This is one of the few studies to describe the presentation and epidemiology of severe malaria in Western Cambodia, a low transmission setting with multidrug-resistant P. falciparum, and an increasing predominance of P. vivax malaria. The study provides baseline information on the burden of severe malaria in a referral hospital near the epicentre of global anti-malarial drug resistance (WHO Zone 1) during the 2.5 years preceding the Artemisinin Resistance Containment Project and supports other preliminary evaluations reporting success in containment and reduction of mortality rates . These intense efforts led by WHO and others provided bed net distribution, and trained local village malaria workers to provide earlier case detection and treatment free of charge, resulting in declines in falciparum malaria cases [5, 6]. Following the downward trend in other Containment Project provinces, severe malaria incidence and CFR in Battambang Province reported to the National Malaria Control Program continued to decline significantly after 2009 with only two deaths out of 116 severe cases in 2010 and one death out of 101 severe cases in 2011 . Other likely contributors to the reduction in severe disease in the interim have included malaria case management training, a ban on artemisinin monotherapy, a government crack-down on counterfeit drugs and illegal pharmacies, improved supply of good quality anti-malarials, an increased programme focus on migrant and mobile populations (including the military), and basic improvements in infrastructure such as road access in Western Cambodia. The relationship between level of artemisinin tolerance and pathogenicity of malaria parasites is unclear. High levels of differentiation in artemisinin-resistant P. falciparum subpopulations have recently been demonstrated in Cambodia  and future research may or may not link these to different levels in pathogenicity.
On review of the hospital records, it was often apparent that malaria was a co-existing infection of another serious condition, such as meningitis, sepsis and gastrointestinal haemorrhage which is not unexpected, given the recent evidence of falciparum malaria infection as a risk factor for bacteraemia in African children . Bacterial cultures that could have ruled out bacteraemia, were not available at BRH for this population.
Despite substantial limitations, diagnostic and treatment guidelines were reasonably well adhered to where possible at this facility, likely contributing to an overall CFR of 14.2% which was intermediate compared to other reports from the region. CFR in other retrospective studies in the region have varied from 1.8% in Thailand , 6.3% in the Philippines , to 35% in Malaysia . This compares to recent mortality rates in African studies, largely in children, ranging from 4.5% in Cameroon  to 11.5% in Madagascar  to up to 22% in children with bacteraemia in Mozambique [6, 15]. Despite the emergence of artemisinin resistance in Western Cambodia during the study period, cases of severe malaria and deaths declined in BRH and nationally. Overall CFR was lower in severe malaria patients residing in districts with confirmed artemisinin resistance (Zone 1), likely resulting from increased active case detection and early treatment. Overall malaria incidence in Cambodia increased from 4.1 per 1,000 in 2008 to 6.22 per 1,000 in 2009 attributed to increased migrational movements, while CFR of severe malaria cases continued to decline .
Although life-threatening malaria complications can affect patients of all ages, disease presentation and mortality have been found to be closely related to transmission intensity and age of the patient . In a low transmission setting such as this, where immunity may never be acquired, older patients may have higher mortality rates owing to delayed presentation. The most frequent complications associated with mortality, particularly in older patients, were prostration, respiratory distress and coma, with 35% of comatose patients dying on or soon after admission. Coma and metabolic acidosis have been found to be the most significant risk factors for death in both children and adults in prior studies in Asia [17, 18]. Others have demonstrated that renal function monitoring in these patients may be crucial for survival [16, 19]. The lack of metabolic and chemistry testing inhibited the ability to identify metabolic acidosis and renal dysfunction early, making prognosis and management more challenging. Of the limited diagnostic testing available, mortality did appear to correspond with laboratory abnormalities for both leukocyte and platelet counts, lending some limited prognostic value to these tests. Elevated or depressed leukocyte counts often indicate concomitant bacterial infections, and patients may benefit from empiric antibiotic treatment . Thrombocytopaenia, one of the most common laboratory abnormalities in severe malaria  also had some prognostic value for severe disease though it did not predict bleeding complications.
In addition to diagnostic and prognostic limitations, challenges in management included lack of mechanical ventilation units, renal haemodialysis, centrally administered pressors, exchange transfusion capabilities or real time haemodynamic and metabolic data to guide resuscitation. Limited peritoneal dialysis was available at times, but rarely employed. As a result, renal failure and pulmonary oedema, while rare at this facility (reported in only 7% and 2% patients),were associated with the highest CFR in this group.
Recent descriptions of treatment-seeking behaviour, cultural practices and socio-economic barriers have revealed causes for delays in appropriate malaria treatment in Cambodia, representing an important potential area for intervention to reduce mortality . Several factors appear to have contributed to mortality from severe malaria at the BRH including delayed presentation, delayed admission referral, cultural beliefs, and difficulty accessing health care facilities in this austere setting. The average time between onset of symptoms and admission to BRH was 5.5 days, greater in some of the outlying districts. Although Cambodia has an extensive peripheral health centre network, lack of public sector resources may prompt patients to seek initial treatment directly at the highest level of care possible, bypassing outlying networks. The majority of severe cases (70%) presented directly to the BRH, and were admitted directly for treatment to the intensive care unit, with only the minority (approximately 30%) being referred from outlying centres. Referred patients (especially from the public sector) had worse outcomes, suggesting increased treatment delay and lack of pre-referral treatment such as parenteral artemisinins, suppositories and/or transfusion capability.
Roughly 90% of all patients discharged with a severe malaria diagnosis at BRH received intramuscular artemether on the day of admission, which at the time of publication remains the current national standard of care for severe malaria in Cambodia. A five to seven-day course is used, followed by treatment with mefloquine, but is sometimes unavailable, prompting patients to obtain drugs from private-sector pharmacies risking counterfeit or substandard treatment. Parenteral artesunate was not available in Cambodia during the study period. Parenteral artesunate currently remains the most effective treatment remaining for severe malaria , and was found to be more effective and less expensive than quinine in children in sub-Saharan Africa  and adults in Southeast Asia . Though limited head to head comparisons between intravenous artesunate suggest some degree of inferiority for intramuscular artemether , both were found to be effective, and the relative simplicity of rapid intramuscular administration in critical illness may support its continued use in Cambodia. Availability and frequent of use of this life-saving drug may explain the relatively low overall mortality rates seen, particularly considering the limited array of diagnostic and treatment facilities available. Quinine continues to be the first-line agent for pregnant women in Cambodia.
There has been recent recognition of the substantial proportion of severe malaria cases attributable to P. vivax in tropical regions . Observed rates of severe P. vivax in Southeast Asia and the Pacific have been high in several reports, accounting for up to 25% of severe malaria cases. While some have shown reduced risk of severe disease attributable to P. vivax and/or mixed infection in low transmission settings , others have shown risks of severe disease to be increased, particularly in young children and in areas with high grade chloroquine resistance, though the latter has not been reported in Cambodia . Though P. vivax is typically thought of as a relatively benign disease, 14.5% of patients meeting the case definition of severe malaria at BRH during the study period had slide proven P. vivax, and there were four documented deaths. There were no deaths reported among 17 patients with documented mixed infection. HIV-1 infection has been reported to be an important risk factor for severe malaria and death , but there was only one confirmed case of HIV co-infection in this study population.
The study’s retrospective design placed limits on accurately interpreting the underlying disease burden. Accurately defining the terms ‘impaired consciousness’ and ‘prostration/coma’ retrospectively were challenging. WHO defines impaired consciousness as a ‘rousable mental condition’, and prostration as the inability to sit upright without support or drink. However, varying terms were used by clinicians at BRH, including descriptions such as “somnolence”, “obnubilation”, “agitation”, “delirium”, “irritation”, “pre-coma”, and in some cases a Glasgow Coma Score (GCS) was given. In the retrospective analysis, the study team adopted the term ‘coma’ for those found to have either a clearly documented coma state, or understood to have an unarousable coma based on GCS scores. Limitations on diagnostic capabilities at this facility leaves open the possibility that cases and/or complications may have been missed. The study does not reflect cases that never made it to medical attention, died out of hospital, or were treated at local facilities, in the private sector or at home. As such, the in-patient data are only representative of the referral centre and not of the overall severe malaria burden for this region of Cambodia. Likewise, the non-availability of important diagnostic measurements may have resulted in under-reporting of complications.
A large proportion of patients were slide-negative on admission, though nearly 50% of these patients still responded to anti-malarials alone. In such cases, preliminary microscopic diagnosis in hospital may have been obscured or simply not performed due to pre-treatment out of hospital prior to transfer. Many cases were diagnosed by rapid diagnostic kits or simply treated on clinical grounds. Patients with negative malaria smears in this cohort had higher crude mortality rates at 16% versus 11% in the patients with high parasitaemia, possibly due to delays in diagnosis and appropriate treatment, or earlier parenteral therapy in the higher parasitaemia patients. In this setting, a high index of suspicion for severe malaria remains warranted and may prove lifesaving. However, an empiric treatment approach to severe malaria should not preclude investigation of co-morbidities, which were common.