Changes in the clinical presentation and outcomes of patients treated for severe malaria in a referral French university intensive care unit from 2004 to 2017

Half of the world’s population is still exposed to malaria, causing an estimated 228 million of clinical cases associated to 405,000 deaths in 2018. The African continent is the most impacted by Plasmodium infection, with still 93% of all worldwide clinical malaria cases and 94% of worldwide deaths, mostly in young children. However, although the malaria incidence rate decreased by 21% between 2010 and 2015, thanks to successive health policies aiming to decrease Plasmodium spp. exposition in local populations of endemic countries, it remains stable since 2015 [1].

France is the non-endemic European countries most affected by malaria imported cases, increasing since 2012 [2‐4], from 3580 estimated infected patients in 2012 to 5550 in 2018 (+ 55%). The associated mortality rate reached 0.39%. The increased incidence is likely explained by the growing number of African people visiting friends and relatives (VFR) in sub-Saharan countries and coming back to Western European countries such as France [5].

Importantly, during the last decade, the guidelines for the diagnosis and management of severe malaria cases have undergone major changes in endemic area and in France. Available in compassionate use in France since May 2011, artesunate became the first-line treatment for severe malaria. This drug is associated with a reduced mortality in endemic areas [6, 7], was shown to improve survival versus quinine in South-East Asia and Africa, to reduce parasite clearance time, and to shorten the ICU and hospital lengths of stay in non-endemic countries [8]. Its effectiveness and tolerance made it a good choice to replace intravenous quinine in European countries.

During the past decade, the characteristics of severe imported malaria cases referred to our intensive care unit (ICU) changed markedly. Patients were less often Caucasian tourists, presented less often with multiple organ failures, and seemed to recover more quickly. Therefore, we decided to further assess these epidemiologic changes and the potential impact of the widespread increase in the use of artesunate as a first-choice therapy on the improvement of prognosis.

The aim of this single-center study was to assess the evolution of the epidemiology, clinical presentation and outcome in severe imported malaria patients in an ICU of a referral hospital during the last 14 years. Our first objective was to assess over the years the clinical presentation, treatment and outcome in patients with severe imported malaria. The second one was to evaluate whether the changes in the outcome were correlated with the epidemiological evolution of patients with severe imported malaria, or with the availability of IV artesunate.

The major finding of our study conducted in a referral ICU for severe imported malaria in the Parisian area is that, despite no clear modification of the number and types of WHO criteria of patients throughout both study periods, the patients had a less severe disease as estimated by the SAPS II and a better prognosis during the 2013-2017 time period. These changes in presentation and prognosis were not related to an earlier initiation of therapy and not clearly related to the widespread use of artesunate, but were associated with changes in the population over time. Patients were hospitalized with a significantly lower SAPS II scores, but without significant modifications of the number of severity criteria at ICU admission.

Among 189 patients admitted in this ICU, the in-hospital mortality was 3.7%, lower than that described in previous studies among patients admitted for severe imported malaria [10‐12]. In the multicentric SIMA study [10], 35 patients (including two deaths) of our ICU were included with a lower mortality rate than in other centers (5.7% vs 10.9%). These results might be explained by the expertise of our ICU in the management of severe imported malaria. Recently, the French Artesunate Working Group analyzed the cohort of all severe imported malaria patients reported from 2011 to 2017, treated with artesunate or quinine, and observed a death rate of 3.2%, comparable to our result [13].

As the mortality associated with severe imported malaria is low, we defined a poor outcome as the composite endpoint of death, need of vasopressors, mechanical ventilation and/or renal replacement therapy. The association between severity criteria of malaria such as serum creatinine level above 265 µmol/L or cardio-circulatory, respiratory or neurological failures and our poor outcome seems obvious, but these criteria are universal predictors of poor prognosis on ICU admission. Acidosis and hyperlactatemia were also associated with a poorer prognosis. Other severity criteria of malaria, such as hyperparasitemia above 4%, did not seem associated with a poorer prognosis. Importantly, patients of African origin living in France, patients with prior exposure to malaria and with a shorter time from onset symptoms to ICU admission, had a better prognosis.

One of the explanations for the rise of severe imported malaria cases for the French national reference center was a significant and regular decrease in the proportion of people taking complete chemoprophylaxis [2]. We did not observe such a drop in our population over time, as our rate of patients who took complete anti-malarial chemoprophylaxis remained steadily very low. This shows that an important work on the education of these patients is still needed.

On the other hand, the French Reference Center explained the decreasing mortality rate in the recent years by the preponderant part of African-origin patients in severe imported malaria cases having a self-reported previous history of malaria [2]. A prior exposure to Plasmodium falciparum seems to induce a protection against severe malaria by generating antibody levels which are able to significantly reduce the circulating and sequestered parasite burden [13]. A persistence of some kind of protection after leaving malaria endemic areas is suspected, but the number of years covered by that protection is not well defined and needs further studies. In our work, we also observed a better outcome for patients with prior exposure, but we did not identify any correlation between a positive malaria serology and a good outcome. Data were missing for 51 patients (27%), mostly because those patients were transferred from another hospital. This finding questioned the need to develop better immunological tools to identify pre-exposed patients. While the number of travellers remained stable over the years, the proportion of patients living in endemic areas or VFR increased since 2008 (Fig. 1). Numerous associations between genetic polymorphisms and prognosis of severe malaria have been advocated [14‐20], but formal confirmations using large multicenter worldwide cohorts are lacking. Independently of definite pathophysiological explanation, the changes in population may be one of the reasons for the better outcome of patients with severe imported malaria during the second period.

We observed several cases of African patients living in Africa hospitalized for severe imported malaria in our hospital. This population of African people travelling in France to visit friends and relatives was limited, but it exemplified that African adults may present severe malaria which needs ICU management in European countries. The worldwide decreased exposure to Plasmodium species with the rise of preventive measures induced a decreased incidence of malaria cases [21]. Perraut et al. found that immunity with antigen-specific antibody declined in the youngest population in endemic areas. The consequence of this waning immunity might be an increased incidence of cases of severe imported malaria in the future [22].

The development of new diagnostic tools as well as new recommendations for malaria management such as the introduction of artesunate as the first-line of treatment for severe imported malaria since 2013 could also have had an impact on the mortality rate of severe imported malaria. However, no difference were observed in the time interval between symptoms onset to ICU admission across both periods. SIMA and PALUREA, the two largest studies of imported malaria in France [10, 11], were conducted before the availability of artesunate. Their mortality rates were higher than in our study, with death occurring during the first week of hospitalization in three out of four patients. In these two studies, the proportion of patients needing the use of vasopressors, mechanical ventilation or renal replacement therapy is shown in table E1, as well as a review of other studies of severe imported malaria [8, 23, 24]. The risk factors associated with mortality in the SIMA cohort study were an older age, a low Glasgow Coma Scale score and a high parasitemia. In the PALUREA study, three host-related biomarkers were associated with severe malaria, namely a high level of procalcitonin and sTREM-1, and a low level of albumin. As parasitemia only reflects the circulating parasites, which are less pathogenic than the sequestered parasites, another parasite-related biomarker, PfHRP2, is usually considered more relevant than parasitemia to identify severe malaria [25]. However, this biomarker does not allow to differentiate severe malaria with organ injuries from a “simple” hyperparasitemic severe malaria case [13, 26]. All those biomarkers were not systematically collected in our retrospective study and could not be analyzed.

The TropNet severe malaria study showed that a treatment with artesunate reduced the parasite clearance time and was associated with shorter ICU and hospital lengths-of-stay [8]. The initiation of an anti-malarial treatment is an emergency and previous studies demonstrated that a better prognostic was associated with a shorter time between the first symptoms and the initiation of treatment administration [27, 28]. However, we could not demonstrate that patients with better outcome had an earlier initiation of treatment. In our study, even a treatment started before ICU admission was not significantly associated with a better outcome. Nevertheless, we observed that 3/7 deaths occurred in patients transferred from another hospital without any administration of anti-malarial agents. We did not analyze the anti-malarial treatment that may have followed the initial administration of artesunate or quinine, because we estimated that the outcome of severe malaria would depend of the first anti-malarial treatment.

The main limitation of our study is the retrospective and monocentric design in a referral French ICU specialized in infectious diseases. Mortality might have been biased by the fact that our ICU had a long experience in treating severe imported malaria. The absence of difference between artesunate and quinine treatment in this study might be explained by a large experience in IV quinine use and the use of up-to-date standard of ICU care. Adverse effects reported with quinine use were very rare with only three symptomatic episodes of hypoglycemia. The absence of difference may also be due to a lack of study power because of an insufficient number of patients. In 2012, a retrospective study in the United Kingdom compared 24 patients treated with artesunate to 167 patients treated with quinine [29]. The length of stay was shorter in the artesunate group. The authors mentioned that this improvement might have been due either to the artesunate use or to a change in the population admitted. Indeed, they observed a shift in the origins of the patients with a higher proportion of African patients in the artesunate group. We also observed a change in the profile of our patients over time, with a higher proportion of African patients visiting friends or relatives or living in endemic countries.

The French Artesunate Working Group has also yielded the absence of significant impact of artesunate use in France. Indeed, in a country with a high level of care, no difference was found in term of mortality rate or duration of stay of severe malaria treated with artesunate versus quinine [30]. However, artesunate is a safe and effective treatment of severe malaria that became a standard of care, even in high-income countries and our aim was not to question its superiority, but to identify other parameters responsible for the change in prognosis. Post-artesunate delayed hemolysis occurred in 9.5% of the patients, which seems very low compared to other studies [25]. This event was collected from follow-up consultation reports and may have been underestimated.

In our unit, we did not observe any treatment failure when using artesunate. Treatment failure was defined by the WHO as the inability to clear malarial parasitemia or prevent recrudescence after treatment. Factors identified by the WHO to contribute to treatment failure were poor patient compliance, drug interactions and resistance [26]. In our study, 96% of the patients with severe imported malaria were coming back from West and Central Africa and only four patients travelled in Asia where cases of artesunate resistance have been described. The oral treatment following intravenous artesunate was artemisin-based combination therapy in most patients. Compliance to the oral treatment was not assessed in our study, as patients were usually already discharged from our ICU at this time.

In our ICU, the majority of patients admitted with severe imported malaria were of African origin and acquired their infection in West and Central Africa. On admission, those patients were less severe during the period of artesunate use than before. These trends could be partially explained by changes in the exposed population, with an increasing proportion of patients of African origin in the second period.