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 and Maitland, 2014
). However, it is almost impossible to exclude co-infection in the resource-limited settings in which these children are usually managed (Evans et al., 2004
). 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, 2014
).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, 2014
). This belief was based significantly on data from large studies performed in Vietnam between 1991 and 2003, which were unpublished until recently (Phu et al., 2020
). 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 et al., 2020
).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 and Carroll, 2010
). 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 et al., 2019
). 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 et al., 2019
)–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 et al., 1975
, Komori et al., 2020
).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” (), 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 et al., 1996
). In the second study of 370 patients, 141 (38%) were reported to have co-infection (Phu et al., 2010
).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 et al., 2018
, Nyein et al., 2016
); 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 et al., 2010
)) 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 et al., 2017
, Ye Lynn et al., 2019
). 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 et al., 2018
).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 et al., 1997
). In another French study, 5/40 (13%) patients were bacteraemic at the time of intensive care unit (ICU) admission (Gachot et al., 1995
). In a Swiss study, sepsis was reported in 3/23 (13%) patients admitted to the ICU (Nuesch et al., 2000
). One large meta-analysis of imported malaria identified community-acquired bacterial co-infection in 8% of all patients (Marks et al., 2014
). Meanwhile, bacterial sepsis was responsible for 38% of the deaths in the first 7 days in a large Indian ICU series (Krishnan and Karnad, 2003
).It is estimated that malaria can account for more than half of all cases of bacteraemia in children in malaria-endemic areas (
Scott et al., 2011
). 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 et al., 2013
, White, 2011
). Simultaneously, the host’s immune system appears less able to respond to bacterial pathogens (Takem et al., 2014
). Haemolysis–central to the parasite’s life cycle–induces the cytoprotective heme oxygenase-1, impairing neutrophil killing (Cunnington et al., 2012
) and also leads to quenching of nitric oxide (Yeo et al., 2009
). Meanwhile, parasite digestive vacuoles are rapidly phagocytosed by neutrophils, causing their functional exhaustion (Dasari et al., 2011
). Impaired humoral immunity has been documented and macrophage dysfunction may also play a role (Takem et al., 2014
).If the fundamental pathophysiology of falciparum malaria in adults and children is the same (
White et al., 2013
), 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 et al., 1985
), increased gastrointestinal permeability is well documented (Leopold et al., 2019
, Wilairatana et al., 1997
), and in the Myanmar series, enteric gram-negative organisms–particularly Salmonella species–were the most commonly isolated pathogens (Aung et al., 2018
). 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.
| Children | Adults | |
|---|---|---|
| Microvascular sequestration documented in the intestine | Yes ( White, 2011 ) | Yes ( MacPherson et al., 1985 ) |
| Increased gastrointestinal permeability documented in studies | Yes ( Olupot-Olupot et al., 2013 ) | Yes ( Leopold et al., 2019 , Wilairatana et al., 1997 ) |
| Haemolysis that may lead to neutrophil dysfunction | Yes | Yes |
| Microbiological spectrum of bacteraemia identified in studies | Gram-negative organisms more common ( Church and Maitland, 2014 ) | Gram-negative organisms more common ( Aung et al., 2018 ) |
| Is shock a common finding? | Yes ( World Health Organization, 2014 ) | Yes, more common than in children and increases with age ( Dondorp et al., 2005a , World Health Organization, 2014 ) |
| Empirical antibacterial therapy if very high parasite count? | Yes ( World Health Organization, 2014 ) | Yes () |
| Empirical antibacterial therapy if low parasite count? | Yes ( World Health Organization, 2014 ) | Yes () |
| Can bacterial sepsis masquerade clinically as severe malaria? | Yes ( World Health Organization, 2014 ) | Yes () |
| Case-fatality rate when treated with artesunate in resource-limited setting | 8.5% ( Dondorp et al., 2010 ) | 15% ( Dondorp et al., 2005a ) |
| Empirical antibiotic therapy recommended in international guidelines? | Yes ( World Health Organization, 2014 ) | No ( World Health Organization, 2014 ) |
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 et al., 2013
, World Health Organization, 2014
). In the largest ever study of adults with severe malaria, 11.6% had shock at enrolment (Dondorp et al., 2005a
). 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 and Karnad, 2003
). 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 et al., 2013
; Bruneel et al., 1997
, Nguyen et al., 2011
), 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 et al., 2012
). Gastrointestinal haemorrhage and splenic rupture are both very rare (World Health Organization, 2014
).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 (). 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 (). 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 et al., 2005b
). 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 et al., 2007
). 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 et al., 2013
, Newton et al., 2013
, World Health Organization, 2014
). 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 et al., 2014
, Marks et al., 2013
, Newton et al., 2013
). 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, 2018
, Minejima et al., 2019
, Singer et al., 2016
), the intervention with the greatest impact on mortality in patients with sepsis in resource-poor locations (Phua et al., 2011
, Thwaites et al., 2019
).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 et al., 2010
); if they have bacterial sepsis this figure is about 19% (Rudd et al., 2018
). 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 et al., 2005b
, Hendriksen et al., 2012
). 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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Article Info
Publication History
Published online: October 02, 2020
Accepted:
September 25,
2020
Received in revised form:
September 25,
2020
Received:
August 24,
2020
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© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.
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