Skin Lesions with Loss of Tissue and Cutaneous-Onset Sepsis: The Skin Infection–Sepsis Relationship

Infectious and inflammatory dermatoses featuring skin lesions with loss of tissue expose skin layers to microbial invasions, disrupt the normal skin microbiome, and potentially lead to sepsis. However, literature data on the incidence of cutaneous-onset sepsis are scarce. This retrospective observational study assessed hospital admissions for primary skin lesions without bacterial infections and sepsis during 2020–2022 in the largest emergency hospital in NE Romania. Of 509 patients, 441 had infected lesions, 78 had sepsis caused by venous ulcers from microbial eczema cellulitis, superinfected bullous dermatoses, erysipelas, and erythroderma. Cultured samples revealed S. aureus, P. aeruginosa, and E. coli; and K. pneumoniae and S. β-hemolytic associated with sepsis, even if this was rarer. Clinical manifestations included ulcerations, erosions, fissures, excoriations, bullae, vesicles, pruritus, tumefaction, edema, fever, chills, pain, adenopathy, and mildly altered mental status. Underlying chronic heart failure, atrial fibrillation, anemia, and type-1 diabetes mellitus were comorbidities associated with infection and sepsis. Significant associations and risk factors, including their combined effects, are discussed to draw attention to the need for further research and adequate management to prevent sepsis in adult patients of any age presenting with infected skin lesions (especially cellulitis) and comorbidities (especially type 1 diabetes mellitus and anemia).


Introduction
Acute skin infections, regardless of etiology (bacterial, viral, or fungal), are very frequent in dermatological practice.Whether superficial or deep, mild or severe, they can aggravate further and lead to sepsis, triggering a complex cascade of dysfunction and even failure across multiple organs and body systems.Addressing the first clinical signs of skin infections promptly and effectively is the most appropriate therapeutic approach [1].
Sepsis of any type is a serious threat to public health, and the international research community seeks to establish sepsis definitions, treatments, and preventive measures [2].The understanding of sepsis has undergone reconceptualization over time.In 1991, the American College of Chest Physicians described sepsis as a systemic inflammatory response syndrome (SIRS) caused by infection, with possible further aggravation to severe sepsis in case of organ dysfunction with hypoperfusion or hypotension; and to septic shock in case of hypotension despite adequate volemic resuscitation.In 2016, the Third International Consensus Definitions for Sepsis and Septic Shock defined sepsis-3 as life-threatening organ dysfunction, acknowledging the severe, lethal threat of a pathogen invading the body [3,4].The diagnosis of organ dysfunction is now based on Sequential Organ Failure Assessment (SOFA) score changes of at least two points as a result of acute infection [5].
According to public health data, the sepsis-related mortality rate was 41% in Europe and 28.3% in the United States in 2012 [6].In 2017, 48.9 million cases of sepsis were reported worldwide, resulting in 11 million deaths, or 19.7% of all deaths that year [7].These numbers are still cited, suggesting a need for more updated epidemiological reports.
The starting point of infection in sepsis patients has been described, but few studies highlight the importance of skin semiology in the early recognition of sepsis.One such study conducted in Colombia on a group of patients diagnosed with sepsis showed that skin and soft tissue infections were the fourth leading cause of sepsis (9.4%) after urinary tract infections (27.6%), lower respiratory tract infections (27.4%), and intra-abdominal infections (10.8%).Almost a quarter of sepsis episodes originating in skin infections progressed to septic shock, and 28% of these patients had to be transferred to intensive care units.Of them, 8% succumbed to their conditions [8].
The skin is home to an incredibly diverse microbiome, normally maintained in a healthy balance.When the skin's defense mechanisms are overrun by proliferating pathogens, the ensuing acute skin infections can be cellulitis, erysipelas, trophic ulcers in advanced stages of chronic venous insufficiency, bullous dermatoses (pemphigus, pemphigoid, erythema multiforme) with extensive denudation, and erythroderma.The bacterial agents most often involved are Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, species of the genus Streptococcus, Klebsiella pneumoniae, Proteus mirabilis, and Enterococcus [9].The onset of infectious dermatoses is abrupt, with soft tissue erythema, induration, local heat, pain, fever, followed by the deterioration of vital functions and single/multiple organ dysfunction as sepsis complications.
The appropriate management of acute skin infections depends on their severity.Mild forms can be effectively resolved with topical antibiotics, while severe infections require systemic antibiotic therapy.Initiation should be prompt and with agents empirically proven to be sensitive to gram-positive microorganisms, such as penicillinase-resistant penicillin, cephalosporins, macrolides, or fluoroquinolones.In case of severe sepsis, adequate treatment is multifactorial and multidisciplinary, including the administration of vasopressor agents, steroids, anticoagulants, anti-inflammatories, as well as glycemic control, ventilation support, and even (early) resuscitation [10,11].Medical teams must consider the infection gateway, the pathogens involved, the patient's age, and comorbidities.In most cases, a broad-spectrum empiric antibiotic with good tissue penetration is administered first, followed by switching to a narrow-spectrum antibiotic therapy based on the antibiogram results [12].

Study Aims
In this study, we assessed the incidence of skin lesions with loss of tissue that can become infected and complicated further by cutaneous-onset sepsis, in the context of tertiary care provided by the dermatology unit of the largest emergency hospital in NE Romania.The specific objectives included: (1) surveying hospital records, (2) compiling a comprehensive database on all patients admitted with skin lesions featuring loss of tissue, (3) analyzing the data to identify statistically significant associations, and (4) reporting results internationally to update awareness and understanding of relevant issues.
The study is relevant considering the scarcity of incidence data on cutaneous-onset sepsis in the literature and the implications for multidisciplinary clinical practice and further research.Skin lesions are not typically regarded as emergencies, but lack of timely diagnosis and treatment can lead to infections and then to sepsis, delaying recovery, increasing treatment complexity and financial costs, undermining quality of life, and even threatening the patient's life.

Study Coordinates; Inclusion and Exclusion Criteria
This was a retrospective observational study of patients admitted to the Clinic of Dermatology-Venereology of the Emergency Clinical County Hospital "Sf.Spiridon" Ias , i in NE Romania between January 2020 and December 2022.The study was conducted with the formal approval of the institutional Research Ethics Committees of the hospital and the medical university.
The study enrolled adult patients admitted consecutively for the diagnosis and treatment of skin lesions (ulcerations, erosions, fissures, excoriations) and symptoms indicative of associated inflammatory processes (edema, tumefaction, erythema, fever, pain, etc.).Completing a bacteriological examination on admission was a key criterion for inclusion.Patients younger than 18 with concomitant SARS-CoV-2 infection in sepsis of non-cutaneous cause and/or with Glasgow Coma Scores < 13) were excluded from the study.
A detailed clinical analysis of skin manifestations was performed, and the patient data were organized in three study groups:

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group A-infected skin lesions and sepsis; • group B-infected lesions without sepsis; • group C-non-infected skin lesions (negative bacteriological examination results).
The three datasets were compared to identify significant associations between clinical manifestations (cutaneous, systemic) and patient characteristics (demographics, comorbidities, mental status), as well as to assess risk factors.

Definitions
The types of skin lesions with loss of tissue considered in this study were: erosions (loss of tissue down to the skin's basal membrane), ulcerations (deep loss of tissue), fissures (linear lesion-related skin dehydration, thickening, compromised elasticity), excoriations (superficial loss of skin tissue, e.g., due to scratching).The presence of bullae and vesicles was also noted.Necrotizing fasciitis and abscesses could not be included in the analysis due to lack of cases during the studied period.
Sepsis was defined as infection-related systemic inflammatory response syndrome (SIRS) and established when two or more of the following criteria were met: body temperature >38 • C or <36 • C, tachycardia, tachypnea, leukocytosis/leukocytopenia.The differential diagnosis of cutaneous-onset sepsis was based on the identification of primary skin lesions and the confirmation of bacterial agents in cultured samples from the lesions, distinguishing it from sepsis of other causes, e.g., neoplasms, respiratory, urogenital, etc.
Single-use swab tubes with Amies medium were used to collect skin lesion specimens on admission.This type of swab and medium maintains the viability of pathogens during transport.The samples were taken to the hospital's laboratory within 4 h of being harvested, where they were cultured and tested for sensitivity to antibiotics.
A mild deterioration of mental status on the Glasgow Coma Scale (scores of 13 and 14) was also considered to be indicative of sepsis.This scale is commonly used to assess brain injury, and assigning a GCS score is standard procedure in emergency admissions.Fully awake, responsive, cognitively agile patients receive the maximum score of 15; scores 9-12 describe moderate impairment; and scores of 8 or less indicate severe coma states of unconsciousness.Severely altered mental status occurs in septic shock, which was not the object of our study (patients would not have been referred to the dermatology unit of the hospital; they would have been treated in the ICU of the emergency department instead).

Statistical Analysis
The statistical analysis was performed using the SPSS version 29.0 software package (SPSS Inc., Chicago, IL, USA).Categorical variables were presented as frequencies and percentages, and continuous variables were presented as means ± standard deviation.Categorical variables were compared between groups using the Pearson chi-squared test, and the associated risks (OR) were also calculated.Continuous variables were compared between groups using the Mann-Whitney test (because the pre-condition of normal repartition of values was not verified).To investigate the combined action of the statistically significant risk factors for infection and sepsis, the multivariate analysis was performed using a model for binary logistic regression.Statistical significance was assessed relative to the threshold of p < 0.05, and the confidence interval (CI) was set at 95%.

General Demographic Characteristics
During the three-year research period, 509 admitted patients were diagnosed with infectious dermatoses and met the criteria for inclusion.The patients were between 18 and 92 years old (mean age: 64.22 ± 14.699).In 441 cases, lesions were infected, and sepsis was confirmed in 78 of these cases (group A).Patients with sepsis were older (mean age: 65.23 ± 14.056), but not significantly so (weak statistical significance, p = 0.046).These age characteristics are summarized in Table 1.The 441 patients with infected lesions and sepsis were mostly men (56.2%) and mostly rural residents (57.4%) (see Table 2).Statistically non-significant differences were noted relative to the presence or absence of sepsis, but sex and background differences were significant within each group.Namely, acute skin infections were more common in men than in women (57.0% vs. 43%) and in patients from rural rather than urban areas (58.1% vs. 41.9%).Similarly, sepsis was more common in men (52.6%) and rural residents (53.8%).Male patients appeared to be 2.282 times more at risk of skin infections than women, while urban residence seemed to provide some protection, considering the 0.474-fold higher risk associated with rural background.Overall, the main clinical manifestations recorded were skin ulcerations, erosions, fissures, excoriations, bullae, vesicles, pruritus, tumefaction, as well as fever, chills, pain, edema, and adenopathy (see Figure 1, Tables 3 and 4).

Clinical Manifestations-Cutaneous and Systemic, including Conscious State
Overall, the main clinical manifestations recorded were skin ulcerations, erosions, fissures, excoriations, bullae, vesicles, pruritus, tumefaction, as well as fever, chills, pain, edema, and adenopathy (see Figure 1, Tables 3 and 4).The topography of skin lesions was consistent across groups, with non-significant differences between patients with sepsis versus those with uncomplicated infections.Most skin manifestations occurred in the lower limbs (97.4% in group A, 93.9% in group B), and a minority of patients also had lesions on their torsos (23.1% in both groups), upper limbs (17.9% in group A, 18.5% in group B), and faces (10.3% in group A, 8.8% in group B).The location of the studied lesions was not a significant factor in the patients' aggravation towards sepsis.The same can be said about the number of lesions: patients with multiple lesions were not more likely to progress to sepsis compared to those presenting a single lesion.
While most patients across groups had skin ulcerations, erosions, fissures, and excoriations, significantly fewer patients with sepsis had such lesions (89.7%) compared to patients without complicated infections (97.8%, p = 0.003) or those without infections altogether (95.6%).Similarly, bullae or vesicles were least present in patients with sepsis (only 21.8% compared to 29.2% in group B, p < 0.001), and pruritus occurred in only 29.5% of patients with sepsis compared to more than 60% of patients in groups B and C (p < 0.001).Tumefaction was the only exception, occurring in a majority of cases in all three groups, but mostly in sepsis (p = 0.016).
The opposite could be seen in manifestations reaching beyond the skin, such as edema.Relative to the 80.8% of patients with sepsis who manifested edema, significantly fewer patients with uncomplicated infections had it (59.2%),and only 30.9% of uninfected patients did (p < 0.001).This confirms edema as a risk factor for both infection (3.251) and sepsis (2.891).
In addition, patients with sepsis experienced systemic signs and symptoms significantly more than the other patients.Fever and chills were, by far, most common in patients with sepsis (80.8%) and were much rarer in the other groups (22.3% and 20.6%, respectively, p < 0.001).This translates to a 14.622-fold increased risk of sepsis in the presence of fever, which is not surprising considering what sepsis entails.Similarly, pain was reported by almost all the patients with sepsis and infection (96.2% and 89.0%, respectively), compared to 61.8% of uninfected patients (p < 0.001).The risk analysis pointed to pain as the second highest risk factor for infection (4.999), suggesting that painful symptoms can betray infective aggravation even more than edema, an indicative sign of inflammation.
Regarding adenopathy, even if it occurred in only 17.9% of sepsis cases, it was significantly rarer in the group with uncomplicated infections (5.2%, p < 0.001).A 3.961-fold increased risk of developing sepsis in the presence of adenopathy was calculated, but note that adenopathy also occurred in 10.3% of uninfected patients (p = 0.158).
Furthermore, a mildly altered state of consciousness (Glasgow scores of 13 or 14) was significantly associated with the presence of sepsis.Of the 13 patients with such scores, most had confirmed sepsis (9% relative to the size of group A vs. 1.7% in group B, p = 0.003, see Table 5).The risk assessment associated Glasgow scores of 13 or 14 with a 5.866-fold higher risk of sepsis.This relationship between sepsis and mildly impaired brain function highlights the importance of addressing and preventing sepsis not just generally, but also in the context of treating skin lesions with infective complications.

Main Acute Skin Conditions and the Etiological Agents Responsible for Infections
As summarized in Table 6, the types of diagnosed skin infections were venous ulcers (68.3%), microbial eczema (61.9%), cellulitis (21.1%), superinfected bullous dermatosis such as pemphigus, pemphigoid, Stevens-Johnson syndrome (6.6%), erysipelas (5%), and erythroderma (2%).Other dermatoses featuring loss of tissue or the disruption of the skin barrier, such as atopic dermatitis, psoriasis, vasculitis, and ulcerated skin neoplasms, amounted to 27%.While venous ulcers were almost equally present in groups A and B (66.7% and 68.6%, respectively), they were by far the least common in uninfected patients (13.2%, p < 0.001), see Table 7. Concurrently, microbial eczema was significantly more frequent among patients with uncomplicated infections (68.9%) than both sepsis patients (29.5%) and uninfected patients (27.9%) (p < 0.001).However, 48.7% of patients with sepsis had cellulitis, while only 15.2% of patients with uncomplicated infections and just one uninfected patient did (p < 0.001).Erysipelas was infrequent in all groups, but rarest among patients with uncomplicated infections (3.9% in group B vs. 10.3% in group A, p = 0.038, and 17.6% in group C, p < 0.001, respectively).Overall, cellulitis presented the highest risk for sepsis (5.320), followed by erythroderma (3.870) and erysipelas (2.849).Other differences in the incidence of venous ulcers, erythroderma, superinfected bullous dermatosis, and other dermatoses disruptive of the skin barrier were not significant.The bacterial agents evidenced in the cultured samples from the 441 patients with uncomplicated infections and with sepsis were Staphylococcus aureus (43.3%),Pseudomonas aeruginosa (33.8%),Escherichia coli (12.9%),Klebsiella pneumoniae (9.8%), and group A Streptococcus β-hemolytic (5.9%).As can be seen in Table 8, only K. pneumoniae and S. β-hemolytic were significantly more common in the sepsis group (17.9% vs. 8%, p = 0.007, and 11.5% vs. 4.7%, p = 0.031, respectively).The noted differences contributed to a risk of sepsis that was 2.655 times higher in streptococcal infections and a 2.519-fold increase in the presence of K. pneumoniae.In addition, various other species of bacteria were detected (30.4%) without apparent significant impact on sepsis (Proteus mirabilis, Serratia marcescens, Citrobacter freundii, Providencia stuartii, Stenotrophomonas maltophilia, Morganella morganii, and Enterobacter genus).The same can be said about the viral agents found in 9.5% of cases.The hepatitis B and C viruses identified were inactive and did not play an active role in the studied pathologies.

Comorbidities
The associated pathologies of the patients enrolled in the study included cardiovascular diseases (hypertension/HT, chronic heart failure/CHF, atrial fibrillation/AF, obliterating arteriopathy of the lower limbs/OALL), microcytic hypochromic anemia, diabetes mellitus types 1 and 2 (T1DM and T2DM); and neurological, renal/genital, and respiratory conditions summarized in Figure 2 and in Tables 9 and 10.

Comorbidities
The associated pathologies of the patients enrolled in the study included cardiovascular diseases (hypertension/HT, chronic heart failure/CHF, atrial fibrillation/AF, obliterating arteriopathy of the lower limbs/OALL), microcytic hypochromic anemia, diabetes mellitus types 1 and 2 (T1DM and T2DM); and neurological, renal/genital, and respiratory conditions summarized in Figure 2 and in Tables 9 and 10.Overall, the most common underlying conditions were cardiovascular, of which hypertension was prevalent in all groups, with a non-significant 10% difference between patients with sepsis versus uninfected lesions.Established chronic heart failure was significantly more frequent among patients with sepsis and those with uncomplicated infections (compared to uninfected patients).The risk of infection was 1.924 times higher in the presence of stage I and II CHF according to the classification of the New York Heart Association (NYHA).The same can be said about established atrial fibrillation, which increased the risk of infection 2.527-fold according to our analysis.Lower limb arteriopathy was the least common, and related differences were not conclusive.
Microcytic hypochromic anemia stood out as significantly more common in the sepsis group (55.1% vs. 37.2%, p = 0.003).A 2.075-fold increase in the risk of sepsis was thus calculated for patients with anemia, which suggests the importance of timely, adequate treatment of both the underlying hematological condition and of any incipient infection of skin lesions in patients with anemia.
Regarding diabetes mellitus, type 1 was significantly associated with sepsis, although patient numbers were too small to make a reliable determination (only seven cases).This does not mean that T1DM patients are unlikely to develop skin conditions with related infections or sepsis, but rather that it is possible that such patients were prioritized for emergency or diabetes treatment (or treatment in another department).The fact that all T1DM patients admitted in our unit had infected lesions or even sepsis is suggestive of the risks associated with T1DM.The 6.486-fold increased risk among these patients invites further targeted research of the role of underlying T1DM in the progression to sepsis of skin lesion infections.By contrast, type 2 diabetes was more common (104 vs. 7 patients overall), and it was noted in all three study groups.Even if it was most frequent in patients with sepsis (25.6%) and with infected lesions (20.1%), and less so in uninfected patients (16.2%), these differences did not constitute statistical significance.
Concurrently, neurological conditions were significantly more common in patients with sepsis (32.1%) and infected lesions (29.8%) than in the uninfected group (16.2%).Neurological health plays a role in the body's ability to heal and to fight off pathogens, as this result appears to illustrate this with regard to the skin barrier.The distribution of other respiratory or renal/genital conditions noted in our patients was not associated with our patients' status relative to infection and sepsis.

Multivariate Logistic Regression Analyses of Risk Factors for Infection and Sepsis
Six-step logistic regression models were built to assess the combined risk effects of parameters previously identified as significantly associated with infection and, respectively, with sepsis.
The model generated to assess the combined risk for infection explained 42.5% of the variations recorded in the incidence of infected skin lesions and adequately classified 87.2% of cases with 97.5% sensitivity and 32.4% specificity (p < 0.001).The Nagelkerke R 2 coefficient was used to determine to what extent infection could be explained by the variables of interest (the risk factors flagged as statistically significant in Table 11).The cumulated statistical effect of various combinations of these risk factors was also analyzed to establish the probability of infection (absent-0/present-1, relevant risk > 0.5).As can be seen in Table 12, the risk of infection was highest (especially with E. coli) in rural residents with histories of neurological conditions who were admitted with venous ulcers, cellulitis, and microbial eczema.The risk remained at the highest level even in the absence of one or two of these factors.The probability of sepsis in the combined presence of significant individual risk factors is explored in Table 14.The risk was highest in patients with underlying type-1 diabetes numerous studies.For instance, Gabriel Wardi et al. reported close correlations between the severity of associated pathologies and both extent of organ dysfunction and unfavorable prognosis [17].However, our analysis of a significant sample of patients of all adult ages showed that age differences made far less of a difference than comorbidities, a key finding in our study.
Information on sepsis epidemiology and patterns in patients under the age of 60 is limited but not altogether absent.Carmen Bouza surveyed the national Spanish health data between 2006 and 2015, finding 28,351 cases of sepsis in patients aged 20-44 years, which amounted to 3.06‰ of all hospitalizations for this age group [18].Considering the overall age characteristics of our patients (age range 18 to 92, mean age 64.22, median 65), it is worth noting that cutaneous-onset sepsis occurred in patients of all ages (18-88); they were in fact younger on average (mean 61.33, median 62) compared to patients without sepsis, at a weakly significant p = 0.046.This result challenges existing notions related to age and sepsis, inviting further research into other potentiating factors such as comorbidities.It also underscores the importance of addressing skin lesions before they become contaminated.
Regarding background, rural residence has generally been proven to limit or delay access to health services.Primary and secondary outpatient or hospital care services are more readily available in towns and cities.Delayed diagnosis and management lead to further aggravation and complications that statistically show up as higher rates of infection, sepsis, and mortality among patients from rural areas [19].Our data, which are focused exclusively on skin lesions, make this distinction very clear for all three studied situations: sepsis, uncomplicated infections, and uncontaminated lesions.

In-Depth Discussion of Studied Lesions
The onset of infectious dermatoses is often sudden, with soft tissue erythema, induration, local heat, and pain, followed by more generalized symptoms such as fever, deterioration of vital functions, and single or multiple organ dysfunction in the case of septic complications.Careful analysis of local and systemic manifestations facilitates correct diagnosis and prompt initiation of appropriate treatment.The acute skin infections diagnosed in our patients included trophic ulcers in advanced stages of chronic venous insufficiency, microbial eczema, cellulitis, erysipelas, bullous dermatoses (pemphigus, pemphigoid, erythema multiforme, Stevens-Johnson syndrome), erythroderma, and other dermatoses (ulcerated cutaneous neoplasms, atopic dermatitis in the exudative phase, tinea pedis intertriginosa).
Cellulitis typically involves a bacterial infection of the dermis and subcutaneous cellular tissue, most commonly the lower limbs (70-80% of cases) [20].A recurrent medical emergency, it starts abruptly with soft tissue erythema, warmth, and local tenderness, and is most often caused by Streptococcus pyogenes and/or Staphylococcus aureus.In our study, more than 90% of the 93 patients with cellulitis had lower limb lesions, and just one patient was not infected.In approximately 40% of cases, multiple types of bacteria were evidenced, the other 60% being monobacterial infections.The main species found were P. aeruginosa (38.7%) and Staphylococcus (35.48%), while K. pneumoniae, E. coli, and β-hemolytic Streptococcus were present in 10-15% of cases.Some patients were also positive for P. mirabilis, S. marcescens, C. freundi, P. stuartii, S. maltophilia, M. morganii, and Enterobacter.
Venous ulcers are a manifestation of chronic venous insufficiency (CVI), and they begin as small, round ulcerations that gradually expand to sometimes encompass the entire circumference of the calf.Edges are irregular, smooth, or slightly elevated, and the surface is covered with cellular debris from microbial colonization.Venous ulcers are typically located in the distal 1/3 of the calf, the internal malleolar region (60-70% of cases), less often on the calf's middle third (18-20%), and most infrequently on the upper third (4-6%) or higher up the leg (3-4%) [22].Venous ulcers were the most common pathology diagnosed in our patients (>60% of sepsis and uncomplicated infection cases), associated with bacterial superinfection with S. aureus, P. aeruginosa, K. pneomoniae, E. coli, as well as with para-venous microbial eczema.
Bullous dermatoses (pemphigus, bullous pemphigoid, erythema multiforme, Stevens-Johnson syndrome) can compromise the integrity of the epithelium and mucous membranes, thus undermining systemic homeostasis.Their etiopathogenic polymorphism is facilitated by numerous predisposing or favoring factors, to the detriment of good prognosis and quality of life [23].In pemphigus, for instance, intraepidermal bullae are caused by the multifactorial activation of the immune system.The vesiculobullous lesions initially form in the mucous membranes and subsequently extend to the trunk.The buccal mucosa is damaged by flaccid vesicles that rupture easily and leave painful erosions, undermining the patient's ability and willingness to eat, leading to weight loss and malnutrition.The cutaneous phase usually occurs after a latent period of several days to several months and consists of a bullous, monomorphic rash that spreads rapidly, sometimes over the entire body [24].To achieve a good outcome, early bacteriological investigations, antibacterial therapy, and electrolyte and nutritional support are necessary [25].Bullous pemphigoid is another such autoimmune condition that can progress to sepsis; in staphylococcal or streptococcal infection, autoantibodies can be triggered against multiprotein complexes that normally help basal epithelial cells adhere to the base membrane [26].Even if less frequent, such cases constitute dermatological emergencies.In our study, aggravation to severe forms with septic complications and substantial hydro-electrolyte imbalance occurred in 3.8% of the 29 patients with superinfected bullous dermatoses.
As the name suggests, erythroderma is clinically expressed as redness (erythema), and it is diagnosed as such when more than 90% of the body surface is affected.Redness is not always a sign of infection; it can also occur in neoplasia or as hypersensitivity to medication.The estimated incidence is 1 in 100,000 adults, mostly men and typically aged 41-61, without racial predilection [27,28].Typically, erythroderma is triggered by the exacerbation of a pre-existing dermatosis such as psoriasis (23% of cases), atopic dermatitis, and contact dermatitis [29].Altered hemodynamic parameters, fever, hypoproteinemia/hypoalbuminemia, co-occurrence of edema, loss of fluids, electrolyte and/or acid-base imbalance, superinfection with risk of (or confirmed) sepsis justify taking this condition seriously [30].Erythroderma was rare in our study (11 patients), but their clinical presentation data agrees with the literature.
Finally, a minority of patients also suffered from other dermatoses causing lesions disruptive of the skin barrier, e.g., psoriasis, atopic dermatitis, dermatitis herpetiformis, vasculitis, and ulcerated skin neoplasms.The absence from our analysis of conditions such as necrotizing fasciitis does not imply that such cases did not occur in our region during the studied period.Rather, our aims and methodology were not appropriate for the research of rare and severe skin infections that advance very quickly and require prompt surgical intervention.

The Role of Comorbidities in Acute Skin Infections and Related Sepsis
Comorbidities weaken the body's defense mechanisms and can facilitate the spread of infection and eventually lead to sepsis by promoting the release of pro-inflammatory cytokines and altering coagulation processes, etc.In a previously cited Spanish study, 44% of patients hospitalized for soft tissue and skin infections had comorbidities; specifically, diabetes and heart disease were significant risk factors for major adverse events [15].The patients included in our study presented a range of underlying conditions typical of the broader trends of illness in modern society.The multivariate analysis flagged type 1 diabetes mellitus and anemia as the most substantial risk factors for infection and sepsis, particularly in patients with cellulitis.
Hypertension was the most common comorbidity across all studied groups, especially in the sepsis group (69.2% vs. 58.8% of non-infected patients), but with non-significant differences.On the other hand, while 41% of patients with sepsis had established chronic heart failure, less than a quarter of patients with uncontaminated lesions did (23.5%).Importantly, sepsis is known to suppress myocardial function, favor diastolic dysfunction, and decrease the cardiac index and output.According to research data, patients with preserved ejection fraction are at a higher risk of mortality (2.4%) from sepsis than those without heart failure (0.4%), explained by insufficient cardiovascular reserves during systemic infection [31].In our study, the infectious risk of patients was 1.924-fold higher in the presence of NYHA stage I and II heart failure.
During sepsis, the systemic release of pro-inflammatory cytokines, elevated levels of stress hormones, and changes in intravascular volume can compromise cardiovascular function, including electrical function.This can aggravate pre-existing arrhythmias or cause new-onset arrhythmias, particularly atrial fibrillation [32].In our study, an established history of atrial fibrillation was significantly more frequent in the sepsis group (32.1%) compared to 27.8% of patients with uncomplicated infections and only 13.2% of noninfected patients.Established atrial fibrillation appeared to increase infectious risk by 2.527 times.Other published data show that sepsis is a risk factor for fibrillation, with new-onset atrial fibrillation being associated with a higher mortality rate than pre-existing fibrillation [33].
In our study, microcytic hypochromic anemia was present in 37.2% of patients with acute skin infections and 55.1% of patients with sepsis, suggesting that patients with anemia are twice as likely to develop sepsis.Similar results were obtained in a prospective study of ICU-admitted sepsis patients, where 42% had iron deficiency anemia.Iron is essential for host immunity and hemoglobin synthesis, which explains why patients with anemia are more vulnerable to sepsis [34].In another study on 70 patients with sepsis and septic shock, as many as 82.6% had various forms of anemia related to chronic illness and hemolysis in severe stages of sepsis, recurring phlebotomy, and hemodilution.Hemolysis has been attributed to increased concentrations of hem, haptoglobin, hemopexin, and haemoxygenase-1 [35].Although the cases of anemia in our study were limited in type to disturbances of systemic iron homeostasis, our results align with reports in the literature.Markers of hemolysis could be featured in future research of prognostic factors for cutaneous-onset sepsis.
Diabetes is a common underlying condition in patients who develop sepsis, yet sepsis prognosis in these patients is controversial [36,37].Severe infections may be facilitated by inadequate glycemic control as insulin and oral antihyperglycemic drugs have been associated with lower incidence of sepsis.Diabetes is said to not increase the risk of mortality for sepsis patients, although it can promote kidney failure [38].In both types 1 and 2, the pathological mechanisms contributing to higher risk of infection are complex and multifactorial.Glycemic imbalance can promote lesions via the irreversible glycation of protein chains, as well as by undermining the immune response and by generating oxygen-reactive species.Neuropathy and vascular lesions are diabetes-related complications that can further increase infection risk by interfering with leukocyte migration towards affected tissues, while peripheral artery disease reduces blood flow, limiting the effectiveness of antibiotic treatment and allowing bacteria to proliferate instead [37].We found that as many as a quarter of patients with cutaneous-onset sepsis and a fifth of those with uncomplicated infections had type 2 diabetes mellitus.In addition, despite the narrowly defined nature of our study, patients with type 1 diabetes were at a particularly high (6.486-foldincreased) risk of sepsis.

Further Comments on the Predictive Role of Mildly Altered Mental Status
Altered mental status is a major reason for concern in all medical specialties.It manifests as decreased cognitive function and level of awareness, confusion, behavioral changes, lack of alertness, and even coma.The Glasgow coma scores are often used to assess and monitor such types of neurological impairment [39].Sometimes, the nervous system may be the first to show signs of dysfunction, particularly in elderly and immunocompromised patients, leading to a variety of clinical syndromes including sepsis-associated encephalopathy (SAE), seizures, stroke, and neuromuscular disorders [40].
Manifestations of sepsis-associated encephalopathy range from mild delirium to severe coma and are linked to increased long-term physical, mental, and cognitive dysfunction and increased mortality rates [41,42].Reported incidence ranges from 9% to 71% [43][44][45].Although SAE is a reversible syndrome, mild to moderate residual neuropsychiatric symptoms, including depression, anxiety, or cognitive impairment, may persist for up to one year in 40% of patients [46,47].
In the updated definition (sepsis-3), altered mental status expressed as Glasgow coma scores is an important predictor of sepsis.Its relevance has also been acknowledged for the Sequential Organ Failure Assessment (SOFA) score and the Quick SOFA version (qSOFA).These assess the degree of respiratory, renal, cardiovascular, neurological, hepatic, and hematological impairment, and qSOFA is used in the emergency department for faster organ failure scoring, taking into account respiratory rate, hypotension, and the Glasgow coma score [48,49].Higher mortality rates have been reported in patients with GCSs < 15, as well as neurological impairment in 25-33% of patients with sepsis [50,51].
In our study, mildly altered mental status was associated with a substantially higher risk of sepsis (5.866-fold increase), and the multivariate analysis also identified it as a significant predictor alongside typical systemic manifestations of infectious processes (fever, chills, adenopathy).More severely impaired patients would not have been referred from the emergency department to the dermatology unit.Nonetheless, our results suggest that dermatologists can be valuable contributors in cases involving cutaneous-onset sepsis.

Study Limitations and Further Research Opportunities
This study is intended as the first in a series for which our initial focus has been to assess the incidence of cutaneous-onset sepsis and infections in our region.The data hereby reported do not describe treatments and outcomes, which we could not collect in sufficient detail and with sufficient consistency from the type of electronic medical records to which we had access for the purposes of this study.The reported results provide a helpful basis for a prospective study (which we have already initiated) to assess specific biomarkers in patients who present to the emergency department with aggravated lesions.We are also in the process of reviewing diagnostic and therapeutic approaches separately to put forth a pilot algorithm for more prompt and efficient management of cutaneous-onset sepsis.
Readers should also be aware that, regarding the group of patients with uninfected lesions on admission, negative lab samples do not definitively rule out the possibility that these patients' skin lesions had been infected previously.The opposite is suggested by the fact that these patients presented the clinical signs and symptoms typical of the studied conditions, which is why numbers for group C were not zero (e.g., the patient with clear signs of cellulitis but a negative bacteriological exam).It is common for patients to attempt to treat skin conditions at home using traditional antibiotic remedies, over the counter or prescription medication, ointments, etc., not always seeking or complying fully with professional advice from GPs or secondary care providers.This background information was not collected in this study, but it would be worth including it in future studies, whenever feasible.
Last but not least, this study did not and, indeed, could not have enrolled patients presenting in emergency departments with the primary skin lesions of interest as well as other complications or concomitant viral infections for which protocols required transfer to other units.Notably, the study period overlapped with the COVID-19 pandemic, so any patients carrying the SARS-CoV-2 virus were automatically directed to the hospital for infectious diseases.

Conclusions
Three years of admissions data at the largest emergency hospital in NE Romania were retrospectively assessed to establish the incidence of infections and sepsis relating specifically to primary skin lesions featuring loss of tissue.Over five hundred cases of adult patients were analyzed to identify which general characteristics, clinical manifestations, dermatological diagnoses, and established comorbidities were significant risk factors for infection and cutaneous-onset sepsis.
Patients presented ulcerations, erosions, fissures, excoriations, bullae, vesicles, pruritus, tumefaction, edema, fever, chills, pain, and adenopathy.They were diagnosed with venous ulcers, microbial eczema, cellulitis, superinfected bullous dermatoses, erysipelas, erythroderma, and other dermatoses.Of these, cellulitis was the strongest predictor of both infection and sepsis.While S. aureus, P. aeruginosa, and E. coli were the most common bacterial species evidenced in the cultured samples harvested from lesions on admission, K. pneumoniae and S. β-hemolytic were flagged as significant risk factors for infection.Mildly altered mental status was also found to be predictive of sepsis, especially in patients with type 1 diabetes mellitus and/or anemia.In fact, comorbidities were more strongly associated with the risk of infection (chronic heart failure, pre-existing atrial fibrillation) and sepsis (type 1 diabetes mellitus, anemia) than age, sex, or background, even if infections were more common in men and in rural residents.
These results contribute meaningfully to currently scarce research data on cutaneousonset sepsis, indicating which primary skin lesions with loss of tissue can aggravate and become medical emergencies and which patients are most vulnerable.Further research ideas are put forth, including the study of biomarkers for cutaneous-onset sepsis that can be measured quickly and affordably, as well as the development of a pilot algorithm for effective management.

Figure 1 .
Figure 1.Clinical manifestations (skin-related and systemic) in the three study groups.

Figure 1 .
Figure 1.Clinical manifestations (skin-related and systemic) in the three study groups.

Figure 2 .
Figure 2. Comorbidities in the three study groups.

Figure 2 .
Figure 2. Comorbidities in the three study groups.

Table 1 .
Patient age data in the three study groups.

Table 2 .
Demographic characteristics-group A vs. group B.

Table 2 .
Demographic characteristics-group A vs. group B.

Table 3 .
Clinical manifestations in patients with infected lesions (with vs. without sepsis).

Table 4 .
Clinical manifestations in patients with infected vs. non-infected lesions.

Table 5 .
Glasgow scores-patient group A vs. group B.

Table 6 .
Acute skin conditions in patients with vs. without sepsis.

Table 7 .
Acute skin conditions in patients with uncomplicated infections vs. without infection.

Table 8 .
Etiological agents in the infected lesions (with vs. without sepsis).

Table 9 .
Comorbidities in patients with infected lesions-with vs. without sepsis.

Table 9 .
Comorbidities in patients with infected lesions-with vs. without sepsis.

Table 10 .
Comorbidities in patients with infected lesions (without sepsis) vs. non-infected lesions.

Table 11 .
Multivariate analysis of risk factors for infection.

Table 12 .
Risk of infection in the combined presence of individual risk factors.

Table 13 .
Multivariate analysis of risk factors for sepsis.