Distinct Biomarker Profiles Distinguish Malawian Children with Malarial and Non-malarial Sepsis

Kortz, Teresa; Nyirenda, James; Tembo, Dumizulu; Elfving, Kristina; Baltzell, Kimberly; Bandawe, Gama; Rosenthal, Philip J.; Macfarlane, Sarah B.; Mandala, Wilson L.; Nyirenda, Tonney S.

doi:10.4269/ajtmh.18-0635

Cited by 5 publications

(4 citation statements)

References 65 publications

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“…Parasitic infections, which are frequently found in LMIC, did not influence CRP levels; hence there would be no need to rule out these infections to interpret the results of CRP. On the other hand, in accordance with previous evidence [ 7 , 12 ], malaria increased CRP, though to levels that were significantly lower than those found in bacterial infections. Malaria RDTs are systematically used in acute febrile illnesses in malaria-endemic countries.…”

Section: Discussionsupporting

confidence: 92%

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study

et al. 2021

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Biomarkers, especially CRP, have demonstrated their relevance to differentiate viral from bacterial infection, even though a reliable threshold is far to being found. In low- and middle-income countries, affordable and user-friendly rapid diagnostic tests based on biomarkers can be widely adopted to help health workers in the management of non-malarial fever. The primary objective of this study is to assess the best CRP cut-off to distinguish viral from bacterial infections. Other biomarkers were evaluated for the same purpose, alone or in combination with CRP. We retrospectively collected data from two referral hospital departments for infectious and tropical diseases in Italy. Areas under the ROC curve (AUC) were calculated and then compared using the DeLong test. Overall, we included 1193 febrile cases (viral 20.74% vs. bacterial 79.25%). We also collected malaria (n = 202) and intestinal parasite (n = 186) cases to establish their impact on biomarkers. CRP had the best accuracy in differentiating viral from bacterial infections. The best performance of CRP was a cut-off of 11 mg/L. All other biomarkers studied had significantly lower accuracy. Median CRP values were within the normal ranges in parasitic infections, while they were higher in malaria. None of the combinations of CRP with other biomarkers significantly increased the accuracy of CRP alone.

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Section: Discussionsupporting

confidence: 92%

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study

et al. 2021

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“…These results might be due to studies that focused solely on microscopy failed to consider low density infected patients who had elevated IL-6 separately, further reducing the significance between uncomplicated malaria and febrile controls, as febrile control groups were not truly Plasmodium negative or with submicroscopic infection. Nevertheless, the meta-analysis results were in contrast to a case-controlled study that demonstrated patients with malarial fever had higher IL-6 levels than those with non-malaria fever 66 , indicating the increase in IL-6 levels might be specific for malaria compared to other febrile diseases. Previous studies showed that IL-6 concentrations in healthy individuals were typically low; that is, in the range of 0.2–7.8 pg/mL 67 .…”

Section: Discussioncontrasting

confidence: 84%

Increased interleukin-6 levels associated with malaria infection and disease severity: a systematic review and meta-analysis

Wilairatana

Mala

Milanez

et al. 2022

Sci Rep

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Interleukin-6 (IL-6) is generated by immune cells during infection with malaria parasites and they are associated with the immunopathogenesis of malaria. The present systematic review and meta-analysis aimed to compare the differences in IL-6 levels between several groups of patients with malaria and healthy control groups. The systematic review was registered at PROSPERO with a registration number: CRD42021290753. Systematic literature searches were conducted in PubMed, Web of Science, and Scopus until November 7, 2021 to obtain studies that documented IL-6 levels in patients with malaria. The quality of the included studies was assessed using critical appraisal tools from the Joanna Briggs Institute. Differences in the mean IL-6 levels among patients with: (1) severe and non-severe malaria, (2) uncomplicated malaria and controls, (3) uncomplicated and asymptomatic malaria, (4) asymptomatic malaria and healthy controls, and (5) those that died or survived were estimated using a random-effects model. Forty-three of 1,969 studies were included in the systematic review. Results of the meta-analysis showed that patients with severe malaria had higher mean IL-6 levels than those with non-severe malaria [P = 0.04, weight mean difference (WMD) = 96.63 pg/mL, 95% confidence interval (CI) = 0.88 − 19.38 pg/mL, I2 = 99.9%, 13 studies]. Patients with uncomplicated malaria had higher mean IL-6 levels than the controls (P < 0.001, WMD = 42.86 pg/mL, 95% CI = 30.17 − 55.56 pg/mL, I2 = 100%, 17 studies). No differences in the mean levels of IL-6 were found between patients with uncomplicated malaria and those with asymptomatic malaria (P = 0.063, WMD = 42.07 pg/mL, 95% CI = − 2.23 pg/mL to − 86.37 pg/mL, I2 = 99.1%, 8 studies), or between patients with asymptomatic malaria and healthy controls (P = 0.45, WMD = 1.67 pg/mL, 95% CI = − 2.73 pg/mL to − 6.07 pg/mL, I2 = 98.1%, 2 studies). A higher mean level of IL-6 was observed in patients who died compared with the levels of those who survived (P = 0.007, WMD = 1,399.19 pg/mL, 95% CI = 384.16 − 2,414.2 pg/mL, I2 = 93.1%, 4 studies). Our meta-analysis of the pooled evidence can be used to guide future studies in which IL-6 levels are measured during malaria outbreaks to monitor malaria severity. Heterogeneity of the effect estimate among the included studies was the main limitation of this analysis. In conclusion, significantly increased levels of IL-6 were observed in patients with severe malaria compared with those in patients with non-severe malaria, which indicates that IL-6 is a candidate marker for severe malaria. Future studies should investigate the sensitivity and specificity of increased IL-6 levels to determine the effectiveness of assessments of IL-6 levels monitoring of malaria infection and severity.

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“…22 Furthermore, concomitant conditions like HIV infection and malnutrition could influence the expression of biomarkers, for example, lowering CRP concentrations, thus potentially causing bacterial infections being underdiagnosed and undertreated. 23 Conversely, some biomarkers, CRP in particular, can be elevated in case of malaria, 24 which makes it impossible to rule out or rule in other infections in patients with concomitant malaria infection.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of C-Reactive Protein and Other Host BioMarker Point-of-Care Tests in the Assessment of Non-Malarial Acute Febrile Illnesses: A Systematic Review with Meta-Analysis

Bertoli

Ronzoni

Silva

et al. 2020

The American Journal of Tropical Medicine and Hygiene

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In low-and middle-income countries, in resource-limited settings, the implementation of diagnostic tools discriminating bacterial from nonbacterial fever is a matter of primary concern. The introduction of malaria rapid diagnostic tests highlighted the need for point-of-care tests (POCTs) supporting clinical decision-making for non-malarial febrile illnesses. The purpose of this work was to review the use of host biomarker POCTs for the assessment of acute nonmalarial fever in resource-constraint settings. Specific objectives were as follows: 1) to estimate the accuracy of such tests in differentiating fever of bacterial from nonbacterial origin and 2) to assess the impact of host biomarkers on antibiotic prescription and clinical outcome. We conducted a systematic review searching PubMed, Embase, the Cochrane Library, and Bireme. The protocol was registered with PROSPERO (n CRD42019141735). Data on the accuracy of C-reactive protein (CRP) for the detection of bacterial infections were meta-analyzed using the hierarchical summary receiver operating characteristic model, obtaining a summary ROC (SROC). We identified 2,192 articles, eight of which were included in the review. Among the different biomarkers evaluated, CRP was the one most frequently studied. The SROC presented an area under the curve = 0.77 (CI: 0.73-0.81), which indicates good accuracy to distinguish bacterial from nonbacterial infections. However, the optimal cutoff of CRP could not be assessed, and we found insufficient evidence about its impact on antibiotic prescription and clinical outcome. The role of CRP and other host biomarker POCTs for the assessment of acute non-malarial febrile illnesses in resource-constraint settings deserves further studies.

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Distinct Biomarker Profiles Distinguish Malawian Children with Malarial and Non-malarial Sepsis

Cited by 5 publications

References 65 publications

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study

C-Reactive Protein for the Early Assessment of Non-Malarial Febrile Patients: A Retrospective Diagnostic Study

Increased interleukin-6 levels associated with malaria infection and disease severity: a systematic review and meta-analysis

Usefulness of C-Reactive Protein and Other Host BioMarker Point-of-Care Tests in the Assessment of Non-Malarial Acute Febrile Illnesses: A Systematic Review with Meta-Analysis

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