Malaria is a febrile illness and its clinical features are highly nonspecific. The diagnosis depends on a high degree of clinical suspicion and confirmation by detecting the asexual form of Plasmodium in peripheral blood smear. Microscopy is the gold standard for the diagnosis and it can estimate parasite density, identify the parasite species involved, provide clues about platelet and leukocyte counts and can help to differentiate malaria from many other conditions. However, it has certain disadvantages, too: False negative results may be encountered in patients with low parasitemia, maturation of sequestered parasites in broods, partial treatment with anti–malarial drugs or receipt of effective chemoprophylaxis.
Technical problems with light microscopy have spawned interest in the test based on parasite–derived proteins like HRP–II (Histidine Rich protein–II). The test has become relatively popular due to its simplicity and high levels of sensitivity and specificity. Its limitations are that HRP–II may continue to be positive up to two–four weeks, even when parasites are no more detected in the peripheral blood.
Common manifestations of severe malaria in children include severe anaemia, cerebral malaria and acidosis. However, adults suffer from multi–organ involvement like acute renal failure, respiratory distress, apart from cerebral malaria.
Multi–organ failure is encountered much more frequently than before and this changing scenario could be ascribed to high transmission of falciparum malaria and drug–resistance to commonly used anti–malarial agents.
About 2 million confirmed malaria cases and 1,000 deaths are
Multi–organ failure is encountered much more frequently than before and this changing scenario could be ascribed to high transmission of falciparum malaria and drug–resistance to commonly used anti–malarial agents.reported annually, although 15 million cases and 20,000 deaths are estimated by WHO South East Asia Regional Office. India contributes 77% of the total malaria in Southeast Asia. In India, nine Anopheline vectors are involved in transmitting malaria in diverse geo–ecological paradigms. Multi–organ involvement/ dysfunction is reported in both P. falciparum and P. vivax cases. The profound impact of complicated malaria in pregnancy includes
anaemia, abortions, low birth weight in neonates, still births, and maternal mortality.1
At Rourkela, in eastern India, 526 adults (aged >12 years) who each satisfied the World Health Organization’s criteria for cerebral malaria were admitted to Ispat General Hospital between 1995 and 2001. The most common presenting symptoms were fever (97.7%), vomiting (54.6%), headache (30.8%) and seizures (17.1%). Most (62.4%) of the cases had associated severe complications: jaundice (47.5%), acute renal failure (28.9%), and/or severe anaemia (9.7%). Overall, 175 (23%) of the cases were fatal, mortality being particularly high (59%) among those with multi–organ failure. Of the fatal cases, 107 (61%) died within the first 24 h of hospitalization, presumably indicative of late presentation.2
All patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized), should be treated with intravenous therapy until the patient is well enough to continue with oral treatment.
The treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contraindications to quinine.3
Patients with severe or complicated malaria should be managed in a high dependency or intensive care environment. They may require haemodynamic support and management of acute respiratory distress syndrome, disseminated intravascular coagulation, renal impairment/failure, seizures, and severe intercurrent infections including Gram–negative bacteraemia/septicaemia.
In India, both adults and children are affected by severe malaria, invariably caused by P. falciparum. Early diagnosis and prompt treatment will reduce the mortality due to malaria. Cerebral malaria should always be suspected in a patient with altered sensorium in a malaria–endemic area. Children are more prone for developing anaemia and convulsions as manifestations of severe malaria, while acute renal failure and jaundice are more common among adults. Pregnant women are vulnerable to hypoglycemia, anaemia and pulmonary complications. Of late, multi–organ failure and high mortality figures are being reported increasingly from different parts of India. A recent multi–centric study has demonstrated the efficacy of intravenous artesunate in reducing the mortality by 30%.4 Parenteral artesunate is also now the treatment of choice in low–transmission areas and in the 2nd and 3rd trimesters of pregnancy, and research is underway into whether it should replace quinine as the treatment of choice. The development of artesunate suppositories offers another exciting prospect, the ability to treat
patients with severe disease in remote rural settings, delaying the evolution of disease and buying them time to reach a health care facility.5
The National Vector Borne Disease Control Programme (NVBDCP) of the Ministry of Health, Government of India, is reporting about 2 million parasite positive cases each year, although case incidence is 30–fold or more under–estimated. Forty five to fifty percent of Plasmodium infections are caused by Plasmodium falciparum, the killer parasite. Anti–malaria drug policy (2007) of the NVBDC recommends chloroquine as the first line of drug for the treatment of all malarias. In a Primary Health Centre (PHC) reporting 10% or more cases of chloroquine resistance in P. falciparum, artemisinin–based combination therapy (ACT) blister pack is recommended and, so far, the policy has been adopted in 261 PHCs of 71 districts.
The NVBDCP, however still depends on chloroquine to combat malaria and, as a result, P. falciparum has taken deep roots in malaria–endemic regions, causing unacceptable levels of morbidity and mortality. This policy was a subject of criticism in recent Nature and Lancet articles questioning the World Bank’s decision to supply chloroquine to the NVBDCP. Switchover to ACT in the treatment of all P. falciparum cases, ban on artemisinin monotherapy and effective vector control (treated nets/efficient insecticide spraying) would be a rational approach to malaria control in India.6
Artesunate is an antimalarial agent, available in oral, rectal and parenteral formulations, that provides a rapid clinical effect in patients with P. falciparum malaria. The rapidity of effect, availability of an intravenous and intramuscular formulation and convenient dosage regimen makes artesunate an ideal candidate for the treatment of severe malaria, including cerebral disease. When given as monotherapy, treatment should be continued for at least 5 to 7 days to prevent recrudescence.7
Combination therapy with mefloquine allows artesunate to be administered over 3 days or less, with a satisfactory clinical outcome maintained. Although optimal dosages remains to be determined,
this combination continues to provide the rapid onset of clinical effect observed with artesunate monotherapy, but decreases the rate of recrudescence to 2% (i.e. radical cure rate of 98%) when used as treatment in patients with uncomplicated malaria from areas with a high risk of multidrug–resistance falciparum malaria. In certain areas, mefloquine when combined to an artemisnin derivate (artesunate) and used as a 3–days combination therapy, lead to the highest sustained efficacy rates (figure 1).
Clinical findings to date have not revealed any pattern of resistance to artesunate after use of the drug. However, given the history of the development of resistance to other antimalarial drugs (figure 2), the use of artesunate should be restricted to areas of multidrug resistance, the drug should be used in combination with a longer acting agent such as mefloquine, and it should be used in regimens that provide radical cure rates of 90 to 100%.7
Experts did an open–label randomized controlled trial in patients admitted to hospital with severe falciparum malaria in Bangladesh, India, Indonesia, and Myanmar. They assessed all patients randomized for the primary endpoint. Mortality in artesunate recipients was 15% (107 of 730) compared with 22% (164 of 731) in quinine recipients; an absolute reduction of 34.7% (95% CI 18.5–47.6%; p=0.0002). Treatment with artesunate was well tolerated, whereas quinine was associated with hypoglycaemia (relative risk 3.2, 1.3–7.8; p=0.009). Artesunate should become the treatment of choice for severe falciparum malaria in adults.8
Experts analyzed all randomized controlled trials comparing intravenous, intramuscular, or rectal artesunate with intravenous or intramuscular quinine for treating adults and children with severe malaria. Six Asian trials enrolling 1938 participants (1664 adults and 274 children) met the inclusion criteria.
Treatment with artesunate significantly reduced the risk of death (RR 0.62, 95% CI 0.51 to 0.75; 1938 participants, 6 trials), reduced parasite clearance time (WMD 8.14 h, 95% CI 11.55 to 4.73; 292 participants, 3 trials), and hypoglycaemia, detected by routine monitoring (RR 0.46, 95% CI 0.25 to 0.87; 185 participants, 2 trials). There was no evidence of a difference in neurological sequelae, coma recovery time, time to hospital discharge, fever clearance time, or adverse effects, other than hypoglycaemia. Intravenous artesunate was hence considered the drug of choice for adults with severe malaria, particularly if acquired in Asia.9