Defining the complex phenotype of severe systemic loxoscelism using a large electronic health record cohort

Abstract

Objective: Systemic loxoscelism is a rare illness resulting from the bite of the recluse spider and, in its most severe form, can lead to widespread hemolysis, coagulopathy, and death. We aim to describe the clinical features and outcomes of the largest known cohort of individuals with moderate to severe loxoscelism.

Methods: We performed a retrospective, cross sectional study from January 1, 1995, to December 31, 2015, at a tertiary-care academic medical center, to determine individuals with clinical records consistent with moderate to severe loxoscelism. Age-, sex-, and race-matched controls were compared. Demographics, clinical characteristics, laboratory measures, and outcomes of individuals with loxoscelism are described. Case and control groups were compared with descriptive statistics and phenome-wide association study (PheWAS).

Results: During the time period, 57 individuals were identified as having moderate to severe loxoscelism. Of these, only 33% had an antecedent spider bite documented. Median age of individuals diagnosed with moderate to severe loxoscelism was 14 years old (IQR 9.0-24.0 years). PheWAS confirmed associations of systemic loxoscelism with 29 other phenotypes, e.g., rash, hemolytic anemia, and sepsis. Hemoglobin level dropped an average of 3.1 g/dL over an average of 2.0 days (IQR 2.0-6.0). Lactate dehydrogenase and total bilirubin levels were on average over two times their upper limit of normal values. Eighteen individuals of 32 tested had a positive direct antiglobulin (Coombs') test. Mortality was 3.5% (2/57 individuals).

Conclusion: Systemic loxoscelism is a rare but devastating process with only a minority of patients recalling the toxic exposure; hemolysis reaches a peak at 2 days after admission, with some cases taking more than a week before recovery. In endemic areas, suspicion for systemic loxoscelism should be high in individuals, especially children and younger adults, presenting with a cutaneous ulcer and hemolysis or coagulopathy, even in the absence of a bite exposure history.

Fig 1. Cumulative Distribution of Cases by Age.

Each point represents a case of either moderate-severe (mod-severe, red) loxoscelism or cutaneous/mild loxoscelism (cutaneous or mild, blue). The cumulative proportions of patients at or under a specific age are represented by each line. The median age of individuals with severe loxoscelism (14 years, IQR 9.0–24.0 yrs), was significantly lower than the median age (30 years old, IQR 19.0–46.0 yrs) of those identified with only cutaneous or mild systemic symptoms (p = 2.0 x 10⁻⁷).

Fig 2. Hemoglobin Fluctuation During Loxoscelism.

(A) Each line represents one individual with time and hemoglobin (HGB) graphed relative to the time point at the lowest HGB level (HGB Nadir) and the highest recorded HGB for each individual. Most HGB levels decline after admission and return to baseline. (B) ICU patients have lower interquartile ranges of HGB at presentation and at the HGB nadir, as compared to non-ICU patients. By the time of hospital discharge, the relative HGB level is similar between the two populations.

Fig 3. Phenotypes and PheWAS of Individuals with Moderate-Severe Loxoscelism.

(A) Manhattan plot representing the number of individuals with moderate to severe loxoscelism with each phenotype. The most frequent phenotypes validated the loxoscelism definition and included the toxic effect of venom, acquired hemolytic anemia, fever of unknown origin, and rash/skin eruption. (B) PheWAS for moderate-severe loxoscelism. The blue line represents significance level without correction (p = 0.05). The red line is representative of the adjusted significance threshold using the Bonferroni correction for multiple comparisons (p = 1.2 x 10⁻⁴). 29 phenotypes showed a significant correlation (p < 1.2 x 10⁻⁴) with the loxoscelism phenotype when compared to controls.