This case series highlights the misdiagnosis of severe knowlesi malaria due to continued reporting of P. knowlesi as P. malariae. It also highlights the lack of recognition of non-falciparum Plasmodium species as potential causes of severe and fatal malaria, and the fatal consequences of initial oral therapy for severe malaria of any species, particularly P. knowlesi.
In this series patients with deaths directly attributable to P. knowlesi were older than those with fatal P. falciparum (median age 51 [IQR 50-65] vs 22 [IQR 9-55] years, p = 0.06). The older age group affected, and the complications experienced by the fatal knowlesi malaria patients, are consistent with those already reported [1, 11, 14]. In particular, respiratory distress (oxygen saturation <94% and respiratory rate >30 breaths/minute) occurs commonly in knowlesi malaria [11, 14], and was present in all patients. Diffuse infiltrates were seen on chest radiograph in four patients, and three of these patients met the criteria for acute respiratory distress syndrome (ratio of the partial pressure of oxygen to the fraction of inspired oxygen [PaO2:FiO2] <200). All patients required ventilatory support, and respiratory failure contributed directly to cause of death in at least four patients. Renal failure has been reported to occur in 30–55% of patients with severe knowlesi malaria [11, 14], and occurred in four of five (80%) patients in this series.
Hypotension is also a common complication of severe knowlesi malaria, and occurred in four of five (80%) patients with deaths directly attributable to P. knowlesi. Pre-antibiotic blood cultures were taken in three of these patients and were all negative. Relatively low rates of clinically significant bacteraemia have been reported previously in severe knowlesi malaria , suggesting that bacteraemia is unlikely to account for hypotension in most patients with P. knowlesi. Nevertheless, one patient in this series who presented with uncomplicated knowlesi malaria had Enterobacter cloacae bacteraemia on admission, with bacterial septic shock the likely cause of death. This species was also identified in the only other report of clinically significant bacteraemia in a patient with severe knowlesi malaria . Gram-negative bacteraemia is a well-recognized complication of severe falciparum malaria in children, and is associated with increased mortality [20–25]. The proposed mechanisms of the association between falciparum malaria and bacteraemia include an increased risk of non-typhoidal Salmonella due to malaria-induced haemolysis and neutrophil dysfunction , impaired macrophage function due to haemozoin deposition in monocytes [27–29], and nitric oxide quenching . Bacterial translocation into the blood stream has also been hypothesized as a result of microvascular sequestration of P. falciparum in gut mucosa, and parasite accumulation in multiple organs was demonstrated in the single P. knowlesi autopsy report. Further studies are required to investigate mechanisms of bacteraemia in P. knowlesi infection.
Coma has not been reported to occur in knowlesi malaria, despite the only autopsy report demonstrating cerebral accumulation of parasitized red blood cells . One patient in this study was reported to have had reduced consciousness and hypotension just prior to death. His altered conscious state however likely reflected his agonal state and is not consistent with cerebral malaria.
In contrast to other human malarias, P. knowlesi has a 24-hour replication cycle, which can lead to rapid increases in parasitaemia. Diagnosis of this malaria species is therefore critical in order that its potential to cause severe disease is recognized, appropriate treatment instituted without delay, and further complications and fatalities avoided. In this series, no patient was correctly diagnosed with P. knowlesi. Rather, all received a diagnosis of P. malariae, despite a very low incidence of this species in Sabah, with P. malariae detected by nested PCR in only 2 of 318 (0.6%) microscopy-diagnosed P. malariae cases referred to the Sabah State Public Health Laboratory in 2009 . On thick film microscopy, P. knowlesi is indistinguishable from P. malariae. While there may be very subtle morphological differences between the late stages of P. knowlesi and P. malariae on thin film microscopy, these are not consistent and cannot be relied upon in clinical practice . P. malariae causes a relatively benign acute illness, with low parasitaemia and only very rare reports of acutely severe malaria [33, 34]. Current textbook descriptions and treatment guidelines reflect this. As has been previously recommended , this case series highlights the need for blood films positive for malaria parasites resembling P. malariae to be reported as P. knowlesi in Sabah, in order to direct clinicians in the recognition and management of this potentially fatal species.
Moreover, this case series illustrates the importance of a unified treatment policy for all patients with severe malaria, regardless of species . Although the optimal treatment of knowlesi malaria has not been determined, severe disease should be treated as for severe falciparum malaria, including immediate institution of parenteral artesunate. Plasmodium knowlesi is also sometimes misdiagnosed as P. vivax (as occurred initially in one patient in this series) and P. vivax can also cause severe and fatal disease [36, 37]. For both these reasons, P. vivax should also be treated with intravenous artesunate if signs of severity are present, particularly as oral chloroquine may be poorly absorbed in acutely unwell patients and chloroquine-resistant P. vivax is increasingly prevalent in Southeast Asia . This unified treatment strategy for severe malaria from all species, including P. knowlesi, has been Sabah state policy since 2008 and has been adopted in the latest WHO severe malaria management guidelines . Despite this policy, in this case series only two of five patients with knowlesi malaria who met severity criteria on admission received immediate parenteral treatment, with the others receiving oral chloroquine. Similarly, the one patient with vivax malaria, who also met severity criteria on admission, was treated only with oral chloroquine. In contrast, six of seven patients with severe falciparum malaria received parenteral treatment within two hours of diagnosis (p = 0.07 for fatal P. falciparum vs non-falciparum; Yates corrected Chi2). These findings suggest a lack of recognition of the potential of the non-falciparum malarias to cause severe disease and the need for treatment with intravenous artesunate for all severe malaria patients.
This study had several limitations, the major one being its retrospective design resulting in unavoidably incomplete laboratory and clinical data. Blood culture results were not available for two patients, and for these patients bacterial sepsis cannot be excluded as contributing to poor outcome. Lack of accurate parasite density counts also made assessment of parasite burden difficult. Post-mortem examination was not performed for any patient, preventing detailed description of the pathogenic mechanisms of severe malaria and death.