DOI: https://doi.org/10.21203/rs.2.17341/v1
Background: With less than one severe case per year in average, P. vivax is very rarely associated with severe imported malaria in France. We report two cases of P. vivax severe malaria in patients with no evident co-morbidity. Interestingly, both cases did not occur at the primary infection but during relapses.
Case presentations Patient 1 A 27-year old male, born in Afghanistan and living in France since 2012, was admitted on August 2015 to our hospital because of abdominal pain, intense headache, fever and hypotension. The patient was hemodynamically unstable despite 5 liters of filling solution. A thin blood film showed Plasmodium vivax trophozoites within the red blood cells. To take care of the septic shock, the patient was given rapid fluid resuscitation, norepinephrine (0.5 mg/h), and intravenous artesunate. Nested polymerase chain reactions of the SSUrRNA gene were negative for P. falciparum but positive for P. vivax. The patient became apyretic in less than 24H and the parasitaemia was negative at the same time. Patient 2 A 24-year old male, born in Pakistan and living in France, was admitted on august 2016 to our hospital because of fever, abdominal pain, headache, myalgia, and nausea. The last travel of the patient in a malaria endemic area occurred in 2013. A thin blood film showed Plasmodium vivax trophozoites within the red blood cells. The patient was treated orally by artenimol-piperaquine and recovered rapidly. Nine months later, the patient returned to our hospital with a relapse of P. vivax malaria. The malaria episode was uncomplicated and the patient recovered rapidly. Three months later, the patient came back again to our hospital with a third episode of P. vivax malaria. Following a rapid hemodynamic deterioration, the patient was transferred to the intensive care unit of the hospital. In all the patient received 10 liters of filling solution to manage the septic shock. After 5 days of hospitalization and a specific treatment, the patient was discharged in good clinical conditions.
Conclusion: Clinicians should be aware of the potential severe complications associated with P. vivax in imported malaria, even though the primary infection is uncomplicated.
France is the European country reporting the highest number of imported malaria cases with an estimated number of cases exceeding 4000 each year [1]. More than 85% of cases are caused by P. falciparum, followed by P. ovale (5,6%), P. vivax (4%); P. malariae and mixed infections amounting to 1,7% each.
In endemic areas, P. falciparum is responsible for the large bulk of the morbidity and mortality of malaria [2] even though it has been shown recently that the morbidity and mortality of P. vivax have been underestimated, particularly in patients who have other comorbidities, such as malnutrition, HIV, or coexisting infections [3, 4, 5, 6].
In France, P. falciparum appears as the species responsible for almost all severe cases and deaths in travelers [1]. With less than one severe case per year in average, P. vivax is very rarely associated with severe imported malaria in France. We report two cases of P. vivax severe malaria in patients with no evident co-morbidity. Interestingly, both cases did not occur at the primary infection but during relapses.
Patient 1
A 27-year old male, born in Afghanistan, living in France since 2012 and having not traveled in an endemic area since that date, was admitted on 2nd of August 2015 to the emergency unit of our hospital because of abdominal pain, intense headache, fever for 24h and fatigue. At presentation, he was febrile (38.9°C), hypotensive (79/48 mm Hg) and tachycardic (110 beats per minute). There were no meningeal signs and the Glasgow Coma Score was normal (15/15). The patient was hemodynamically unstable despite 5 liters of filling solution. Oxygen saturation while breathing ambient air was 94% (PO2 80 mm Hg). The lactatemia was 2.5 mmol/L and total bilirubinemia was 20 mol/L. Abdominal-thorax-pelvis computed tomography was done in emergency and was normal. He was then transferred to the intensive care unit (ICU) of the hospital. Severe malaria was suspected and a thin blood film showed Plasmodium vivax trophozoites within the red blood cells (parasitaemia 0.3%). Laboratory examination revealed disseminated intravascular coagulation with a platelet count of 37 × 109/L, a diminished PT (53%) and fibrinogen (1.65 g/L) and a high D-Dimer concentration (6595 ng/mL). A moderate hepatic cytolysis (aspartate aminotransferase, 76 IU/L and alanine aminotransferase, 148 IU/L), and a systemic inflammation (C-reactive protein, 19 mg/L and procalcitonine, 9.33µg/L) were also shown. To take care of the septic shock, the patient was given rapid fluid resuscitation, norepinephrine (0.5 mg/h), intravenous artesunate, cefotaxime, metronidazole and gentamicine.HHH No other infections were identified despite microbiologic investigations including blood and urine cultures. Serological tests for HIV1&2 were negative. He did not smoke or drink alcohol and he declared not to use other drugs. No comorbidities were known for this subject otherwise healthy. Nested polymerase chain reactions (PCRs) of the SSUrRNA gene with specific species primers were performed at the French Malaria Reference Center and were negative for both P. falciparum and P. knowlesi but positive for P. vivax. The patient became apyretic in less than 24H and the parasitaemia was negative at the same time. He was then transferred to the Department of Infectious and Tropical Diseases where he was given chloroquine orally (25 mg/kg on 3 days). After 5 days of hospitalization, the patient was discharged in good clinical conditions. A follow up performed two days later showed no parasites on thin and thick blood films and the patient remained apyretic.
Two other relapses occurred ten weeks and 16 weeks later but without criteria of severity. A radical treatment with primaquine, 30 mg per day for two weeks, was proposed to the patient who followed it successfully.
Patient 2
A 24-year old male, born in Pakistan and living in France since 2010, was admitted on 15th of August 2016 to the emergency unit of our hospital for fever, abdominal pain, headache, myalgia, and nausea. The last travel of the patient in a malaria endemic area (Pakistan) occurred in 2013. Laboratory examination revealed a thrombopenia (platelet count, 61× 109/L), a systemic inflammation (C-reactive protein, 145 mg/L), and a thin blood film showed P. vivax trophozoites within the red blood cells (parasitaemia 0.22%). The patient was hospitalized due to abnormalities in biological parameters including hyperbilirubinemia (102 mol/L). The patient received intravenous quinine on Day 0, due to uncontrollable vomiting, and, according to the French recommendations, was treated orally by artenimol-piperaquine the three following days [7]. Then the patient recovered rapidly. A radical treatment with primaquine was proposed to the patient who did not adhere to the proposition.
The patient returned to the hospital more than nine months later (on 29th of May 2017) when he presented with a relapse of P. vivax malaria (parasitaemia 0.3%). The patient had still not traveled in a malaria endemic area since his last hospitalization. The malaria episode was uncomplicated. As the patient presented again with vomiting he was given intravenous quinine on Day 0 and oral chloroquine, 25 mg/kg, on the three following days.
Three months later, the patient came back again for fever (38.5°C), headache, arthralgia, myalgia, abdominal pain and subsequently, vomiting and diarrhoea. A thin blood film revealed the presence of P. vivax trophozoites (parasitaemia 0.38%). Following a rapid hemodynamic deterioration, the patient was transferred to the ICU. At the admission, the patient was hypotensive (92/48 mm Hg) and tachycardic (100 beats per minute). Lactataemia was 2,3 mmol/L and total bilirubinemia was 52 mol/L. In all the patient received 10 liters of filling solution to manage the septic shock. As the patient suffered from uncontrollable vomiting he was given intravenous quinine on Day 0 and was treated orally by chloroquine the three following days. No other infections were identified despite extensive microbiologic investigations. Nested polymerase chain reactions (PCRs) of the SSUrRNA gene with specific species primers were negative for both P. falciparum and P. knowlesi but positive for P. vivax. After 5 days of hospitalization, the patient was discharged in good clinical conditions. A follow up performed two days later showed no parasites on thin and thick blood films and the patient remained apyretic. After two other relapses, which were uncomplicated, occurring in the following months, a radical treatment with primaquine was once again proposed to the patient who was then compliant.
P. vivax is increasingly recognized as responsible for severe malaria in endemic areas and also in imported malaria [8, 9]. In a recent retrospective study conducted in Sweden, Wangdahl et al. claimed that 7.7% of imported P. vivax cases were severe, which was comparable to the proportion seen with P. falciparum (9.4%) [9]. Those surprising results may reflect an increase or a better diagnosis of severe cases due to P. vivax during the last decades. However, as single nor mixed infections in their series were not systematically confirmed by PCR, it is possible that the number of severe P. vivax cases was over estimated due to unrecognized association with P. falciparum. In the both cases presented here, we confirmed by PCR assays that P. vivax was the unique species involved in the malaria episodes.
Both patients suffered from septic shock, which is a criterion frequently reported for P. vivax severe malaria [6, 9, 10]. Patient 2 showed a marked hyperbilirubinemia (102 mol/L) on his first visit as a clinically uncomplicated malaria episode was diagnosed. The current WHO criteria for severe forms of malaria include hyperbilirubinemia with a threshold > 50 mol/L [11, 12]. We agree with other authors that hyperbilirubinemia, when isolated, does not seem to be a suitable criterion for imported severe malaria [9]. At his third visit, as patient 2 developed a severe episode, the bilirubinemia was slightly above the threshold (52 mol/L). Patient 1 had a value below the threshold (20 mol/L) during his severe episode.
In nonendemic areas, older age is a risk factor for severe malaria for P. falciparum and for other species [9, 13]. It may be underlined that both patients were young and thus were not particularly at risk for this point.
To our knowledge, imported malaria episodes due to other species than P. falciparum usually do not evolve towards the death of travelers [9, 14] but in some instances they may have led to serious complications and important residual damages [15]. As their condition deteriorated, both patients presented here were rapidly admitted in ICU where they received appropriate treatments. Thus, both patients recovered without sequelae.
Both patients had not traveled recently in a malaria endemic area and did not live near an airport. None of the patients had reported an episode of severe malaria when they were still in endemic area. P. vivax is prevalent in Afghanistan and Pakistan and hepatic dormant forms (hypnozoites) may persist several years in the liver of infected subjects [16, 17]. There are different strains of P. vivax according to geographical region/endemicity areas, with relapse patterns that vary by latency (time to first relapse), likelihood of relapse, and frequency of relapses [17]. The temperate strains, including those found in Afghanistan and in the North of Pakistan, relapse much more slowly than other strains (up to two years or more) [17]. They may also exhibit extended incubation period (7–14 months) [16, 18, 19]. Much longer incubations (> three years) are exceptionally reported for P. vivax in the literature [20]. We inferred that Patient 1 presented at his first visit to our hospital during a relapse because he had not traveled in endemic area since at least three years. However, as we did not observe the primary episode by ourselves, we cannot formally exclude an exceptionally long incubation for this case.
The cases presented here are particular in that the severity of the attacks revealed itself not at the primary infection but on relapses. Severe P. vivax episodes have been already reported in endemic areas after 2–3 relapses in the case of strains with long incubation [20]. To our knowledge, such cases have not been reported previously in imported malaria. It is generally admitted that a relapse originates from a single genotype which is dormant in the liver [21, 22]. As infections are often polyclonal [23, 24], the clonal parasite population responsible of the relapse may be different from the one giving the primary infection or other subsequent relapses. Relapses may also result from activation of heterologous latent hypnozoites acquired from previous inoculations [25]. Thus, the parasites responsible for a severe relapse may be more virulent than the parasites observed during other episodes. It is also possible that the patients experienced a degradation of their health during their stay in France due to difficult conditions of living of immigrants or refugees.
In conclusion, clinicians should be aware of the potential severe complications associated with P. vivax in imported malaria, even though the primary infection is uncomplicated. A radical treatment with primaquine or tafenoquine should be implemented whenever possible in order to avoid relapses, severe or not [26, 27].
ICU: intensive care unit
PCR: polymerase chain reaction
PT: prothrombin time
SSUrRNA: small subunit ribosomal ribonucleic acid
WHO: World Health Organization
Ethics approval
Data used in the paper are not subject to ethical clearance as they form part of routine diagnosis and clinical management of malaria cases.
Consent for publication
Written consent was obtained from the patients for publication.
Competing interests
The authors declare that they have no competing interests.
Availability of data and materials
Not applicable
Funding
No particular funding was received for this work
Contributions
CL, YC and OB contributed to the clinical diagnosis of the cases and to the management of the patients. RD and AI contributed to the laboratory diagnosis of the case. SC performed the molecular analysis of the samples. RD supervised the study and wrote the draft of the paper. CL, SC, AI, and OB helped draft and critically analysed the manuscript. All authors read and approved the final manuscript.
Acknowledgements
We thank the department of infectious diseases, the department of emergency, and the ICU, particularly Dr Maxence Rouiller, of Avicenne hospital for contributing with medical records.
Authors’informations
1 Service de Parasitologie- Mycologie, CHU Avicenne, Assistance Publique-Hôpitaux de Paris, 125 rue de Stalingrad, 93009 Bobigny Cedex, France.2 Unité des Virus Émergents (UVE: Aix-Marseille Univ-IRD 190-Inserm 1207-IHU Méditerranée Infection), Marseille. 3 UFR SMBH, Université Paris 13, Bobigny.4 UMR 8076 CNRS BioCIS, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry. 5 Centre National de Référence du Paludisme, hôpital Bichat-Claude Bernard, APHP, Paris. 6 Service de Pédiatrie générale, CHU Jean Verdier, Bondy. 7 Réanimation Médico-Chirurgicale, CHU Avicenne, Bobigny.8 Service de Maladies Infectieuses et Tropicales, CHU Avicenne, Bobigny.