A single-blind parallel group randomized controlled clinical trial was performed on patients with a primary admission diagnosis of cellulitis or skin and soft tissue infection. Samples were also taken to assess gene expression in the adipose tissue of the affected patients with a comparison to healthy non-inflamed control patients.
Eligible patients were adults admitted to the inpatient internal medicine ward with a primary diagnosis of suspected cellulitis that did not have features of purulence or necrosis. Patients were excluded if they had any associated surgery to the affected area in the last 90 days, malignancy, pregnant or breast feeding, facial involvement, or any visible skin tear within 10 cm of the affected area. Incarcerated individuals and direct hospital transfers were excluded.
Eligible patients were screened daily via medical record number searches. After consent, the participants were assigned a unique patient number and a random number generator was used to randomize participants to the interventional or standard of care group. The standard care group did not have skin biopsy or tissue culture results reported in the electronic health record (EHR) unless medically necessary, such as bacterial culture results not being treated. The interventional group had skin biopsy and tissues culture released to the EHR, allowing the primary medical team to monitor pending cultures for positivity.
Encrypted photographs were taken of the patient’s skin condition. Subsequently, three 4-6mm punch biopsies were obtained from the most proximal portion of erythema. The first biopsy was sent for histopathologic analysis by a dermatopathologist, utilizing standard histopathologic stains including Gram, Grocott’s methenamine silver, and acid-fast stains. The second biopsy was sent for tissue culture (bacterial, fungal, and anaerobic), and the third biopsy was flash frozen for corollary SAT analysis. Acid-fast cultures were performed only if the dermatopathologist had suspicions based on the histopathology.
The patients and the dermatopathologist were blinded to their assignment. The inpatient physicians were aware of the study and had to agree to patient participation but were not explicitly told of the randomization assignment unless requested. These physicians could request a standard inpatient dermatologic consultation at any time if deemed appropriate. Following the hospital stay, the research coordinator collected data related to the outcome measures including length of stay, antibiotic type and duration of use, re-hospitalization rate, as well as skin biopsy and tissue culture results. Patients were later contacted by phone 30 days after hospital discharge to inquire about additional antibiotic use, hospitalizations, and medical care post-discharge.
Patient demographics were analyzed to demonstrate the effect of the randomization. The data were analyzed in an intention-to-treat format, without accounting for laboratory errors, unblinding, and/or patients leaving against medical advice. The primary outcome measure was the hospitalization length of stay, with secondary outcome measures including antibiotic de-escalation defined as length of use of broad-spectrum intravenous (IV) MRSA coverage (vancomycin, daptomycin) and broad-spectrum IV pseudomonal coverage (carbapenems, anti-pseudomonal penicillins, ceftazidime and 4th generation cephalosporins, ciprofloxacin and levofloxacin). In addition, total antibiotic (IV and oral) length, death, 30-day readmission, and associations of culture positivity were considered secondary outcomes. Exploratory outcomes included the evaluation of structural and inflammatory gene changes in patients’ adipose tissue in comparison with healthy controls.
According to the CDC, an average hospital length of stay for the diagnosis of cellulitis and abscess is 4.4 hospital days, but has substantial variation.14 However, a randomized experiment using outcomes such as length of stay and antibiotic de-escalation based on skin biopsy and tissue cultures had not previously been performed. Based on NIH guidelines as a pilot study, we determined 60 patients were needed to assess patient flow, effect magnitude, and exploratory hypothesis analysis, while staying within budget constraints. Ultimately, 56 participants were enrolled before the shutdown of human trial research due to COVID-19 and lapse of funding.
Descriptive statistics are reported as mean ± standard deviation (std dev), median (IQR) or total number and percentage. Normality of data was assessed after visual inspection of the data and with the Shapiro Wilk normality test. Continuous data, such as length of stay and duration of antibiotics, were analyzed using a t-test for normally distributed data and a Wilcoxon Rank-sums test for skewed data. Categorical data, such as re-hospitalization within 30 days, were analyzed using a chi-squared or Fisher exact test as appropriate. Significance level was set at α ≤ 0.05. The data were analyzed using JMP 14PRO and Statistical Analysis Software, version 9.4 (SAS Institute Inc., Cary, NC, USA)
Healthy, non-obese patients were compared with patients diagnosed with cellulitis enrolled in this study. Adipose tissue was harvested at the time of elective surgery for lean patients and via a skin biopsy of patients with cellulitis. The tissue was homogenized, RNA was extracted, and cDNA was generated. Primers were purchased from Sigma and gene expression was calculated using the delta CT method as previously described.15 For all statistical analyses, GraphPad Prism 7.0 was utilized. Data normality was assessed, and student’s t-tests were performed for normally distributed data and Mann Whitney U tests were performed for non-normally distributed data.
This study was conducted exclusively at the Ohio State University Wexner Medical Center. This was approved by the IRB (OSU:2018H0147), funded internally through a patient safety advancement grant, and published on clinicaltrials.gov (NCT03785834). Written informed consent was obtained from all subjects prior to their participation in the study. Enrollment began in August 2018 and was continued through March 2020.