parasitized and non-parasitized red cells and decreased deformability of the infected red cells further increases the clogging of the microcirculation. It has been observed that the adhesiveness is greater with the mature parasites. Obstruction to the cerebral microcirculation results in hypoxia and increased lactate production due to anaerobic glycolysis. The parasitic glycolysis may also contribute to lactate production. In patients with cerebral malaria, C.S.F. lactate levels are high and significantly higher in fatal cases than in survivors. The adherent erythrocytes may also interfere with gas and substrate exchange throughout the brain. However, complete obstruction to blood flow is unlikely, since the survivors rarely have any permanent neurological deficit.

Vascular permeability is found to be mildly increased, however, no definite evidence of cerebral edema has been found on imaging studies. 80% children with cerebral malaria have raised ICT, due to increased cerebral blood volume and biomass rather than increased permeability. The mechanism of coma is not clearly known. Increased cerebral anaerobic glycolysis, intereference with neurotransmission by sequestered and highly metabolically active parasites have been blamed. Cytokines induce nitric oxide synthesis in leukocytes, smooth muscle cells, microglia and endothelium and NO is a potent inhibitor of neurotransmission.

See Pathology

Neurological signs in cerebral malaria:

As per the definition, patient should have unarousable coma, not responding to noxious stimuli with a Glasgow coma scale of <7/15. Mild neck stiffness may be seen, however, neck rigidity and photophobia and signs of raised intracranial tension are absent. Retinal haemorrhages occur in about 15% of cases, exudates are rare. Pupils are normal. Papilloedema is rare and should suggest other possibilities. A variety of transient abnormalities of eye movements, especially dysconjugate gaze, are observed. Fixed jaw closure and tooth grinding (bruxism) are common. Pouting may occur or a pout reflex may be ellicitable, but other primitive reflexes are usually absent. The corneal reflexes are preserved except in case of deep coma. Motor abnormalities like decerebrate rigidity, decorticate rigidity and opisthotonus can occur. Deep jerks and plantar reflexes are variable. Abdominal and cremasteric reflexes are not ellicitable. These signs help in distinguishing from behavioural problems due to fever of other causes.

These patients may also have anemia, jaundice and hepatosplenomegaly.

Investigations: Lumbar puncture and CSF analysis may have to be done in all doubtful cases and to rule out associated meningitis. In malaria, CSF pressure is normal to elevated, fluid is clear and WBCs are fewer than 10/µl; protein and lactic acid levels are elevated.

EEG may show non-specific abnormalities. CT scan of the brain is usually normal.

Malarial Retinopathy:

A large, prospective autopsy study of children dying with cerebral malaria in Malawi found that malarial retinopathy was better than any other clinical or laboratory feature in distinguishing malarial from non-malarial coma. The malarial retinopathy consists of four main components: retinal whitening, vessel changes, retinal hemorrhages, and papilledema. The first two of these abnormalities are specific to malaria, and are not seen in other ocular or systemic conditions.

See Beare NAV, Taylor TE, Harding SP, Lewallen S, Molyneux ME. Malarial Retinopathy: A Newly Established Diagnostic Sign in Severe Malaria. Am. J. Trop. Med. Hyg. 2006;75(5):790-797. Full Text Available at

A case of severe retinal whitening has also been reported in an adult with cerebral malaria.

See Maude RJ, Hassan MU, Beare NAV. Severe Retinal Whitening in an Adult with Cerebral Malaria. Am. J. Trop. Med. Hyg., 2009;80(6):881. Available at

Cerebral malaria in children


1. Nursing care: Meticulous nursing is the most important aspect of management in these patients.

  • Maintain a clear airway. In cases of prolonged, deep coma, endotracheal intubation may be indicated.
  • Turn the patient every two hours.
  • Avoid soiled and wet beds.
  • Comatose patients should be placed in a semirecumbent position to reduce the risk for aspiration.
  • Naso-gastric aspiration to prevent aspiration pneumonia.
  • Maintain strict intake/output record. Observe for high coloured or black urine.
  • Monitor vital signs every 4-6 hours.
  • Changes in levels of sensorium, occurrence of convulsions should also be observed.
  • If the temperature is above 390 C, tepid sponging and fanning must be done.
  • Serum sodium concentration, arterial carbon dioxide tension, blood glucose, and arterial lactate concentration should be monitored frequently.

2. Urethral catheter can be inserted for monitoring urine output.

3. Seizures should be treated promptly with anticonvulsants, but their prophylactic use is still in dispute.[1] Diazepam by slow intravenous injection, (0.15 mg/kg, maximum of 10 mg), or intrarectally (0.5-1.0 mg/kg), or intramuscular paraldehyde are the drugs of choice.

4. Do not administer the following: Corticosteroids; other anti inflammatory drugs; anti oedema drugs like mannitol, urea, invert sugar; low molecular weight dextran; adrenaline; heparin; pentoxifylline; hyperbaric oxygen; ciclosporin etc. The efficacy of hypertonic mannitol in treatment of cerebral edema is not proven. Therapy with monoclonal antibodies against TNF-a shortens the duration of fever, but has no impact on mortality in patients with severe and complicated malaria, and may increase morbidity due to neurologic sequelae. Although corticosteroids were used in the past to treat patients with cerebral malaria, a controlled trial has shown that they are harmful. Those who received dexamethasone had a longer duration of coma and worse outcome than did patients who received antimalarial chemotherapy alone. Results of studies of antipyretics, pentoxifylline, hyperimmune serum, and iron chelators (deferoxamine) have shown no effect on outcome.[1]

5. Antimalarial treatment: Parenteral Quinine has been traditionally the treatment of choice for cerebral malaria. Artemisinin derivatives have been proved to be equally, if not more, effective in treating cerebral malaria. (For details see Treatment of Severe P. falciparum malaria)

Prognosis: Cerebral malaria carries a mortality of around 20% in adults and 15% in children. Residual deficits are unusual in adults (<3%). About 10% of the children (particularly those with recurrent hypoglycemia, severe anemia, repeated seizures and deep coma), who survive cerebral malaria may have persistent neurological deficits.

Cerebellar dysfunction: Rarely, cases of falciparum malaria may present with cerebellar ataxia with unimpaired consciousness. It may even occur 3-4 weeks after an attack of falciparum malaria. It completely recovers over 1-2 weeks.

Malarial psychosis: Occasionally patients with malaria may present with organic brain syndrome. More often it can develop due to drugs like chloroquine and mefloquine. It can also develop during convalescence after attacks of otherwise uncomplicated malaria. Malaria can also exacerbate pre-existing psychiatric illness. Patients can manifest with depression, paranoia, delusions and personality changes. Most of these are self-limiting and improve in a matter of days.

In a study of 118 cases of malaria in Mangalore, Nagesh Pai, Satish Rao and B.S. Kakkilaya found varied psychiatric manifestations. Most of these patients were already on antimalarial treatment at the time of referral to the psychiatric service (unpublished data).

Feature (n=118) Feature (n=118)
Delirium 22 Organic hallucinosis 12
Organic catatonic disorder 4 Organic delusional disorder 9
Organic mania 7 Organic Depressive disorder 13
Organic anxiety 26 Organic dissociative disorder 2
Mild cognitive disorder 4 Multiple vague complaints > 7days 8
Headache >7 days 11


  1. Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria Critical Care 2003;7:315-323 Available at
  2. Guidelines for the treatment of malaria. World Health Organization. Geneva, 2006. pp 41-61. Available at


© ©BS Kakkilaya | Last Updated: Mar 11, 2015

Severe Malaria

Severe falciparum malaria is defined by the demonstration of asexual forms of P. falciparum in a patient with a potentially fatal manifestation or complication of malaria in whom other diagnoses have been excluded.

Even though the complications are almost unique to P. falciparum infection, that DOES NOT mean that all cases of P. falciparum malaria invariably develop complications. The case fatality of P. falciparum malaria is around 1 per cent and this accounts for more than half a million deaths per year all over the world; 80% of these deaths are caused by cerebral malaria.

In 1990, the World Health Organization (WHO) established criteria for severe malaria and these were revised in the year 2000 to include other clinical manifestations and laboratory values that portend a poor prognosis based on clinical experience in semi-immune patients (Table 1). The major complications of severe malaria include cerebral malaria, pulmonary edema, acute renal failure, severe anemia, and/or bleeding. Acidosis and hypoglycemia are the most common metabolic complications. Any of these complications can develop rapidly and progress to death within hours or days.[1]

The presentation of severe malaria varies with age and geographical distribution. In areas of high malaria transmission, severe malaria mainly affects children under five years of age. The mortality rate is higher in adults than in children but African children develop neuro-cognitive sequelae following severe malaria more frequently. In children, the complications include metabolic acidosis (often caused by hypovolaemia), hypoglycaemia, hyperlacticacidaemia, severe anaemia, seizures and raised intracranial pressure and concomitant bacterial infections occur more frequently. In adults, renal failure and pulmonary oedema are more common causes of death.[2]

In many patients, several of these complications exist together or evolve in rapid succession within a few hours. In clinical practice, patients must be assessed for any of these signs or symptoms that suggest an increased risk for developing complications and must be treated immediately. In various studies risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).[1]

Predisposing factors for complications and death from P. falciparum malaria:

In various studies, risk factors for severe malaria and death include age greater than 65 years, female sex (especially when associated with pregnancy), nonimmune status, coexisting medical conditions, no antimalarial prophylaxis, delay in treatment, and severity of the illness at admission (coma, acute renal failure, shock, pulmonary edema, coagulation disorders). In tropical countries with a high transmission of malaria (hyperendemic areas), severe malaria is predominantly a disease of young children (1 month to 5 years of age).[1]

Lab. abnormalities:

Thrombocytopenia is the most common laboratory abnormality (60% of cases), followed by hyperbilirubinemia (40%), anemia (30%), and elevated hepatic aminotransferase levels (25%). The leukocyte count is usually normal or low, but neutrophilia with a marked increase in band forms (left shift) is present in the majority of cases. The erythrocyte sedimentation rate, C-reactive protein, and procalcitonin are almost invariably elevated. The severity of malaria corresponds to the degree of the laboratory abnormalities. In one study of travelers who returned from the tropics, thrombocytopenia and hyperbilirubinemia had a positive predictive value of 95% for malaria.[1]

Severe manifestations and complications of P. falciparum malaria

In a patient with falciparum malaria in whom other diseases have been excluded, the presence of one or more of the following manifestations is sufficient for a diagnosis of severe falciparum malaria.

Table 1: Indicators of severe malaria and poor prognosis [1,3-5]
Manifestation Features
Initial World Health Organization criteria from 1990 [3]
1. Cerebral malaria: Unarousable coma not attributable to any other cause, with a Glasgow Coma Scale score ≤9; Coma should persist for at least 30 min after a generalized convulsion
2. Severe anemia Hematocrit <15% or hemoglobin < 50 g/l in the presence of parasite count >10000/µl
3. Renal failure Urine output <400 ml/24 hours in adults (<12 ml/kg/24 hours in children) and a serum creatinine >265 µmol/l (> 3.0 mg/dl) despite adequate volume repletion
4. Metabolic (Lactic) Acidosis/acidosis Metabolic acidosis is defined by an arterial blood pH of <7.35 with a plasma bicarbonate concentration of <22 mmol/L; hyperlactatemia is defined as a plasma lactate concentration of 2-5 mmol/L and lactic acidosis is characterized by a pH <7.25 and a plasma lactate >5 mmol/L.
5. Pulmonary edema or acute respiratory distress syndrome (ARDS) Breathlessness, bilateral crackles, and other features of pulmonary oedema. The acute lung injury score is calculated on the basis of radiographic densities, severity of hypoxemia, and positive end-expiratory pressure
6. Hypoglycemia Whole blood glucose concentration of less than 2.2 mmol/l (less than 40 mg/dl).td
7. Hypotension and shock (algid malaria) Systolic blood pressure <50 mmHg in children 1-5 years or <70 mm Hg in patients ≥5 years; cold and clammy skin or a core-skin temperature difference >100C
8. Abnormal bleeding and/or disseminated intavascular coagulation Spontaneous bleeding from the gums, nose, gastrointestinal tract, retinal haemorrhages and/or laboratory evidence of disseminated intravascular coagulation.
9. Repeated generalised convulsions ≥3 generalized seizures within 24 hours
10. Haemoglobinuria Macroscopic black, brown or red urine; not associated with effects of oxidant drugs or enzyme defects (like G6PD deficiency)
Added World Health Organization criteria from 2000 [4]
11. Impaired consciousness Various levels of impairment may indicate severe infection although not falling into the definition of cerebral malaria. These patients are generally arousable
12. Prostration Extreme weakness, needs support
13. Hyperparasitemia 5% parasitized erythrocytes or > 250 000 parasites/µl (in nonimmune individuals)
14. Hyperpyrexia Core body temperature above 400C
15. Jaundice (Hyperbilirubinemia) Serum bilirubin of more than 43m mol/l (2.5 mg/dl).
16. Fluid and electrolyte disturbances [5] Dehydration, postural hypotension, clinical evidence of hypovolemia
17. Vomiting of oral drugs Patients with persistent vomiting may have to be admitted for parenteral therapy.
18. Complicating or associated infections Aspiration bronchopneumonia, septicemia, urinary tract infection etc.
19. Other indicators of poor prognosis [5] Leukocyte count >12,000/cumm; high CSF lactate (>6 mmol/l)and low CSF glucose; more than 3-fold elevation of serum enzymes (aminotransferases); increased plasma 5′-nucleotidase; low antithrombin III levels; peripheral schizontemia; papilloedema/retinal oedema
20. Malarial Retinopathy A large, prospective autopsy study of children dying with cerebral malaria in Malawi found malarial retinopathy to be a better indicator of malarial coma. Similar retinopathy in an adult has also been reported.

Differential Diagnosis: The differential diagnosis of fever in a severely ill patient is broad. Coma and fever may result from meningoencephalitis or malaria. Cerebral malaria is not associated with signs of meningeal irritation (neck stiffness, photophobia, Kernig sign) but the patient may be opisthotonic. As untreated bacterial meningitis is almost invariably fatal, a diagnostic lumbar puncture should be performed to exclude this condition. There is also considerable clinical overlap between septicaemia, pneumonia and severe malaria – and these conditions may coexist. In malaria endemic areas particularly, where parasitaemia is common in the young age group, it is often impossible to rule out septicaemia in a shocked or severely ill obtunded child. Where possible, blood should always be taken on admission for culture, and if there is any doubt, empirical antibiotic treatment should be started immediately along with antimalarial treatment.[6]

Evaluation of the Patient

Malaria is a very simple disease to diagnose and treat; yet it claims more lives than any other infectious disease in the world. It is therefore very essential that every case of malaria be assessed thoroughly.

Clinical examination:

General: Functional status, prostration, breathlessness, level of consciousness, hydration, toxicity, puffiness of face and lids, etc.

Vital signs: Pulse rate, blood pressure (hypotension), temperature (hyperpyrexia), respiratory rate (tachypnoea, acidotic breathing).

Other signs: Pallor, Jaundice, Cyanosis, Edema, etc.

Abdomen: Liver, spleen, bowel sounds – Tender hepato/ splenomegaly is more common in acute malaria.

Respiratory system: Basal crackles, wheezes; sometimes, associated pneumonia and its bronchial breath sounds.

C.N.S.: Level of sensorium, convulsions, neck stiffness, ocular fundii, any focal deficits.


Hemoglobin: Anemia is common in malaria. Rapid reduction in level of hemoglobin is seen in falciparum malaria and less than 7 g/ dl should be a warning.

Total leukocyte count: It can vary from low to high, and neutrophilic leukocytosis is common in severe malaria with or without associated bacterial infection. Leukopenia is seen in severe malaria with septicemia, and chronic hypersplenism.

Platelet count: Thrombocytopenia is common in P. falciparum and P. vivax malaria, but it does not correlate with the severity of the infection.

Parasite count: This is a simple yet very important and useful method of assessing the severity of infection in falciparum malaria. It should be done routinely in all cases of falciparum malaria.

How to do a parasite count?

Thick film: The density of malarial parasites can be read against the leukocytes and an approximate parasite count can be calculated.

  1. Count the number of asexual forms of the parasite ( rings, trophozoites and schizonts) against 100 leukocytes and multiply by 75, this gives an approximate total per micro liter (mm3).
  2. The average leukocyte count per microscopic field is about ten. Therefore, multiply the average number of parasites per field by 750, this also gives an approximate total per micro liter.

Thin film: Count the number of parasites within 1000 red blood cells and divide this by 10. This gives the percentage of parasitemia.

A parasite count of 100000 or more per mm3 (or 5% and more) is considered as severe infection.

See details

Blood Glucose: Hypoglycemia is a common problem encountered in malaria and may remain undetected because the symptoms and signs of hypoglycemia viz. sweating, tachycardia etc., are even otherwise seen in malaria. It is very important to monitor the blood glucose levels once at least 6 hours in falciparum malaria, particularly if the patient is pregnant or is receiving quinine.

Other investigations:

Moderate elevation in blood urea and creatinine are common. Significant increase is suggestive of renal impairment.

Hyperbilirubinemia is common in malaria, particularly due to hemolysis. Some patients with falciparum malaria may have very high levels of conjugated bilirubin due to associated hepatocyte dysfunction.

Serum albumin levels may be reduced, some times markedly.

Serum aminotransferases, 5′ – nucleotidase and lactic dehydrogenase are elevated.

Prothrombin time and partial thromboplastin time are elevated in 20% of patients with cerebral malaria. Some may have features of disseminated intravascular coagulation.

Hyponatremia is common and needs careful management.

Lactic acidosis is seen in severely ill patients, especially in patients with hypoglycemia and renal dysfunction. It can be suspected if there is a wide anion gap.

Urine examination may show albuminuria, microscopic hematuria, hemoglobinuria and red cell casts. With massive intravascular hemolysis, urine may be black in colour.

Indications for hospitalisation of malarial cases:

  1. Persistence of fever even after 48 hours of initial treatment.
  2. Continuously worsening headache.
  3. Persistent vomiting.
  4. Any complications of P. falciparum malaria– altered sensorium, convulsions, anemia, jaundice, hyperpyrexia, bleeding and clotting disorders, breathlessness, high coloured urine etc.
  5. Patients who are at higher risk for development of complications of P. falciparum malaria-extremes of age, pregnancy etc.
  6. Patients who appear sick and prostrated
  7. Significant dehydration


  1. Andrej Trampuz, Matjaz Jereb, Igor Muzlovic, Rajesh M Prabhu. Clinical review: Severe malaria. Critical Care 2003;7:315-323 Available at
  2. Njuguna PW, Newton CR. Management of severe falciparum malaria. J Postgrad Med [serial online] 2004;50:45-50. Available at
  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.
  5. Management of Severe Malaria: A practical handbook. Second edition. World Health Organization. Geneva, 2000. Available at
  6. Guidelines for the treatment of malaria. World Health Organization. Geneva, 2006. pp 41-61. Available at
  7. Jagannath Sarkar et al. Risk factors for malaria deaths in Jalpaiguri district, West Bengal, India: evidence for further action. Malaria Journal 2009;8:133 Available at


© ©BS Kakkilaya | Last Updated: Mar 11, 2015