Risk Stratification for Cellulitis Versus Noncellulitic Conditions of the Lower Extremity: A Retrospective Review of the NEW HAvUN Criteria

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Risk Stratification for Cellulitis Versus Noncellulitic Conditions of the Lower Extremity: A Retrospective Review of the NEW HAvUN Criteria
Author(s)
Harib H. Ezaldein, MD
Abigail Waldman, MD
Karl Grunseich, MD
Karen Jubanyik, MD

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.1 Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Figure1
Figure 1. Cellulitis presenting as an extensive soft-tissue infection of the right leg, with a unilateral, well-demarcated, red, warm plaque.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.2

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.3

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.4 This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.7

Figure2
Figure 2. Lipodermatosclerosis with bilaterally thickened, cobble-stoned plaques with venous ulcers on the medial malleolus.

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.13 Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.14 These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

 

 

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

  • acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
  • erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence4,15
  • pyrexia: body temperature greater than 100.4°F
  • history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
  • tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
  • unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall18
  • leukocytosis: white blood cell count greater than 10.0×109/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ2 analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).



A history of associated trauma had an OR of 36.0 for cellulitis, with 50% (10/20) and 3% (1/37) prevalence in cellulitis cases and noncellulitis cases, respectively (P<.001). Tenderness, documented in 90% (18/20) of cellulitis cases and 43% (16/37) of noncellulitis cases, had an OR of 11.8 (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ2 analysis (Table 3).

 

 

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Figure 3. Clinical criteria score (1 point each for 7 clinical criteria) stratified by final diagnosis of cellulitis or noncellulitis. A score of 4 was a distinct inflection point for either clinical outcome.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

References
  1. Leppard BJ, Seal DV, Colman G, et al. The value of bacteriology and serology in the diagnosis of cellulitis and erysipelas. Br J Dermatol. 1985;112:559-567.
  2. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Int Med. 2004;164:1669-1674.
  3. Bergan JJ, Schmid-Schönbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med. 2006;355:488-498.
  4. Bruce AJ, Bennett DD, Lohse CM, et al. Lipodermatosclerosis: review of cases evaluated at Mayo Clinic. J Am Acad Dermatol. 2002;46:187-192.
  5. Heymann WR. Lipodermatosclerosis. J Am Acad Dermatol. 2009;60:1022-1023.
  6. Vesić S, Vuković J, Medenica LJ, et al. Acute lipodermatosclerosis: an open clinical trial of stanozolol in patients unable to sustain compression therapy. Dermatol Online J. 2008;14:1.
  7. Keller EC, Tomecki KJ, Alraies MC. Distinguishing cellulitis from its mimics. Cleve Clin J Med. 2012;79:547-552.
  8. Dong SL, Kelly KD, Oland RC, et al. ED management of cellulitis: a review of five urban centers. Am J Emerg Med. 2001;19:535-540.
  9. Ellis Simonsen SM, van Orman ER, Hatch BE, et al. Cellulitis incidence in a defined population. Epidemiol Infect. 2006;134:293-299.
  10. Manfredi R, Calza L, Chiodo F. Epidemiology and microbiology of cellulitis and bacterial soft tissue infection during HIV disease: a 10-year survey. J Cutan Pathol. 2002;29:168-172.
  11. Pascarella L, Schonbein GW, Bergan JJ. Microcirculation and venous ulcers: a review. Ann Vasc Surg. 2005;19:921-927.
  12. Hepburn MJ, Dooley DP, Ellis MW. Alternative diagnoses that often mimic cellulitis. Am Fam Physician. 2003;67:2471.
  13. David CV, Chira S, Eells SJ, et al. Diagnostic accuracy in patients admitted to hospitals with cellulitis. Dermatol Online J. 2011;17:1.
  14. Hay RJ, Adriaans BM. Bacterial infections. In: Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. 8th ed. Br J Clin Pharmacol. 2011;71:684-700.
  15. Hay RJ, Adriaans BM. Bacterial infections. In: Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology. 8th ed. Hoboken, NJ: John Wiley & Sons, Inc; 2004:1345-1426.
  16. Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology In General Medicine. 7th ed. New York, NY: McGraw-Hill; 2003.
  17. Sommer LL, Reboli AC, Heymann WR. Bacterial infections. In: Bolognia J, Schaffer J, Cerroni L, et al. Dermatology. Vol 4. Philadelphia, PA: Elsevier Saunders; 2012:1462-1502.
  18. Cox NH. Management of lower leg cellulitis. Clin Med. 2002;2:23-27.
  19. Strazzula L, Cotliar J, Fox LP, et al. Inpatient dermatology consultation aids diagnosis of cellulitis among hospitalized patients: a multi-institutional analysis. J Am Acad Dermatol. 2015;73:70-75.
  20. Pinder R, Sallis A, Berry D, et al. Behaviour change and antibiotic prescribing in healthcare settings: literature review and behavioural analysis. London, UK: Public Health England; February 2015. https://assets.publishing.service.gov.uk/government/
    uploads/system/uploads/attachment_data/file/405031
    /Behaviour_Change_for_Antibiotic_Prescribing_-_FINAL.pdf. Accessed May 7, 2018.
  21. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ. 2013;346:f1493.
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Author and Disclosure Information

From the Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

The authors report no conflict of interest.

Correspondence: Karen Jubanyik, MD, Yale School of Medicine, Department of Emergency Medicine, 464 Congress Ave, Ste 260, New Haven, CT 06519-1315 ([email protected]).

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Author(s)
Harib H. Ezaldein, MD
Abigail Waldman, MD
Karl Grunseich, MD
Karen Jubanyik, MD
Author(s)
Harib H. Ezaldein, MD
Abigail Waldman, MD
Karl Grunseich, MD
Karen Jubanyik, MD
Author and Disclosure Information

From the Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

The authors report no conflict of interest.

Correspondence: Karen Jubanyik, MD, Yale School of Medicine, Department of Emergency Medicine, 464 Congress Ave, Ste 260, New Haven, CT 06519-1315 ([email protected]).

Author and Disclosure Information

From the Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.

The authors report no conflict of interest.

Correspondence: Karen Jubanyik, MD, Yale School of Medicine, Department of Emergency Medicine, 464 Congress Ave, Ste 260, New Haven, CT 06519-1315 ([email protected]).

Article PDF
CT102001008_e.PDF
Article PDF
CT102001008_e.PDF

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.1 Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Figure1
Figure 1. Cellulitis presenting as an extensive soft-tissue infection of the right leg, with a unilateral, well-demarcated, red, warm plaque.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.2

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.3

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.4 This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.7

Figure2
Figure 2. Lipodermatosclerosis with bilaterally thickened, cobble-stoned plaques with venous ulcers on the medial malleolus.

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.13 Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.14 These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

 

 

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

  • acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
  • erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence4,15
  • pyrexia: body temperature greater than 100.4°F
  • history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
  • tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
  • unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall18
  • leukocytosis: white blood cell count greater than 10.0×109/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ2 analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).



A history of associated trauma had an OR of 36.0 for cellulitis, with 50% (10/20) and 3% (1/37) prevalence in cellulitis cases and noncellulitis cases, respectively (P<.001). Tenderness, documented in 90% (18/20) of cellulitis cases and 43% (16/37) of noncellulitis cases, had an OR of 11.8 (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ2 analysis (Table 3).

 

 

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Figure 3. Clinical criteria score (1 point each for 7 clinical criteria) stratified by final diagnosis of cellulitis or noncellulitis. A score of 4 was a distinct inflection point for either clinical outcome.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

Cellulitis is defined as an acute or subacute, bacterial-induced inflammation of subcutaneous tissue that can extend superficially. The inciting incident often is assumed to be invasion of bacteria through loose connective tissue.1 Although cellulitis is bacterial in origin, it often is difficult to culture the offending microorganism from biopsy sites, swabs, or blood. Erythema, fever, induration, and tenderness are largely seen as clinical manifestations. Moderate and severe cases may be accompanied by fever, malaise, and leukocytosis. The lower extremity is the most common location of involvement (Figure 1), and usually a wound, ulcer, or interdigital superficial infection can be identified and implicated as the source of entry.

Figure1
Figure 1. Cellulitis presenting as an extensive soft-tissue infection of the right leg, with a unilateral, well-demarcated, red, warm plaque.

Effective treatment of cellulitis is necessary because complications such as abscesses, underlying fascia or muscle involvement, and septicemia can develop, leading to poor outcomes. Antibiotics should be administered intravenously in patients with suspected fascial involvement, septicemia, or dermal necrosis, or in those with an immunological comorbidity.2

The differential diagnosis of lower extremity cellulitis is wide due to the existence of several mimicking dermatologic conditions. These so-called pseudocellulitis conditions include stasis dermatitis, venous ulceration, acute lipodermatosclerosis, pigmented purpura, vasculopathy, contact dermatitis, adverse medication reaction, and arthropod bite. Stasis dermatitis and lipodermatosclerosis, both arising from venous insufficiency, are by far 2 of the most common skin conditions that imitate cellulitis.

Stasis dermatitis is a common condition in the United States and Europe, usually manifesting as a pigmented purpuric dermatosis on anterior tibial surfaces, around the ankle, or overlying dependent varicosities. Skin changes can include hyperpigmentation, edema, mild scaling, eczematous patches, and even ulceration.3

Lipodermatosclerosis is a disorder of progressive fibrosis of subcutaneous fat. It is more common in middle-aged women who have a high body mass index and a venous abnormality.4 This form of panniculitis typically affects the lower extremities bilaterally, manifesting as erythematous and indurated skin changes, sometimes described as inverted champagne bottles (Figure 2). At times, there can be accompanying painful ulceration on the erythematous areas, features that closely resemble cellulitis.5,6 Lipodermatosclerosis is commonly misdiagnosed as cellulitis, leading to inappropriate prescription of antibiotics.7

Figure2
Figure 2. Lipodermatosclerosis with bilaterally thickened, cobble-stoned plaques with venous ulcers on the medial malleolus.

Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting. With a reported incidence of 24.6 per 100 person-years, cellulitis constitutes 1% to 14% of emergency department visits and 4% to 7% of hospital admissions.Therefore, prompt appropriate diagnosis and treatment can avoid life-threatening complications associated with infection such as sepsis, abscess, lymphangitis, and necrotizing fasciitis.8-11

It is estimated that 10% to 20% of patients who have been given a diagnosis of cellulitis do not actually have the disease.2,12 This discrepancy consumes a remarkable amount of hospital resources and can lead to inappropriate or excessive use of antibiotics.13 Although the true incidence of adverse antibiotic reactions is unknown, it is estimated that they are the cause of 3% to 6% of acute hospital admissions and occur in 10% to 15% of inpatients admitted for other primary reasons.14 These findings illustrate the potential for an increased risk for morbidity and increased length of stay for patients beginning an antibiotic regimen, especially when the agents are administered unnecessarily. In addition, inappropriate antibiotic use contributes to antibiotic resistance, which continues to be a major problem, especially in hospitalized patients.

There is a lack of consensus in the literature about methods to risk stratify patients who present with acute dermatologic conditions that include and resemble cellulitis. We sought to identify clinical features based on available clinical literature-derived variables. We tested our scheme in a series of patients with a known diagnosis of cellulitis or other dermatologic pathology of the lower extremity to assess the validity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.

 

 

Materials and Methods

This retrospective chart review was approved by the Yale University (New Haven, Connecticut) institutional review board (HIC#1409014533). Final diagnosis, demographic data, clinical manifestations, and relevant diagnostic laboratory values of 57 patients were obtained from a database in the dermatology department’s consultation log and electronic medical record database (December 2011 to December 2014). The presence of each clinical symptom—acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis—was assigned a score equal to 1; values were tallied to achieve a final score for each patient (Table 1). Patients who were seen initially as a consultation for possible cellulitis but given a final diagnosis of stasis dermatitis or lipodermatosclerosis were included (Table 2).

Clinical Criteria
The clinical criteria were developed based largely on clinical experience and relevant secondary literature.15-17 At the patient encounter, presence of each of the variables (Table 1) was assessed according to the following definitions:

  • acute onset: within the prior 72 hours and more indicative of an acute infective process than a gradual and chronic consequence of venous stasis
  • erythema: a subjective clinical marker for inflammation that can be associated with cellulitis, though darker, erythematous-appearing discolorations also can be seen in patients with chronic venous hypertension or valvular incompetence4,15
  • pyrexia: body temperature greater than 100.4°F
  • history of associated trauma: encompassing mechanical wounds, surgical incisions, burns, and insect bites that correlate closely to the time course of symptomatic development
  • tenderness: tenderness to light touch, which may be more common in patients afflicted with cellulitis than in those with venous insufficiency
  • unilaterality: a helpful distinguishing feature that points the diagnosis away from a dermatitislike clinical picture, especially because bilateral cellulitis is rare and regarded as a diagnostic pitfall18
  • leukocytosis: white blood cell count greater than 10.0×109/L and is reasonably considered a cardinal metric of inflammatory processes, though it can be confounded by immunocompromise (low count) or steroid use (high count)

Statistical Analysis
Odds ratios (ORs) were calculated and χ2 analysis was performed for each presenting symptom using JMP 10.0 analytical software (SAS Institute Inc). Each patient was rated separately by means of the clinical feature–based scoring system for the calculation of a total score. After application of the score to the patient population, receiver operating characteristic curves were constructed to identify the optimal score threshold for discriminating cellulitis from dermatitis in this group. For each clinical feature, P<.05 was considered significant.

Results

Our cohort included 32 male and 25 female patients with a mean age of 63 and 61 years, respectively. The final clinical diagnosis of cellulitis was made in 20 patients (35%). An established diagnosis of cellulitis was assigned based on a dermatology evaluation located within our electronic medical record database (Table 2).

Each clinical parameter was evaluated separately for each patient; combined results are summarized in Table 3. Acute onset (≤3 days) was a clinical characteristic seen in 80% (16/20) of cellulitis cases and 22% (8/37) of noncellulitis cases (OR, 14.5; P<.001). Erythema had similar significance (OR, 10.3; prevalence, 95% [19/20] vs 65% [24/37]; P=.012). Pyrexia possessed an OR of 99.2 for cellulitis and was seen in 85% (17/20) of cellulitis cases and only 5% (2/37) of noncellulitis cases (P<.001).



A history of associated trauma had an OR of 36.0 for cellulitis, with 50% (10/20) and 3% (1/37) prevalence in cellulitis cases and noncellulitis cases, respectively (P<.001). Tenderness, documented in 90% (18/20) of cellulitis cases and 43% (16/37) of noncellulitis cases, had an OR of 11.8 (P<.001).

Unilaterality had 100% (20/20) prevalence in our cellulitis cohort and was the only characteristic within the algorithm that yielded an incalculable OR. Noncellulitis or stasis dermatitis of the lower extremity exhibited a unilateral lesion in 11 cases (30%), of which 1 case resulted from a unilateral tibial fracture. Leukocytosis was seen in 65% (13/20) of cellulitis cases and 8% (3/37) of noncellulitis cases, with an OR for cellulitis of 21.0 (P<.001).

All parameters were significant by χ2 analysis (Table 3).

 

 

Comment

We found that testing positive for 4 of 7 clinical criteria for assessing cellulitis was highly specific (95%) and sensitive (100%) for a diagnosis of cellulitis among its range of mimics (Figure 3). These cellulitis criteria can be remembered, with some modification, using NEW HAvUN as a mnemonic device (New onset, Erythema, Warmth, History of associated trauma, Ache, Unilaterality, and Number of white blood cells). This aid to memory could prove a valuable tool in the efficient evaluation of a patient in an emergency, inpatient, or outpatient medical setting.

Figure 3. Clinical criteria score (1 point each for 7 clinical criteria) stratified by final diagnosis of cellulitis or noncellulitis. A score of 4 was a distinct inflection point for either clinical outcome.

Consistent with the literature, pyrexia, history of associated trauma, and unilaterality also were predictors of cellulitis diagnosis. Unilaterality often is used as a diagnostic tool by dermatologist consultants when a patient lacks other criteria for cellulitis, so these findings are intuitive and consistent with our institutional experience. Interestingly, leukocytosis was seen in only 65% of cellulitis cases and 8% of noncellulitis cases and therefore might not serve as a sensitive independent predictor of a diagnosis of cellulitis, emphasizing the importance of the multifactorial scoring system we have put forward. Additionally, acuity of onset, erythema, and tenderness are not independently associated with cellulitis when assessing a patient because several of those findings are present in other dermatologic conditions of the lower extremity; when combined with the other criteria, however, these 3 findings can play a role in diagnosis.

Effective cellulitis diagnosis provides well-recognized challenges in the acute medical setting because many clinical mimics exist. The estimated rate of misdiagnosed cellulitis is certainly well-established: 30% to 75% in independent and multi-institutional studies. These studies also revealed that patients admitted for bilateral “cellulitis” overwhelmingly tended to be stasis clinical pictures.13,19

Cost implications from inappropriate diagnosis largely regard inappropriate antibiotic use and the potential for microbial resistance, with associated costs estimated to be more than $50 billion (2004 dollars).20,21 The true cost burden is extremely difficult to model or predict due to remarkable variations in the institutional misdiagnosis rate, prescribing pattern, and antibiotic cost and could represent avenues of further study. Misappropriation of antibiotics includes not only a monetary cost that encompasses all aspects of acute treatment and hospitalization but also an unquantifiable cost: human lives associated with the consequences of antibiotic resistance.

Conclusion

There is a lack of consensus or criteria for differentiating cellulitis from its most common clinical counterparts. Here, we propose a convenient clinical correlation system that we hope will lead to more efficient allocation of clinical resources, including antibiotics and hospital admissions, while lowering the incidence of adverse events and leading to better patient outcomes. We recognize that the small sample size of our study may limit broad application of these criteria, though we anticipate that further prospective studies can improve the diagnostic relevance and risk-assessment power of the NEW HAvUN criteria put forth here for assessing cellulitis in the acute medical setting.

Acknowledgement—Author H.H.E. recognizes the loving memory of Nadia Ezaldein for her profound influence on and motivation behind this research.

References
  1. Leppard BJ, Seal DV, Colman G, et al. The value of bacteriology and serology in the diagnosis of cellulitis and erysipelas. Br J Dermatol. 1985;112:559-567.
  2. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Int Med. 2004;164:1669-1674.
  3. Bergan JJ, Schmid-Schönbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med. 2006;355:488-498.
  4. Bruce AJ, Bennett DD, Lohse CM, et al. Lipodermatosclerosis: review of cases evaluated at Mayo Clinic. J Am Acad Dermatol. 2002;46:187-192.
  5. Heymann WR. Lipodermatosclerosis. J Am Acad Dermatol. 2009;60:1022-1023.
  6. Vesić S, Vuković J, Medenica LJ, et al. Acute lipodermatosclerosis: an open clinical trial of stanozolol in patients unable to sustain compression therapy. Dermatol Online J. 2008;14:1.
  7. Keller EC, Tomecki KJ, Alraies MC. Distinguishing cellulitis from its mimics. Cleve Clin J Med. 2012;79:547-552.
  8. Dong SL, Kelly KD, Oland RC, et al. ED management of cellulitis: a review of five urban centers. Am J Emerg Med. 2001;19:535-540.
  9. Ellis Simonsen SM, van Orman ER, Hatch BE, et al. Cellulitis incidence in a defined population. Epidemiol Infect. 2006;134:293-299.
  10. Manfredi R, Calza L, Chiodo F. Epidemiology and microbiology of cellulitis and bacterial soft tissue infection during HIV disease: a 10-year survey. J Cutan Pathol. 2002;29:168-172.
  11. Pascarella L, Schonbein GW, Bergan JJ. Microcirculation and venous ulcers: a review. Ann Vasc Surg. 2005;19:921-927.
  12. Hepburn MJ, Dooley DP, Ellis MW. Alternative diagnoses that often mimic cellulitis. Am Fam Physician. 2003;67:2471.
  13. David CV, Chira S, Eells SJ, et al. Diagnostic accuracy in patients admitted to hospitals with cellulitis. Dermatol Online J. 2011;17:1.
  14. Hay RJ, Adriaans BM. Bacterial infections. In: Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. 8th ed. Br J Clin Pharmacol. 2011;71:684-700.
  15. Hay RJ, Adriaans BM. Bacterial infections. In: Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology. 8th ed. Hoboken, NJ: John Wiley & Sons, Inc; 2004:1345-1426.
  16. Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology In General Medicine. 7th ed. New York, NY: McGraw-Hill; 2003.
  17. Sommer LL, Reboli AC, Heymann WR. Bacterial infections. In: Bolognia J, Schaffer J, Cerroni L, et al. Dermatology. Vol 4. Philadelphia, PA: Elsevier Saunders; 2012:1462-1502.
  18. Cox NH. Management of lower leg cellulitis. Clin Med. 2002;2:23-27.
  19. Strazzula L, Cotliar J, Fox LP, et al. Inpatient dermatology consultation aids diagnosis of cellulitis among hospitalized patients: a multi-institutional analysis. J Am Acad Dermatol. 2015;73:70-75.
  20. Pinder R, Sallis A, Berry D, et al. Behaviour change and antibiotic prescribing in healthcare settings: literature review and behavioural analysis. London, UK: Public Health England; February 2015. https://assets.publishing.service.gov.uk/government/
    uploads/system/uploads/attachment_data/file/405031
    /Behaviour_Change_for_Antibiotic_Prescribing_-_FINAL.pdf. Accessed May 7, 2018.
  21. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ. 2013;346:f1493.
References
  1. Leppard BJ, Seal DV, Colman G, et al. The value of bacteriology and serology in the diagnosis of cellulitis and erysipelas. Br J Dermatol. 1985;112:559-567.
  2. Hepburn MJ, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Int Med. 2004;164:1669-1674.
  3. Bergan JJ, Schmid-Schönbein GW, Smith PD, et al. Chronic venous disease. N Engl J Med. 2006;355:488-498.
  4. Bruce AJ, Bennett DD, Lohse CM, et al. Lipodermatosclerosis: review of cases evaluated at Mayo Clinic. J Am Acad Dermatol. 2002;46:187-192.
  5. Heymann WR. Lipodermatosclerosis. J Am Acad Dermatol. 2009;60:1022-1023.
  6. Vesić S, Vuković J, Medenica LJ, et al. Acute lipodermatosclerosis: an open clinical trial of stanozolol in patients unable to sustain compression therapy. Dermatol Online J. 2008;14:1.
  7. Keller EC, Tomecki KJ, Alraies MC. Distinguishing cellulitis from its mimics. Cleve Clin J Med. 2012;79:547-552.
  8. Dong SL, Kelly KD, Oland RC, et al. ED management of cellulitis: a review of five urban centers. Am J Emerg Med. 2001;19:535-540.
  9. Ellis Simonsen SM, van Orman ER, Hatch BE, et al. Cellulitis incidence in a defined population. Epidemiol Infect. 2006;134:293-299.
  10. Manfredi R, Calza L, Chiodo F. Epidemiology and microbiology of cellulitis and bacterial soft tissue infection during HIV disease: a 10-year survey. J Cutan Pathol. 2002;29:168-172.
  11. Pascarella L, Schonbein GW, Bergan JJ. Microcirculation and venous ulcers: a review. Ann Vasc Surg. 2005;19:921-927.
  12. Hepburn MJ, Dooley DP, Ellis MW. Alternative diagnoses that often mimic cellulitis. Am Fam Physician. 2003;67:2471.
  13. David CV, Chira S, Eells SJ, et al. Diagnostic accuracy in patients admitted to hospitals with cellulitis. Dermatol Online J. 2011;17:1.
  14. Hay RJ, Adriaans BM. Bacterial infections. In: Thong BY, Tan TC. Epidemiology and risk factors for drug allergy. 8th ed. Br J Clin Pharmacol. 2011;71:684-700.
  15. Hay RJ, Adriaans BM. Bacterial infections. In: Burns T, Breathnach S, Cox N, et al. Rook’s Textbook of Dermatology. 8th ed. Hoboken, NJ: John Wiley & Sons, Inc; 2004:1345-1426.
  16. Wolff K, Goldsmith LA, Katz SI, et al. Fitzpatrick’s Dermatology In General Medicine. 7th ed. New York, NY: McGraw-Hill; 2003.
  17. Sommer LL, Reboli AC, Heymann WR. Bacterial infections. In: Bolognia J, Schaffer J, Cerroni L, et al. Dermatology. Vol 4. Philadelphia, PA: Elsevier Saunders; 2012:1462-1502.
  18. Cox NH. Management of lower leg cellulitis. Clin Med. 2002;2:23-27.
  19. Strazzula L, Cotliar J, Fox LP, et al. Inpatient dermatology consultation aids diagnosis of cellulitis among hospitalized patients: a multi-institutional analysis. J Am Acad Dermatol. 2015;73:70-75.
  20. Pinder R, Sallis A, Berry D, et al. Behaviour change and antibiotic prescribing in healthcare settings: literature review and behavioural analysis. London, UK: Public Health England; February 2015. https://assets.publishing.service.gov.uk/government/
    uploads/system/uploads/attachment_data/file/405031
    /Behaviour_Change_for_Antibiotic_Prescribing_-_FINAL.pdf. Accessed May 7, 2018.
  21. Smith R, Coast J. The true cost of antimicrobial resistance. BMJ. 2013;346:f1493.
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Risk Stratification for Cellulitis Versus Noncellulitic Conditions of the Lower Extremity: A Retrospective Review of the NEW HAvUN Criteria
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Practice Points

  • Distinguishing cellulitis from noncellulitic conditions of the lower extremity is paramount to effective patient management in the emergent setting, given that misdiagnosis consumes hospital resources and can lead to inappropriate or excessive use of antibiotics.  
  • We evaluated the specificity and sensitivity of the following 7 clinical criteria: acute onset, erythema, pyrexia, history of associated trauma, tenderness, unilaterality, and leukocytosis.
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