CEREBRAL MALARIA

Vision Projects

  • Papua New Guinea

'to establish HBO as an adjunctive care for children & adults suffering the effects of Cerebral Malaria. It is our vision that mobile shipping containers housing small multiplace chambers can be specifically located via truck or helicopter into remote regions to assist communities impacted by the devastating effects of Malaria'

Hyperbaric Oxygen & Cerebral Malaria

 

Immunological analyses have revealed that HBO therapy significantly decreases the levels of TNF-α and IL-1β secreted by monocytes and macrophage collected from rats or from human peripheral blood after stimulation with LPS [22], [23]. In an experimental model for ischemia, HBO reduces immunocompetent cell sequestration and the synthesis of TNF-α [24]; probably by decreasing ICAM-1 expression levels [25].

Moreover, HBO reduces the expression of the cyclooxygenase-2 (COX-2) mRNA, an enzyme involved in inflammation, and the hypoxia-inducible factor-1α (HIF-1α), a transcriptional factor associated with low oxygen concentrations [26], [27].

 

  • HBO therapy has been used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis, due to its capacity to decrease cerebral edema and brain infarction while maintaining BBB integrity, reducing neuronal death and improving blood flow in damaged areas of the brain [28].

Introduction

Cerebral malaria (CM) causes 1–2 million deaths annually; mainly in sub-Saharan African children aged 2–6. It is estimated that 250,000 children that do not succumb to CM will develop neurocognitive impairments per year [1] and most CM patients die before the beneficial effects of drug treatment are observed [2]; thus indicating the need to explore new supportive therapies.

 

  • CM is a multi-factorial syndrome characterized by neurological signs, seizures and coma, which can, in turn, lead to death.

  • This syndrome can be associated with a loss of cerebrospinal fluid spaces and ischemia [3], alterations in cerebral blood flow velocity [4], a decrease in cerebral oxygen consumption in CM comatose patients [5] and an increase in the lactate levels of the cerebrospinal fluid [6] which decreases after patients recover consciousness [7]. Recent imaging and postmortem analyses have revealed the presence of Durck granulomas, blood-brain barrier (BBB) dysfunction and diffuse cerebral edema with multiple petechial hemorrhages and ischemic changes in the brain of adults with CM [8], [9].

 

Although the CM pathogenic process is controversial and still not fully understood, evidence suggests that the host's immune system plays a major role in expressing certain cytokines, e.g. TNF-α and IFN-γ, and activating immunocompetent cells [10][15]. In fact, recent immunological analyses have shown that, unlike individuals with mild and severe non-cerebral malaria, CM patients present elevated levels of a specific cluster of cytokines, which include TGF-β, TNF-α, IL-1β and IL-10 [16].

  • Hyperbaric oxygen therapy (HBO; pO2 = 760 mmHg) has been successfully used against bacterial and fungal infections and as an adjunct therapy in surgeries [17][19].

  • In addition, reports have recently shown that HBO therapy transiently suppresses the inflammatory process of ischemic wounding and trauma [20], [21].

  • Indeed, immunological analyses have revealed that HBO therapy significantly decreases the levels of TNF-α and IL-1β secreted by monocytes and macrophage collected from rats or from human peripheral blood after stimulation with LPS [22], [23].

  • In an experimental model for ischemia, HBO reduces immunocompetent cell sequestration and the synthesis of TNF-α [24]; probably by decreasing ICAM-1 expression levels [25].

  • Moreover, HBO reduces the expression of the cyclooxygenase-2 (COX-2) mRNA, an enzyme involved in inflammation, and the hypoxia-inducible factor-1α (HIF-1α), a transcriptional factor associated with low oxygen concentrations [26], [27].

  • HBO therapy has been used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis, due to its capacity to decrease cerebral edema and brain infarction while maintaining BBB integrity, reducing neuronal death and improving blood flow in damaged areas of the brain [28].

  • Nevertheless, depending on the protocol used for treatment, HBO therapy has potential side effects associated to ear and sinus barotraumas, myopia and convulsion [29].

 

In an early study, HBO was observed to alter the parasitemia levels of mice infected with a non-cerebral line of Plasmodium berghei [30]. However, the HBO effect on the entire curve of parasitemia, on the clinical symptoms and on the mechanisms of the illness were not further investigated. Moreover, although the pathological process involved in CM displays some features in common with brain stroke, the effect of HBO on CM, to our knowledge, has never been assessed. Here we show that in conditions also suitable for human use, HBO therapy prevents CM clinical symptoms in C57BL/6 mice infected with P. berghei ANKA, a model widely used for experimental cerebral malaria (ECM) [31].

Summary

In summary, we have presented evidence of the beneficial effects induced by HBO therapy against ECM.

 * We also demonstrated that the administration of pressurized oxygen down-regulates IFN-γ, TNF-α and IL-10 cytokine expression and the migration to the brain of T lymphocytes, preventing BBB breakdown and severe mice hypothermia without directly affecting iRBC viability and infectivity. Since complementary therapies such as steroids, sodium bicarbonate and heparin are deleterious in CM, and treatment with an anti-TNF-α monoclonal can worsen neurological symptoms [62].

 

The data presented here create promising perspectives for further investigation of additional HBO's neuroprotective mechanisms and to consider it as a new supportive therapy that could act alone or in association with conventional treatment or with recently discovered neuroprotective or anti-inflammatory molecules to improve poor CM outcomes [63], [64].

 

 

Further Reading​

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria.

Infect Immun 2016 Apr 24;84(4):874-82. Epub 2016 Mar 24.

Laboratory of Tropical Diseases-Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution and Bioagents, Institute of Biology, University of Campinas, Campinas, SP, Brazil

  • April 2016

Over 200 million people worldwide suffer from malaria every year, a disease that causes 584,000 deaths annually.

In recent years, significant improvements have been achieved on the treatment of severe malaria, with intravenous artesunate proving superior to quinine. However, mortality remains high, at 8% in children and 15% in adults in clinical trials, and even worse in the case of cerebral malaria (18% and 30%, respectively). Moreover, some individuals who do not succumb to severe malaria present long-term cognitive deficits. These observations indicate that strategies focused only on parasite killing fail to prevent neurological complications and deaths associated with severe malaria, possibly because clinical complications are associated in part with a cerebrovascular dysfunction.

Consequently, different adjunctive therapies aimed at modulating malaria pathophysiological processes are currently being tested. However, none of these therapies has shown unequivocal evidence in improving patient clinical status.

Recently, key studies have shown that gaseous therapies based mainly on nitric oxide (NO), carbon monoxide (CO), and hyperbaric (pressurized) oxygen (HBO) alter vascular endothelium dysfunction and modulate the host immune response to infection.

  • Considering gaseous administration as a promising adjunctive treatment against severe malaria cases, we review here the pathophysiological mechanisms and the immunological aspects of such therapies.

 

 

Adjunctive therapy for severe malaria: a review and critical appraisal.

Malar J 2018 Jan 24;17(1):47. Epub 2018 Jan 24.

Centro de Investigação em Saúde de Manhiça, Rua 12, vila da Manhiça, 1929, Maputo, Mozambique.

  • January 2018

Background: Despite recent efforts and successes in reducing the malaria burden globally, this infection still accounts for an estimated 212 million clinical cases, 2 million severe malaria cases, and approximately 429,000 deaths annually.

Even with the routine use of effective anti-malarial drugs, the case fatality rate for severe malaria remains unacceptably high, with cerebral malaria being one of the most life-threatening complications. Up to one-third of cerebral malaria survivors are left with long-term cognitive and neurological deficits. From a population point of view, the decrease of malaria transmission may jeopardize the development of naturally acquired immunity against the infection, leading to fewer total cases, but potentially an increase in severe cases. The pathophysiology of severe and cerebral malaria is not completely understood, but both parasite and host determinants contribute to its onset and outcomes. Adjunctive therapy, based on modulating the host response to infection, could help to improve the outcomes achieved with specific anti-malarial therapy.
Results And Conclusions: In the last decades, several interventions targeting different pathways have been tested. However, none of these strategies have demonstrated clear beneficial effects, and some have shown deleterious outcomes. This review aims to summarize evidence from clinical trials testing different adjunctive therapy for severe and cerebral malaria in humans. It also highlights some preclinical studies which have evaluated novel strategies and other candidate therapeutics that may be evaluated in future clinical trials.

 

Travel Med Infect Dis 2011 Sep;9(5):223-30. doi: 10.1016/j.tmaid.2011.07.003. Epub 2011 Jul 31.

Oxygen therapy for cerebral malaria

Bruce-Hickman D.

Author information

  • UCL Medical School & Department of Neuroscience, Physiology and Pharmacology, Gower Street, London WC1E 6BT, United Kingdom. d.bruce-hickman@ucl.ac.uk

Abstract

Malaria is an important global health issue, killing nearly one million people worldwide each year. There is a disproportionate disease burden, since 89% of cases are of African origin, and 85% of deaths worldwide occur in children under 5 years of age of age.(1) Cerebral malaria (CM) is the most serious complication of infection.

Despite prompt anti-malarial treatment, fatalities remain high - mortality rates while undergoing treatment with Artemisinin or quinine-based therapy reach 15% and 22% respectively.(2) There is, therefore, a need to develop an adjunct therapy to preserve neurological function during the treatment period. Recent experimental research has indicated hyperbaric oxygenation (HBO) to be a rational and effective adjunct therapy.(3) This article examines the current understanding of CM, and the possible benefits provided by HBO therapy.

 

PLoS One. 2008 Sep 4;3(9):e3126. doi: 10.1371/journal.pone.0003126.

Hyperbaric oxygen prevents early death caused by experimental cerebral malaria

Blanco YC, Farias AS, Goelnitz U, Lopes SC, Arrais-Silva WW, Carvalho BO, Amino R, Wunderlich G, Santos LM, Giorgio S, Costa FT.

Author information

  • Department of Microbiology & Immunology, State University of Campinas, Campinas, São Paulo, Brazil.

Abstract

BACKGROUND:

Cerebral malaria (CM) is a syndrome characterized by neurological signs, seizures and coma. Despite the fact that CM presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. Hyperbaric oxygen (HBO) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.

METHODOLOGY/PRINCIPAL FINDINGS:

C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were exposed to daily doses of HBO (100% O(2), 3.0 ATA, 1-2 h per day) in conditions well-tolerated by humans and animals, before or after parasite establishment.

Cumulative survival analyses demonstrated that HBO therapy protected 50% of PbA-infected mice and delayed CM-specific neurological signs when administrated after patent parasitemia.

Pressurized oxygen therapy reduced peripheral parasitemia, expression of TNF-alpha, IFN-gamma and IL-10 mRNA levels and percentage of gammadelta and alphabeta CD4(+) and CD8(+) T lymphocytes sequestered in mice brains, thus resulting in a reduction of blood-brain barrier (BBB) dysfunction and hypothermia.

CONCLUSIONS/SIGNIFICANCE:

The data presented here is the first indication that HBO treatment could be used as supportive therapy, perhaps in association with neuroprotective drugs, to prevent CM clinical outcomes, including death.

Travel Med Infect Dis 2011 Sep;9(5):223-30. doi: 10.1016/j.tmaid.2011.07.003. Epub 2011 Jul 31.

Oxygen therapy for cerebral malaria

Bruce-Hickman D.

Author information

  • UCL Medical School & Department of Neuroscience, Physiology and Pharmacology, Gower Street, London WC1E 6BT, United Kingdom. d.bruce-hickman@ucl.ac.uk

Abstract

Malaria is an important global health issue, killing nearly one million people worldwide each year. There is a disproportionate disease burden, since 89% of cases are of African origin, and 85% of deaths worldwide occur in children under 5 years of age of age.(1) Cerebral malaria (CM) is the most serious complication of infection.

Despite prompt anti-malarial treatment, fatalities remain high - mortality rates while undergoing treatment with Artemisinin or quinine-based therapy reach 15% and 22% respectively.(2) There is, therefore, a need to develop an adjunct therapy to preserve neurological function during the treatment period. Recent experimental research has indicated hyperbaric oxygenation (HBO) to be a rational and effective adjunct therapy.(3) This article examines the current understanding of CM, and the possible benefits provided by HBO therapy.

 

PLoS One. 2008 Sep 4;3(9):e3126. doi: 10.1371/journal.pone.0003126.

Hyperbaric oxygen prevents early death caused by experimental cerebral malaria

Blanco YC, Farias AS, Goelnitz U, Lopes SC, Arrais-Silva WW, Carvalho BO, Amino R, Wunderlich G, Santos LM, Giorgio S, Costa FT.

Author information

  • Department of Microbiology & Immunology, State University of Campinas, Campinas, São Paulo, Brazil.

Abstract

BACKGROUND:

Cerebral malaria (CM) is a syndrome characterized by neurological signs, seizures and coma. Despite the fact that CM presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. Hyperbaric oxygen (HBO) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.

METHODOLOGY/PRINCIPAL FINDINGS:

C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were exposed to daily doses of HBO (100% O(2), 3.0 ATA, 1-2 h per day) in conditions well-tolerated by humans and animals, before or after parasite establishment.

Cumulative survival analyses demonstrated that HBO therapy protected 50% of PbA-infected mice and delayed CM-specific neurological signs when administrated after patent parasitemia.

Pressurized oxygen therapy reduced peripheral parasitemia, expression of TNF-alpha, IFN-gamma and IL-10 mRNA levels and percentage of gammadelta and alphabeta CD4(+) and CD8(+) T lymphocytes sequestered in mice brains, thus resulting in a reduction of blood-brain barrier (BBB) dysfunction and hypothermia.

CONCLUSIONS/SIGNIFICANCE:

The data presented here is the first indication that HBO treatment could be used as supportive therapy, perhaps in association with neuroprotective drugs, to prevent CM clinical outcomes, including death.