Leptospirosis Coinfections Enter Focus in BMJ Open Review Protocol
Leptospirosis remains easy to miss in settings where dengue, malaria, hantavirus, melioidosis, and borreliosis are already circulating. Its early clinical picture can overlap with those infections so closely that the diagnosis may be delayed, incomplete, or assigned to the wrong pathogen entirely. In low-income and middle-income countries, where tropical and subtropical exposure is common and diagnostic resources may be limited, that overlap has direct consequences for surveillance, treatment decisions, and mortality tracking.
This systematic review protocol in BMJ Open is built around a straightforward but clinically important question: how often does leptospirosis occur with other infections, what risk factors are reported, and how do symptoms and outcomes differ when coinfection is present? The investigators are targeting a gap that has persisted in the literature for years. Even though coinfection is repeatedly mentioned in case reports and observational work, the field still lacks a consolidated synthesis of frequency, clinical presentation, and mortality patterns across published studies.
The clinical value of the project lies in its attempt to separate a common zoonotic infection from the diagnostic noise around it. Leptospirosis does not always present as a clean, isolated syndrome. In endemic regions, fever, myalgia, headache, and systemic illness can belong to several competing diagnoses at once. When two infections occur together, the picture becomes even less distinct, and the consequences may include under-reporting, missed treatment windows, and a distorted estimate of disease burden.
A Search Strategy Built to Capture Decades of Evidence
The review will search LILACS, ProQuest, PubMed, and Scopus without restrictions on publication date. That broad time window matters because the search reaches back to 1950 and extends through May 2022, allowing the team to capture both older case literature and more recent observational studies. Grey literature will also be included, widening the net beyond standard indexed journal articles.
Two reviewers will screen titles and abstracts independently using Rayyan software. That kind of duplicate screening is standard in systematic review methodology, but in this topic it has special importance because the literature spans multiple disease categories, reporting styles, and geographic settings. A coinfection may be described under a primary syndrome, a laboratory diagnosis, or a case report centered on another pathogen entirely. Broad database coverage and independent review reduce the chance that these cases disappear during study selection.
Eligibility is limited to peer-reviewed research articles written in English or Spanish. The protocol includes observational studies, cohort studies, case-control studies, cross-sectional studies, ecological studies, and case reports. The inclusion of case reports is especially relevant here, because rare or unusual coinfections are often first recognized in that format before they appear in larger datasets.
The investigators will include studies that describe leptospirosis cases with coinfection or co-occurrence. That phrasing is important because it signals a broad clinical lens rather than a narrow microbiologic one. In practice, coinfection may mean simultaneous detection, overlapping illness, or clinical coexistence in a patient who has more than one active infectious process. Capturing that range should help the review reflect how clinicians actually encounter the disease at the bedside.
Why Coinfection Changes the Diagnostic Problem
Leptospirosis can be clinically deceptive even when it occurs alone. Add another endemic infection, and the diagnostic pathway becomes far less straightforward. Fever syndromes in tropical medicine rarely arrive in tidy form, and the same patient may carry more than one plausible explanation for jaundice, renal dysfunction, pulmonary involvement, thrombocytopenia, or sepsis-like illness.
The protocol focuses on four areas that matter to clinicians: risk factors, symptom patterns, mortality in coinfected patients, and the frequency of coinfection. Each of those endpoints addresses a different failure point in routine care. Risk factors can point to exposure patterns and vulnerable populations. Symptom descriptions can clarify when leptospirosis is being missed because another illness dominates the presentation. Mortality data can reveal whether coinfection worsens prognosis. Frequency estimates can help public health teams understand whether the overlap is a rare curiosity or a recurring problem in endemic settings.
One sentence in the protocol carries particular weight: leptospirosis coinfections have not been treated as a neglected public health concern. That gap is not just academic. In regions where febrile illnesses are common and laboratory confirmation may be delayed, the absence of systematic data can shape clinical habits, surveillance priorities, and outbreak response.
Evidence Extraction Will Focus on Descriptive Clinical Patterns
Data extraction will use a standardized form in Excel. The protocol does not commit to a pooled clinical endpoint in advance, which is appropriate for a topic with likely heterogeneity in study design, case definitions, and reporting depth. Observational studies, ecological studies, and individual case reports do not always measure the same outcomes in the same way, so a careful descriptive synthesis may be more informative than a single numerical summary.
The planned review is also explicit about what it is not doing. It will not involve new patient enrollment or collection of primary data, so ethical approval is not required. Instead, the work will translate already published evidence into a more organized account of where leptospirosis coinfections appear, how they are described, and what clinical signals may point to them.
That approach is especially useful in diseases with overlapping syndromes. When fever and systemic illness are shared across multiple endemic infections, the practical question is not simply whether leptospirosis exists in a given region. The harder question is when clinicians should think about it alongside another diagnosis rather than instead of that diagnosis.
A Protocol Aimed at Clinical Recognition, Not Just Counting Cases
The planned review, registered under CRD42021234754, is designed to bring structure to an area that has long been scattered across case reports and regional studies. Its strength lies in scope: multiple databases, gray literature, no date restriction, and inclusion of both broad observational work and individual cases. Its main limitation is inherent to the topic itself. Coinfection studies are likely to vary widely in design, laboratory confirmation, and reporting quality, which may make direct comparisons difficult.
Even so, the question is clinically consequential. In endemic settings, leptospirosis may not present as a single disease entity at all, but as part of a mixed infectious picture that shifts the differential diagnosis and complicates treatment. A review that maps those patterns more clearly could give clinicians a more realistic framework for recognizing the disease when another infection is already on the chart.