• 1.

    Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K, 1999. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. QJM 92: 151157.

    • Search Google Scholar
    • Export Citation
  • 2.

    Lampah DA, Yeo TW, Hardianto SO, Tjitra E, Kenangalem E, Sugiarto P, Price RN, Anstey NM, 2011. Coma associated with microscopy-diagnosed Plasmodium vivax: a prospective study in Papua, Indonesia. PLoS Negl Trop Dis 5: e1032.

    • Search Google Scholar
    • Export Citation
  • 3.

    Song HH, Kim OS, Moon SH, Kim SH, Yoon JB, Koo JW Jr, Hong KS, Lee MG, Kim DJ, Shin DH, Kang SH, Choi MG, Lee KH, 2003. Clinical features of Plasmodium vivax malaria. Korean J Intern Med 18: 220224.

    • Search Google Scholar
    • Export Citation
  • 4.

    Haeusler GM, Tebruegge M, Curtis N, 2012. Question 1. Do febrile convulsions cause CSF pleocytosis? Arch Dis Child 97: 172175.

  • 5.

    Laman M, Hwaihwanje I, Davis TM, Manning L, 2010. Cryptococcal meningitis in immunocompetent Papua New Guinean children. Trop Doct 40: 6163.

  • 6.

    Manning L, Laman M, Edoni H, Mueller I, Karunajeewa HA, Smith D, Hwaiwhanje I, Siba PM, Davis TM, 2011. Subacute sclerosing panencephalitis in Papua New Guinean children: the cost of continuing inadequate measles vaccine coverage. PLoS Negl Trop Dis 5: e932.

    • Search Google Scholar
    • Export Citation
  • 7.

    Manning L, Laman M, Rosanas-Urgell A, Turlach B, Aipit S, Bona C, Warrell J, Siba P, Mueller I, Davis TM, 2012. Rapid antigen detection tests for malaria diagnosis in severely ill Papua New Guinean children: a comparative study using Bayesian latent class models. PLoS ONE 7: e48701.

    • Search Google Scholar
    • Export Citation
  • 8.

    World Health Organization, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1): S1S90.

  • 9.

    van der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE, 2006. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol 22: 503508.

    • Search Google Scholar
    • Export Citation
  • 10.

    Manning L, Rosanas-Urgell A, Laman M, Edoni H, McLean C, Mueller I, Siba P, Davis TM, 2012. A histopathologic study of fatal paediatric cerebral malaria caused by mixed Plasmodium falciparum/Plasmodium vivax infections. Malar J 11: 107.

    • Search Google Scholar
    • Export Citation
  • 11.

    Manning L, Laman M, Law I, Bona C, Aipit S, Teine D, Warrell J, Rosanas-Urgell A, Lin E, Kiniboro B, Vince J, Hwaiwhanje I, Karunajeewa H, Michon P, Siba P, Mueller I, Davis TM, 2011. Features and prognosis of severe malaria caused by Plasmodium falciparum, Plasmodium vivax and mixed Plasmodium species in Papua New Guinean children. PLoS ONE 6: e29203.

    • Search Google Scholar
    • Export Citation
  • 12.

    Laman M, Manning L, Hwaiwhange I, Vince J, Aipit S, Mare T, Warrel J, Karunajeewa H, Siba P, Mueller I, Davis TM, 2010. Lumbar puncture in children from an area of malaria endemicity who present with a febrile seizure. Clin Infect Dis 51: 534540.

    • Search Google Scholar
    • Export Citation
 
 
 

 

 
 
 

 

 

 

 

 

 

Prevalence and Implications of Cerebrospinal Fluid Leukocytosis in Papua New Guinean Children Hospitalized with Severe Malaria

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  • School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, Freemantle, Western Australia, Australia; Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea

Cerebrospinal fluid (CSF) leukocytosis in severe malaria was assessed in 87 children in Papua New Guinea participating in a detailed longitudinal observational study who had undergone lumbar puncture for further investigation of altered consciousness and/or convulsions. After rigorous exclusion of non-malarial infection, 16 (20.5%) of 78 children with Plasmodium falciparum monoinfection but 0 of 9 with P. vivax/mixed-species malaria had a detectable CSF leukocytosis, which was unrelated to prior, including complex, seizures. There were eight children with a CSF leukocyte density > 10 cells/μL (9.2% of the total sample), half of whom had cerebral malaria (4 of 22, 18.1%). Cerebrospinal fluid leukocytosis is infrequent in severe pediatric malaria, especially in children with P. vivax infections, and it is generally mild. Its presence in a blood slide–positive child should prompt consideration of alternative diagnoses and empiric antibiotic therapy.

Studies reporting cerebrospinal fluid (CSF) leukocytosis in cases of pediatric cerebral malaria have been conducted mainly in sub-Saharan Africa where Plasmodium falciparum monoinfections predominate. Approximately 10% of children with cerebral malaria and no bacteriologic evidence of acute bacterial meningitis have CSF pleocytosis of > 10 cells/μL in this setting.1 Plasmodium vivax is increasingly recognized as a cause of severe malarial illness in Oceania and parts of Asia and South America.

There is limited evidence that CSF leukocytosis can also be found in patients with P. vivax malaria and altered consciousness,2,3 but these studies did not rigorously exclude co-infections with bacterial and, as in studies in Africa of cerebral malaria caused by P. falciparum,1 viral, or fungal pathogens. Febrile seizures caused by non-malarial infections may also cause CSF leukocytosis in some children4 and are a common feature of pediatric severe malaria, thus further exacerbating diagnostic uncertainties when a severely ill child seeks treatment in a malaria-endemic setting. Therefore, there is a need for a prospective study that determines whether severe pediatric malaria caused by P. falciparum or P. vivax can cause CSF leukocytosis after other infective causes of encephalopathy have been excluded and after taking prior febrile seizures into account.

We studied hospitalized children in Papua New Guinea who were enrolled in a detailed observational study of severe pediatric infections conducted in coastal Madang Province where there is transmission of multiple Plasmodium species. The study was approved by the Papua New Guinea Institute of Medical Research Institutional Review Board and the Medical Research Advisory Committee of Papua New Guinea (MRAC 10.08), and parental written consent was obtained before recruitment in all cases. To rule out acute bacterial meningitis in children in Papua New Guinea, routine lumbar puncture is usually performed if a child has impaired consciousness or after febrile seizures but has no clinical evidence of increased intracranial pressure.5 Cerebrospinal fluid leukocytes at presentation were quantified by microscopic examination using the Neubauer improved chamber (BoeCo, Hamburg, Germany). When erythrocytes were present, an adjusted leukocyte count calculated as leukocytes − [erythrocytes/100] was used5 (Table 1). Semi-quantitative CSF glucose and protein levels were obtained by using a dipstick method (Acon Laboratories, San Diego, CA).

Table 1

Clinical and laboratory characteristics of children in sub-groups of rigorously defined severe malaria, Papua New Guinea*

CharacteristicCerebral malaria (n = 22)Malaria with cerebral involvement (n = 43)Malaria admissions (n = 22)P
Male sex5963520.71
Age (months)39.5 (23–60)35 (27.2–48)31 (18.9–44.3)0.73
Axillary temperature (°C)38.4 (37.4–39)37.9 (37.8–38.1)37.9 (37–38.5)0.55
Pre-hospital antipyretic use5954650.049
Plasmodium falciparum/P. vivax/mixed-species malaria21/0/137/3/320/0/2
Neurologic manifestations
 Cerebral malaria10000< 0.001
 Impaired consciousness0440< 0.001
 Multiple seizures36610< 0.001
 Prolonged seizures141900.32
 Focal seizures0500.35
CSF leukocyte count/μL0 (0–0.35)0 (0–0)0 (0–0)0.26
 072.781.491.3
 < 5000
 5–99.1140
 10–2013.64.68.7
 > 204.600
CSF protein level ≥ 1 g/L9090.51
CSF glucose level < 5 mmol/L000
Deaths000

Values are medians (interquartile ranges) or percentages. CSF = cerebrospinal fluid.

After excluding children who did not have an admission lumbar puncture and those with a primary or co-incident non-malarial illness caused by locally prevalent bacterial, viral, or fungal pathogens as confirmed by blood/CSF culture, and/or specific antigen, serologic, and/or polymerase chain reaction testing, as well as Indian ink staining,57 children with blood slide–positive malaria confirmed by polymerase chain reaction were assigned to one of three sub-groups: 1) cerebral malaria (Blantyre coma score ≤ 28 and > 1,000 P. falciparum or > 250 P. vivax asexual parasites/μL); 2) malaria with cerebral involvement (parasitemia as in sub-group 1 but a Blantyre coma score of 3 or 4 and/or complex febrile seizures); and 3) malaria admissions (any parasite density and a normal level of consciousness with or without other signs of severity,8 including single convulsions). Complex seizures were defined as multiple (≥ 2 episodes), prolonged (≥ 15 minutes), or focal (unilateral).

Over a 30-month recruitment period, 638 children were enrolled and 87 (13.6%) had confirmed malaria without co-infection, as well as CSF examination. Of this latter group, nine had P. vivax or mixed Plasmodium species infections and 78 had P. falciparum monoinfection. Twenty-two had cerebral malaria, 43 had malaria with cerebral involvement, and 22 had malaria admissions (Table 1). The three children with P. vivax monoinfection had multiple convulsions. Of the six children with mixed-species infections, one was in a deep coma after multiple convulsions, one had two convulsions before admission, two had a single prolonged convulsion, one had a single short convulsion and associated severe anemia (hemoglobin level = 48 g/L), and one was admitted because of severe anemia (hemoglobin level 39 g/L). All 87 children were treated according to Papua New Guinea national treatment guidelines and none of the children died.

There were 16 children with leukocytes detected in CSF and this was pleocytosis in 12 (75%). None of the nine children with either a P. vivax or mixed-species malarial infection had any CSF leukocytosis compared with 16 of the 78 with P. falciparum monoinfection (P = 0.20, by Fisher's exact test). There were eight children with a CSF leukocyte density > 10 cells/μL (9.2% of the total sample), half of whom were in the cerebral malaria group (4 of 22, 18.1%). There was no significant difference in total CSF leukocyte counts in children with multiple seizures compared with those without seizures (P = 0.60, by Mann-Whitney U test).

The present data show that children in Papua New Guinea who are hospitalized with severe P. falciparum malaria and have indications for lumbar puncture can have a CSF leukocytosis that is not explained by co-incident central nervous system infection or febrile convulsions. The percentage of the cerebral malaria patients (all but one with P. falciparum monoinfection) with a CSF leukocyte density > 10 cells/μL (18.1%) was, given limited number of patients in this group, broadly consistent with that in a larger study in Africa of children of similar ages with cerebral malaria (9.2%).1 Cerebral microvascular sequestration of parasitized erythrocytes containing mature forms of P. falciparum may promote a low-grade local inflammatory response,9 which promotes CSF leukocytosis. Consistent with this hypothesis, there is no evidence that P. vivax sequesters in the brain of patients with severe P. vivax or mixed-species malarial infections and altered consciousness,10 and a lack of sequestration-associated inflammation could explain why all such patients in the present series had no CSF leukocytosis. In addition, all but one of these patients had at least one convulsion, and we could not find any association between multiple seizures and CSF leukocytosis in the series as a whole. These observations are consistent with those of a recent systematic review, which showed that CSF pleocytosis occurs in < 6% of children with a febrile convulsion,4 and which found insufficient data to support the notion that complex and/or prolonged convulsions cause higher rates of CSF pleocytosis than simple febrile convulsions.

The present study had limitations. The group with severe P. vivax or mixed-species infections was small, consistent with a low incidence of complications relative to patients with P. falciparum malaria.11 However, even in areas with hyperendemic transmission of P. vivax, large-scale studies may not provide an adequate sample size.2 We did not have detailed data relating to the interval between seizures and when the lumbar puncture was performed, a potentially important variable in interpretation of the relationship between seizure activity and CSF pleocytosis.4 Nevertheless, the lack of a relationship between complex seizures and CSF leukocytosis in the present study suggests that even when a lumbar puncture is performed in the immediate post-ictal period, there is unlikely to be an increased likelihood of CSF pleocytosis.

The present data have several important clinical implications in geoepidemiologic situations similar to coastal Papua New Guinea. First, most pediatric patients with cerebral malaria associated with P. falciparum, and an even greater majority, if not all, of those with altered consciousness caused by severe P. vivax infections, have no leukocytes in the CSF. In resource-poor settings such as Papua New Guinea, where blood and CSF cultures, as well as facilities to enable appropriate clinical and laboratory monitoring may not be available, the presence of CSF pleocytosis should prompt consideration of diagnoses other than severe malaria and empiric antimicrobial therapy in addition to antimalarial therapy. Depending on the clinical situation,12 there may even be a case for withholding such empiric therapy in children with malaria parasites on a peripheral blood smear or a positive rapid diagnostic test result and no CSF leukocytes, and monitoring the response to antimalarial therapy alone. Second, an increased CSF leukocyte density should not be attributed to seizures, whether caused by fever or malaria, even if they are complex. Last, lumbar puncture remains a safe and important diagnostic tool in the evaluation of altered consciousness in a severely ill child in even basic healthcare settings.

ACKNOWLEDGMENTS

We thank the staff of the Pediatric Ward at Modilon Hospital, the Papua New Guinea Institute of Medical Research staff at Modilon Hospital, and the Yagaum campus for assistance, and the patients and their families for participating in the study.

  • 1.

    Berkley JA, Mwangi I, Mellington F, Mwarumba S, Marsh K, 1999. Cerebral malaria versus bacterial meningitis in children with impaired consciousness. QJM 92: 151157.

    • Search Google Scholar
    • Export Citation
  • 2.

    Lampah DA, Yeo TW, Hardianto SO, Tjitra E, Kenangalem E, Sugiarto P, Price RN, Anstey NM, 2011. Coma associated with microscopy-diagnosed Plasmodium vivax: a prospective study in Papua, Indonesia. PLoS Negl Trop Dis 5: e1032.

    • Search Google Scholar
    • Export Citation
  • 3.

    Song HH, Kim OS, Moon SH, Kim SH, Yoon JB, Koo JW Jr, Hong KS, Lee MG, Kim DJ, Shin DH, Kang SH, Choi MG, Lee KH, 2003. Clinical features of Plasmodium vivax malaria. Korean J Intern Med 18: 220224.

    • Search Google Scholar
    • Export Citation
  • 4.

    Haeusler GM, Tebruegge M, Curtis N, 2012. Question 1. Do febrile convulsions cause CSF pleocytosis? Arch Dis Child 97: 172175.

  • 5.

    Laman M, Hwaihwanje I, Davis TM, Manning L, 2010. Cryptococcal meningitis in immunocompetent Papua New Guinean children. Trop Doct 40: 6163.

  • 6.

    Manning L, Laman M, Edoni H, Mueller I, Karunajeewa HA, Smith D, Hwaiwhanje I, Siba PM, Davis TM, 2011. Subacute sclerosing panencephalitis in Papua New Guinean children: the cost of continuing inadequate measles vaccine coverage. PLoS Negl Trop Dis 5: e932.

    • Search Google Scholar
    • Export Citation
  • 7.

    Manning L, Laman M, Rosanas-Urgell A, Turlach B, Aipit S, Bona C, Warrell J, Siba P, Mueller I, Davis TM, 2012. Rapid antigen detection tests for malaria diagnosis in severely ill Papua New Guinean children: a comparative study using Bayesian latent class models. PLoS ONE 7: e48701.

    • Search Google Scholar
    • Export Citation
  • 8.

    World Health Organization, 2000. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1): S1S90.

  • 9.

    van der Heyde HC, Nolan J, Combes V, Gramaglia I, Grau GE, 2006. A unified hypothesis for the genesis of cerebral malaria: sequestration, inflammation and hemostasis leading to microcirculatory dysfunction. Trends Parasitol 22: 503508.

    • Search Google Scholar
    • Export Citation
  • 10.

    Manning L, Rosanas-Urgell A, Laman M, Edoni H, McLean C, Mueller I, Siba P, Davis TM, 2012. A histopathologic study of fatal paediatric cerebral malaria caused by mixed Plasmodium falciparum/Plasmodium vivax infections. Malar J 11: 107.

    • Search Google Scholar
    • Export Citation
  • 11.

    Manning L, Laman M, Law I, Bona C, Aipit S, Teine D, Warrell J, Rosanas-Urgell A, Lin E, Kiniboro B, Vince J, Hwaiwhanje I, Karunajeewa H, Michon P, Siba P, Mueller I, Davis TM, 2011. Features and prognosis of severe malaria caused by Plasmodium falciparum, Plasmodium vivax and mixed Plasmodium species in Papua New Guinean children. PLoS ONE 6: e29203.

    • Search Google Scholar
    • Export Citation
  • 12.

    Laman M, Manning L, Hwaiwhange I, Vince J, Aipit S, Mare T, Warrel J, Karunajeewa H, Siba P, Mueller I, Davis TM, 2010. Lumbar puncture in children from an area of malaria endemicity who present with a febrile seizure. Clin Infect Dis 51: 534540.

    • Search Google Scholar
    • Export Citation

Author Notes

* Address correspondence to Timothy M. E. Davis, School of Medicine and Pharmacology, University of Western Australia, Fremantle Hospital, PO Box 480, Fremantle, Western Australia 6959, Australia. E-mail: tim.davis@uwa.edu.au

Financial support: This study was a sub-study of the Papua New Guinea Severe Childhood Illness Study supported by a National Health and Medical Research Council (NHMRC) grant (#513782) and infrastructure support from the Malaria Genomic Epidemiology Network. Viral and bacterial CSF molecular investigations were supported by a World Health Organization Tropical Diseases Small Research Grant. Moses Laman was supported by a Fogarty Foundation scholarship, Laurens Manning was supported by a Basser scholarship from the Royal Australasian College of Physicians and an NHMRC scholarship, and Timothy M. E. Davis was supported by an NHMRC Practitioner Fellowship.

Authors' addresses: Moses Laman, Papua New Guinea Institute of Medical Research, Madang, Papua New Guinea and University of Western Australia and School of Medicine and Pharmacology, Fremantle Hospital, Fremantle, Western Australia, Australia, E-mail: drlaman@yahoo.com. Laurens Manning and Timothy M. E. Davis, University of Western Australia, School of Medicine and Pharmacology, Fremantle Hospital, Fremantle, Western Australia, Australia, E-mails: laurens.manning@uwa.edu.au and tim.davis@uwa.edu.au. Peter M. Siba, Papua New Guinea Institute of Medical Research, Goroka, Eastern Highlands Province, Papua New Guinea, E-mail: peter.siba@pngimr.org.pg.

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