Skip to main content

Table 3 Critical summary of the sixteen articles that were filtered after the initial search

From: Blood biomarkers differentiating viral versus bacterial pneumonia aetiology: a literature review

Author (REF)

Date

Country

Age range

Type of the study

No. of CAP cases

No. of viral and bacterial cases

Markers tested

Conclusion and notes

Bhuiyan et al. [14]

2019

Australia

≤17 years

Prospective cohort

n = 230

Bacterial n = 30

CRP, WBC, absolute neutrophil count (ANC)

CRP, WBC, and ANC were higher in definite bacterial pneumonia. The median blood CRP concentration was more than 6 times higher in definite bacterial cases than viral.

Viral n = 118

Other n = 82

Huang et al. [15]

2019

China

1 to 13 years old

Prospective cohort

n = 40

HAdV pneumonia n = 20

miRNAs

miRNAs biomarkers for HAdV pneumonia, at least in the cohort experiment. Importantly, neither pair of miRNAs could independently distinguish HAdV-infected patients from healthy children, highlighting the requirement for combining the two miRNA pairs identified in the present study.

Healthy n = 20

Yang et al. [16]

2018

China

0.8 to 9.6 years

Retroperspective cohort

n = 321

Healthy controls n = 50

YKL-40, IL-6, IL-10, TNF-α, CRP

No significant difference between the levels of YKL-40 in the serum in all 3 pneumonia subgroups. The levels of YKL-40 in the BALF specimens of patients with bacterial pneumonia were significantly higher than with viral pneumonia. The levels of IL-6, TNF-α, and C-reactive protein were positively correlated with the serum levels of YKL-40. IL-10 levels were negatively correlated with YKL-40 levels in all pneumonia subgroups.

Viral = 104

Bacterial = 110

Co-infection = 66

Wallihan et al. [17]

2018

United States (Ohio)

2 months to 18 years old

Prospective cohort

n = 152

Healthy controls n = 39

WBC, CRP, PCT

CRP, and PCT values were highter in patients with pyogenic bacteria than those with viral pneumonia or M. pneumonia.

Pyogenic bacteria = 16

M.pneumoniae = 41

Viral n = 78

Undetermined n = 14

Yang et al. [18]

2018

China

≤10 years

Prospective cohort

n = 82

Healthy controls = 21

HPR

HPR is higher in the mycoplasma pneumonia and the viral pneumonia than in the bacterial pneumonia.

Bacterial = 21

M.pneumoniae = 21

HPR is a potential biomarker differentiate bacterial pneumonia and non-bacterial pneumonia.

Viral = 19

Higdon et al. [19]

2017

Bangladesh, Gambia, Kenya, Mali, South Africa,

Thailand, Zambia

<5 years

Case-control study

n = 3981

HIV-negative tested controls n = 601

CRP

CRP was highter with bacterial pneumonia and negatively associated with RSV pneumonia. CRP may be useful for distinguishing bacterial from RSV-associated pneumonia, although its role in discriminating against other respiratory viral pneumonia needs further study.

HIV-negative with comfirmed bacterial pneumonia n = 119

HIV-negative with comfirmed viral pneumonia n = 556

Esposito et al. [20]

2016

Italy

< 14 years old

Prospective cohort

110 radiologically confirmed CAP

n = 20 no aetiology identified

Lcn2, SYN4, CRP, WBC

Lcn2 and SYN4 cannot predict aetiology. CRP together with WBC and clinical data, when combined, is the best predictor.

Bacterial n = 74;

Viral n = 16;

Confirmed with PCR from nasopharyngeal swab positive

Valim et al. [21]

2016

Mozambique

< 10 years

Prospective cohort

n = 117

Bacterial n = 23;

Fifty-six markers in a multiplex immunoassay. Hap, TNF receptor 2 or IL-10. The full list of markers was beyond the scope of this review.

Combination of three proteins (Hap), TNF receptor 2 or IL-10, and tissue inhibitor of metalloproteinases 1 provided the best tool to differentiate bacteria from the virus.

Viral n = 30;

Bacteria isolated from blood or pleural fluid;

Viruses identified with PCR.

Esposito et al. [22]

2016

Italy

4 months-14 years

Prospective cohort Multicentre

433 radiologically confirmed CAP

Bacterial n = 235;

CRP and PCT, MR-proANP, MR-proADM, WBC, neutrophil percentages

CRP and PCT are better at predicting viral and bacterial aetiology than others.

One or more viruses n = 111;

Unknown n = 87; real-time PCR tests on blood samples and nasopharyngeal swabs were used to identify agents.

PCT and MR-proANP helped to identify severe cases.

Naydenova et al. [23]

2016

Gambia

2–59 months

Retrospective Case-control

780 clinically and radiologically confirmed CAP

Only in 84 cases, the aetiology was identified using blood culture.

CRP, Lcn2, Hap and CD163 protein

Aetiology can be determined using three vital signs (RR, HR, and SaO2) and a newly proposed biomarker (lipocalin-2) (81.8% sensitivity and 90.6% specificity). Lcn2 values below 200 ng ml are suggestive of a viral cause. Note: cases with no bacterial growth in blood culture were diagnosed as viral pneumonia. This is not reliable, as blood cultures are not always positive in bacteria CAP. This can lead to diagnostic bias.

22 bacterial and 62 viral.

Zhu et al. [24]

2016

China

10 months to 7 years

Prospective cohort

65 based on criteria provided by IDSA and American Thoracic Society

Bacterial n = 34;

PCT

Bacterial pneumonia had far greater levels of PCT than non-bacterial. Also, statically significant changes in PCT level were tested before, and after treatment. Therefore, PCT is an important marker.

Non-bacterial n = 32

Note: The type of detection used to isolate the agents are not disclosed in this study.

Moreover, there is a mismatch between the sample size given in abstract, methods and results.

Engelmann et al. [25]

2015

France

0–16 years

Prospective cohort Multicentre

n = 41

Viral clinically* diagnosed n = 4.

MxA1

Over 200 ng/ml of MxA has very high sensitivity and specificity in diagnosing a viral infection.

CRP

Viral microbiologically confirmed n = 6

NOTE: Not all cases were microbiologically confirmed as the study design did not accommodate this. The request for confirmation was based on the decision of the treating physician.

Bacterial clinically* diagnosed n = 16

Bacterial microbiologically confirmed n = 6

No data n = 9

*clinical diagnosis included signs and symptoms, and routine laboratory workup such as CRP

Hoshina et al. [26]

2014

Japan

< 15 years old

Retrospective cohort

n = 31

Bacterial n = 21

WBC, neutrophil counts, CRP, PCT

PCT was a very useful marker to differentiate bacterial pneumonia. Neutrophil count helped to discriminate bacterial bronchitis.

Viral n = 10

Bacterial CAP was confirmed by sputum culture.

Viral CAP was confirmed by nasopharyngeal aspirate, sputum or throat swab

Elemraid et al. [27]

2014 and 2013

United Kingdom

≤16 years

Two prospective aetiological studies

n = 241 (in 2002)

2002:

CRP, total WBC, and absolute neutrophil count

CRP and WBC/ neutrophil count can indicate aetiology to a great extent when combined

Elemraid et al. [28]

n = 160 (in 2011) based on signs and symptoms and radiographic findings

Viral n = 47

Bacterial n = 58

Mixed n = 12

2011:

Viral n = 50

Bacterial n = 28

Mixed n = 20

Zhou et al. [29]

2011

China

0.11–2.57 years

Prospective cohort

n = 78

Bacteria n = 27

CRP, WBC, IgA, IgG, IgM, percent of T, Tc, Th, B, NK, CD23+, and CD25+cells and degree of expression of HMGB1 mRNA

HMGB1 and WBC can differentiate between bacterial, viral and co-infected cases of bronchial pneumonia

Viruses n = 25

Bacteria and viruses n = 26

  1. REF Reference, n, Sample size, Lcn2 Lipocalin 2, SYN4, Syndecan 4, CRP C-reactive protein, WBC White blood cell, IL-10 Interleukin 10, MR-proADM Midregional Proadrenomedullin MR-proANP Midregional proatrial natriuretic peptide, PCT Procalcitonin, Hap Haptoglobin, TNF Tumor necrosis factor, TNF-α Turmos necrosis factor – alpha, MxA1 Myxoma resistance protein 1, IgA Immunoglobulin A, IgG Immunoglobulin G, IgM Immunoglobulin M, T T-lymphocyte, Tc Cytotoxic Tlymphocyte, Th Helper T-lymphocyte, B B lymphocyte, NK Natural Killer, CD Cluster of differentiation, HMGB1 High mobility group box 1 protein, HPR Haptoglobin related protein, ANC Absolute neutrophil count, HAdV Human Adenovirus, mRNA Messenger Ribonucleic Acid, YKL-40 Chitinase-like protein, BALF Bronchoalveolar lavage fluids, HIV Human immunodeficiency virus