Case Report
Severe cases of Plasmodium falciparum infection on the ICU: diagnostic challenges and management
Inhoud:

    Auteur(s):

    C. Nederstigt (1,5), V.C. van Dam (2), E.H. Jeninga (3), B.W. Haak (4), M. Schouten (4), M. Michels (4)
    Departments of 1. Intensive Care, 3. Clinical Chemistry and 4. Internal Medicine, Tergooi Medical Center, Hilversum, the Netherlands, 2. Department of Intensive Care, BovenIJ Hospital, Amsterdam, the Netherlands, 5. Department of Intensive Care, Saxenburgh Medical Center, Hardenberg, the Netherlands

    Correspondentie:

    C. Nederstigt - c.nederstigt@sxb.nl
    Case Report

    Severe cases of Plasmodium falciparum infection on the ICU: diagnostic challenges and management

    Abstract
    We present two cases of severe falciparum malaria (malaria tropica) in the Netherlands in two different hospitals in December 2021. Both patients presented with a high parasitic load and serious complications including haematological disorders, metabolic acidosis and acute kidney injury and were consequently in need of admission to the intensive care unit. In this overview we describe the current challenges and latest insights with respect to diagnosis and treatment of severe falciparum malaria, as a guide to any physician encountering patients with acute severe falciparum malaria in an acute care setting.

    Introduction
    Falciparum malaria is caused by Plasmodium falciparum, a tropical parasite transmitted by Anopheles mosquitoes in endemic areas including Africa (accounting for 95% of the cases), South East Asian and Eastern Mediterranean regions. Clinical presentation varies from mild febrile illness to severe disease with multiorgan failure and shock (table 1). In endemic areas, severe malaria only accounts for 1% of the infections,[1] but up to 10% of immunologically naive travellers to areas where malaria is present develop severe malaria.[2,3] The incubation period for P. falciparum infection is usually 12 to 14 days (range 7 to 30 days) and it should be ruled out in all travellers with (sub)febrile disease who have visited endemic areas, irrespective of the use of prophylaxis.[4] Relapses, sometimes occurring years following initial infection, are seen in other Plasmodium infections, in particular P. vivax and P. ovale, generally associated with a milder clinical picture (table 2). Around 200 cases of malaria are reported in the Netherlands each year, 75% of which are caused by Plasmodium falciparum.[5] One epidemiological study from 2017 reported hospitalisation in 53.3% of all notified malaria cases in the Netherlands and a case fatality rate for P. falciparum of 0.5%.[6]

    Case 1
    A 58-year-old otherwise healthy male of Dutch descent presented to the emergency department with dyspnoea and altered level of consciousness. The patient could not speak, but his son revealed that he had returned from an eight week visit to Ghana a week ago, when he did not use malaria prophylaxis. In the days prior to presentation he showed abnormal behaviour; he avoided contact and had been downplaying his physical complaints. At presentation jaundice was apparent and he had a tachycardia and a high respiratory rate with signs of increased respiratory effort. His blood pressure was 160/100 mmHg and his temperature 35 °C. The arterial blood gas sample showed a pH <6.75, with a pO2 of 28.2 kPa, pCO2 of 1.6 kPa and non-detectable bicarbonate consistent with severe metabolic acidosis. Further analysis showed a lactate of 19.7 mmol/l, haemolytic anaemia (Hb 6.8, reference value 8.5-11 mmol/l, haptoglobin <0.1 g/l), disseminated intravascular coagulation (thrombocytes 19 x 109/l, a prolonged APTT of 60 sec) and acute kidney injury. Because of the recent trip to Ghana and aforementioned clinical presentation, diagnostic tests for malaria were immediately performed including microscopic examination of thick and thin blood smear and an immunochromatographic rapid diagnostic test for malaria (RDT; BinaxNOWTM (Abbott)). Although the RDT was only positive for non-Falciparum plasmodium species, the blood smears showed trophozoites, schizonts and gametocytes of P. falciparum consistent with severe falciparum malaria with a parasitic load of 23% (figure 1a).

    F1a Severe cases of Plasmodium falciparum infection on the ICU diagnostic challenges and management

    Upon diagnosis, the patient was admitted to the ICU and immediately treated with artesunate 2.4 mg/kg intravenously. In addition, he was intubated as he showed signs of impending respiratory exhaustion. Continuous renal replacement therapy was initiated and he was treated with sodium bicarbonate to manage the acidosis. Despite rapid initiation of the treatment, the patient’s condition deteriorated quickly as he needed increasing amounts of vasopressors and fluids. Unfortunately, his lactate increased further to 25.8 mmol/l and the pH stayed under 7.0. Shortly after, the patient developed multi-organ failure and refractory shock with cardiac failure and he died 17 hours after presentation in the presence of his family. The case was reported to the designated authorities.

    Case 2
    A 54-year-old male with a medical history of type 2 diabetes, for which he used metformin, and two previous episodes of malaria presented to the emergency department because of fever after returning from the Ivory Coast two weeks ago. He was born in the Ivory Coast and had lived in the Netherlands for 17 years. He had visited the Ivory Coast for two weeks and had not used any malaria prophylaxis. His symptoms started a day before returning to the Netherlands. At presentation a restless man was seen with a high respiratory rate and good oxygen saturation. He had a tachycardia and his blood pressure was 85/60 mmHg. His temperature was 38.1 °C. The chest X-ray showed no evident abnormalities. The arterial blood gas sample showed a pH of 7.34, with a pO2 of 11.7 kPa (without oxygen), pCO2 of 2.7 kPa, and bicarbonate of 10.7 mmol/l. Further analysis showed a lactate of 13 mmol/l, thrombocytes of 14 x 109/l and acute kidney injury. His glucose was 14.6 mmol/l and the total bilirubin 171 µmol/l (direct bilirubin 131 µmol/l). The RDT (BinaxNOWTM (Abbott)) was positive for Plasmodium falciparum (or mixed infection) and the blood smear showed trophozoites and schizonts consistent with falciparum malaria with a parasitic load of 8.2% (figure 1b).

    F1b Severe cases of Plasmodium falciparum infection on the ICU diagnostic challenges and management

    The patient was admitted to the ICU and treated with artesunate 2.4 mg/kg intravenously (260 mg on T= 0, 12, 24, 48, 72 hours). He needed fluids and vasopressors. Shortly after, his lactate levels dropped and his kidney function improved. After two days he was transferred to a nursing ward and discharged from the hospital at day 12.

    Discussion
    During the treatment of the aforementioned patients, diagnostic as well as clinical challenges became apparent.

    The first challenge was diagnostic, as the RDT in the first patient was positive for the pan-malarial aldolase antigen and negative for the P. falciparum specific HRP2 antigen, suggesting an infection with non-falciparum Plasmodium species. This was not consistent with the clinical picture, as severe malaria is usually caused by P. falciparum and to lesser extent P. knowlesi which is not endemic in Ghana (and the Ivory Coast). However, as treatment is the same in all severe cases of malaria, it did not influence the timing and initiation of the treatment. The RDT that was used can produce a false-negative result for the P. falciparum specific HRP2 antigen as a consequence of antigen excess in cases with very high parasitaemia (prozone effect). This is described in cases with loads greater than 4%.[7-9] Interestingly, this can also occur in case of a P. falciparum variant that lacks specific antigens,[10] which is also found in Ghana, were this patient had been infected. Therefore antigen testing should always be combined with subsequent testing compliant with the latest guidelines. Blood smear microscopy was used in our cases, but alternatives include loop-mediated isothermal amplification (LAMP) and, in specialised laboratories, quantitative buffy coat (QBC).

    In this case, dilution of the blood sample (1:10) resulted in a positive result (figure 2) for the P. falciparum specific HRP2 antigen, demonstrating that the initially negative test result was due to a prozone effect. A positive result for both the P. falciparum specific HRP2 antigen (T1) and the pan-malarial aldolase antigen (T2) could theoretically suggest a co-infection of P. falciparum and other Plasmodium species (figure 2). Co-infection with other Plasmodium species was not very likely based on the microscopic examination of the blood smears and ruled out by PCR in our patient. Remarkably, the parasitaemia was so apparent and longstanding that even gametocytes and schizonts were observed in the blood smears next to trophozoites (up to five per red blood cell in this case).

    F2Severe cases of Plasmodium falciparum infection on the ICU diagnostic challenges and management

    Artesunate is the pro-drug of artemisinin and is a highly effective treatment against all erythrocytic asexual stages of the malaria parasite. As early treatment is associated with better outcomes, prompt administration is advised irrespective of further species diagnosis as severe malaria is generally caused by P. falciparum. The exact mode of action is unknown and it is advised to monitor patients for new anaemia, which can arise days to weeks after administration due to the clearance of previously infected erythrocytes. Alternatives to artesunate are quinine and artemether, yet these are considered inferior to artesunate and parasite clearance is usually slower.[11,12] Furthermore, quinine can aggravate hypoglycaemia significantly. Resistance to artemisinin derivatives is of increasing concern in Southeast Asia. Expansion of empiric treatment with artesunate combined with other therapies in these areas is under discussion.[13] Resistance to artemisinin derivatives in African regions is currently low but increasing and may become relevant in the near future.[14]

    Although diagnosis can be established rapidly and treatment is readily available in the majority (although not all) of the hospitals in the Netherlands, severe malaria can be accompanied with severe metabolic lactate acidosis, haematological abnormalities and acute kidney failure. Supportive treatment can be challenging as patients may experience rapid deterioration of the clinical picture.

    Hyperlactatemia in falciparum malaria is multifactorial and is partially caused by direct parasitaemic lactate production. Other important mechanisms, especially in severe disease with high parasitaemia, is sequestration of parasites in the microvascular circulation causing anaerobic glycolysis, which is worsened by co-existing anaemia and insufficient hepatic and renal lactate clearance.[15] In the first patient the severe acidosis was largely attributable to lactate production based on the calculated anion gap, maintained by acute kidney injury and impaired bicarbonate reabsorption. In addition, metformin use coinciding with acute kidney injury may have contributed to the lactate acidosis in the second patient. Longstanding acidosis contributes to the development of cardiogenic shock,[16] as seen in the first patient. Although hypotension and shock are rare at admission of severe malaria patients,[17,18] cardiogenic shock frequently develops in fatal cases. Besides port-mortem evidence of sequestration of parasitised erythrocytes in the cardiac microvasculature,[19] an association was found between mortality and reduced cardiac index reserve and relative hypovolaemia. On the other hand, aggressive fluid administration is not advised as it does not correct the acidosis and is associated with higher mortality including complications of fluid overload.[20] The cardiac function prior to admission of our patients was unknown.

    Severe haemolysis is caused by sequestration and clearance of infected erythrocytes and suppressed erythropoiesis in the septic patient. Although mild coagulopathies are common, disseminated intravascular coagulation occurs in less than 5% of the patients with severe malaria. However, in non-immune patients with severe P. falciparum malaria it is observed more frequently and it is associated with high mortality. In the second patient, the thrombocytopenia was considered to be a malaria-induced secondary thrombotic microangiopathy as other coagulation parameters were within the normal range, which is not consistent with disseminated intravascular coagulation. Thrombotic microangiopathy has been described in severe malaria infections and is mediated by upregulation of the von Willebrand factor (vWF) and decreased ADAMTS13 activity following massive endothelial activation. As the half-life of vWF is short, the response to therapy is usually fast.[21]

    Acute renal failure is a serious complication of malaria, with a reported mortality of 15 to 45% in endemic areas, which may be lower in dedicated medical centres.[22] Also, hypoglycaemia is a common complication, caused by diminished hepatic gluconeogenesis and depletion of the liver glycogen store. Acute renal failure and hypoglycaemia, together with severe acidosis and jaundice, are all independently associated with high mortality and the prognosis of severe malaria in this stage is poor.[23]

    We hypothesise that the first malaria patient may have suffered from cerebral malaria as the family noticed strange behaviour and the patient was underestimating his obvious physical deterioration. The blood smear showed that the infection was already longstanding due to the presence of yellow malarial pigment (haemozoin crystals) in neutrophilic granulocytes, which become apparent after neutrophilic phagocytosis of Plasmodium parasites. In the second patient, with previous exposure to malaria and probable reduced susceptibility to malaria as he was born in the Ivory Coast, no signs of cerebral involvement were noted. Along with adult travellers, it has been shown that children in endemic areas, with no previously developed immunity to malaria, are at risk for cerebral malaria,[2] further supporting our hypothesis that the first patient was more at risk for cerebral involvement.

    Exchange transfusion
    For decades exchange transfusion was a cornerstone in the treatment of severe malaria. After the introduction of potent antimalarials as first-line treatment for severe malaria, a study in 2013 showed no statistically significant association between exchange transfusion and survival.[24] Until then, exchange transfusion was recommended as adjunctive therapy to quinidine in patients with parasitaemia over 10%,[25] as it was thought that parasitaemia declined more rapidly with exchange transfusion than with quinidine alone.[26] Another (small) Dutch randomised control study from 2013 showed no additive effect on parasite clearance of exchange transfusion in artesunate-treated patients with severe malaria.[27] Since 2013, the Centers for Disease Control and Prevention no longer recommend the use of exchange transfusion as an adjunct to antimalarial drugs for the treatment of severe malaria.[25]

    Role of chemoprophylaxis
    None of the chemoprophylaxis regimens available provide absolute protection against malaria transmission. Effectivity of atovaquone/proguanil and mefloquine prophylaxis are estimated at around 96 and 91%, respectively[28,29] and are comparable with doxycycline.[30,31] Although this seems high, effectivity depends greatly on the compliance of the user and prophylaxis is frequently discontinued because of side effects. A study from 2017 showed 1.4% of the cases of P. falciparum malaria were in travellers residing in the Netherlands despite self-reported use of chemoprophylaxis according to the Dutch guidelines.[6] Notably, in the same study none of the deceased malaria patients had been using chemoprophylaxis.

    Conclusion
    Around 200 cases of malaria are reported in the Netherlands each year, 75% of which are caused by Plasmodium falciparum.[5] There are no data on the number of patients presenting to the ICU, but if not treated in time falciparum malaria develops into a severe disease, complicated by lactate acidosis and multi-organ failure. The primary diagnostic tool is a rapid antigen test always combined with a confirmation test. The interpretation of these tests requires some expertise. Adequate knowledge about the clinical picture, incubation periods and epidemiology can further support the diagnosis.

    Early initiation of therapy is associated with better outcomes. The main treatment is artesunate 2.4 mg/kg intravenously for seven days; the exact mechanism of action is as yet unknown, but this is effective in all erythrocytic stages of the P. falciparum (and P. vivax) life cycle. As treatment with artesunate has shown to reduce the parasite load rapidly, there is no longer a role for adjunctive exchange transfusion.

    Although malaria is not a frequent flyer on the Dutch ICUs, it needs to be considered in patients with a recent travel history to endemic countries, independent of the use of prophylaxis. Treatment is available and effective, provided it is initiated early. Malaria is a class C notifiable disease.

    Disclosures
    Informed consent for publication of this case report was obtained from the patient’s next of kin (case 1) and the patient (case 2). All authors declare no conflict of interest. No funding or financial support was received.

    Vragen

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    Zie ook de richtlijn Malaria Diagnostiek op de richtlijnendatabase

    Referenties Nederlandse versie:

    1. Rijksinstituut voor Volksgezondheid en Milieu, informatie over Malaria [Available from: https://www.rivm.nl/malaria.
    2. de Gier B, Suryapranata FS, Croughs M, van Genderen PJ, Keuter M, Visser LG, et al. Increase in imported malaria in the Netherlands in asylum seekers and VFR travellers. Malar J. 2017;16(1):60.
    3. Dondorp A, Nosten F, Stepniewska K, Day N, White N. Artesunate versus quinine for treatment of severe falciparum malaria: a randomised trial. Lancet. 2005;366(9487):717-25.
    4. Phu NH, Tuan PQ, Day N, Mai NT, Chau TT, Chuong LV, et al. Randomized controlled trial of artesunate or artemether in Vietnamese adults with severe falciparum malaria. Malar J. 2010;9:97.
    5. Nair AA, Tripathy KP, Behera PK. Artesunate Resistance – An Emerging Threat. J Assoc Physicians India. 2022;70(4):11-2.
    6. Balikagala B, Fukuda N, Ikeda M, Katuro OT, Tachibana SI, Yamauchi M, et al. Evidence of Artemisinin-Resistant Malaria in Africa. N Engl J Med. 2021;385(13):1163-71.
    7. Tan KR, Wiegand RE, Arguin PM. Exchange transfusion for severe malaria: evidence base and literature review. Clin Infect Dis. 2013;57(7):923-8.
    8. Centers for Disease Control and Prevention 2013 [Available from: https://www.cdc.gov/malaria/new_info/2013/exchange_transfusion.html.