Kounis syndrome (KS), an allergic acute coronary syndrome, remains incompletely characterized because available evidence is largely limited to case reports and small case series. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis with pooled patient-level data to quantitatively synthesize demographic patterns, clinical features, management strategies, and outcomes across published KS cases. A PubMed search identified 892 records, of which 3 studies met eligibility criteria, yielding 71 extractable cases. Study-level proportions were pooled using random-effects models with assessment of between-study heterogeneity. Age distribution varied by trigger, with contrast-related cases occurring at older ages, cephalosporin-associated cases at intermediate ages, and nonsteroidal anti-inflammatory drug–related cases at younger ages. Male predominance was consistent, with pooled estimates approximating 75%. ST-segment elevation was common, and angiographic abnormalities were present in 42%. Subtype distribution demonstrated substantial heterogeneity, particularly for Type I KS. Allergic-directed therapies, including corticosteroids and antihistamines, were frequently reported, whereas ischemia-directed therapies and invasive procedures were inconsistently documented. Recovery was the predominant outcome (94%), while mortality was low (4%). Shock and cardiac arrest occurred in a minority of cases, and pooled estimates demonstrated only a weak association between severity markers and mortality. In conclusion, this systematic review and meta-analysis provide a quantitative synthesis of KS, demonstrating trigger-specific demographic patterns, consistent male predominance, and generally favorable outcomes, although reporting variability limits definitive inference.
Kounis syndrome (KS) is an uncommon but clinically important condition in which an acute allergic or hypersensitivity reaction precipitates coronary vasospasm, plaque destabilization, or stent thrombosis, resulting in acute coronary syndrome (ACS). Although increasingly recognized since its initial description in 1991, its true incidence remains uncertain and likely underdiagnosed. A nationwide US inpatient analysis reported KS in approximately 1.1% of hospitalizations for allergic reactions, with a disproportionate share of inpatient mortality of 7%; however, such administrative data cannot establish causality. In a cohort of 200 patients presenting to the emergency department with allergic symptoms, approximately half of those with elevated cardiac biomarkers met diagnostic criteria for KS, raising concern for underrecognition of allergic-associated myocardial injury. The syndrome reflects the interaction between inflammatory mediators released during allergic activation and the coronary circulation and is categorized into 3 subtypes based on the presence of underlying coronary disease or stent involvement. Clinical presentation may overlap with both anaphylaxis and myocardial ischemia, creating diagnostic and therapeutic challenges, particularly when balancing allergic-directed therapy with conventional ischemia-directed management. Evidence guiding treatment and prognosis remains limited to case reports and small case series. The objective of this systematic review and pooled analysis is to synthesize all available case-level evidence on KS to characterize its clinical outcomes—including mortality, shock, cardiac arrest, and recovery. Secondary aims are to describe the clinical spectrum of presentation, including ST-segment elevation and other electrocardiographic (ECG) changes, angiographic findings, and subtype distribution, and to summarize reported management strategies.
Methods
Eligibility criteria
This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance. Studies were eligible if they provided extractable patient-level data on adult individuals diagnosed with KS—defined as ACS temporally associated with an allergic or anaphylactic reaction.
Inclusion criteria
Studies were eligible if they met the following criteria: (1) adult human patients ≥18 years diagnosed clinically with KS in any healthcare setting; (2) a clearly documented or presumed allergic trigger, including medications, foods, contrast media, or insect stings; (3) reporting of at least one Kounis-relevant clinical feature such as subtype classification, ECG findings, angiographic findings, biomarker abnormalities, treatment details, or clinical outcomes; (4) case reports or case series providing individual-level data; and (5) no language restrictions, with non-English articles translated when necessary.
Exclusion criteria
Studies were excluded if they involved animal or in vitro experiments; were reviews, commentaries, or meta-analyses without extractable patient-level data; were abstract-only publications without sufficient clinical detail; lacked a clearly identifiable allergic trigger; failed to provide essential diagnostic or outcome data; or represented duplicate reporting of the same patient(s), in which case the most complete dataset was retained.
Information sources
A systematic search of PubMed and EBSCO MEDLINE Complete was performed, covering all years and languages from database inception to the final search date. No restrictions on publication type were applied. Reference lists of eligible studies and review articles were screened to identify additional reports missed by database searching.
Search strategy
The primary search term used was “Kounis Syndrome,” selected for maximum sensitivity to capture all published cases of allergic acute coronary events.
Selection process
Two reviewers independently screened titles and abstracts, followed by full-text assessment of potentially eligible articles. Studies were included if they reported a human case of KS temporally associated with an allergic reaction and provided sufficient patient-level data to classify clinical presentation, interventions, or outcomes. Reasons for exclusion during full-text review were documented. Disagreements were resolved by consensus, with input from a third reviewer when necessary. The PRISMA 2020 flow diagram illustrates the study selection process.
Data collection process
Data were independently extracted by 2 reviewers using a standardized, pilot-tested collection form. Extracted variables included demographic characteristics (age and sex), allergen exposure, KS subtype classification, ECG findings, biomarker data, angiographic findings, treatment strategies (including steroids, epinephrine, vasodilators, antiplatelets, anticoagulants, and percutaneous coronary intervention), and clinical outcomes (recovery, shock, cardiac arrest, and mortality). Unreported values were coded as “NR” and addressed in sensitivity analyses. Duplicate cases were identified through demographic and clinical timeline matching, and only the most complete version was retained.
Study risk of bias assessment
Because all included studies were case series, conventional risk of bias tools were not applicable. Instead, a qualitative assessment was performed focusing on clarity of diagnosis and temporal association with allergic exposure, completeness of clinical reporting, documentation of subtype and angiographic findings, transparency of outcome reporting, and potential selective reporting or survivorship bias. These considerations were integrated into the interpretation of results.
Effect measures
Categorical variables were summarized as proportions, whereas continuous variables were expressed as medians with interquartile ranges. Study-level proportions were synthesized using fixed-effect and DerSimonian–Laird random-effects models with logit transformation.
Synthesis methods
Descriptive analyses summarized demographic characteristics, triggers, clinical features, treatments, and outcomes. Heterogeneity was assessed using Cochran’s Q, I², and τ² statistics. Forest plots were generated to illustrate study-specific and pooled effect estimates with 95% confidence intervals (CIs). Sensitivity analyses were conducted to evaluate the impact of missing data under prespecified assumptions.
All statistical analyses and visualizations were performed using Python (pandas, numpy, scipy, matplotlib) in a reproducible pipeline.
Reporting bias assessment
Selective reporting and risk of missing results were evaluated qualitatively. Assessment focused on internal consistency of case reporting across studies, patterns and proportions of nonreported (NR) variables, and comparison between included and excluded articles during the screening process. Particular attention was given to the frequency of missing intervention and outcome data, as well as potential preferential publication of more severe or clinically striking cases. Sensitivity analyses were conducted to explore the impact of missing data assumptions on pooled estimates. Because all included studies were case reports or case series, a formal funnel plot assessment was not feasible.
Certainty assessment
Certainty of evidence was assessed qualitatively using GRADE-analogous domains, acknowledging inherent limitations of case-based evidence (see Table 1 ). Findings were interpreted with caution, given the observational nature and high risk of publication bias.
Table 1
Certainty assessment
| Evidence category | Certainty judgment | Rationale |
|---|---|---|
| Core clinical outcomes (e.g., mortality, shock) | Moderate | Consistently reported |
| ECG/angiographic characteristics | Low | Partial reporting |
| Treatment effects | Very low | Extensive NR and imprecision |
Results
The database search initially identified 892 records from PubMed using the term “Kounis syndrome”. No additional studies were retrieved from other information sources. Title and abstract screening was conducted for 548 case reports and reviews identified through publication-type filters. After removal of articles without clinical relevance—including mechanistic investigations, narrative discussions, and reports lacking patient-level data—12 potentially eligible records progressed to full-text evaluation. Of these, 3 studies met all predefined inclusion criteria and were incorporated into both the qualitative synthesis and pooled patient-level analysis. The complete screening and eligibility determination process is illustrated in the PRISMA 2020 flow diagram ( Figure 1 ).
PRISMA flow diagram of study selection for the systematic review and meta-analysis of Kounis syndrome. Records were identified through PubMed database searching, screened for eligibility, and assessed for inclusion. Studies lacking extractable patient-level data or representing duplicate cases were excluded. Three studies comprising 71 patients met the inclusion criteria and were included in the pooled analysis. Abbreviation: PRISMA = Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
Participant characteristics
a. Age Distribution Across Trigger Categories
Age distributions demonstrated distinct demographic profiles according to allergen class. Contrast-triggered KS (n = 26) showed a unimodal kernel density estimation peak at 70 to 75 years, reflecting an older imaging-dependent inpatient population. Cephalosporin-triggered cases (n = 25) peaked around 60 to 65 years, consistent with typical antibiotic use demographics. In contrast, NSAID-triggered KS (n = 18) demonstrated a notably younger distribution, peaking at 50 to 55 years with a narrower spread.
b. Age Distribution by Gender
Gender-stratified analyses showed that women presented at significantly older ages, with a median age of approximately 72 years and upper-range values extending into the late 80s to 90s. Men, who represented the majority of cases, showed a lower median age (∼60 years) with a narrower interquartile range, indicating earlier onset.
c. Gender Distribution
Across the included studies, male predominance was consistent, ranging from 0.68 (95% CI 0.50–0.86) in Fang 2022 to 0.73 (95% CI 0.56–0.90) in Wang 2022 and 0.90 (95% CI 0.77–1.00) in Pejčić 2023. Pooled proportions demonstrated a stable estimate: Fixed-effect model was 0.74 (95% CI 0.62–0.84), and random-effects model: 0.75 (95% CI 0.61–0.86).
Statistical heterogeneity was modest (Q = 2.86, p = 0.240; I² = 30.0%; τ² = 0.113), supporting consistency of this demographic feature.
Clinical features
a. Electrocardiographic Findings
ST-segment elevation occurred in 43/71 cases (0.61). The random-effects pooled estimate was 0.69 (95% CI 0.54–0.81) with moderate heterogeneity (Q = 3.20; I² = 37.6%).
b. Angiographic Findings
Coronary angiography abnormalities were present in 30/71 cases (0.42). The pooled proportion was 0.42 (95% CI 0.31–0.54) with no measurable heterogeneity (I² = 0.0%), reflecting consistent reporting across studies.
c. Subtype Distribution
Subtype-specific patterns revealed pronounced differences in the clinical expression of KS. Type I KS, characterized by vasospasm without underlying coronary disease, showed widely divergent proportions across studies, ranging from 0.10 in some series to 0.90 in others. This produced a high-heterogeneity pooled estimate (Q = 20.74, p < 0.001; I² = 90.4%; τ² = 3.764), indicating substantial between-study variation. Type II KS, representing plaque rupture or supply-demand ischemia superimposed on underlying atherosclerosis, showed more moderate and consistent proportions (pooled ≈ 0.24) with borderline heterogeneity (Q = 5.91, p = 0.052; I² = 66.1%; τ² = 0.703), implying meaningful but not extreme study-to-study variation. Type III KS, the rarest form involving stent thrombosis, was reported with low but consistent frequency across the dataset. Study proportions ranged from 0.05–0.20, yielding a pooled proportion of 0.12 with moderate heterogeneity (Q = 4.50, p = 0.105; I² = 55.6%; τ² = 1.498).
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