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Table of Contents
Year : 2021  |  Volume : 58  |  Issue : 3  |  Page : 246-256

Early indicators of high disease severity in imported falciparum malaria and their implications for supportive therapy

Department of Respiratory Medicine, Clinic-Group Ernst von Bergmann, Potsdam and Bad Belzig, Niemegker Straße 45, 14806 Bad Belzig, Germany

Date of Submission02-Apr-2020
Date of Acceptance05-Aug-2020
Date of Web Publication15-Feb-2022

Correspondence Address:
Bodo Hoffmeister
Department of Respiratory Medicine, Clinic-Group Ernst von Bergmann, Potsdam and Bad Belzig, Niemegker Straβe 45, 14806 Bad Belzig
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0972-9062.326187

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Background & objectives: In imported falciparum malaria various life-threatening complications involving multiple organ systems can ensue rapidly and unpredictably. Early recognition of high disease severity is mandatory to provide optimal care, thereby reducing mortality. However, validated tools allowing precise assessment of disease severity are unavailable for imported malaria. This study aimed to identify indicators of high disease severity apparent on admission.
Methods: Fifty-four adult cases of severe imported falciparum malaria treated between 2001 and 2015 on various intensive care units of the Charité University Hospital, Berlin, were retrospectively grouped according to their admission coma-acidosis malaria (CAM) score. The association of sociodemographic and clinical parameters with disease severity was assessed by multivariable logistic regression.
Results: Nineteen female (35%) and 35 male (65%) patients (median age: 44 years) were enrolled. The admission CAM score was 0 in n=24, 1 in n=15, 2 in n=10, 3 in n=3, and 4 in n=2 subjects. Thus, 5 patients (9.3%) had a predicted mortality risk of >20%. Higher maximum heart rates (p=0.002), lower baseline haematocrit (p<0.001), increased oxygen demand (p<0.001), and infiltrates on the admission chest X-ray (p=0.019) were independently associated with higher disease severity in multivariable analysis.
Interpretation & conclusion: In addition to the prognostic key parameters metabolic acidosis and impaired consciousness reflected by the CAM score, symptoms of respiratory distress and shock as well as profound anaemia help identify patients with highest disease severity. These indicators may guide clinicians to prompt targeted interventions at the earliest possible stage and may thus help improving survival.

Keywords: Imported malaria; Plasmodium falciparum; disease severity; supportive care

How to cite this article:
Hoffmeister B. Early indicators of high disease severity in imported falciparum malaria and their implications for supportive therapy. J Vector Borne Dis 2021;58:246-56

How to cite this URL:
Hoffmeister B. Early indicators of high disease severity in imported falciparum malaria and their implications for supportive therapy. J Vector Borne Dis [serial online] 2021 [cited 2023 Mar 29];58:246-56. Available from: http://www.jvbd.org//text.asp?2021/58/3/246/326187

  Introduction Top

Falciparum malaria has a unique and complex pathophysiology, which is still only incompletely understood[1]. Clinical manifestations and severity vary considerably depending on a multitude of different factors. Up to one quarter of the total variability in malaria severity is believed to be determined by host genetic factors[2]. Environmental conditions (e.g., the transmission intensity) as well as parasite properties play a role. In individuals living in endemic areas repeated encounters with the parasite in early life and thereafter result in a state of semi-immunity that slowly wanes in expatriates. Co-infection with HIV predisposes to more severe courses[3]. In imported malaria, age is a prominent risk factor[4],[5], probably due to age-related chronic co-morbidities facilitating the development of complications[6],[7].

In acute falciparum malaria, the parasite biomass increases 6- to 20fold per replication cycle. Disease dynamics can therefore be rapid and life-threatening complications may ensue abruptly and in an unpredictable manner. Most deaths occur within 24–48 hours of hospital admission[8]. The window for successful treatment is therefore narrow. Derived from various large studies, the life-threatening complications of falciparum malaria are now well-defined[9]. These so-called criteria of severe malaria [Table 1], however, differ considerably in their prognostic relevance. While death is unlikely to occur in patients with prostration or jaundice as sole criteria for severe disease, mortality in individuals with simultaneous impairment of consciousness, acute renal failure (ARF), and respiratory distress is known to be high. However, it is unclear why an individual develops certain complications while others do not. To better predict the outcome of adults with severe malaria and thereby guide clinical decision taking, more precisely several predictive scores and models have been developed in recent years[10]. Yet, their generalizability is limited. Only two of the eight different scores and models developed for adults so far have been validated externally. The first of these, the malaria score for adults (MSA), was proposed in 2007[11]. Yet, this scoring system is of little use on presentation since it defines “respiratory distress” as a need for ventilatory support. Similar to ARF (another MSA criterion) severe respiratory complications tend to occur later in the course of severe malaria. Furthermore, the score does not encompass metabolic acidosis, the single most important prognostic parameter in severe malaria[12]. To overcome these limitations, the Coma Acidosis Malaria (CAM) score was proposed in 2010 [Table 2][13]. Derived from the largest ever prospective trial involving adults with severe malaria[14], this score relies only on the base deficit and the level of consciousness. These two parameters actually encompass three of the most important prognostic markers for severe malaria: in addition to acidosis and neurological dysfunction a decreasing capacity of the kidneys to sustain metabolic compensation of acidosis as an early marker of incipient ARF is reflected. Both, the MSA and the CAM score, have been validated in areas where malaria is endemic. Yet, validated tools that can assess severity of imported disease are still unavailable. This means a dilemma for clinicians in areas where malaria is rare. Not only being confronted with a disease with a rather unfamiliar pathopyhsiology and protean manifestations they also cannot rely on tools that reliably identify patients at high risk of death. The objective of the present study was to identify readily and ubiquitously available parameters associated with high disease severity on presentation in patients with imported falciparum malaria.
Table 1: Criteria of severe malaria and their frequencies on presentation in 54 patients with severe falciparum malaria imported to Berlin, Germany, between 2001 and 2015

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Table 2: The Coma-Acidosis-Malaria (CAM) score

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The CAM score (0–4) is calculated as the base deficit score (0–2) plus the Glasgow Coma Score (GCS; 0–2)[13]

  Material & Methods Top

Inclusion criteria

Only patients aged ≥18 years hospitalized between 2001 and 2015 with severe imported falciparum malaria in the tertiary care Charité University Hospital, Berlin, Germany were enrolled. The study represents a subgroup analysis of a larger observational study[7].

Case definition

Diagnosis relied on thin and thick blood smears. Parasitaemia was expressed as percentage of parasitized erythrocytes with 1% parasitaemia corresponding to about 50.000 parasites/μl. Based on the 2015 WHO definition[9] severe malaria was defined by the presence of at least one malaria-specific complication [Table 1].

Assessment of disease severity

The CAM score, which is based on the base deficit and the level of consciousness according to the Glasgow coma scale (GCS), was considered the most appropriate tool to assess severity of imported falciparum malaria. The worst values during the admission period, i.e., the first 24 treatment hours, were used to calculate the score. This required repeated blood gas analyses and recording of the GCS in at least in 8-hourly intervals. Hence, only patients treated on the intensive care unit (ICU) were included. To support the analysis, several other prognostic scores that are commonly used on the ICU and that have previously been applied in malaria patients, namely the Acute Physiology And Chronic Health (APACHE II) score[15], the Simplified Acute Physiology Score (SAPS II)[16], and the Sequential Organ Failure Assessment (SOFA)[17], were also calculated for each patient. Since arterial lines had only been placed if strictly indicated (for instance, in patients with shock or respiratory failure), in the subset of patients without evidence for such complications and unavailable arterial blood gas analyses normal values for oxygen tension were used to calculate these scores.

Data collection

All cases were recorded using an electronic patient data management system (COPRA5, COPRA System GmbH, Germany) that allowed for continuous documentation of vital signs, laboratory parameters including blood gas analyses, and level of consciousness. Prior to statistical analysis all relevant parameters extracted from these electronic records and the medical reports were anonymized and then transferred into a database (IBM SPSS version 24).


History of or active malignancy as well as chronic cardiovascular, pulmonary, gastrointestinal, rheumatologic, renal, endocrine, metabolic, acute and chronic infectious, psychiatric, and neurologic diseases were considered relevant co-morbidities. To weigh seriousness of the underlying disorders an age-adjusted Charleson co-morbidity index (CA-CCI)[18] was calculated for every patient.

Data analysis

The primary outcome parameter (i.e., the dependent variable) of the analysis was disease severity according to the admission CAM score. As this score has five categories ranging from 0 to 4, ordinal logistic regression was used for univariate analysis. All associations with p-values <0.05 were included in a multivariable ordinal regression model with stepwise backward elimination of non-significant associations, until the final model included only associations with a level of significance <5%. Appropriate model fit was confirmed by -2 log likelihood and the Pearson and deviance goodness-of-fit tests. The key assumption of proportional odds was checked by using the test of parallel lines. Multicollinearity was excluded by use of a correlation matrix. For the other prognostic scores, which were measured on a continuous scale, multivariable linear regressions were used.

Ethical statement

The study was approved by the institutional review board (Ethics Committee of the Charité University Hospital, Berlin, identifier EA1/209/18).

  Results Top

Basic demographics

Between January 2001 and December 2015, a total of 558 adult cases of imported falciparum malaria were treated as in-hospital patients in the Department of Infectious Diseases, Respiratory and Critical Care Medicine of the Charité University Hospital, Berlin [Figure 1]. Eighty patients (14.3%) fulfilled the criteria for severe falciparum malaria, 59 of them requiring intensive care treatment. Five of these cases had to be excluded from the analysis because an admission CAM score could not be calculated. The remaining 19 female (35%) and 35 male (65%) subjects finally enrolled were between 19 and 76 years of age (median: 44 years). Twenty-eight cases (52%) originated from countries where malaria is endemic. Of these, 22 individuals were expatriates living in Berlin visiting friends and relatives (VFR) in their home countries, while 6 patients were visitors from endemic regions developing symptomatic malaria during their stay in Berlin. The remaining 26 cases (48%) were travellers from non-endemic countries [Table 3], mainly tourists. The majority of infections of either group had been acquired in sub-Saharan Africa. In only 6 cases the malaria had been contracted in Asian countries. Median time between onset of symptoms and diagnosis was 5 days (range 1–10 days). Most patients had no history of previous malaria episodes and had not taken regular chemoprophylaxis. Twenty-one patients (39%) had at least one relevant chronic condition (range 0–3) - the most common being arterial hypertension, cardiovascular diseases, endocrine/metabolic and chronic infectious disorders. With a median CA-CCI of 1 (range 0–7), however, the overall patient population was rather healthy. Four patients were HIV-positive while one case each had chronic hepatitis B and C co-infections, respectively.
Figure 1: Flowchart of patients excluded and included in the study population.

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Table 3: Characteristics of 54 adult cases of severe falciparum malaria imported to Berlin, Germany, between 2001 and 2015

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The median number of malaria-specific complications on presentation was 1 (range: 1–8), with hyperparasitaemia being the most common one. Median parasitaemia on admission was 8.0% (range: 0.5–35%). Ten patients were shocked on admission, 8 of them requiring vasopressors. One patient had cardiac arrest within hours after ICU admission and had to be resuscitated. Seven individuals had evidence of acute pulmonary oedema, while 2 patients suffered from manifest acute respiratory distress syndrome (ARDS). In 4 individuals’ mechanical ventilation was required during the admission period. Renal replacement therapy (RRT) had to be instituted in 4 of the 8 cases with ARF within the first 24 treatment hours. Seven patients had metabolic acidosis, 6 impaired consciousness. While the median admission haematocrit of the whole patient group was normal (37%), it showed a considerable range (12-50%), indicating that some individuals presented with severe malarial anaemia while others had signs of haemoconcentration due to fluid losses. All patients survived to discharge.

Disease severity

The admission CAM score was 0 in n = 24 (44.4%), 1 in n = 15 (27.8%), 2 in n = 10 (18.5%), 3 in n = 3 (5.6%), and 4 in n = 2 (3.7%) subjects [Figure 2]. Thus, 9.3% of the 54 patients enrolled and 0.9% of the total 558 adult cases of imported falciparum malaria have had an estimated mortality risk of >20%. There was a strong association between the CAM score and the other prognostic scores [Figure 2]. The parameters associated with higher disease severity in univariate analysis [Table 3] were chronic co- infections with either HIV, hepatitis B or C; decompensated shock, indicated by higher heart rates; respiratory distress, indicated by higher spontaneous respiratory rates, oxygen demand and infiltrates on the admission chest X-ray; haemolytic anaemia, indicated by a low haematocrit and high lactate dehydrogenase (LDH) levels; ARF, indicated by high blood urea nitrogen levels; marked systemic inflammation, indicated by leucocytosis; and bleeding diathesis, indicated by a prolonged activated partial thromboplastine time (aPTT). In multivariable analysis a lower haematocrit, higher maximum heart rates within the first 24 treatment hours, higher oxygen demand, and infiltrates on the admission chest X-ray were independently associated with higher admission CAM scores [Table 4]. These 4 parameters also showed strong associations with disease severity assessed by the other prognostic scores [Table 4].
Figure 2: The admission Coma-Acidosis-Malaria (CAM) score showed strong associations with three others, less malaria-specific, prognostic scores widely used on intensive care units to assess disease severity that have previously also been applied in malaria patients, namely the Acute Physiology And Chronic Health (APACHE) score II (A), the Simplified Acute Physiology Score (SAPS) II (B), and the Sequential Organ Failure (SOFA) score (C). P-values were determined by ordinal regression analysis.

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Table 4: Parameters independently associated with disease severity in multivariable analysis in 54 adults with severe falciparum malaria imported to Berlin, Germany, between 2001 and 2015

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  Discussion Top

Falciparum malaria is a disease with a unique pathophysiology, rapid dynamics, and protean clinical manifestations. Its severity depends on a multitude of different factors, many of which are difficult or even impossible to assess, especially when it would matter most, i.e., upon admission of a severely affected patient. In critically ill patients prompt institution of optimal medical care has priority, not uncommon with limited resources. How to achieve this goal in the absence of tools that allow a reliable assessment of the actual disease severity? This question is of particular importance for non-endemic regions. Here, clinicians do not only face a disease with a rather unfamiliar pathophysiology. To add to the difficulties encountered in management, the immunologic background (and thus a major determinant of disease severity) of the two populations mostly affected in non-endemic regions, i.e., malaria-naïve travellers and expatriates with slowly waning semi-immunity, is highly diverse. Furthermore, the relative rarity of this imported disease in general, and of fatal courses in particular, makes high quality prognostic studies difficult to realize in non-endemic regions. Among the 558 adult imported falciparum malaria cases treated between 2001 and 2015 in the Department of Infectious Diseases, Respiratory and Critical Care Medicine of the Charité University Hospital, Berlin, for instance, there were no fatalities. Although this result was the desired clinical outcome, it made a direct evaluation of risk factors for death impossible. The prognostic models currently available for clinical management of malaria and its complications in children and adults have all been developed in endemic regions. Only recently they underwent an in-depth review[10]. A major result of this study was that the majority of these models lack generalizability due to lacking external validation. Another important finding, however, was that the most important predictors of disease severity were consistent among the various studies. In adults, these essential predictors are neurological dysfunction, acidosis, and respiratory distress. In addition, shock and ARF play important prognostic roles.

The results of the present study are in line with this finding. In order to identify parameters associated with high disease severity on admission, the enrolled cases were retrospectively grouped according to their admission CAM score. The score showed strong associations with three other prognostic scores that are widely used on ICUs and that have, although not being malaria-specific, previously been applied in falciparum malaria patients. This allowed the conclusion that the CAM score adequately reflected overall disease severity in the imported malaria cases. Two of the four parameters independently associated with high disease severity in all scores besides impaired consciousness, acidosis, and incipient ARF were markers of respiratory distress. Infiltrates on the admission chest X-ray are primarily an early indicator of systemically increased vascular permeability, which in turn is an important reason for impaired oxygenation and subsequently increased oxygen demand. Higher maximum heart rates in those most heavily affected were likely the result of various pathophysiologic mechanisms such as fever, hypoxia, and anaemia, with shock being an important contributor. Finally, haemolytic anaemia appeared to play a pivotal role among the enrolled patients.

Although the complex pathophysiology of malaria is still incompletely understood, recent research has revealed that four elements play a central role [Figure 3]. Parasitized as well as unparasitized erythrocytes become less deformable[19],[20] and are cleared from the circulation[19],[21]. The resulting haemolytic anaemia reduces the haemoglobin (Hb) level and contributes to a compensatory increase in heart rate (HR). Cell-free Hb released from ruptured erythrocytes acts as a nitric oxide (NO) scavenger[22] and increases the plasma concentration of asymmetric dimethylarginine (ADMA), an NO synthase inhibitor. Reduced NO bioavailability further compounds endothelial dysfunction with subsequently impaired vasodilation[22]. Reduced RBC deformability also promotes microvascular obstruction[20],[23], the extent of which correlates with metabolic acidosis[23] and cerebral malaria[24]. A higher baseline systemic vascular resistance (SVR) has been described in patients who died from severe malaria compared to survivors[25]. Increases in the SVR may contribute to decreases in stroke volumes (SV). With decreasing SV and increasing HR, the cardiac cycle becomes less efficient and cardiac output (CO) diminishes[26]. Simultaneously, parasite toxins such as P. falciparum histidine-rich protein-2 (PfHRP-2) systemically activate endothelial cells leading to release of Angipoietin-2 and von-Willebrand factor. Angiopoietin-2 promotes breakdown of endothelial barrier integrity and thus increased vascular permeability, leading to cerebral, peripheral and pulmonary oedema formation[27]. Microvascular obstruction of the pulmonary vasculature and reduced NO bioavailability result in increased pulmonary pressures[28], further promoting pulmonary oedema formation with subsequent impairment of oxygenation. Acute pulmonary oedema and ARDS are serious complications of falciparum malaria and associated with high mortality[25]. Finally, nearly all patients with severe malaria present with some degree of hypovolaemia[25] due to fluid losses from fever, perspiration, vomiting, diarrhoea, insufficient oral fluid intake, increased vascular permeability, and other reasons. Hypovolaemia adds to the decrease in SV and increase in HR. This unique pathophysiology interferes with oxygen delivery (DO2) to peripheral tissues on multiple levels[7]. These considerations highlight the pivotal roles the parameters associated with high disease severity in the present study play in the pathophysiology of falciparum malaria. Comparable to the acid base status and the level of consciousness they are easily and ubiquitously available in the acute care setting. More importantly, these parameters have direct implications for supportive therapy, since all of them can be targeted by specific interventions.
Figure 3: The parameters associated with high disease severity in the present study (dark grey boxes) play pivotal roles in malaria pathophysiology. Oxygen delivery (DO2) depends on heart rate (HR), stroke volume (SV), haemoglobin level (Hb) and arterial oxygen saturation (SaO2). Under physiologic conditions, one parameter can be compensated for by others. However, the four key elements of falciparum malaria pathophysiology, i.e., fluid losses, microvascular obstruction, reduced red blood cell deformability, and endothelial dysfunction, interfere with all components of oxygen delivery simultaneously. The processes may also augment each other. This figure has been adapted and modified from reference[7]. APO—Acute pulmonary oedema; ARDS—Acute respiratory distress syndrome; CaO2, —Arterial oxygen content; CO— Cardiac output; DO2—Oxygen delivery; Hb—Haemoglobin level; HR—Heart rate; PaO2—Partial arterial oxygen pressure; RBC—Red blood cell; SaO2—Arterial oxygen saturation; SV—Stroke volume; SVR—Systemic vascular resistance.

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Undoubtably, the most important therapeutic intervention in severe falciparum malaria is the immediate institution of an effective antimalarial. Antimalarials address reduced RBC deformability, microvascular obstruction, and endothelial dysfunction simultaneously and in a causative manner. Artemisinins achieve the fastest parasite clearance of all antimalarials and are therefore the treatment of choice for severe cases[29]. Yet, anti- malarial therapy is not the only important intervention. Much depends on optimal supportive care meeting the specific pathophysiologic requirements of the illness. A recent British study reported a strong, inverse correlation between mortality and the number of cases encountered in a given region[5]. The largest study on severe imported malaria carried out so far enrolled 400 patients treated on 45 different intensive care units in France[4]. The mortality of these patients was 10.5%. When treatment takes place in specialized centres only, the case fatality rate can be kept below 2%[30].

Most patients with severe falciparum malaria are hypovolaemic on presentation[25]. Tachycardia is a useful clinical indicator of fluid needs in patients with high disease severity. Due to increased vascular permeability with simultaneous obstruction of the microcirculation, however, fluid management is a balancing act in severe falciparum malaria[31]. Although data is still scarce there is increasing evidence that an excessively liberal fluid management can be harmful for falciparum malaria patients, the most vulnerable organ system being the lung[25]. The fact that aggressive fluid resuscitation has become a common intervention on ICUs poses a certain risk to falciparum malaria patients treated on high dependency units unexperienced with malaria. In the French multicentre study 67.5% of patients had received aggressive fluid resuscitation. Survivors had significantly fewer undergone fluid resuscitation than none-survivors, many of which had died from respiratory complications[4].

Impaired oxygenation due to incipient pulmonary oedema can readily be detected by pulse oximetry, arterial blood gas analyses, and chest X-rays. Early application of positive end-expiratory pressures (PEEP) together with a cautious fluid management may help prevent progression to overt ARDS. In severe falciparum malaria skeletal muscle function is impaired, while its oxygen consumption is increased[32]. Mechanical ventilation combines ventilatory support with simultaneous application of PEEP and oxygen, if needed. Non-invasive mechanical ventilation may be an option for patients with APO and mild to moderate forms of ARDS and absent contraindications, including impaired consciousness.

Malarial anaemia has a complex pathophysiology on its own[33] and plays a central role in the pathophysiology of the illness, especially in children and pregnant women. However, the impact of the baseline haemoglobin level on disease severity has also been demonstrated for non-pregnant adults in previous studies[34]. Physiologic compensatory mechanisms, such as an increase in cardiac output and oxygen extraction, normally allow patients without significant comorbidities to tolerate even severe anaemia, as long as isovolaemia is maintained[35]. However, as outlined above, these mechanisms are hampered by the complex pathophysiology of falciparum malaria on multiple levels. Severely reduced RBC deformability is strongly predictive of mortality[19]. Transfusion improves RBC deformability. Although a recent meta-analysis found no prognostic benefit of exchange transfusions[36], there is evidence that less intense transfusion protocols may improve the outcome not only through its effect on anaemia, but also on microcirculatory obstruction[21].

The present study has several limitations, the main being its retrospective nature. Small case number, long observation period, and monocentric design further limit the quality of the data. Yet, severe imported falciparum malaria is a rare condition in most non-endemic regions. This makes high-quality prospective trials with sufficient caseload difficult to realize in the non-endemic setting. Retrospective analyses therefore continue to provide an important source of evidence. Results from studies in endemic regions cannot be generalized recklessly, for instance due to different baseline haemoglobin levels or immunologic backgrounds. This includes usage of a prognostic score developed in an endemic region. The strong association of the CAM score with three prognostic scoring systems not specific for malaria, however, supported the basic assumption of the study that the CAM score adequately reflected overall disease severity in imported malaria cases.

Despite these limitations, the study also has several strengths. Due to usage of an electronic patient management system data capture was high. Frequent monitoring of vital signs, level of consciousness, blood gases and acid-base-status, as well as chest X-rays available for all but two individuals on admission allowed for a detailed and systematic analysis. Secondly, the analysis focused on parameters ubiquitously available in the acute care setting rather than relying on sophisticated and time-consuming laboratory investigations. Most importantly, objective of the study was to interpret the findings on the basis of the underlying unique pathophysiology of falciparum malaria itself rather than developing another scoring system with its inherent limitations.

  Conclusion Top

Assessing the actual disease severity of patients with complicated imported falciparum malaria is not an easy task, not least because validated prognostic scores are missing. In the present study about 1% of the total imported falciparum malaria cases hospitalized between 2001 and 2015 in the Department of Infectious Diseases, Respiratory and Critical Care Medicine of the Charité University Hospital, Berlin, and about 10% of those requiring intensive care had a predicted mortality rate of >20% on admission. In face of the rapid disease dynamics, recognition of severely affected individuals at the earliest possible stage is mandatory to provide optimal supportive care meeting the unique pathophysiologic requirements of falciparum malaria. Together with the immediate institution of an effective antimalarial this may help to reduce mortality to a minimum. Comparable to endemic areas, indicators of high disease severity on admission (and their respective surrogate parameters) in imported disease appear to be metabolic acidosis and incipient ARF (both: base deficit), impaired consciousness (GCS), respiratory distress (radiologic infiltrates, oxygen demand), and shock (tachycardia). In addition, anaemia (haematocrit) seems to play an important prognostic role in imported cases.

Conflict of interest: None

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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