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Time for pragmatic, prospective clinical trials to determine the role of empirical antibacterial therapy in critically ill adults hospitalized with malaria

  • Josh Hanson
    Correspondence
    Corresponding author at: The Kirby Institute, University of New South Wales, Sydney, Australia.
    Affiliations
    The Kirby Institute, University of New South Wales, Sydney, Australia

    University of Medicine 2, North Okkalapa Township, Yangon, Myanmar

    Myanmar Australia Research Collaboration for Health (MARCH), Yangon, Myanmar
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  • Phyo Pyae Nyein
    Affiliations
    Myanmar Australia Research Collaboration for Health (MARCH), Yangon, Myanmar

    Mingaladon Specialist Hospital, Mingaladon Township, Yangon, Myanmar
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  • Ne Myo Aung
    Affiliations
    University of Medicine 2, North Okkalapa Township, Yangon, Myanmar

    Myanmar Australia Research Collaboration for Health (MARCH), Yangon, Myanmar

    Insein General Hospital, Insein Township, Yangon, Myanmar
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  • Mar Mar Kyi
    Affiliations
    University of Medicine 2, North Okkalapa Township, Yangon, Myanmar

    Myanmar Australia Research Collaboration for Health (MARCH), Yangon, Myanmar

    Insein General Hospital, Insein Township, Yangon, Myanmar
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Open AccessPublished:October 02, 2020DOI:https://doi.org/10.1016/j.ijid.2020.09.1472

      Highlights

      • Children with severe malaria commonly have a concomitant invasive bacterial infection.
      • Empirical antibacterial therapy is therefore recommended in these children.
      • Recent data have challenged the dogma that bacterial co-infection is rare in adults.
      • It is difficult to confidently exclude bacterial co-infection in adults with malaria.
      • Empirical antibiotics should also be considered in critically ill adults with malaria.

      Abstract

      Background

      Children with severe falciparum malaria in malaria-endemic regions are predisposed to developing life-threatening bacterial co-infection. International guidelines therefore recommend empirical broad-spectrum antibacterial therapy in these children. Few studies have examined co-infection in adults, although it has been believed to be relatively rare; antibacterial therapy is therefore not routinely recommended in adults with falciparum malaria.

      Discussion

      However, the fundamental pathophysiology of falciparum malaria in adults and children is the same; it is therefore unclear why adults would not also be predisposed to bacterial infection. Indeed, recent studies have identified bacteraemia in >10% of adults hospitalized with malaria. Some have suggested that these adults probably had bacterial sepsis, with the parasitaemia an incidental finding. However, it is usually impossible in resource-limited settings to determine–at presentation–whether critically ill, parasitaemic adults have severe malaria, bacterial sepsis, or both. Given the significant case-fatality rates of severe malaria and bacterial sepsis, the pragmatic initial approach would be to cover both possibilities.

      Conclusions

      Life-threatening bacterial co-infection may be more common in critically ill adults with malaria than previously believed. While further prospective data are awaited to confirm these findings, it might be more appropriate to provide empirical aantibacterial cover in these patients than current guidelines suggest.

      Keywords

      A meta-analysis of 7208 African children with severe malaria identified concomitant bacteraemia in 6.4%. Children with co-infection in these studies had a far worse prognosis: 24.1% dying compared with 10.2% of those with severe malaria alone (
      • Church J.
      • Maitland K.
      Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review.
      ). However, it is almost impossible to exclude co-infection in the resource-limited settings in which these children are usually managed (
      • Evans J.A.
      • Adusei A.
      • Timmann C.
      • May J.
      • Mack D.
      • Agbenyega T.
      • et al.
      High mortality of infant bacteraemia clinically indistinguishable from severe malaria.
      ). It is therefore recommended that all children presenting with severe malaria in areas of intermediate and high transmission receive broad-spectrum antibiotics in addition to antimalarial therapy (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      ).
      While there have been numerous studies to examine bacterial co-infection in children with malaria, there have been remarkably few to explore the issue in adults. The prevailing belief has been that co-infection is rare in adults and accordingly, unlike children, they should not receive empirical antibacterial therapy, unless they have a clinical syndrome compatible with serious bacterial infection (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      ). This belief was based significantly on data from large studies performed in Vietnam between 1991 and 2003, which were unpublished until recently (
      • Phu N.H.
      • Day N.P.J.
      • Tuan P.Q.
      • Mai N.T.H.
      • Chau T.T.H.
      • Van Chuong L.
      • et al.
      Concomitant bacteremia in adults with severe falciparum malaria.
      ). Only 9/845 (1.07%, 95% confidence interval (CI) 0.37–1.76%) adults in these studies were bacteraemic at enrolment. Despite this, the bacteraemic adults were more likely to die than adults without bacteraemia (risk ratio 3.44, 95% CI 1.62–7.29). They were also more likely to be hyperparasitaemic: 5.2% with >20% parasitaemia had concomitant bacteraemia compared with 0.65% of those with <20% parasitaemia (risk ratio 8.1, 95% CI 2.2–29.5). But given the infrequent overall finding of bacteraemia in the studies, the authors concluded that while empirical antibiotics, in addition to artesunate, are warranted in those patients with very high parasitaemias, they are not indicated in most adults with severe falciparum malaria (
      • Phu N.H.
      • Day N.P.J.
      • Tuan P.Q.
      • Mai N.T.H.
      • Chau T.T.H.
      • Van Chuong L.
      • et al.
      Concomitant bacteremia in adults with severe falciparum malaria.
      ).
      However, there are reasons to believe that the reported figure of 1.07% underestimates the true rate of life-threatening bacterial co-infection in these patients. The studies employed a manual blood culture system before September 1997, which may have been less sensitive (
      • Riedel S.
      • Carroll K.C.
      Blood cultures: key elements for best practices and future directions.
      ). An automated blood culture system was used subsequently, however only 5–8 ml of blood was collected for culture, significantly less than the 40–60 ml that is recommended for optimal sensitivity (
      • Henning C.
      • Aygul N.
      • Dinnetz P.
      • Wallgren K.
      • Ozenci V.
      Detailed analysis of the characteristics of sample volume in blood culture bottles.
      ). Patients were enrolled in a research ward at a referral hospital in Ho Chi Minh City. The authors assert that antibacterial therapy prior to study enrolment–which would reduce the blood culture yield by almost 40% (
      • Cheng M.P.
      • Stenstrom R.
      • Paquette K.
      • Stabler S.N.
      • Akhter M.
      • Davidson A.C.
      • et al.
      Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis: a diagnostic study.
      )–was unusual in their patients, but do not report how many did receive antibiotics. It is also important to remember that many patients with life-threatening bacterial infection are not bacteraemic (
      • Gilman R.H.
      • Terminel M.
      • Levine M.M.
      • Hernandez-Mendoza P.
      • Hornick R.B.
      Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever.
      ,
      • Komori A.
      • Abe T.
      • Kushimoto S.
      • Ogura H.
      • Shiraishi A.
      • Saitoh D.
      • et al.
      Characteristics and outcomes of bacteremia among ICU-admitted patients with severe sepsis.
      ).
      A follow-up article stated that “the majority of patients in the Vietnam series did not receive antibiotics during their hospital stay and recovered uneventfully” (
      • White N.J.
      Bacteremia in adults with severe malaria.
      ), but a significant proportion of the patients were reported to have co-infection in the original papers, and presumably did receive antibacterial therapy at some point during their hospitalization. Among 560 patients enrolled in the first study, 120 (21.4%) had a chest infection and 48 (8.6%) had a urinary tract infection. Antibiotics were also prescribed for suspected bacterial sepsis, although the number of patients receiving therapy for this indication was not reported (
      • Tran T.H.
      • Day N.P.
      • Nguyen H.P.
      • Nguyen T.H.
      • Tran T.H.
      • Pham P.L.
      • et al.
      A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria.
      ). In the second study of 370 patients, 141 (38%) were reported to have co-infection (
      • Phu N.H.
      • Tuan P.Q.
      • Day N.
      • Mai N.T.
      • Chau T.T.
      • Chuong L.V.
      • et al.
      Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria.
      ).
      More recent studies have also suggested that the rate of concomitant bacterial infection in adults hospitalized with malaria may be higher than previously believed. In studies from Myanmar, 13/87 (14.9%) adults were bacteraemic on admission (
      • Aung N.M.
      • Nyein P.P.
      • Htut T.Y.
      • Htet Z.W.
      • Kyi T.T.
      • Anstey N.M.
      • et al.
      Antibiotic therapy in adults with malaria (ANTHEM): high rate of clinically significant bacteremia in hospitalized adults diagnosed with falciparum malaria.
      ,
      • Nyein P.P.
      • Aung N.M.
      • Kyi T.T.
      • Htet Z.W.
      • Anstey N.M.
      • Kyi M.M.
      • et al.
      High frequency of clinically significant bacteremia in adults hospitalized with falciparum malaria.
      ); bacteraemic patients had more severe disease than non-bacteraemic patients (respiratory coma acidosis malaria (RCAM) median score 2 (interquartile range 1–4) versus 1 (interquartile range 1–2), p = 0.02 (
      • Hanson J.
      • Lee S.J.
      • Mohanty S.
      • Faiz M.A.
      • Anstey N.M.
      • Charunwatthana P.
      • et al.
      A simple score to predict the outcome of severe malaria in adults.
      )) and were more likely to die (2/13 (15.4%) versus 1/74 (1.4%), p = 0.01). In these studies, local clinicians prescribed empirical antibacterial therapy–in addition to antimalarial therapy–in 71/87 (81.6%). This was largely a pragmatic decision, as diagnostic and intensive care support is profoundly limited in the hospitals in which the studies were performed (
      • Thit S.S.
      • Aung N.M.
      • Htet Z.W.
      • Boyd M.A.
      • Saw H.A.
      • Anstey N.M.
      • et al.
      The clinical utility of the urine-based lateral flow lipoarabinomannan assay in HIV-infected adults in Myanmar: an observational study.
      ,
      • Ye Lynn K.L.
      • Hanson J.
      • Mon N.C.N.
      • Yin K.N.
      • Nyein M.L.
      • Thant K.Z.
      • et al.
      The clinical characteristics of patients with sepsis in a tertiary referral hospital in Yangon, Myanmar.
      ). Indeed, bacterial co-infection was suspected clinically in only 5/13 (38.5%) bacteraemic patients. However, the frequency of co-prescription of antibacterial therapy and artesunate may have contributed to the studies’ excellent outcomes. Although 42/87 (48.3%) had an RCAM score of ≥2 (with an expected case-fatality rate (CFR) of at least 23%), only 3/42 (7.1%) died. Indeed, among the 11 patients with an RCAM score of 3 (expected CFR 34%) and the 7 patients with an RCAM score of 4 (expected CFR of 56%) there were no deaths at all (
      • Aung N.M.
      • Nyein P.P.
      • Htut T.Y.
      • Htet Z.W.
      • Kyi T.T.
      • Anstey N.M.
      • et al.
      Antibiotic therapy in adults with malaria (ANTHEM): high rate of clinically significant bacteremia in hospitalized adults diagnosed with falciparum malaria.
      ).
      Other studies have reported significant rates of bacterial co-infection in adults with malaria. In one French study, seven of 14 adults with falciparum malaria who developed shock had confirmed bacterial infection (
      • Bruneel F.
      • Gachot B.
      • Timsit J.F.
      • Wolff M.
      • Bedos J.P.
      • Regnier B.
      • et al.
      Shock complicating severe falciparum malaria in European adults.
      ). In another French study, 5/40 (13%) patients were bacteraemic at the time of intensive care unit (ICU) admission (
      • Gachot B.
      • Wolff M.
      • Nissack G.
      • Veber B.
      • Vachon F.
      Acute lung injury complicating imported Plasmodium falciparum malaria.
      ). In a Swiss study, sepsis was reported in 3/23 (13%) patients admitted to the ICU (
      • Nuesch R.
      • Scheller M.
      • Gyr N.
      Hospital admissions for malaria in Basel, Switzerland: an epidemiological review of 150 cases.
      ). One large meta-analysis of imported malaria identified community-acquired bacterial co-infection in 8% of all patients (
      • Marks M.
      • Armstrong M.
      • Walker D.
      • Doherty T.
      Imported falciparum malaria among adults requiring intensive care: analysis of the literature.
      ). Meanwhile, bacterial sepsis was responsible for 38% of the deaths in the first 7 days in a large Indian ICU series (
      • Krishnan A.
      • Karnad D.R.
      Severe falciparum malaria: an important cause of multiple organ failure in Indian intensive care unit patients.
      ).
      It is estimated that malaria can account for more than half of all cases of bacteraemia in children in malaria-endemic areas (
      • Scott J.A.
      • Berkley J.A.
      • Mwangi I.
      • Ochola L.
      • Uyoga S.
      • Macharia A.
      • et al.
      Relation between falciparum malaria and bacteraemia in Kenyan children: a population-based, case-control study and a longitudinal study.
      ). Several mechanisms have been proposed to explain this association. Microvascular sequestration, the pathological hallmark of falciparum malaria, is believed to have a crucial role and is hypothesized to result in end-organ ischaemia, leading to translocation of enteric bacteria from the intestine (
      • Olupot-Olupot P.
      • Urban B.C.
      • Jemutai J.
      • Nteziyaremye J.
      • Fanjo H.M.
      • Karanja H.
      • et al.
      Endotoxaemia is common in children with Plasmodium falciparum malaria.
      ,
      • White V.A.
      Malaria in Malawi: inside a research autopsy study of pediatric cerebral malaria.
      ). Simultaneously, the host’s immune system appears less able to respond to bacterial pathogens (
      • Takem E.N.
      • Roca A.
      • Cunnington A.
      The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review.
      ). Haemolysis–central to the parasite’s life cycle–induces the cytoprotective heme oxygenase-1, impairing neutrophil killing (
      • Cunnington A.J.
      • Njie M.
      • Correa S.
      • Takem E.N.
      • Riley E.M.
      • Walther M.
      Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction.
      ) and also leads to quenching of nitric oxide (
      • Yeo T.W.
      • Lampah D.A.
      • Tjitra E.
      • Gitawati R.
      • Kenangalem E.
      • Piera K.
      • et al.
      Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria.
      ). Meanwhile, parasite digestive vacuoles are rapidly phagocytosed by neutrophils, causing their functional exhaustion (
      • Dasari P.
      • Reiss K.
      • Lingelbach K.
      • Baumeister S.
      • Lucius R.
      • Udomsangpetch R.
      • et al.
      Digestive vacuoles of Plasmodium falciparum are selectively phagocytosed by and impair killing function of polymorphonuclear leukocytes.
      ). Impaired humoral immunity has been documented and macrophage dysfunction may also play a role (
      • Takem E.N.
      • Roca A.
      • Cunnington A.
      The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review.
      ).
      If the fundamental pathophysiology of falciparum malaria in adults and children is the same (
      • White N.J.
      • Turner G.D.
      • Day N.P.
      • Dondorp A.M.
      Lethal malaria: Marchiafava and Bignami were right.
      ), it is unclear why these factors would not also predispose adults to bacterial infection (Table 1). Adults also have intense intestinal sequestration of parasites (
      • MacPherson G.G.
      • Warrell M.J.
      • White N.J.
      • Looareesuwan S.
      • Warrell D.A.
      Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration.
      ), increased gastrointestinal permeability is well documented (
      • Leopold S.J.
      • Ghose A.
      • Allman E.L.
      • Kingston H.W.F.
      • Hossain A.
      • Dutta A.K.
      • et al.
      Identifying the components of acidosis in patients with severe plasmodium falciparum malaria using metabolomics.
      ,
      • Wilairatana P.
      • Meddings J.B.
      • Ho M.
      • Vannaphan S.
      • Looareesuwan S.
      Increased gastrointestinal permeability in patients with Plasmodium falciparum malaria.
      ), and in the Myanmar series, enteric gram-negative organisms–particularly Salmonella species–were the most commonly isolated pathogens (
      • Aung N.M.
      • Nyein P.P.
      • Htut T.Y.
      • Htet Z.W.
      • Kyi T.T.
      • Anstey N.M.
      • et al.
      Antibiotic therapy in adults with malaria (ANTHEM): high rate of clinically significant bacteremia in hospitalized adults diagnosed with falciparum malaria.
      ). The parasite’s lifecycle, which has been linked to immune dysfunction in children, is the same in adults.
      Table 1Comparison of pathophysiological findings, clinical findings, and management strategies in adults and children hospitalized with malaria.
      ChildrenAdults
      Microvascular sequestration documented in the intestineYes (
      • White V.A.
      Malaria in Malawi: inside a research autopsy study of pediatric cerebral malaria.
      )
      Yes (
      • MacPherson G.G.
      • Warrell M.J.
      • White N.J.
      • Looareesuwan S.
      • Warrell D.A.
      Human cerebral malaria. A quantitative ultrastructural analysis of parasitized erythrocyte sequestration.
      )
      Increased gastrointestinal permeability documented in studiesYes (
      • Olupot-Olupot P.
      • Urban B.C.
      • Jemutai J.
      • Nteziyaremye J.
      • Fanjo H.M.
      • Karanja H.
      • et al.
      Endotoxaemia is common in children with Plasmodium falciparum malaria.
      )
      Yes (
      • Leopold S.J.
      • Ghose A.
      • Allman E.L.
      • Kingston H.W.F.
      • Hossain A.
      • Dutta A.K.
      • et al.
      Identifying the components of acidosis in patients with severe plasmodium falciparum malaria using metabolomics.
      ,
      • Wilairatana P.
      • Meddings J.B.
      • Ho M.
      • Vannaphan S.
      • Looareesuwan S.
      Increased gastrointestinal permeability in patients with Plasmodium falciparum malaria.
      )
      Haemolysis that may lead to neutrophil dysfunctionYesYes
      Microbiological spectrum of bacteraemia identified in studiesGram-negative organisms more common (
      • Church J.
      • Maitland K.
      Invasive bacterial co-infection in African children with Plasmodium falciparum malaria: a systematic review.
      )
      Gram-negative organisms more common (
      • Aung N.M.
      • Nyein P.P.
      • Htut T.Y.
      • Htet Z.W.
      • Kyi T.T.
      • Anstey N.M.
      • et al.
      Antibiotic therapy in adults with malaria (ANTHEM): high rate of clinically significant bacteremia in hospitalized adults diagnosed with falciparum malaria.
      )
      Is shock a common finding?Yes (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      Yes, more common than in children and increases with age (
      • Dondorp A.
      • Nosten F.
      • Stepniewska K.
      • Day N.
      • White N.
      South East Asian Quinine Artesunate Malaria Trial g. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
      ,

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      Empirical antibacterial therapy if very high parasite count?Yes (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      Yes (
      • White N.J.
      Bacteremia in adults with severe malaria.
      )
      Empirical antibacterial therapy if low parasite count?Yes (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      Yes (
      • White N.J.
      Bacteremia in adults with severe malaria.
      )
      Can bacterial sepsis masquerade clinically as severe malaria?Yes (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      Yes (
      • White N.J.
      Bacteremia in adults with severe malaria.
      )
      Case-fatality rate when treated with artesunate in resource-limited setting8.5% (
      • Dondorp A.M.
      • Fanello C.I.
      • Hendriksen I.C.
      • Gomes E.
      • Seni A.
      • Chhaganlal K.D.
      • et al.
      Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial.
      )
      15% (
      • Dondorp A.
      • Nosten F.
      • Stepniewska K.
      • Day N.
      • White N.
      South East Asian Quinine Artesunate Malaria Trial g. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
      )
      Empirical antibiotic therapy recommended in international guidelines?Yes (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      No (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      )
      There are additional clinical observations to suggest that bacterial co-infection is common in adults. The incidence of shock with malaria (‘algid malaria’) increases with age, but its pathophysiology remains poorly understood (
      • Gaieski D.F.
      • Goldman J.D.
      • Holtzman D.L.
      • Shoff W.H.
      • Shepherd S.M.
      • Mehta N.
      • et al.
      Algid malaria treated with early goal-directed therapy.
      ,

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      ). In the largest ever study of adults with severe malaria, 11.6% had shock at enrolment (
      • Dondorp A.
      • Nosten F.
      • Stepniewska K.
      • Day N.
      • White N.
      South East Asian Quinine Artesunate Malaria Trial g. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial.
      ). Meanwhile, in a large Indian ICU series of falciparum malaria, 7% had shock on admission to the ICU, with another 14% developing this complication in the ensuing 48 h (
      • Krishnan A.
      • Karnad D.R.
      Severe falciparum malaria: an important cause of multiple organ failure in Indian intensive care unit patients.
      ). It seems likely that bacterial co-infection contributes to many of these cases of shock, as other potential explanations appear uncommon. Invasive cardiac monitoring of adults with severe malaria demonstrates that cardiac output is preserved (
      • Hanson J.
      • Lam S.W.
      • Mohanty S.
      • Alam S.W.
      • Pattnaik R.
      • Mahanta K.C.
      • et al.
      Fluid resuscitation of adults with severe falciparum malaria: effects on acid-base status, renal function, and extravascular lung water.
      ;
      • Bruneel F.
      • Gachot B.
      • Timsit J.F.
      • Wolff M.
      • Bedos J.P.
      • Regnier B.
      • et al.
      Shock complicating severe falciparum malaria in European adults.
      ,
      • Nguyen H.P.
      • Hanson J.
      • Bethell D.
      • Nguyen T.H.
      • Tran T.H.
      • Ly V.C.
      • et al.
      A retrospective analysis of the haemodynamic and metabolic effects of fluid resuscitation in Vietnamese adults with severe falciparum malaria.
      ), and although most adults presenting with severe malaria in low and middle income (LMIC) settings are hypovolaemic–some profoundly so–volume status has little correlation with blood pressure (
      • Hanson J.
      • Lam S.W.
      • Mahanta K.C.
      • Pattnaik R.
      • Alam S.W.
      • Mohanty S.
      • et al.
      Relative contributions of macrovascular and microvascular dysfunction to disease severity in falciparum malaria.
      ). Gastrointestinal haemorrhage and splenic rupture are both very rare (

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      ).
      It has been conceded that bacterial co-infection is more common in adults with very high parasitaemias–and antibacterial therapy is recommended–although the optimal cut-off for a very high parasitaemia has not been defined (
      • White N.J.
      Bacteremia in adults with severe malaria.
      ). It has also been argued that the relatively low parasite count in the aforementioned Myanmar studies suggests that the high frequency of bacteraemia can be explained by the enrolment of patients with a primary diagnosis of bacterial sepsis, with the parasitaemia an incidental finding (
      • White N.J.
      Bacteremia in adults with severe malaria.
      ). While this is probably true in some of the cases–and indeed this is likely to be the case in almost all published studies of severe malaria–it is only possible for the attending clinician to establish a primary diagnosis of bacterial sepsis in a parasitaemic patient with the benefit of hindsight. Furthermore, it can be dangerous to place too much emphasis on the peripheral parasite count, as most parasites in severe disease are sequestered in the microvascular circulation and critically ill adults with malaria will not infrequently have a relatively low peripheral parasitaemia (
      • Dondorp A.M.
      • Desakorn V.
      • Pongtavornpinyo W.
      • Sahassananda D.
      • Silamut K.
      • Chotivanich K.
      • et al.
      Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.
      ). Moreover, if it is suggested that a low parasite count increases the likelihood of bacterial sepsis explaining a patient’s presentation, the logical conclusion is that empirical antibacterial therapy should be prescribed in critically ill patients with low parasitaemias as well.
      Notwithstanding these observations, using parasite density to guide therapy is challenging. Reliable microscopy requires well-trained microscopists, infrastructure maintenance, and robust quality assurance (
      • Wongsrichanalai C.
      • Barcus M.J.
      • Muth S.
      • Sutamihardja A.
      • Wernsdorfer W.H.
      A review of malaria diagnostic tools: microscopy and rapid diagnostic test (RDT).
      ). This laboratory support is unavailable in most malaria-endemic regions where–outside of a trial setting–malaria is diagnosed with rapid diagnostic tests (RDTs).
      Clinical assessment therefore assumes more importance, but it may be impossible for even experienced healthcare workers in resource-limited settings to determine whether the critically ill adult is presenting with malaria, a bacterial infection, or both. Impaired consciousness and the degree of metabolic acidosis have repeatedly been shown to be both important clinical signs of severe malaria in adults and the findings with the greatest prognostic significance (
      • Marks M.E.
      • Armstrong M.
      • Suvari M.M.
      • Batson S.
      • Whitty C.J.
      • Chiodini P.L.
      • et al.
      Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London.
      ,
      • Newton P.N.
      • Stepniewska K.
      • Dondorp A.
      • Silamut K.
      • Chierakul W.
      • Krishna S.
      • et al.
      Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand.
      ,

      World Health Organization. Severe malaria. Trop Med Int Health. 2014/09/13 ed2014. 7-131.

      ). The RCAM score–calculated using the patient’s respiratory rate (a surrogate for metabolic acidosis) and Glasgow Coma Score at presentation–is able to rapidly identify the high-risk patient (
      • Hanson J.
      • Lee S.J.
      • Mohanty S.
      • Faiz M.A.
      • Anstey N.M.
      • Price R.N.
      • et al.
      Rapid clinical assessment to facilitate the triage of adults with falciparum malaria, a retrospective analysis.
      ,
      • Marks M.E.
      • Armstrong M.
      • Suvari M.M.
      • Batson S.
      • Whitty C.J.
      • Chiodini P.L.
      • et al.
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      ,
      • Newton P.N.
      • Stepniewska K.
      • Dondorp A.
      • Silamut K.
      • Chierakul W.
      • Krishna S.
      • et al.
      Prognostic indicators in adults hospitalized with falciparum malaria in Western Thailand.
      ). However tachypnoea and impaired consciousness also define two of the three indices in the quick Sequential Organ Failure Assessment (qSOFA) score, which is used to prompt the clinician to consider the diagnosis of sepsis and to expedite the prescription of antibiotics (
      • Evans T.
      Diagnosis and management of sepsis.
      ,
      • Minejima E.
      • Delayo V.
      • Lou M.
      • Ny P.
      • Nieberg P.
      • She R.C.
      • et al.
      Utility of qSOFA score in identifying patients at risk for poor outcome in Staphylococcus aureus bacteremia.
      ,
      • Singer M.
      • Deutschman C.S.
      • Seymour C.W.
      • Shankar-Hari M.
      • Annane D.
      • Bauer M.
      • et al.
      The third international consensus definitions for sepsis and septic shock (Sepsis-3).
      ), the intervention with the greatest impact on mortality in patients with sepsis in resource-poor locations (
      • Phua J.
      • Koh Y.
      • Du B.
      • Tang Y.Q.
      • Divatia J.V.
      • Tan C.C.
      • et al.
      Management of severe sepsis in patients admitted to Asian intensive care units: prospective cohort study.
      ,
      • Thwaites C.L.
      • Lundeg G.
      • Dondorp A.M.
      • Adhikari N.K.J.
      • Nakibuuka J.
      • Jawa R.
      • et al.
      Infection management in patients with sepsis and septic shock in resource-limited settings.
      ).
      So, does the patient with a positive Plasmodium falciparum RDT, tachypnoea, and impaired consciousness have severe malaria, a bacterial infection, or both? In a resource-limited setting, if they have malaria approximately 33% of these patients will die before discharge (
      • Hanson J.
      • Lee S.J.
      • Mohanty S.
      • Faiz M.A.
      • Anstey N.M.
      • Charunwatthana P.
      • et al.
      A simple score to predict the outcome of severe malaria in adults.
      ); if they have bacterial sepsis this figure is about 19% (
      • Rudd K.E.
      • Seymour C.W.
      • Aluisio A.R.
      • Augustin M.E.
      • Bagenda D.S.
      • Beane A.
      • et al.
      Association of the quick sequential (Sepsis-Related) organ failure assessment (qSOFA) score with excess hospital mortality in adults with suspected infection in low- and middle-income countries.
      ). Limited ICU support in these locations means that if the critically ill febrile patient’s initial empirical therapy is chosen poorly, they may not get a second chance. Even if the patient is able to have a comprehensive work-up for bacterial infection–and in many LMIC hospitals this is not the case–results will not be available for many hours, with identification of a pathogen and its antimicrobial sensitivities only possible several days later. In these settings, the sensible, pragmatic decision is to initially cover both potential aetiologies, with prompt de-escalation when laboratory results are available.
      From a pathophysiological perspective, there appears no reason why adults with falciparum malaria would not share African children’s predisposition to bacterial co-infection. Indeed, recent studies suggest that co-infection may be more common than previously believed. However, even if, as suggested, these studies have enrolled patients with bacterial sepsis–with the parasitaemia an incidental finding–it is frequently impossible to determine this at presentation and it is wise for the clinician to cover both potential aetiologies. In an era of evolving antimicrobial resistance, this is not a call for broad-spectrum antibacterial therapy in every adult with a positive RDT. It is, instead, a call for more prospective clinical trials that might inform the optimal management of the critically ill adult with a diagnosis of malaria in the resource-limited setting. These trials should routinely report whether antibacterial therapy has been prescribed prior to admission or is prescribed concurrently with antimalarial therapy. Patients should have a complete septic work-up, with adequate volumes of blood collected for culture, prior to the administration of antibacterial therapy where this is possible. Quantitative P. falciparum histidine-rich protein 2 (PfHRP-2) measurement could assist in the differentiation of severe malaria from bacterial sepsis with incidental parasitaemia and might be used to correlate the risk of bacteraemia with the sequestered parasite load in the microcirculation (
      • Dondorp A.M.
      • Desakorn V.
      • Pongtavornpinyo W.
      • Sahassananda D.
      • Silamut K.
      • Chotivanich K.
      • et al.
      Estimation of the total parasite biomass in acute falciparum malaria from plasma PfHRP2.
      ,
      • Hendriksen I.C.
      • Mwanga-Amumpaire J.
      • von Seidlein L.
      • Mtove G.
      • White L.J.
      • Olaosebikan R.
      • et al.
      Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement.
      ). Measures of immune dysfunction could also be linked with the incidence of life-threatening bacterial infection. However, until these trials are performed, a conservative, pragmatic approach in these critically ill patients may be more appropriate than current guidelines suggest.

      Funding statement

      None declared.

      Ethics statement

      This perspective piece did not require ethical approval.

      Conflict of interest

      None declared.

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