Skip to content

Advertisement

  • Case Report
  • Open Access

Imported Plasmodium vivax malaria with severe thrombocytopaenia: can it be severe malaria or not?

  • 1Email author,
  • 2,
  • 1,
  • 1,
  • 1,
  • 1 and
  • 1
Malaria Journal201615:105

https://doi.org/10.1186/s12936-016-1150-8

  • Received: 17 September 2015
  • Accepted: 4 February 2016
  • Published:

Abstract

Background

Thrombocytopaenia is the most frequent malaria-associated haematologic alteration observed with all five Plasmodium parasites causing disease in humans. Although not included in the World Health Organization criteria for severe Plasmodium falciparum malaria, severe thrombocytopaenia has been increasingly mentioned as an indicator of P. vivax malaria severity.

Case

Here, it is described a case of imported P. vivax malaria in a 37-year old man from Pakistan who presented with severe thrombocytopaenia (5 × 109/L). He was admitted to the intensive care unit and initially treated with a 1-day course of intravenous quinine followed by oral chloroquine and primaquine. The patient’s platelet count increased as early as 4 hours after treatment inception and the clinical course was favourable and uneventful.

Discussion

This case report, along with a review of published cases focusing on the relationship between thrombocytopaenia and severe P. vivax malaria, suggests that the prognostic role of severe thrombocytopaenia is ambiguous in absence of severe haemorraghic complications and its use as diagnostic criterion of malaria severity may lead to overestimation of severe P. vivax malaria cases.

Conclusion

Due to the lack of high quality studies it is at present unclear if severe thrombocytopaenia in the setting of P. vivax malaria should be considered indicative of severe malaria.

Keywords

  • Plasmodium vivax
  • Severe thrombocytopaenia
  • Severe malaria
  • Imported malaria
  • Bleeding

Background

Plasmodium vivax is responsible for nearly half of all malaria cases diagnosed outside sub-Saharan Africa and it exhibits the widest geographical distribution of human malaria parasites with an estimated 2.49 billion individuals living in areas at risk of infection [1]. Plasmodium vivax malaria has been long known as “benign tertian malaria” as opposed to the “malignant tertian or sub-tertian malaria” caused by P. falciparum [2]. However, in recent years an increasing number of studies, especially from the Indian subcontinent and South America, have highlighted the role of P. vivax as a cause of severe and even fatal malaria [37]. For this reason, Baird recommended, in his revision of the nomenclature of human malaria, to include vivax malaria as an “acute pernicious” entity in terms of clinical presentation and evolution [6].

However, conflicting issues emerge from cases of severe P. vivax malaria that are increasingly reported in the literature, partly because of the lack of a clear definition of the severity criteria, and partly from the possible interference of concomitant morbidities and infections on the clinical presentation and outcome [8].

Low platelet counts are commonly encountered in all types of malaria, and values lower than 60,000/μL have been reported in 29–46 % of patients affected with vivax malaria [9, 10]. However, thrombocytopaenia is not regarded as a severity biomarker in falciparum malaria, and it has not as yet been validated as an independent severity parameter in vivax malaria. Of note, in several studies and case reports, severe thrombocytopaenia was described as the most prevalent severity sign of vivax malaria [1115]. Therefore, it cannot be excluded that the use of such an indicator may lead to an overestimation of P. vivax malaria severity.

Here, it is described a case of imported P. vivax malaria characterized by severe thrombocytopaenia along with a review of similar cases reported in the literature. Furthermore, it is discussed whether severe thrombocytopaenia should be considered a reliable biomarker of P. vivax malaria severity.

Case report

A 37-year old male from Pakistan arrived in Italy in July 2013 to attend a professional course. After few days, he developed high grade fever (40 °C) associated with chills, headache and one episode of vomiting. He was visited by a primary physician who prescribed him cefixime 400 mg/day and acetaminophen. After 4 days, due to the persistence of fever and the onset of productive cough and asthenia, cefixime was changed to levofloxacin (500 mg/day). However, the fever did not resolve, and therefore the patient was taken to the nearest emergency department (ED). At presentation, he was febrile (39.5 °C), tachycardic (121 beats per min) and hypotensive (90/50 mm Hg); there were no meningeal signs and the Glasgow Coma Score was normal (15). Oxygen saturation while breathing ambient air was 99 %, the respiratory examination and a chest radiograph were both normal. Laboratory investigations were as follows: haemoglobin, 15.9 g/dL; red blood cell count, 5.54 × 109/L; total white cell count, 6.3 × 109/L (with 85 % neutrophils, 11 % lymphocytes and 4 % monocytes); platelet count, 14 × 109/L. With the exception of d-dimer concentration (9376 ng/dL), the other coagulation parameters were within the normal range. Hyponatremia (127 mmol/L) was present as well as raised values of C reactive protein (126 mg/L), total bilirubin (3.3 mg/dL), and lactate dehydrogenase (371 U/L). Serum concentrations of glucose, liver enzymes, urea and creatinine were within normal ranges. An ultrasound scan of the abdomen showed no hepatosplenomegaly and a normal biliary tract. Legionella and pneumococcus urine antigens were negative. A thin blood film showed “malaria parasites” that were not identified at the species level by the laboratory technician. Due to lack of anti-malarial drugs and the expertise for the diagnosis and therapy of malaria, the ED physician contacted the Luigi Sacco hospital in Milan for assistance. Ten hours after presentation at the first ED, the patient was finally admitted to the intensive care unit of Luigi Sacco hospital with a provisional diagnosis of “severe malaria”, based on the results of the laboratory tests (severe thrombocytopaenia and raised bilirubin levels) and the presence of hypotension. On physical examination, when admitted to the ICU, the patient was conscious, fully oriented to time and place with high fever (40 °C) and had severe headache. The pulmonary, cardiovascular and abdominal examinations were reportedly unremarkable. Neither signs of bleeding nor skin petechiae were detected. No previous history of malaria episodes was elicited and no underlying chronic diseases were present. The patient was treated with a loading dose of intravenous quinine (1200 mg). At treatment inception the platelet count was 5 × 109/L, without haemorrhagic manifestations. Examination of the peripheral blood smear by the haematologist did not reveal platelet clumping and a blood sample obtained with sodium citrate confirmed the finding of low platelet counts thus excluding a diagnosis of pseudothrombocytopaenia. In the absence of bleeding the haematologist judged as unnecessary the use of platelet transfusions. Thick and thin blood smear examinations were diagnostic for P. vivax infection with schizonts, gametocytes and ring forms being detected and a very low parasitaemia (0.1 %). Plasmodium vivax monoinfection was subsequently confirmed by DNA polymerase chain reaction performed on a stored blood sample obtained on admission. Blood and urine cultures were obtained but gave negative results. Serology for HIV, CMV, dengue virus, leptospirosis, syphilis, Brucella and typhoid fever were negative.

Platelet counts showed a rapid increase soon after the infusion of quinine (i.e., 13 × 109/L, 16 × 109/L, 20 × 109/L, 32 × 109/L, respectively, after 4, 10, 18 and 24 h). The following morning an infectious diseases consultation was requested which suggested an interruption of intravenous quinine (after two doses administered). In consideration of the stable clinical condition and the diagnosis of P. vivax malaria the patient was transferred to the Infectious Diseases ward where oral chloroquine was started to complete the treatment. Parasite clearance was observed within 48 h after hospital admission as well as improvement or complete disappearance of all accompanying signs and symptoms (fever, headache, nausea, asthenia, myalgia). After completing a 3-day course of chloroquine treatment, and documentation of normal glucose 6-phosphate dehydrogenase activity levels, the patient was started on oral primaquine (15 mg of base in a 26.3 mg tablet per day for 14 days) and discharged the fifth day of hospitalization in good clinical conditions and with platelet counts within the normal range (223 × 109/L).

Discussion

In this case report, a man from Pakistan with imported P. vivax malaria was initially classified as affected by severe malaria and admitted to the ICU on the basis of profound thrombocytopaenia. Despite the initial presentation, the patient’s clinical course was uneventful and the platelet counts recovered very rapidly under anti-malarial treatment [16]. In recent years, an increasing number of case reports and hospital-based studies, have questioned the notion of “benign tertian malaria” by describing severe and even fatal malaria associated with P. vivax infection [38, 1215]. In many instances, severe thrombocytopaenia was used by the authors of these reports as the stand-alone criterion of malaria severity, irrespective of the presence of haemorrhagic events and/or other signs of disease severity.

However, two relevant aspects deserve to be considered when interpreting the findings of these studies. The first concerns the lack of any specific case definition for severe P. vivax malaria and, consequently, the question of whether severe thrombocytopaenia should be considered, in the absence of bleeding, a marker of disease severity.

Thrombocytopaenia (i.e., a platelet count below 150,000/μL) is a frequent haematological finding in all types of malaria and it is observed in 29–93.3 % of patients with P. vivax malaria [9, 17]. The exact mechanisms underlying the decrease in platelet counts is still unknown, but various hypothesis have been advanced including immune-mediated phenomena, oxidative stress, alterations in splenic function and a direct interaction between the parasite and platelets [1822]. Recently, Coelho and coworkers demonstrated that macrophage-driven phagocytosis of platelets may be an important contributory mechanism and that the mean platelet volume was greater in thrombocytopaenic patients with vivax malaria than in controls [23]. The latter finding is particularly interesting because the presence of large circulating platelets and may be viewed as compensatory mechanism in order to preserve primary haemostasis. Accordingly, bleeding is seldomly observed in the course of malaria even among patients with severe thrombocytopaenia. So what is the clinical and prognostic significance of severe thrombocytopaenia in patients with vivax malaria?

Thirty-three case reports of severe thrombocytopaenia (median platelet count: 21,000/μL, range: 2000–45,000/μL) in patients with vivax malaria have been published in the medical literature from 1993 to 2014 (the majority after 2006) [11, 12, 15, 2451]. Ten individuals presented with haemorrhagic manifestations [27, 28, 30, 35, 38, 40, 41, 43, 48] and nine received platelet transfusions: all patients recovered with the exception of one who died because of shock and pancreatitis [45] (Table 1).
Table 1

Published case reports of severe thrombocytopaenia associated with severe Plasmodium vivax malaria

Year of publication/reference

Location of malaria acquisition

Age/sex

Platelet count/μL (nadir)

Other complications

Diagnostic method/parasite density

P. falciparum excluded

Treatment/platelets transfusion (N unit)

Outcome

1997/[15]

Thailand

27/F

22.000

No

Microscopy/serology/0.6 %

Yes

Sulfadoxine-pyrimethamine + primaquine/no

Recovery

1998/[24]

India

20/M

14.000

Severe anemia (Hb 3 g/dL)

Microscopy/NR

No

Chloroquine + primaquine/no

Recovery

1999/[11]

India

43/F

5.000

No

Microscopy/RDT/NR

Yes

Chloroquine + primaquine/no

Recovery

1999/[11]

Colombia

32/M

17.000

Shock; ARDS

Microscopy/PCR/5 %

Yes

Quinidine + primaquine/no

Recovery

2002/[12]

India

43/M

8.000

No

Microscopy/RDT/NR

Yes

Quinine sulphate/yes (6 units)

Recovery

2003/[26]

India

29/M

35.000

Jaundice

Microscopy/PCR/<1 %

Yes

Chloroquine + primaquine/no

Recovery

2003/[27]

Mexico

30/M

6.000

Epistaxis

Microscopy/NR

No

Quinine + doxycycline switched to chloroquine + primaquine/yes (20 units)

Recovery

2004/[28]

Brazil

20/M

2.000

Petechiae, hemorrhagic bullae

Microscopy/PCR/NR

Yes

Chloroquine/yes (1 unit)/prednisone

Recovery ITPa

2005/[29]

Brazil

43/F

17.000

ARDS; shock

Microscopy/RDT/NR

Yes

Chloroquine + artemether + primaquine/No

Recovery

2005/[30]

India

7/M

6.000

Petechial rash, gum bleeding

Microscopy/bone marrow/NR

No

Chloroquine (1 dose) followed by quinine dihydrochloride + primaquine/yes (2 units)/steroids

Recovery

2006/[31]

Venezuela

50/F

25.000

ARDS

Microscopy/PCR/1200/μL

Yes

Mefloquine + primaquine/no

Recovery

2006/[32]

Turkey

22 days/F

17.000

Jaundice

Microscopy/NR

No

Chloroquine + primaquine/yes (NR)

Recovery

2007/[33]

Guyana

59/M

10.000

ARDS; shock; renal failure

Microscopy/PCR/5 %

Yes

Quinine sulphate + doxycycline switched to intravenous quinidine/yes (1 unit)

Recovery

2007/[34]

Pakistan

59/M

39.000

ARDS; renal failure

Microscopy/RDT/PCR/3 %

Yes

Chloroquine + primaquine/no

Recovery

2007/[35]

India

8/M

30.000

Renal failure; petechial rash

Microscopy/RDT/24.000/μL

Yes

Quinine dihydrochloride/no

Recovery

2007/[36]

Republic of Korea

21/M

25.000

Shock

Microscopy/RDT/PCR/2352/μL

Yes

Chloroquine + primaquine/no

Recovery

2007/[36]

Republic of Korea

33/M

40.000

Shock

Microscopy/RDT/12.376/μL

Yes

Chloroquine + primaquine/no

Recovery

2008/[37]

Brazil

14/M

6.000

No

Microscopy/bone marrow/PCR/NR

Yes

Chloroquine + primaquine/no

Recovery

2009/[38]

India

4/F

11.000

Shock; bleeding; increased liver enzymes (AST 1080 U/L)

Microscopy/bone marrow/PCR/RDT/

Yes

Artesunate + mefloquine + primaquine + immunoglobulin/yes

Recovery

2009/[39]

Republic of Korea

27/F

21.000

Myocarditis

Microscopy/PCR/6990/μL

Yes

Chloroquine/no

Recovery

2009/[40]

India

1/M

20.000

Severe anemia; intracranial bleeding; seizures

Microscopy/RDT/NR

No

Cloroquine + quinine dihydrochloride +primaquine/yes

Recovery with hydrocephalus

2010/[41]

Republic of Korea

52/M

40.000

Retinal hemorrhage; jaundice; spleen infarction

Microscopy/9188/μL

No

Chloroquine + primaquine/no

Recovery

2010/[42]

Brazil

16/M

12.000

Rhabdomyolysis, renal failure

Microscopy/PCR/1520/μL

Yes

Chloroquine + artesunate + clindamycin/no

Recovery

2010/[43]

India

8/F

21.000

Petechial rash; severe anemia (Hb 4.7 g/dL); hematemesis

Microscopy/bone marrow/RDT/1.5 %

Yes

Chloroquine + primaquine/no

Recovery

2010/[43]

India

4/F

35.000

Epistaxis; melena

Microscopy/RDT/NR

Yes

Chloroquine + primaquine/yes (NR)

Recovery

2011/[44]

India

50/M

19.000

ARDS, hypotension

Microscopy/NR

No

Artesunate + primaquine/no

Recovery

2012/[45]

India

17/M

34.000

Acute pancreatitis; shock

Microscopy/RDT/NR

Yes

NR/No

Died

2013/[46]

Malaysia

38/M

41.000

ARDS

Microscopy/PCR/16/μL

Yes

Artesunate + primaquine/no

Recovery

2013/[47]

India

19/F

45.000

Acute myocarditis

Microscopy/RDT/NR

Yes

Artesunate + doxycycline/no

Recovery

2013/[48]

India

11/M

27.000

Petechial rash; jaundice; acute renal failure; GI bleeding, shock

Microscopy/RDT/NR

No

Artesunate/yes (NR)

Recovery

2013/[49]

Republic of Korea

59/M

37.000

ARDS; acute renal failure; jaundice; lactic acidosis

Microscopy/RDT/16,380/μL

Yes

Artesunate + chloroquine + primaquine/no

Recovery

2014/[50]

Greece

42/F

24.000

ARDS; jaundice

Microscopy/PCR//0.007 %

Yes

Mefloquine + quinine + doxycycline + primaquine/no

Recovery

2014/[51]

India

8/F

11.000

GCS 7; haemophagocytic syndrome; acute renal failure; hypotension

Microscopy/bone marrow/RDT/NR

Yes

Artesunate + sulphadoxine-pyrimethamine + primaquine/no

Recovery

F female, M male, Hb haemoglobin, NR not reported, RDT rapid diagnostic tests, ARDS acute respiratory distress syndrome, PCR polymerase chain reaction, a ITP idiopathic thrombocytopaenic purpura, AST alanine aminotransferase, GCS Glasgow Coma Score, GI gastrointestinal

Information regarding the relationship between vivax malaria and thrombocytopaenia adopted as a criterion for assessing malaria severity may be also extracted from 17 clinical studies (13 from India [13, 14, 5262], two from Pakistan [63, 64] and one each from Colombia and Sudan [65, 66]). In fifteen of these studies, a cut-off value of less than 50,000 platelets per μL was used to define severe thrombocytopaenia [13, 5260, 6266]. Overall, platelet counts below 50,000/μL were present in 335 out of the 906 cases of severe malaria examined (36.9 %), although the prevalence varied significantly among the studies, from 12.5 % to 93 % (Table 2), because of the different selection criteria employed. Bleeding manifestations (mainly epistaxis) were observed in 108 patients (34.8 %), but only in two patients were they serious enough to directly contribute to death (i.e., disseminated intravascular coagulation and gastrointestinal tract haemorrhage) [54, 58].
Table 2

Clinical studies using severe thrombocytopaenia as a criterion of severe malaria

References

Type of study/country

No patients with severe P.vivax malaria/P. vivax malaria (%)

Exclusion P. falciparum a/Exclusion of other infectious diseases

No patients with severe thrombocytopaenia among those with severe malaria (%)

No patients with bleeding manifestation (tipology)

Death

[13]

Prospective (adults)/India

40/456 (0.08)

Yes (RDT)/PCR/Yes

5 (12.5)

2 (Severe epistaxis requiring blood and platelet transfusions)

2 due to ARDS (none with Thp)

[14]

Prospective (pediatrics)/India

24/35 (68.6)

No/No

17 (70.8)b

2 (Epistaxis)

None

[52]

Retrospective (adults and pediatrics)/India

17/221 (7.7)

No/No

13

NR

3 (Pregnant women with ARDS)

[53]

Retrospective (adults)/India

28/30 (93.3)

No/No

28 (93.3)

None

2:1 ARDS, 1 CM (none with Thp)

[54]

Retrospective (pediatrics)/India

23/108 (21.3)

Yes (RDT)/No

9/23 (39.1)

3 (Petechiae, purpura)

1: GI bleeding, DIC, renal failure

[55]

Retrospective (adults)/India

43/121 (35.5)

Yes (RDT)c/No

43

None

3 due to ARDS (none with Thp)

[56]

Prospective (pediatrics)/India

60/380 (15.8)

Yes (RDT)/Yes

51/60 (85)

44 (Epistaxis); 19 (hematemesis)

None

[57]

Retrospective (adults)/India

107/213 (50.2)

Yes (RDT)/No

17 (15.8)

None

None

[58]

Retrospective (pediatrics)/India

45/131 (21.1)

Yes (RDT)/No

17 (13)

12 (NR)

4:2 ARDS/ARF; 1 CM; 1 DIC

[59]

Retrospective (pediatrics)/India

54/261 (20.7)

Yes (RDT)/Yes

20 (37)

10 (NR)

None

[60]

Prospective (adults and pediatrics)/India

200/900 (22.2)

Yes (RDT)/No

24/200 (12)

4 (Purpuric eruptions)

40

[61]

Prospective (adults)/India

22/198 (11.1)

Yes (RDT + PCR)/No

7/14 (50)d

9 (NR)

2 CM and ARDS (none with Thp)

[62]

Prospective (pediatrics)/India

38/61 (62.3)

Yes (RDT)/No

18/38 (47.4)

NR

5 (3 ARDS)

[63]

Prospective (pediatrics)/Pakistan

397,128 (30.5)

No/No

15 (38.5)

NR

1 with GCS <10, convulsion (without Thp)

[64]

Retrospective (adults)/India

111/296 (37.5)

Yes (RDT + PCR)e/No

58/111 (52.2)

16 (GI, genitourinary or respiratory tracts)

3 8 acute myocardial infarction)

[65]

Retrospective (adults and pediatrics)/India

83/359 (23.1)

No/No

13 (15.7)

4 (NR)

None

[66]

Prospective (pediatrics)/Sudan

18/18 (100)

No/No

4 (22.2)

2 epistaxis

None

Total

 

952/3916 (24.3)

11/17 (64.7)/3/17 (17.6)

359/952 (37.7)

106/3506 (3)/106/310 (34.2)

66/952 (6.9)

aBy polymerase chain reaction (PCR) or rapid diagnostic tests (RDTs)

bAll patients with less than 150.000 per μL were considered

cOnly some patients underwent RDT analysis

dIn this study severe thrombocytopaenia was considered with value <80.000 per μL

eOnly discordant samples

RDT rapid diagnostic test, PCR polymerase chain reaction, NR not reported, Thp thrombocytopaenia, CM cerebral malaria, ARDS acute respiratory distress syndrome

It is noteworthy that mixed P. vivax and P. falciparum infections were not ruled out in 14 out of 17 studies [14, 52, 53, 6366]. In addition, coexisting infections that may contribute to thrombocytopaenia (such as dengue fever, leptospirosis or bacterial sepsis) were not excluded in the majority of the studies [14, 5255, 57, 58, 6066]. Regarding the latter issue, a recent study conducted in the Brazilian Amazon showed that 17.6 % of patients with P. vivax malaria had concomitant dengue infection and these had a higher probability to present with haemorrhagic manifestations and jaundice [67].

Other studies have focused on the prognostic role of thrombocytopaenia in vivax malaria. Leal-Santos and coworkers in a cross-sectional study conducted in 186 patients from the Mato Grosso region showed that mean platelet volume and platelet distribution width (PDW) were significantly associated with the presence of warning signs of severe and complicated malaria (i.e., anaemia, hypotension and elevated creatinine levels) with odds ratios (OR) of 3.47 and 5.44, respectively [68]. In keeping with the above mentioned results, a large study conducted in Papua New Guinea showed that the greatest risk of severe thrombocytopaenia was associated with P. falciparum malaria (OR 6.03 vs 3.73 for P. vivax). However, the mortality risk for patients with severe thrombocytopaenia was higher among patients without malaria (7.9 %) than among those with P. falciparum (2.1 %) or P. vivax (1.5 %) malaria [69]. The authors also found a 16-fold higher risk of death when severe thrombocytopaenia was associated with severe anaemia (haemoglobin concentration below 5 mg/dL), and concluded that severe thrombocytopaenia should serve as a warning sign of poor outcome in patients with malaria particularly when it is accompanied by severe anaemia. Based on their findings, Lampah and coworkers proposed a threshold of ≤20,000 platelets/μL as a defining severity criterion for both P. falciparum and P. vivax malaria [69].

However, in a recent study conducted in Brazil and India on 778 patients with documented P. vivax monoinfection, platelet counts showed a very poor discriminative performance to identify criteria of severe disease and the authors concluded that thrombocytopaenia should not be used to identify patients with P. vivax complications [70].

The second issue that deserves to be addressed when considering disease severity regards mortality. In other words: did patients whose death was attributed to P. vivax malaria die of malaria or with malaria?

This issue has been addressed in one study only which was conducted in Brazil and reported the autopsy findings of 17 patients who died of P. vivax malaria [5]. The authors reported during the study period (1996–2010) a case-fatality rate (CFR) for P. vivax malaria of 0.011 % (19/170.286), but in only four of the seventeen patients who underwent autopsy death could be exclusively attributed to P. vivax malaria, resulting in a CFR of 0.002 % [5]. Of note, the CFR of P. vivax malaria was 16-fold lower than the one observed for P. falciparum malaria in the same period (0.032 %, 12/36.854) [5]. In another study conducted in Papua, Indonesia, between January 2004 and September 2009, a post hoc clinical death audit of cases of pure P. vivax malaria resulted in a CFR of 0.12 per 1000 infections [71]. Of note, of the six fatal cases for whom vivax malaria was considered the primary cause of death, four were young children of less than 2 years of age (two of whom were malnourished), and the other two were adults in whom sepsis was concomitantly documented.

Moreover, in a retrospective analysis of 12.769 cases of imported P. vivax malaria observed in the UK over 27 years (1987–2013), seven deaths were registered, giving an overall mortality of 0.05 %. The median age of deceased patients was 72 years, while no deaths occurred in the 9927 patients aged less than 50 years [72]. In the two studies regarding imported P. vivax malaria conducted by the TropNetEurope and the GeoSentinel network, reporting respectively 618 and 278 patients (either travellers or immigrants), no deaths were recorded among patients affected by this species of Plasmodium [73, 74].

Thus, based on available data, the mortality risk of P. vivax malaria seems to be different in endemic areas as opposed to what is observed in cases of imported disease in Europe or USA. In endemic areas, the risk of death is low and influenced by several factors, such as very young age, severe anaemia at presentation, malnutrition, pregnancy, coexisting comorbidities and concurrent infections [6971, 75]. When imported P. vivax malaria is considered, the risk of death is generally absent or negligible and principally influenced by old age. Another important issue that should be considered when comparing malaria mortality is the lack of high level supportive care in many countries where malaria is endemic a factor that explains the better outcome observed in non-endemic countries where high-quality healthcare is available [76]. Despite these considerations it should be emphasized that the risk of death directly attributable to P. vivax malaria should not be overlooked.

In conclusion, given the lack of high quality studies and the fact that several confounding factors cannot be ruled out in the majority of case reports and studies published so far, the role of severe thrombocytopaenia as an indicator of P. vivax malaria severity cannot at present neither be discarded nor confirmed and it deserves to be addressed in well conducted prospective studies in both endemic and non-endemic countries.

Abbreviations

ED: 

emergency department

WHO: 

World Health Organization

ICU: 

intensive care unit

G6PD: 

glucose-6-phosphate dehydrogenase

PCR: 

polymerase chain reaction

CFR: 

case-fatality rate

DIC: 

disseminated intravascular coagulation

Declarations

Authors’ contributions

All authors contributed to the content of this case report. SA performed the clinical assessments, data collection and drafted the manuscript. AC treated the patient in the ICU. AL R and LM searched the literature and drafted manuscript LG treated the patient until discharge and drafted the manuscript. MC performed the clinical assessments and drafted the manuscript. DR performed the molecular diagnostic and drafted the manuscript. All authors read and approved the final manuscript.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing interests

The authors declare that they have no competing interests.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Clinical and Biomedical Sciences Luigi Sacco, III Division of Infectious Diseases, University of Milano, Via GB Grassi, 74, 20157 Milan, Italy
(2)
Intensive Care Unit Luigi Sacco Hospital, Milan, Italy

References

  1. Gething PW, Elyazar IRF, Moyes CM, Smith DL, Battle KE, Guerra CA, et al. A long neglected world malaria map: Plasmodium vivax endemicity in 2010. PLoS Negl Trop Dis. 2012;6:e1814.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Marchiafava E, Bignami A. Mannaberg J. Two monographs on malaria and the parasites of malarial fevers. London: New Sydenham Society; 1894.Google Scholar
  3. Nurleila S, Syafruddin D, Elyazar IRF, Baird JK. Serious and fatal illness associated with falciparum and vivax malaria among patients admitted to hospital at West Sumba in eastern Indonesia. Am J Trop Med Hyg. 2012;87:41–9.PubMed CentralView ArticlePubMedGoogle Scholar
  4. Alexandre MA, Ferreira CO, Siqueira AM, Magalhaes BL, Mourao MP, Lacerda MV, et al. Severe Plasmodium vivax malaria, Brazilian Amazon. Emerg Infect Dis. 2010;16:1611–4.PubMed CentralView ArticlePubMedGoogle Scholar
  5. Lacerda MV, Fragoso SC, Alecrim MG, Alexandre MA, Magalhaes BM, Siqueira AM, et al. Postmortem characterization of patients with clinical diagnosis of Plasmodium vivax malaria: to what extent does this parasite kill? Clin Infect Dis. 2012;55:e67–74.View ArticlePubMedGoogle Scholar
  6. Baird JK. Evidence and implications of mortality associated with acute Plasmodium vivax malaria. Clin Microbiol Rev. 2013;26:36–57.PubMed CentralView ArticlePubMedGoogle Scholar
  7. Naing C, Whittaker MA, Wai VN, Mak JW. Is Plasmodium vivax malaria a severe malaria?:a systematic review and meta-analysis. PLoS Neglect Trop Dis. 2014;8:e3071.View ArticleGoogle Scholar
  8. Antinori S, Milazzo L, Ridolfo AL, Galimberti L, Corbellino M. Severe Plasmodium vivax malaria: fact or fiction? Clin Infect Dis. 2012;55:1581–3. Erratum in: Clin Infect Dis. 2013;56:1196.Google Scholar
  9. Antinori S, Galimberti L, Gianelli E, Morelli P, Radice A, Acquaviva V, et al. Thrombocytopenia and Plasmodium vivax malaria. Clin Infect Dis. 2005;41:1210–1.View ArticlePubMedGoogle Scholar
  10. Oh MD, Shin H, Shin D, Kim U, Lee S, Kim N, et al. Clinical features of vivax malaria. Am J Trop Med Hyg. 2001;65:143–6.PubMedGoogle Scholar
  11. Kakar A, Bhoi S, Prakash V, Kakar S. Profound thrombocytopenia in Plasmodium vivax malaria. Diagn Microbiol Infect Dis. 1999;35:243–4.View ArticlePubMedGoogle Scholar
  12. Makkar RP, Mukhopadhyay S, Monga A, Gupta AK. Plasmodium vivax malaria presenting with severe thrombocytopenia. Braz J Infect Dis. 2002;6:263–5.View ArticlePubMedGoogle Scholar
  13. Kochar DK, Das A, Kochar SK, Saxena V, Sirohi P, Garg S, et al. Severe Plasmodium vivax malaria: a report of serial cases from Bikaner in Northwestern India. Am J Trop Med Hyg. 2009;80:194–8.PubMedGoogle Scholar
  14. Kaushik JS, Gomber S, Dewan P. Clinical and epidemiological profiles of severe malaria in children from Delhi, India. J Health Popul Nutr. 2012;30:113–6.PubMed CentralView ArticlePubMedGoogle Scholar
  15. Yamaguchi S, Kubota T, Yamagishi T, Okamoto K, Izumi T, Takada M, et al. Severe thrombocytopenia suggesting immunological mechanisms in two cases of vivax malaria. Am J Hematol. 1997;56:183–6.View ArticlePubMedGoogle Scholar
  16. Khattak AL, Ali W, Khan NA, Satti L, Idris M. Response of Plasmodium vivax malaria induced thrombocytopenia to antimalarial treatment. JAMCA. 2014;26:463–5.Google Scholar
  17. Lacerda MV, Mourao MP, Coelho HC, Santos JB. Thrombocytopenia in malaria: who cares? Mem Inst Oswaldo Cruz. 2011;106(Suppl 1):52–63.View ArticlePubMedGoogle Scholar
  18. Skudowitz RB, Katz J, Lurie A, Levin J, Metz J. Mechanisms of thrombocytopenia in malignant tertian malaria. BMJ. 1973;2:515–8.PubMed CentralView ArticlePubMedGoogle Scholar
  19. Touze JE, Mercier P, Rogier C, Hovette P, Schmoor P, Dabanian C, et al. [Platelet antibody activity in malaria thrombocytopenia](in French). Pathol Biol. 1990;38:678–81.PubMedGoogle Scholar
  20. Kelton JG, Keystone J, Moore J, Denomme G, Tozman E, Glynn M, et al. Immune-mediated thrombocytopenia of malaria. J Clin Invest. 1983;71:832–6.PubMed CentralView ArticlePubMedGoogle Scholar
  21. Lee SH, Looareesuwan S, Chan J, Wilairatana P, Vanijanonta S, Chong SM, et al. Plasma macrophage colony-stimulating factor and P-selectin levels in malaria-associated thrombocytopenia. Thromb Haemost. 1997;77:289–93.PubMedGoogle Scholar
  22. Piguet PF, Kan CD, Vesin C. Thrombocytopenia in an animal model of malaria is associated with an increased caspase-mediated death of thrombocytes. Apoptosis. 2002;7:91–8.View ArticlePubMedGoogle Scholar
  23. Coelho HC, Lopes SC, Pimentel JP, Nogueira PA, Costa FT, Siqueira AM, et al. Thrombocytopenia in Plasmodium vivax malaria is related to platelets phagocytosis. PLoS One. 2013;8:e63410.PubMed CentralView ArticlePubMedGoogle Scholar
  24. Raina V, Sharma A, Gujral S, Kumar R. Plasmodium vivax causing pancytopenia after allogenic blood stem cell transplantation in CML. Bone Marrow Transplant. 1998;22:205–6.View ArticlePubMedGoogle Scholar
  25. Carlini ME, White AC, Atmar RL. Vivax malaria complicated by adult respiratory distress syndrome. Clin Infect Dis. 1999;28:1182–3.View ArticlePubMedGoogle Scholar
  26. Lawn SD, Krishna S, Jarvis JN, Joet T, Macallan DC. Case reports:pernicious complications of benign tertian malaria. Trans R Soc Trop Med Hyg. 2003;97:551–3.View ArticlePubMedGoogle Scholar
  27. Holland B, Walker A, Collier R, Stephens J. Severe thrombocytopenia and epistaxis secondary to Plasmodium vivax infection. Internet J Infect Dis. 2003;3:2.Google Scholar
  28. Lacerda MV, Alexandre MA, Santos PD, Arcanjo AR, Alecrim WD, Alecrim MG. Idiopathic thrombocytopenic purpura due to vivax malaria in the Brazilian Amazon. Acta Trop. 2004;90:187–90.View ArticlePubMedGoogle Scholar
  29. Lomar AV, Vidal JE, Lomar FP, Barbas CV. Janot de Matos C, Boulos M. Acute respiratory distress syndrome due to vivax malaria: case report and literature review. Braz J Infect Dis. 2005;9:425–30.View ArticlePubMedGoogle Scholar
  30. Aggarwal A, Rath S. Shashiraj. Plasmodium vivax malaria presenting with severe thrombocytopenia. J Trop Pediatr. 2005;51:120–1.View ArticlePubMedGoogle Scholar
  31. Saleri N, Gulletta M, Matteelli A, Caligaris S, Tomasoni LR, Antonini B, et al. Acute respiratory distress syndrome in Plasmodium vivax malaria in a traveller returning from Venezuela. J Travel Med. 2006;13:112–3.View ArticlePubMedGoogle Scholar
  32. Baspinar O, Bayaraktaroglu Z, Karsligil T, Bayram A, Coskun Y. A rare cause of anemia and thrombocytopenia in a newborn: congenital malaria. Turk J Pediatr. 2006;48:63–5.PubMedGoogle Scholar
  33. Mohin G, Gupta A. Rare case of multiorgan failure associated with Plasmodium vivax malaria. Infect Dis Clin Pract. 2007;15:209–12.View ArticleGoogle Scholar
  34. Kumar S, Melzer M, Dodds P, Watson J, Ord R. P. vivax malaria complicated by shock and ARDS. Scand J Infect Dis. 2007;39:255–6.View ArticlePubMedGoogle Scholar
  35. Kaur D, Wasir V, Gulati S, Bagga A. Unusual presentation of Plasmodium vivax malaria with severe thrombocytopenia and acute renal failure. J Trop Pediatr. 2007;53:210–2.View ArticlePubMedGoogle Scholar
  36. Song JY, Park CW, Jo YM, Kim JY, Yoon HJ, Kim CH, et al. Two cases of Plasmodium vivax malaria with the clinical picture resembling toxic shock. Am J Trop Med Hyg. 2007;77:609–11.PubMedGoogle Scholar
  37. Lacerda MV, Hipolito JR, Passos LN. Chronic Plasmodium vivax infection in a patient with splenomegaly and severe thrombocytopenia. Rev Soc Bras Med Trop. 2008;41:522–3.Google Scholar
  38. Thapa R, Biswas B, Mallick D, Sardar S, Modak S. Childhood Plasmodium vivax malaria with severe thrombocytopenia and bleeding manifestations. J Pediatr Hematol Oncol. 2009;31:758–9.View ArticlePubMedGoogle Scholar
  39. Kim SA, Kim ES, Rhee MY, Choi SI, Huh HJ, Chae SL. A case of myocarditis associated with Plasmodium vivax malaria. J Travel Med. 2009;16:138–40.View ArticlePubMedGoogle Scholar
  40. Harish R, Gupta S. Plasmodium vivax malaria presenting with severe thrombocytopenia, cerebral complications and hydrocephalus. Indian J Pediatr. 2009;76:551–2.View ArticlePubMedGoogle Scholar
  41. Lee JH, Chin HS, Chung MH, Moon YS. Case report: retinal hemorrhage in Plasmodium vivax malaria. Am J Trop Med Hyg. 2010;82:219–22.PubMed CentralView ArticlePubMedGoogle Scholar
  42. Siqueira AM, Alexandre MA, Mourao MP, Santos VS, Nagahashi-Marie SK, Alecrim MG, et al. Case report: severe rhabdomyolysis caused by Plasmodium vivax malaria in the Brazilian Amazon. Am J Trop Med Hyg. 2010;83:271–3.PubMed CentralView ArticlePubMedGoogle Scholar
  43. Bhatia V, Bhatia J. Severe thrombocytopenia with bleeding manifestations in two children secondary to Plasmodium vivax. Platelets. 2010;21:307–9.View ArticlePubMedGoogle Scholar
  44. Sonkar SK, Uniyal R, Sonkar GK. Three unusual presentations of Plasmodium vivax malaria. Trop Doct. 2011;41:240–1.View ArticlePubMedGoogle Scholar
  45. Sharma V, Sharma A, Aggarwal A, Bhardwaj G, Aggarwal S. Acute pancreatitis in a patient with vivax malaria. JOP. 2012;13:215–6.PubMedGoogle Scholar
  46. Rahman AK, Sulaiman FN. Plasmodium vivax malaria presenting as acute respiratory distress syndrome: a case report. Trop Doct. 2013;43:83–5.View ArticlePubMedGoogle Scholar
  47. Ahmad S, Dhar M, Bishnoi S, Shirazi N, Bhat NK. Acute myocarditis in vivax malaria: an extremely rare complication. Trop Doct. 2013;43:35–6.View ArticlePubMedGoogle Scholar
  48. Mehndiratta S, Rajeshwari K, Dubey AP. Multiple-organ dysfunction in a case of Plasmodium vivax malaria. J Vector Borne Dis. 2013;50:71–3.PubMedGoogle Scholar
  49. Lee HJ, Baek JH, Chae MH, Joo H, Lee JS, Chung MH, et al. A case of vivax malaria complicated by adult respiratory distress syndrome and successful management with extracorporeal membrane oxygenation. Korean J Parasitol. 2013;51:551–5.PubMed CentralView ArticlePubMedGoogle Scholar
  50. Gougoutsi A, Karageorgopoulos DE, Dimitriadou A, Melas N, Kranidiotis G, Voutsinas D, et al. Severe Plasmodium vivax malaria complicated with acute respiratory distress syndrome: a case associated with focal autochthonous transmission in Greece. VectorBorne Zoonotic Dis. 2014;14:378–81.View ArticlePubMedGoogle Scholar
  51. Pothapregada S, Kamalakannan B. Hemophagocytic syndrome in Plasmodium vivax malaria. J Vector Borne Dis. 2014;51:144–6.PubMedGoogle Scholar
  52. Sharma A, Khanduri U. How benign is benign tertian malaria? J Vector Borne Dis. 2009;46:141–4.PubMedGoogle Scholar
  53. George P, Alexander LM. A study on the clinical profile of complicated Plasmodium vivax mono-infections. Asian Pac J Trop Med. 2010;4:560–2.View ArticleGoogle Scholar
  54. Singh H, Parakh A, Basu S, Rath B. Plasmodium vivax malaria: is it actually benign? J Infect Public Health. 2011;4:91–5.View ArticlePubMedGoogle Scholar
  55. Gogia A, Kakar A, Byotra SP. Is benign tertian malaria actually benign? Trop Doct. 2012;42:92–3.View ArticlePubMedGoogle Scholar
  56. Tanwar GS, Khatri PC, Chamar CK, Sengar GS, Kochar A, et al. Thrombocytopenia in childhood malaria with special reference to P. vivax monoinfection: a study from Bikaner (Northwestern India). Platelets. 2012;23:211–6.View ArticlePubMedGoogle Scholar
  57. Naha K, Dasan S, Prabhu M. Spectrum of complications associated with Plasmodium vivax infection in a tertiary hospital in South-Western India. Asian Pac J Trop Med. 2012;5:79–82.View ArticlePubMedGoogle Scholar
  58. Yadav D, Chandra J, Aneja S, Kumar V, Kumar P, Dutta AK. Changing profile of severe malaria in North Indian children. Indian J Pediatr. 2012;79:483–7.View ArticlePubMedGoogle Scholar
  59. Sharma S, Aggarwal KC, Deswal S, Raut D, Roy N, Kapoor R. The unusual presentation of a usual organism- the changing spectrum of the clinical manifestations of Plasmodium vivax malaria in children:a retrospective study. J Clin Diagn Res. 2013;7:1964–7.PubMed CentralPubMedGoogle Scholar
  60. Sarkar D, Ray S, Saha M, Chakraborty A, Talukdar A. Clinico-laboratory profile of severe Plasmodium vivax malaria in a tertiary care centre in Kolkhata. Trop Parasitol. 2013;3:53–7.PubMed CentralView ArticlePubMedGoogle Scholar
  61. Jain V, Agrawal A, Singh N. Malaria in a tertiary health care facility of Central India with special reference to severe vivax: implications for malaria control. Pathog Glob Health. 2013;107:299–304.PubMed CentralView ArticlePubMedGoogle Scholar
  62. Singh R, Kumar S, Rana SK, Thakur B, Singh SP. A comparative study of clinical profiles of vivax and falciparum malaria in children at a tertiary care centre in Uttarakhand. J Clin Diagn Res. 2013;7:2234–7.PubMed CentralPubMedGoogle Scholar
  63. Shaik S, Memon H, Shaik A, Ahmed I, Iohano B, Baird KJ. Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan. Malar J. 2012;11:144.View ArticleGoogle Scholar
  64. Zubairi AB, Nizami S, Raza A, Mehraj V, Rasheed AF, Ghanchi NK, et al. Severe Plasmodium vivax malaria in Pakistan. Emerg Infect Dis. 2013;19:1851–4.PubMed CentralView ArticlePubMedGoogle Scholar
  65. Arboleda M, Perez MF, Fernandez D, Usuga LY, Meza M. (Clinical and laboratory profile of Plasmodium vivax malaria patients hospitalized in Apartado, Colombia) (in Spanish). Biomedica. 2012;32(Suppl):58–67.Google Scholar
  66. Mahgoub H, Gasim GI, Musa IR, Adam I. Severe Plasmodium vivax malaria among sudanese children at New Halfa hospital, Eastern Sudan. Parasit Vectors. 2012;5:154.PubMed CentralView ArticlePubMedGoogle Scholar
  67. Magalhaes BM, Siqueira AM, Alexandre MA, Souza MS, Gimaque JB, Bastos MS, et al. P. vivax malaria and dengue fever co-infection: a cross-sectional study in the Brazilian Amazon. PLoS Neglect Trop Dis. 2014;8:e3239.View ArticleGoogle Scholar
  68. Leal-Santos FA, Silva SB, Crepaldi NP, Nery AF, Martin TO, Alves-Junior ER, et al. Altered platelet indices as potential markers of severe and complicated malaria caused by Plasmodium vivax: a cross-sectional study. Malar J. 2013;12:462.PubMed CentralView ArticlePubMedGoogle Scholar
  69. Lampah DA, Yeo TW, Malloy M, Kenangalem E, Douglas NM, Ronaldo D, et al. Severe malarial thrombocytopenia: a risk factor for mortality in Papua, Indonesia. J Infect Dis. 2015;211:623–34.PubMed CentralView ArticlePubMedGoogle Scholar
  70. Siqueira AM, Lacerda MV, Magalhaes BM, Mourao MP, Melo GC, Alexandre MA, et al. Characterization of Plasmodium vivax-associated admissions to reference hospitals in Brazil and India. BMC Med. 2015;13:57.PubMed CentralView ArticlePubMedGoogle Scholar
  71. Douglas NM, Pontororing GJ, Lampah DA, Yeo TW, Kenangalem E, Poespoprodjo JR, et al. Mortality attributable to Plasmodium vivax malaria: a clinical audit from Papua, Indonesia. BMC Med. 2014;12:217.PubMed CentralView ArticlePubMedGoogle Scholar
  72. Broderick C, Nadjm B, Smith V, Blaze M, Checkley A, Chiodini PL, et al. Clinical, geographical, and temporal risk factors associated with presentation and outcome of vivax malaria imported into the United Kingdom over 27 years: observational study. BMJ. 2015;350:h1703.PubMed CentralView ArticlePubMedGoogle Scholar
  73. Muhlberger N, Jelinek T, Gascon J, Probst M, Zoller T, Schunk M, et al. Epidemiology and clinical features of vivax malaria imported to Europe: sentinel surveillance data from TropNetEurope. Malar J. 2004;3:5.PubMed CentralView ArticlePubMedGoogle Scholar
  74. Leder K, Black J, O’Brien D, Greenwood Z, Kain KC, Schwartz E, et al. Malaria in travelers: a review of the GeoSentinel Surveillance Network. Clin Infect Dis. 2004;39:1104–12.View ArticlePubMedGoogle Scholar
  75. Saravu K, Rishikesh K, Kamath A, Shastry AB. Severity in Plasmodium vivax malaria claiming global vigilance and exploration- a tertiary care centre-based cohort study. Malar J. 2014;13:304.PubMed CentralView ArticlePubMedGoogle Scholar
  76. Marks ME, Armstrong M, Suvan MM, Batson S, Whitty CJ, Chiodini PL, et al. Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases. London. BMC Infect Dis. 2013;13:118.View ArticlePubMedGoogle Scholar

Copyright

© Antinori et al. 2016

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Please note that comments may be removed without notice if they are flagged by another user or do not comply with our community guidelines.

Advertisement