Scrub typhus point-of-care testing: A systematic review and meta-analysis

<div><p>Background</p><p>Diagnosing scrub typhus clinically is difficult, hence laboratory tests play a very important role in diagnosis. As performing sophisticated laboratory tests in resource-limited settings is not feasible, accurate point-of-care testing (POCT) for scrub typhus diagnosis would be invaluable for patient diagnosis and management. Here we summarise the existing evidence on the accuracy of scrub typhus POCTs to inform clinical practitioners in resource-limited settings of their diagnostic value.</p><p>Methodology/principal findings</p><p>Studies on POCTs which can be feasibly deployed in primary health care or outpatient settings were included. Thirty-one studies were identified through PubMed and manual searches of reference lists. The quality of the studies was assessed with the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). About half (n = 14/31) of the included studies were of moderate quality. Meta-analysis showed the pooled sensitivity and specificity of commercially available immunochromatographic tests (ICTs) were 66.0% (95% CI 0.37–0.86) and 92.0% (95% CI 0.83–0.97), respectively. There was a significant and high degree of heterogeneity between the studies (I² value = 97.48%, 95% CI 96.71–98.24 for sensitivity and I² value = 98.17%, 95% CI 97.67–98.67 for specificity). Significant heterogeneity was observed for total number of samples between studies (p = 0.01), study design (whether using case-control design or not, p = 0.01), blinding during index test interpretation (p = 0.02), and QUADAS-2 score (p = 0.01).</p><p>Conclusions/significance</p><p>There was significant heterogeneity between the scrub typhus POCT diagnostic accuracy studies examined. Overall, the commercially available scrub typhus ICTs demonstrated better performance when ‘ruling in’ the diagnosis. There is a need for standardised methods and reporting of diagnostic accuracy to decrease between-study heterogeneity and increase comparability among study results, as well as development of an affordable and accurate antigen-based POCT to tackle the inherent weaknesses associated with serological testing.</p></div

Forest plot of sensitivity and specificity of current commercially available POCT.

<p>Forest plot of sensitivity and specificity of current commercially available POCT.</p

IgM ICT sensitivity and specificity range*.

<p>IgM ICT sensitivity and specificity range*.</p

Summary of included studies.

<p>Summary of included studies.</p

Summary of ICT IgM.

<p>Summary of ICT IgM.</p

Total antibody ICT sensitivity and specificity range*.

<p>Total antibody ICT sensitivity and specificity range*.</p

Summary table of total antibody ICT.

<p>Summary table of total antibody ICT.</p

QUADAS-2 finding per domain.

<p>QUADAS-2 finding per domain.</p

Summary of articles on dot-blot, LAMP and other assays.

<p>Summary of articles on dot-blot, LAMP and other assays.</p

Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation?

<p><b><i>Introduction:</i></b> Doxycycline is highly effective, inexpensive with a broad therapeutic spectrum and exceptional bioavailability. However these benefits have been overshadowed by its classification alongside the tetracyclines – class D drugs, contraindicated in pregnancy and in children under 8 years of age. Doxycycline-treatable diseases are emerging as leading causes of undifferentiated febrile illness in Southeast Asia. For example scrub typhus and murine typhus have an unusually severe impact on pregnancy outcomes, and current mortality rates for scrub typhus reach 12-13% in India and Thailand. The emerging evidence for these important doxycycline-treatable diseases prompted us to revisit doxycycline usage in pregnancy and childhood.</p> <p><b><i>Areas Covered:</i></b> A systematic review of the available literature on doxycycline use in pregnant women and children revealed a safety profile of doxycycline that differed significantly from that of tetracycline; no correlation between the use of doxycycline and teratogenic effects during pregnancy or dental staining in children was found.</p> <p><b><i>Expert Opinion:</i></b> The change of the US FDA pregnancy classification scheme to an evidence-based approach will enable adequate evaluation of doxycycline in common tropical illnesses and in vulnerable populations in clinical treatment trials, dosage-optimization pharmacokinetic studies and for the empirical treatment of undifferentiated febrile illnesses, especially in pregnant women and children.</p