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Detection of human malaria using recombinant Plasmodium knowlesi merozoire surface protein-1 (MSP-1₁₉) expressed in Escherichia coli

Sonaimuthu P, Cheong FW, Chin LC, Mahmud R, Fong MY, Lau YL

Exp Parasitol, 2015 Jun;153:118-22.
PMID: 25812552 DOI: 10.1016/j.exppara.2015.03.010

Malaria remains one of the world's most important infectious diseases and is responsible for enormous mortality and morbidity. Human infection with Plasmodium knowlesi is widely distributed in Southeast Asia. Merozoite surface protein-1₁₉ (MSP-1₁₉), which plays an important role in protective immunity against asexual blood stage malaria parasites, appears as a leading immunogenic antigen of Plasmodium sp. We evaluated the sensitivity and specificity of recombinant P. knowlesi MSP-1₁₉ (rMSP-1₁₉) for detection of malarial infection. rMSP-1₁₉ was expressed in Escherichia coli expression system and the purified rMSP-1₁₉ was evaluated with malaria, non-malaria and healthy human serum samples (n = 215) in immunoblots. The sensitivity of rMSP-1₁₉ for detection of P. knowlesi, Plasmodium falciparum, Plasmodium vivax and Plasmodium ovale infection was 95.5%, 75.0%, 85.7% and 100%, respectively. rMSP-1₁₉ did not react with all the non-malaria and healthy donor sera, which represents 100% specificity. The rMSP-1₁₉ could be used as a potential antigen in serodiagnosis of malarial infection in humans.

Matched MeSH terms: Malaria/blood*
Clinical, genetic and fertility studies of Indians with beta S-globin gene and the influence of Hb S on Plasmodium falciparum malaria infection

Joishy SK, Hassan K, Lopes M, Lie-Injo LE

Trans R Soc Trop Med Hyg, 1988;82(4):515-9.
PMID: 3076706

Clinical studies were carried out on mild Indian sickle cell anaemia in Malaysia, and genetic and fertility studies were carried out on 101 families with and without sickle-cell haemoglobin (Hb S). The Indian sickle cell anaemia patients reached adulthood, and pregnancies and deliveries were uneventful without blood transfusion. There was no foetal wastage and the number of children produced was not significantly different from that in families without Hb S. 28 Indian patients hospitalized with Plasmodium falciparum malaria infection were also examined for their beta S genotype. P. falciparum malaria infection occurred much more frequently in individuals without Hb S than in Hb S carriers.

Matched MeSH terms: Malaria/blood
Fulltext Treatment failure of falciparum malaria with Fansidar in Tawau Sabah. January-June, 1982

Tan HS, Tan PE

Med J Malaysia, 1983 Sep;38(3):217-23.
PMID: 6369092

One hundred and ten consecutive patients with falciparum malaria were treated with Fansidar and primaquine. Of the 61 patients who were followed up at one week, 4 (6.5%) failed to clear their parasitemia (1 R III and 3 R Il treatment failures). Of the subsequent 40 patients who were seen again at one month, another 3 (7.5%) had recrudesced (R 1 treatment failure). A total of 7 patients thus experienced some form of treatment failure in the cohort of 40 who completed the one month follow up. Only 1 of these 7patients (with R III treatment) failure) failed to respond to repeat Fansidar treatment, and may be the only one with true Fansidar resistance. The overall treatment failure rate of 17.5% (95% confidence interval: 6-29%) in the cohort who completed the study is consistent with the known clinical efficacy of Fansidar. These results suggest no significant Fansidar resistance in falciparum malaria found in Sabah.

Matched MeSH terms: Malaria/blood
Fulltext Distribution of the Duffy genotypes in Malaysian Borneo and its relation to Plasmodium knowlesi malaria susceptibility

de Silva JR, Amir A, Lau YL, Ooi CH, Fong MY

PLoS One, 2019;14(9):e0222681.
PMID: 31536563 DOI: 10.1371/journal.pone.0222681

The Duffy blood group plays a key role in Plasmodium knowlesi and Plasmodium vivax invasion into human erythrocytes. The geographical distribution of the Duffy alleles differs between regions with the FY*A allele having high frequencies in many Asian populations, the FY*B allele is found predominately in European populations and the FY*Bes allele found predominantly in African regions. A previous study in Peninsular Malaysia indicated high homogeneity of the dominant FY*A/FY*A genotype. However, the distribution of the Duffy genotypes in Malaysian Borneo is currently unknown. In the present study, the distribution of Duffy blood group genotypes and allelic frequencies among P. knowlesi infected patients as well as healthy individuals in Malaysian Borneo were determined. A total of 79 P. knowlesi patient blood samples and 76 healthy donor samples were genotyped using allele specific polymerase chain reaction (ASP-PCR). Subsequently a P. knowlesi invasion assay was carried out on FY*AB/ FY*A and FY*A/ FY*A Duffy genotype blood to investigate if either genotype conferred increased susceptibility to P. knowlesi invasion. Our results show almost equal distribution between the homozygous FY*A/FY*A and heterozygous FY*A/FY*B genotypes. This is in stark contrast to the Duffy distribution in Peninsular Malaysia and the surrounding Southeast Asian region which is dominantly FY*A/FY*A. The mean percent invasion of FY*A/FY*A and FY*A/FY*B blood was not significantly different indicating that neither blood group confers increased susceptibility to P. knowlesi invasion.

Matched MeSH terms: Malaria/blood*
Dynamic assessment of parathyroid function in acute malaria

Davis TM, Singh B, Choo KE, Ibrahim J, Sulaiman SA, Kadir ZA, et al.

J Intern Med, 1998 May;243(5):349-54.
PMID: 9651556

OBJECTIVES: To investigate the dynamic parathyroid response to rapidly induced, sustained hypocalcaemia in patients with acute malaria and in healthy volunteers.
DESIGN: Serum intact parathormone (PTH) concentrations were measured on samples taken before and during a variable-rate tri-sodium citrate infusion designed to 'clamp' the whole blood ionised calcium concentration 0.20 mmol L-1 below baseline for 120 min.
SUBJECTS: Six Malaysian patients aged 17-42 years with acute malaria, four of whom were restudied in convalescence, and 12 healthy controls aged 19-36 years.
MAIN OUTCOME MEASURES: Whole-blood ionised calcium and serum intact PTH concentrations.
RESULTS: The mean (SD baseline ionised calcium was lower in the malaria patients than in controls (1.09 +/- 0.06 vs. 1.18 +/- 0.03 mmol L-1, respectively; P = 0.01) but PTH concentrations were similar (3.0 +/- 1.8 vs. 3.3 +/- 1.3 pmol L(-1); P = 0.33). Target whole-blood ionised calcium concentrations were achieved more rapidly in the controls than the patients (within 15 vs. 30 min) despite significantly more citrate being required in the patients (area under the citrate infusion-time curve 0.95 (0.25 vs. 0.57 +/- 0.09 mmol kg-1; P < 0.01). The ratio of the change in serum PTH to that in ionised calcium (delta PTH/ delta Ca2+), calculated to adjust for differences in initial rate of fall of ionised calcium, was similar during the first 5 min of the clamp (132 +/- 75 x 10(-6) vs. 131 +/- 43 x 10(-6) in patients and controls, respectively, P > 0.05), as were steady-state serum PTH levels during the second hour (7.0 +/- 2.2 pmol L-1 in each case). Convalescent patients had normal basal ionised calcium levels but the lowest serum intact PTH levels before and during the clamp, consistent with an increase in skeletal PTH sensitivity after treatment.
CONCLUSIONS: There is a decreased ionised calcium 'set point' for basal PTH secretion but a normal PTH response to acute hypocalcaemia in malaria. Skeletal resistance may attenuate the effects of the PTH response but patients with malaria appear relatively resistant to the calcium chelating effects of citrated blood products.

Matched MeSH terms: Malaria/blood*
Fulltext Sensitivity and specificity of malaria rapid diagnostic test (mRDT CareStatTM) compared with microscopy amongst under five children attending a primary care clinic in southern Nigeria

Ogunfowokan O, Ogunfowokan BA, Nwajei AI

Afr J Prim Health Care Fam Med, 2020 Jun 17;12(1):e1-e8.
PMID: 32634015 DOI: 10.4102/phcfm.v12i1.2212

BACKGROUND: Malaria diagnosis using microscopy is currently the gold standard. However, malaria rapid diagnostic tests (mRDTs) were developed to simplify the diagnosis in regions without access to functional microscopy.
AIM: The objective of this study was to compare the diagnostic accuracy of mRDT CareStatTM with microscopy.
SETTING: This study was conducted in the paediatric primary care clinic of the Federal Medical Centre, Asaba, Nigeria.
METHODS: A cross-sectional study for diagnostic accuracy was conducted from May 2016 to October 2016. Ninety-eight participants were involved to obtain a precision of 5%, sensitivity of mRDT CareStatTM of 95% from published work and 95% level of confidence after adjusting for 20% non-response rate or missing data. Consecutive participants were tested using both microscopy and mRDT. The results were analysed using EPI Info Version 7.
RESULTS: A total of 98 children aged 3-59 months were enrolled. Malaria prevalence was found to be 53% (95% confidence interval [CI] = 46% - 60%), whilst sensitivity and specificity were 29% (95% CI = 20% - 38%) and 89% (95% CI = 83% - 95%), respectively. The positive and negative predictive values were 75% (95% CI = 66.4% - 83.6%) and 53% (95% CI = 46% - 60%), respectively.
CONCLUSION: Agreement between malaria parasitaemia using microscopy and mRDT positivity increased with increase in the parasite density. The mRDT might be negative when malaria parasite density using microscopy is low.

Matched MeSH terms: Malaria/blood
Development of an optical biosensor for the detection of Trypanosoma evansi and Plasmodium berghei

Theint HT, Walsh JE, Wong ST, Voon K, Shitan M

Spectrochim Acta A Mol Biomol Spectrosc, 2019 Jul 05;218:348-358.
PMID: 31026712 DOI: 10.1016/j.saa.2019.04.008

A laboratory prototype system that correlates murine blood absorbance with degree of infection for Plasmodium berghei and Trypanosoma avensi has been designed, constructed and tested. A population (n = 6) of control uninfected, Plasmodium infected and Trypanosoma infected BALB/c mice were developed and spectral absorption measurements pre and post infection were made every 3 days. A fibre optic spectrometer set-up was used as the basis of a laboratory prototype biosensor that uses the Beer Lambert Law to relate Ultraviolet-Visible-Near-infrared absorbance data to changes in murine blood chemistry post infection. Spectral absorption results indicate a statistically relevant correlation at a 650 nm with infection for Plasmodium from between 4 and 7 sampling days' post infection, in spite of significant standard deviations among the sample populations for control and infected mice. No significant spectral absorption change for Trypanosoma infection was been detected from the current data. Corresponding stained slides of control and infected blood at each sampling date were taken with related infected cell counts determined and these correlate well for Plasmodium absorbance at 650 nm.

Matched MeSH terms: Malaria/blood*
Clinical and laboratory presentation of malaria: an analysis of one thousand subjects with malaria parasitaemia

O'Holohan DR

J Trop Med Hyg, 1976 Sep;79(9):191-6.
PMID: 794512

In the context of this study the ethnic origin of the patients revealed no noteworthy difference in the clinical reaction to the parasite; neither did age or sex of the patients. Any minor differences whcih appeared in length of history before seeking treatment and frequency of repeat attacks were more a reflection of the cultural pattern of response to illness (i.e. resort to traditional medicines) and the distance between the patient's home and the doctor rather than any altered response on the part of the host to the parasite. However, the fact that about 35 per cent of all the episodes had a history of eight or more days (about 10 per cent more than 30 days) suggest that more "malaria consciousness" is called for in what is after all an endemic malaria area. The value (and necessity) of repeated examination of the blood to detect the parasite is confirmed but it is also encouraging to note that in 84% of cases a single careful examination of the blood revealed the parasite. Since in 49% of our malaria episodes the patient was afebrile when the parasite was discovered, it is obvious that in outpatient practice especially blood should be examined when the patient presents for treatment, irrespective of the presence or absence of pyrexia. As always, a prerequisite to the diagnosis of malaria is an awareness of its possible presence.

Matched MeSH terms: Malaria/blood
Fulltext Comparison of the quantitative buffy coat technique with the conventional thick blood film technique for malaria case detection in the field

Mak JW, Normaznah Y, Chiang GL

Singapore Med J, 1992 Oct;33(5):452-4.
PMID: 1455266

The quantitative buffy coat (QBC) technique was compared with the conventional thick blood film technique in a malaria survey carried out in a mesoendemic area of malaria in Betau, Pahang, Malaysia. The QBC technique was found to be a rapid technique but had a sensitivity of about 56% and a specificity of 95%, using the thick blood film method as the "gold standard". Malaria species identification was unsatisfactory with the QBC technique as it could identify parasites correctly in only about 60% of specimens. It was unable to detect as positive about 58% of specimens which had parasite counts < or = 500 per ul but could detect about 94% of those with counts > 500 per ul. This difference in positive detection rate was significantly different (p < 0.05). It cannot quantify parasitemia easily and the specimens cannot be stored for future reference and for quality control purposes. It is therefore concluded that the QBC technique cannot replace the classical thick blood film technique for use in malaria control programmes. Its use may be appropriate in situations like busy blood banks and outpatient clinics where rapid screening of malaria infection is needed but where experienced malaria microscopists may not be available.

Matched MeSH terms: Malaria/blood*
Ovalocytosis protects against severe malaria parasitemia in the Malayan aborigines

Foo LC, Rekhraj V, Chiang GL, Mak JW

Am J Trop Med Hyg, 1992 Sep;47(3):271-5.
PMID: 1524139

The malaria parasite rates and densities were compared in 79 ovalocytic-normocytic pairs of Malayan Aborigines matched for age, sex, proximity of residence to each other, and use of bed nets when sleeping in their jungle settlement in central Peninsular Malaysia. Malaria infection was determined from thick and thin Giemsa-stained blood films collected monthly for a period of six months. Blood films from ovalocytic individuals were found to be positive for malaria less often than in persons with normal red blood cells (P less than 0.05). Malaria infections per 100 person-months at risk were 9.7 in the ovalocytic group compared with 15.19 in the normocytic group. Among individuals parasitemic at any time, heavy infections (greater than or equal to 10,000 parasites/mm3 of blood) with Plasmodium falciparum, P. vivax, and P. malariae were encountered only in normocytic subjects, which comprised approximately 12.5% of the malaria-positive individuals in this group. In an earlier survey of 629 settlers that identified subjects for the above study, the prevalence of ovalocytosis was found to increase significantly with age. The above field observations support the view that ovalocytic individuals might have a survival advantage in the face of malaria. Consideration of the ovalocytic factor is indicated in future evaluations of malaria control measures in areas where ovalocytosis is prevalent.

Matched MeSH terms: Malaria/blood
Pathologic activity of Plasmodium berghei prevented but not reversed by dexamethasone

Franz DR, Lim TS, Baze WB, Arimbalam S, Lee M, Lewis GE

Am J Trop Med Hyg, 1988 Mar;38(2):249-54.
PMID: 3281490

Dexamethasone has recently been shown to block the production of cachectin (implicated in the pathogenesis of cerebral malaria) if administered prior to endotoxin induction of mouse macrophages. Using the hamster cheek pouch-cerebral malaria model, we tested the hypothesis that dexamethasone is effective as a therapeutic agent in severe malaria if given before some yet undefined trigger point in the disease. Infected hamsters were treated with dexamethasone (0.7 mg/kg) daily on days 7-12, 4-12, or 1-12 post-challenge. When treatment was started on day 1, whole body oxygen consumption (used as a measure of erythrocyte transport to sites of diffusion) on day 12 was greater than (P less than 0.05) that of infected control animals, though the degree of anemia was no different in treated and untreated groups. Furthermore, treatment produced a reduction in monocyte accumulation, capillary malfunction, and monocyte/red blood cell aggregate formation observable in the cheek pouch in vivo and a similar reduction in monocyte presence, capillary pathologic change, and multifocal hemorrhage in the brain on postmortem. These data suggest that mediator(s), whose production can be blocked by pretreatment with dexamethasone, are involved in the pathogenesis of disease leading to death of the Plasmodium berghei infected hamster.

Matched MeSH terms: Malaria/blood
Fulltext Effect of HIV and malaria parasites co-infection on immune-hematological profiles among patients attending anti-retroviral treatment (ART) clinic in Infectious Disease Hospital Kano, Nigeria

Jegede FE, Oyeyi TI, Abdulrahman SA, Mbah HA, Badru T, Agbakwuru C, et al.

PLoS One, 2017;12(3):e0174233.
PMID: 28346490 DOI: 10.1371/journal.pone.0174233

BACKGROUND: Human immunodeficiency virus (HIV) and malaria co-infection may present worse health outcomes in the tropics. Information on HIV/malaria co-infection effect on immune-hematological profiles is critical for patient care and there is a paucity of such data in Nigeria.
OBJECTIVE: To evaluate immune-hematological profiles among HIV infected patients compared to HIV/malaria co-infected for ART management improvement.
METHODS: This was a cross sectional study conducted at Infectious Disease Hospital, Kano. A total of 761 consenting adults attending ART clinic were randomly selected and recruited between June and December 2015. Participants' characteristics and clinical details including two previous CD4 counts were collected. Venous blood sample (4ml) was collected in EDTA tube for malaria parasite diagnosis by rapid test and confirmed with microscopy. Hematological profiles were analyzed by Sysmex XP-300 and CD4 count by Cyflow cytometry. Data was analyzed with SPSS 22.0 using Chi-Square test for association between HIV/malaria parasites co-infection with age groups, gender, ART, cotrimoxazole and usage of treated bed nets. Mean hematological profiles by HIV/malaria co-infection and HIV only were compared using independent t-test and mean CD4 count tested by mixed design repeated measures ANOVA. Statistical significant difference at probability of <0.05 was considered for all variables.
RESULTS: Of the 761 HIV infected, 64% were females, with a mean age of ± (SD) 37.30 (10.4) years. Prevalence of HIV/malaria co-infection was 27.7% with Plasmodium falciparum specie accounting for 99.1%. No statistical significant difference was observed between HIV/malaria co-infection in association to age (p = 0.498) and gender (p = 0.789). A significantly (p = 0.026) higher prevalence (35.2%) of co-infection was observed among non-ART patients compared to (26%) ART patients. Prevalence of co-infection was significantly lower (20.0%) among cotrimoxazole users compared to those not on cotrimoxazole (37%). The same significantly lower co-infection prevalence (22.5%) was observed among treated bed net users compared to those not using treated bed nets (42.9%) (p = 0.001). Out of 16 hematology profiles evaluated, six showed significant difference between the two groups (i) packed cell volume (p = <0.001), (ii) mean cell volume (p = 0.005), (iii) mean cell hemoglobin concentration (p = 0.011), (iv) absolute lymphocyte count (p = 0.022), (v) neutrophil percentage count (p = 0.020) and (vi) platelets distribution width (p = <0.001). Current mean CD4 count cell/μl (349±12) was significantly higher in HIV infected only compared to co-infected (306±17), (p = 0.035). A significantly lower mean CD4 count (234.6 ± 6.9) was observed among respondents on ART compared to non-ART (372.5 ± 13.2), p<0.001, mean difference = -137.9).
CONCLUSION: The study revealed a high burden of HIV and malaria co-infection among the studied population. Co-infection was significantly lower among patients who use treated bed nets as well as cotrimoxazole chemotherapy and ART. Six hematological indices differed significantly between the two groups. Malaria and HIV co-infection significantly reduces CD4 count. In general, to achieve better management of all HIV patients in this setting, diagnosing malaria, prompt antiretroviral therapy, monitoring CD4 and some hematology indices on regular basis is critical.

Matched MeSH terms: Malaria/blood
Pharmacokinetic rationale for a malarial suppressant administered once monthly

Peck CC, Lewis AN, Joyce BE

Ann Trop Med Parasitol, 1975 Jun;69(2):141-5.
PMID: 1155986

Serum was collected from six adults participating in a field trial of sulfadoxine and pyrimethamine in combination which was being administered once monthly for malaria suppression. Samples were drawn during each of two consecutive months three hours, and 7, 14 and 28 days following a dose of 1 500 mg sulfadoxine. Serum sulfadoxine concentration was measured using the method of Bratton and Marshall (1939). Initial serum concentrations averaged 19-9 plus or minus 2-4 (SD) mg/100 ml and decayed to 6-2 plus or minus 2-8 mg/100 ml at 14 days. Serum sulfadoxine concentrations were still detectable at 28 days following a dose (2-1 plus or minus 1-5 mg/100 ml). Elimination half-time averaged 195 plus or minus 44 hours. The presistent serum concentrations of sulfadoxine following monthly doses documented here during field-use of this drug are in agreement with the successful clinical results reported for such a regimen (Lewis and Ponnampalam, 1974; O'Holohan and Hugoe-Mathews, 1971; Wolfensberger, 1971).

Matched MeSH terms: Malaria/blood
Fulltext Blood meal analysis of Anopheles vectors of simian malaria based on laboratory and field studies

Jeyaprakasam NK, Low VL, Liew JWK, Pramasivan S, Wan-Sulaiman WY, Saeung A, et al.

Sci Rep, 2022 01 10;12(1):354.
PMID: 35013403 DOI: 10.1038/s41598-021-04106-w

Blood feeding and host-seeking behaviors of a mosquito play an imperative role in determining its vectorial capacity in transmitting pathogens. Unfortunately, limited information is available regarding blood feeding behavior of Anopheles species in Malaysia. Collection of resting Anopheles mosquitoes for blood meal analysis poses a great challenge especially for forest dwelling mosquitoes. Therefore, a laboratory-based study was conducted to evaluate the potential use of mosquitoes caught using human landing catch (HLC) for blood meal analysis, and subsequently to document blood feeding behavior of local Anopheles mosquitoes in Peninsular Malaysia. The laboratory-based experiment from this study revealed that mosquitoes caught using HLC had the potential to be used for blood meal analysis. Besides HLC, mosquitoes were also collected using manual aspirator and Mosquito Magnet. Overall, 47.4% of 321 field-caught Anopheles mosquitoes belonging to six species were positive for vertebrate host DNA in their blood meal. The most frequent blood meal source was human (45.9%) followed by wild boar (27.4%), dog (15.3%) and monkey (7.5%). Interestingly, only Anopheles cracens and Anopheles introlatus (Leucosphyrus Group) fed on monkey. This study further confirmed that members of the Leucosphyrus Group are the predominant vectors for knowlesi malaria transmission in Peninsular Malaysia mainly due to their simio-anthropophagic feeding behavior.

Matched MeSH terms: Malaria/blood
Fulltext Platelets kill circulating parasites of all major Plasmodium species in human malaria

Kho S, Barber BE, Johar E, Andries B, Poespoprodjo JR, Kenangalem E, et al.

Blood, 2018 Sep 20;132(12):1332-1344.
PMID: 30026183 DOI: 10.1182/blood-2018-05-849307

Platelets are understood to assist host innate immune responses against infection, although direct evidence of this function in any human disease, including malaria, is unknown. Here we characterized platelet-erythrocyte interactions by microscopy and flow cytometry in patients with malaria naturally infected with Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, or Plasmodium knowlesi Blood samples from 376 participants were collected from malaria-endemic areas of Papua, Indonesia, and Sabah, Malaysia. Platelets were observed binding directly with and killing intraerythrocytic parasites of each of the Plasmodium species studied, particularly mature stages, and was greatest in P vivax patients. Platelets preferentially bound to the infected more than to the uninfected erythrocytes in the bloodstream. Analysis of intraerythrocytic parasites indicated the frequent occurrence of platelet-associated parasite killing, characterized by the intraerythrocytic accumulation of platelet factor-4 and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling of parasite nuclei (PF4+TUNEL+ parasites). These PF4+TUNEL+ parasites were not associated with measures of systemic platelet activation. Importantly, patient platelet counts, infected erythrocyte-platelet complexes, and platelet-associated parasite killing correlated inversely with patient parasite loads. These relationships, taken together with the frequency of platelet-associated parasite killing observed among the different patients and Plasmodium species, suggest that platelets may control the growth of between 5% and 60% of circulating parasites. Platelet-erythrocyte complexes made up a major proportion of the total platelet pool in patients with malaria and may therefore contribute considerably to malarial thrombocytopenia. Parasite killing was demonstrated to be platelet factor-4-mediated in P knowlesi culture. Collectively, our results indicate that platelets directly contribute to innate control of Plasmodium infection in human malaria.

Matched MeSH terms: Malaria/blood*
Fulltext The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial

Cooper DJ, Plewes K, Grigg MJ, Rajahram GS, Piera KA, William T, et al.

Trials, 2018 Apr 24;19(1):250.
PMID: 29690924 DOI: 10.1186/s13063-018-2600-0

BACKGROUND: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage.
METHODS: PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel-Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity.
DISCUSSION: Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT03056391 . Registered on 12 October 2016.

Matched MeSH terms: Malaria/blood

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