HMGB1 shows promise, but not proof, in canine SIRS prognosis
Bottom line
A new Knowledge Summary in Veterinary Evidence reviewed three prospective observational studies on high mobility group box 1, or HMGB1, as a prognostic biomarker for mortality in dogs with systemic inflammatory response syndrome, or SIRS. The takeaway is cautious: two of the three studies found that higher HMGB1 concentrations were associated with death in dogs with SIRS, but the overall evidence remains inconclusive because the studies were small, used different sampling approaches, and measured HMGB1 at different time points. In the best-known of the underlying studies, a 28-dog prospective cohort found higher HMGB1 concentrations in nonsurvivors than survivors at admission, while related work has also suggested HMGB1 behaves differently from more familiar inflammatory markers such as C-reactive protein. (pubmed.ncbi.nlm.nih.gov)
Why it matters: For veterinary professionals, this is another reminder that a promising biomarker isn't the same thing as a practice-ready prognostic test. Dogs with SIRS and sepsis still carry substantial mortality risk, and more recent observational work continues to show worse short-term outcomes when organ dysfunction is present. HMGB1 may eventually help with early risk stratification, but right now the evidence base is too thin to support routine clinical use on its own, especially when illness-severity scoring, serial exams, clinicopathologic data, and organ dysfunction remain more actionable in day-to-day critical care. (pubmed.ncbi.nlm.nih.gov)
What to watch: The next step is larger, standardized prospective studies that compare HMGB1 directly with established markers and severity scores, and test whether serial measurement improves prognostic value. (veterinaryevidence.org)
Key facts
- Topic
- HMGB1 as a prognostic biomarker for mortality in dogs with SIRS
- Study type
- Knowledge Summary reviewing three prospective observational studies
- Overall finding
- Two of three studies linked higher HMGB1 concentrations with death
- Evidence quality
- Current evidence is limited, small, and methodologically uneven
- Key study size
- 28 dogs
- Key study finding
- Nonsurvivors had significantly higher plasma HMGB1 concentrations at admission than survivors
- Sampling limitation
- Studies used different sampling approaches and measured HMGB1 at different time points
- Clinical takeaway
- HMGB1 is investigational, not ready for routine clinical use on its own
A new Veterinary Evidence Knowledge Summary takes a close look at whether high mobility group box 1, or HMGB1, can help predict mortality in dogs with systemic inflammatory response syndrome. Its conclusion is measured rather than definitive: although two of three prospective observational studies linked higher HMGB1 concentrations with death, the current evidence is still too limited and methodologically uneven to support firm clinical conclusions. (veterinaryevidence.org)
That caution fits the wider state of the field. SIRS has long been used in veterinary emergency and critical care as a practical framework for identifying systemic inflammation, but the evidence behind many prognostic tools in dogs remains patchy. A recent consensus paper on sepsis in dogs and cats noted that evidence supporting SIRS-based criteria for predicting negative outcomes is limited and weak, reflecting a broader shift toward organ dysfunction-focused assessment rather than reliance on inflammatory criteria alone. (pmc.ncbi.nlm.nih.gov)
The biologic rationale for HMGB1 is still compelling. HMGB1 is a nuclear protein that, once released extracellularly during cell injury or inflammation, acts as a damage-associated molecular pattern and amplifies innate immune signaling. In veterinary literature, it has been described as a late inflammatory mediator in sepsis, and prior canine work has suggested circulating concentrations may correlate with mortality in SIRS patients. Separate research has also found HMGB1 elevated across inflammatory canine diseases and distinct in behavior from C-reactive protein, which helps explain why investigators continue to study it as more than just another acute-phase marker. (academic.oup.com)
The strongest-cited primary study in this area remains a 2010 prospective observational study of 28 dogs with naturally occurring disease and SIRS. In that cohort, nonsurvivors had significantly higher plasma HMGB1 concentrations at admission than survivors, and the HMGB1-to-IL-10 ratio also performed relatively well in outcome discrimination. But the study was small, single-center, and based on admission-time sampling, which limits generalizability. More recent biomarker research in canine critical care has underscored the same challenge: some markers show signal, but their prognostic usefulness often weakens when tested across broader case mixes, different disease processes, or different time points. For example, HMGB1 rose in dogs after trauma but did not predict survival in that population. (pubmed.ncbi.nlm.nih.gov)
There doesn't appear to be much published outside commentary specifically reacting to this new Knowledge Summary, but the surrounding literature points to a consistent industry view: biomarker enthusiasm has outpaced validation. Recent studies have continued to evaluate alternatives or complements, including cardiac troponin I, IL-6, nucleated red blood cells, and scoring systems such as APPLE and SOFA-derived approaches, because no single blood marker has clearly emerged as the stand-alone prognostic tool clinicians want. (pubmed.ncbi.nlm.nih.gov)
Why it matters: For veterinarians in emergency, internal medicine, and critical care, the practical message is restraint. SIRS cases are common, heterogeneous, and high stakes, and recent observational data show short-term mortality rises when dogs develop organ dysfunction. That makes early prognostication valuable for treatment intensity, monitoring, referral discussions, and communication with pet parents. But based on the evidence reviewed so far, HMGB1 is better understood as an investigational signal than a ready-for-routine-use prognostic assay. Until larger prospective studies standardize case definitions, assay methods, and sampling times, HMGB1 should be interpreted as background science, not a replacement for serial clinical assessment and established severity tools. (pubmed.ncbi.nlm.nih.gov)
What to watch: Expect future work to focus on standardized multicenter cohorts, serial HMGB1 sampling, and head-to-head comparisons with other biomarkers and organ dysfunction scores to determine whether HMGB1 adds enough incremental value to change clinical decision-making. (pubmed.ncbi.nlm.nih.gov)