Clinical Mimics: An Emergency Medicine-Focused Review of Cellulitis Mimics

The Journal of Emergency Medicine, Vol. 53, No. 4, pp. 475–484, 2017 Published by Elsevier Inc. 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2017.06.002

Clinical Review CLINICAL MIMICS: AN EMERGENCY MEDICINE-FOCUSED REVIEW OF CELLULITIS MIMICS Garrett Blumberg, MD,* Brit Long, MD,† and Alex Koyfman, MD* *Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas and †Department of Emergency Medicine, San Antonio Military Medical Center, Fort Sam Houston, Texas Reprint Address: Brit Long, MD, Department of Emergency Medicine, San Antonio Military Medical Center, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234

, Abstract—Background: Cellulitis is a common clinical condition with low rates of morbidity and mortality if treated appropriately. Mimics of cellulitis presenting with erythema, edema, warmth, and pain can be associated with grave morbidity and mortality if misdiagnosed. Objective: This review investigates the signs and symptoms of cellulitis, mimics of cellulitis, and an approach to the management of both cellulitis and its mimics. Discussion: The current emergency medicine definition of cellulitis includes erythema, induration, warmth, and swelling. Given the common pathophysiologic pathways, cellulitis mimics often present in an analogous manner. These conditions include septic bursitis, septic joint, deep vein thrombosis, phlegmasia cerulea dolens, necrotizing fasciitis, flexor tenosynovitis, fight bite (closed fist injury), orbital cellulitis, toxic shock syndrome, erysipelas, abscess, felon, paronychia, and gouty arthritis. Many of these diseases have high morbidity and mortality if missed by the emergency physician. Differentiating these mimics from cellulitis can be difficult in the fast-paced emergency setting. A combination of history, physical examination, and focused diagnostic assessment may assist in correctly identifying the underlying etiology. For many of the high mortality cellulitis mimics, surgical intervention is necessary. Conclusion: Cellulitis and its mimics present similarly due to the same physiologic responses to skin and soft tissue infections. A combination of

history, physical examination, and diagnostic assessment will help the emergency physician differentiate cellulitis from mimics. Surgical intervention is frequently needed for high morbidity and mortality mimics. Published by Elsevier Inc. , Keywords—mimics; cellulitis; septic bursitis; septic joint; deep vein thrombosis; phlegmasia cerulea dolens; necrotizing fasciitis; flexor tenosynovitis; fight bite; orbital cellulitis; toxic shock syndrome; erysipelas; abscess; felon; paronychia; gout

INTRODUCTION Cellulitis is a common condition managed in the emergency department (ED), with 2.3 million ED visits annually in the United States (1). The rate of admission has been steadily increasing by 73% from 1997 to 2011, with 330,000 admissions in 1997 to 652,000 admissions in 2011 (2,3). Patients with cellulitis commonly present with nonspecific physical examination findings of inflammation including erythema (rubor), edema (tumor), warmth (calor), and pain (dolor) that develop over days (3–6). However, of the 652,000 patients admitted to the hospital every year, approximately 30% are misdiagnosed by emergency physicians (1,3,7,8). There are several definitions of cellulitis, often leading to confusion (Table 1). Per the Infectious Diseases Society of America (IDSA) 2014 guidelines on skin and soft

This review does not reflect the views or opinions of the U.S. government, Department of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

RECEIVED: 25 May 2017; ACCEPTED: 2 June 2017 475

476

G. Blumberg et al.

tissue infections, cellulitis ‘‘refer[s] to diffuse, superficial spreading skin infection . [the definition of cellulitis] is not appropriate for cutaneous inflammation associated with collections of pus such as septic bursitis, furuncles, or skin abscesses (6).’’ Classic signs of cellulitis include rubor, tumor, calor, and dolor. However, these findings were initially used to describe inflammation (9). Additional physical examination findings may include edematous skin. This may result in peau d’orange, which is skin resembling an orange peel. Painful regional lymphadenopathy may also be noted (3). Cellulitis is nearly always unilateral (10). Bilateral cellulitis is unusual, as are chronic findings lasting over several months, or pruritus (10). These findings suggest another condition. Laboratory findings may include elevated white blood cell count in 34–50%, elevated erythrocyte sedimentation rate in 59–91%, and elevated C-reactive protein in 77–97% (3,11,12). Blood cultures are low yield and not recommended, except in patients who are immunocompromised, neutropenic, and seriously ill (including septic shock) (6). These physical examination and laboratory findings are highly nonspecific and are often present with cellulitis mimics. These nonspecific findings account for why many patients are misdiagnosed and fail outpatient treatment of cellulitis. Fortunately, many of the cellulitis mimics are benign if missed: venous stasis, lymphedema, gout, paronychia, and contact dermatitis (3). Although nonemergent cellulitis mimics have been discussed in the literature, there is a lack of focus on emergent diagnoses (3). This article seeks to illustrate diagnoses that emergency physician should not miss when considering cellulitis on the differential diagnosis.

METHODS Authors conducted a literature search of Medline, EBSCO, and Google Scholar for search terms including mimics, cellulitis, septic bursitis, septic joint, deep vein thrombosis, phlegmasia cerulea dolens, necrotizing fasciitis, flexor tenosynovitis, fight bite, orbital cellulitis, toxic shock syndrome, erysipelas, abscess, felon, paronychia, and gouty arthritis. Guidelines on cellulitis were included. Articles in English were included. Authors agreed on articles to include by consensus. DISCUSSION Why Does Erythema, Induration, Warmth, and Swelling Occur in Cellulitis? Cellulitis is characterized by erythema, warmth, edema, and pain due to the underlying pathophysiology. A nidus of inflammation, such as bacteria penetrating through the skin, triggers immune system response. Histamine, prostaglandins, and bradykinins are released into the soft tissue, causing vasodilation with subsequent erythema and warmth. Histamine also acts on endothelial cells, resulting in leakage of plasma into the interstitium and tissue space, leading to edema (9). Increased pain at the site of cellulitis is due to sensitization of sensory nerve endings by bradykinin and prostaglandin E2 (PGE2). Lastly, systemic symptoms such as fever can occur due to the release of interleukin-1 and tumor necrosis factor from macrophages. Release of these cytokines stimulates cyclooxygenase activity and the release of PGE2. Elevated levels of PGE2 act on the hypothalamus to increase the set point temperature of the body, resulting in fever (15).

Table 1. Definitions of Cellulitis from Various Sources Society IDSA 2014 Journal of the American Academy of Dermatology Tintinalli’s Emergency Medicine: A Comprehensive Study Guide

Rosen’s Emergency Medicine Concepts and Clinical Practice (13)

Harrison’s Principles of Internal Medicine (14) IDSA = Infectious Diseases Society of America.

Definition Diffuse, superficial spreading skin infection. The cellulitis definition is not appropriate for cutaneous inflammation associated with collections of pus such as septic bursitis, furuncles, or skin abscesses (6). Clinicians should use the term ‘‘cellulitis’’ for superficial spreading skin infections without an underlying collection of pus (4). Cellulitis is an infection of the dermis and subcutaneous tissues of the skin. Cellulitis is divided clinically as purulent or nonpurulent, and management of the two types is different. Purulent cellulitis is cellulitis with an abscess, or cellulitis with drainage or exudate in the absence of a drainable abscess. Nonpurulent cellulitis has no purulent drainage or exudate and no associated abscess (5). Cellulitis is an infection of the skin tissue denoted by erythema, swelling, and local tenderness. Unfortunately, the literature on soft tissue infections is often confusing with respect to definition and therapy, in part because the nomenclature has been based on individual names, anatomic areas, or events (e.g., postsurgical gangrene). Cellulitis is an acute inflammatory condition of the skin that is characterized by localized pain, erythema, swelling, and heat.

An Emergency Medicine-Focused Review of Cellulitis Mimics

Cellulitis Risk Factors A warm and damp environment provides an optimal site for bacterial growth, and one of the most common sites includes the interdigital spaces between lowerextremity digits. Organisms require only a small break in the skin to gain access to the subcutaneous tissue. Interdigital intertrigo is a significant risk factor for lower-limb cellulitis, with an odds ratio of 5.35 (95% confidence interval 2.73–14.63) (16). Cellulitis located in the lower extremity is often caused by Streptococcus, a frequent colonizer of the interdigital toe spaces, though Staphylococcus is another common organism (4). Additionally, when venous or lymphatic drainage is obstructed, bacteria are better able to cause infection. Venous and lymphatic drainage, when working properly, act to clear microbes that have breached the skin. When these systems that normally remove lymph and interstitial fluid are obstructed, bacteria collect and continue to spread through local superficial tissue. As a result, venous insufficiency and lymphedema are two major risk factors for lower-extremity cellulitis (10). In diseases that lead to swelling of the skin, microtears serve as entry portals for bacteria. Obesity is thought to be a risk factor for cellulitis due to the compression of the lymphatic flow by excess adipose tissue (16). Common bacterial infectious causes include Staphylococcus aureus, Streptococcus species, anaerobes, and polymicrobial infection. Risk factors as stated include obstructed drainage return (venous insufficiency, saphenous venectomy in coronary artery bypass), breaks in the skin (trauma, ulceration, edema), inflammatory disease involving the skin (allergic contact dermatitis, atopic dermatitis, venous eczema), older age, edema, and obesity (Table 2). However, alcohol intake and smoking are not associated with increased risk of acute cellulitis (10,12,16–18). Cellulitis Management (6) The 2014 IDSA guidelines divide skin and soft tissue infections into nonpurulent and purulent infections. Cellulitis is a form of nonpurulent skin infection and does not include abscesses, carbuncles, and furuncles. Cellulitis is further divided into categories by severity: mild, moderate, and severe (Table 3). Mild cellulitis includes typical cellulitis without systemic signs (defined as temperature > 38 C, heart rate > 90 beats/min, respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg, and white blood cells < 4000 or > 12,000 or > 10% band forms) (6). For these patients, antibiotics should cover Streptococci species. These antibiotics include oral penicillin, cephalosporin, dicloxacillin, or clindamycin. However, if a patient has systemic signs of infection as defined

477

above, then intravenous antibiotics should be administered covering methicillin-susceptible S. aureus and Streptococci species: intravenous penicillin, ceftriaxone, cefazolin, or clindamycin. Severe cellulitis occurs if the patient has a history of trauma, intravenous drug use, nasal colonization with methicillin-resistant S. aureus (MRSA), concurrent MRSA infection, hypotension, immunosuppression (malignancy on chemotherapy, neutropenia, severe cell-mediated immunodeficiency), immersion injuries, or animal bites. If severe cellulitis is diagnosed, physicians should consider necrotizing skin infections and provide empiric antibiotics such as vancomycin and piperacillin/tazobactam with clindamycin. Given that these patients are high risk and have a severe form of cellulitis, MRSA and Streptococci species should be covered. Alternative antibiotics include imipenem or meropenem. Treatment duration for 5 days is usually sufficient, but may continue out to 10 days if the cellulitis is not improved. Nonsteroidal anti-inflammatory agents or systemic corticosteroids have been shown to improve clinical symptoms of cellulitis when compared with antimicrobials alone (14). However, at this time, regular use of corticosteroids for cellulitis requires further study. If steroids are to be given, physicians should evaluate for deeper soft tissue infection such as a necrotizing infection. The IDSA recommends against routine blood cultures for patients with cellulitis. However, blood cultures are recommended for populations with unusual circumstances (malignancy with chemotherapy, neutropenia, severe cell-mediated immunodeficiency, immersion injuries, and animal bites), as well as septic shock. Additional general recommendations include elevating the affected area to improve swelling. If the patient has lower-extremity cellulitis, the IDSA advises a thorough interdigital toe space examination to diagnose and treat any fissuring, scaling, or maceration, as this is the likely source of the patient’s lower-extremity cellulitis (6). Along these lines, it is prudent to treat any underlying predisposing factors such as edema and cutaneous disorders. Patients can be safely managed as outpatient cellulitis if they do not meet systemic inflammatory response syndrome (SIRS) criteria, do not have altered mental status, and have normal vital signs. Patients who improve with resuscitation including antibiotics and intravenous fluids Table 2. Lower Extremity Cellulitis Risk Factors (10,16) Risk Factors

Odds Ratio (95% Confidence Interval)

Lymphedema Leg ulcer Overweight Saphenectomy Toe web intertrigo Venous insufficiency Varicose veins

71.2 (5.6–908) (10) 5.44 (2.14–1.84) (16) 2.0 (1.1–3.7) (10) 10.50 (3.60–30.59) (16) 5.35 (2.73–14.63) (16) 2.9 (1.0–8.7) (10) 1.04 (0.55–1.95) (16)

478

G. Blumberg et al.

Table 3. Nonpurulent Cellulitis Categories (6) Severity

Findings

Bacteria

Mild

Typical cellulitis No risk factors No systemic symptoms*

Streptococci

Moderate

Typical cellulitis No risk factors Systemic symptoms

Streptococci MSSA

Severe

Risk Factors – penetrating trauma – evidence of MRSA infection elsewhere – nasal colonization with MRSA – injection drug use, Hypotension Signs of necrotic infection Fail outpatient treatment Deeper signs of infection

Streptococci MRSA Gram Negative Anaerobes

Treatment Oral – Penicillin – Dicloxacillin – Cephalosporins – Clindamycin Intravenous – Penicillin – Ceftriaxone – Cefazolin – Clindamycin Intravenous – Vancomycin – Piperacillin/Tazobactam Early surgical consultation if concern for necrotizing infection.

General treatment: – Raise affected extremity – Antibiotic duration 5 days. Continue to 10 days if not improving. – Lower extremity cellulitis = check interdigital toe space and treat if abnormal MSSA = methicillin-susceptible Staphylococcus aureus; MRSA = methicillin-resistant Staphylococcus aureus. Adapted from (6). * Systemic symptoms include: temperature > 38 C, tachycardia (heart rate > 90 beats/min), tachypnea (respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg).

are appropriate for discharge if the patient is reliable and has adequate follow-up. Hospitalization is encouraged for patients who have severe cellulitis or if there is suspicion of necrotizing infection. Other indications for admission include failure of outpatient therapy, severe immunocompromised state, and medical noncompliance. Cellulitis Mimics Cellulitis mimics are commonly misdiagnosed as cellulitis, with up to 30% of patients misdiagnosed with cellulitis and 92% of patients receiving unnecessary antibiotics (1). These diseases produce erythema, warmth, edema, and pain, which make them difficult to differentiate. Mimics include septic bursitis, septic arthritis, deep vein thrombosis/phlegmasia cerulea dolens, necrotizing fasciitis, flexor tenosynovitis, fight bite, orbital cellulitis, and toxic shock syndrome. Less emergent diagnoses include erysipelas, abscess, felon, paronychia, and gouty arthritis. Cellulitis mimics are shown in Table 4 with diagnosis and treatment pearls (4–6,19–42). ED Approach Cellulitis is a frequent diagnosis in the ED. However, the emergency physician must be able to diagnose and manage severe, life-threatening mimics of cellulitis. With the significant overlap in clinical presentation,

cellulitis and its mimics may be challenging to differentiate. Several considerations are important in the ED: 1. Resuscitation: Not all patients with skin and soft tissue infections will require resuscitation. Resuscitation is indicated for patients who present with sepsis as defined by meeting two of four SIRS criteria with confirmed or suspected source of infection such as a skin and soft tissue infection. Intravenous fluids and early antibiotics should be provided, with vasopressors for those who do not respond to fluid rehydration. Although cellulitis can lead to sepsis, emergency physicians must remain vigilant for emergent cellulitis mimics. 2. After resuscitation, a focused history and physical examination to evaluate for other possible causes of skin and soft tissue infection is recommended. If the patient is nontoxic and hemodynamically stable, the physician can begin with the history and physical examination. a. History: The duration of symptoms and mechanism of injury should be discussed. Duration of symptoms is important to consider as cellulitis begins over 2–3 days and typically will resolve within 24–48 h after initiating antibiotics. Many cellulitis mimics are diagnosed after failed treatment with antibiotics. Patients with symptoms over weeks to months or with pruritus are unlikely to have cellulitis. Additionally, the mechanism of

Clinical Condition

Diagnosis

Abscess

– – – –

Deep vein thrombosis

– 25% present with tenderness and erythema in swollen extremity. – Homan’s sign is neither sensitive nor specific and should not be used in clinical practice to rule in or rule out diagnosis. Likelihood ratios of positive Features (19): – Calf swelling 1.45 (95% CI 1.25–1.69) – Difference in calf size 1.8 (95% CI 1.5–2.2) – DVT history 2.25 (95% CI 1.57–3.23) – Malignant disease 2.71 (95% CI 2.16–3.39) – Recent immobilization 1.98 (95% CI 1.70–2.30) Likelihood ratios of negative features: – Calf swelling 0.67 (95% CI 0.58-0.78). – Difference in calf diameters 0.57 (95% CI 0.44-0.72). – Ultrasound is 95% sensitive and specific. – D-dimer is sensitive to rule out DVT in low-risk patients based on Wells Criteria. – Negative ultrasound in moderate to high-risk per Wells Criteria require follow-up ultrasound in 5-7 days. – Form of cellulitis that presents with a well-demarcated border. – Located anywhere on the body, but most commonly the face and legs. – Infections most commonly due to Staphylococcus aureus and Streptococcus species. – Diagnosis by defined boarder of erythema noted on physical examination. – Infection of the pulp of the fingertip. – Painful swollen, tense, erythematous distal fingertip. – Mechanism of inoculation indicates what bacteria should be suspected. – Commonly due to MRSA, Streptococcus pyogenes, anaerobes, or polymicrobial bacteria.

Erysipelas

Felon

Fight bite (5)

Collection of pus within the dermis and deeper skin tissue. Walled off infection. Painful, tender, fluctuant red nodule with rim of erythema and swelling. Ultrasound will reveal well-defined pocket of fluid.

– Injury to 3rd, 4th, or 5th metacarpophalangeal joint after the patient has hit opponent in the teeth during an altercation. – Inoculation of the joint space with bacteria. – Polymicrobial: Staphylococcus, Streptococcus species, Eikenella corrodens, Fusobacterium, Peptostreptococcus, and Candida. – Obtain radiographs to rule out fracture and foreign body such as tooth fragments.

Treatment – All abscesses should be drained by incision and drainage (6). – Antibiotics given if concern for Staphylococcus aureus infection as evidenced by presence or absence of SIRS criteria. – Antibiotics against MRSA are recommended if fail outpatient treatment of abscess or carbuncles, if immunocompromised, or present with SIRS with hypotension (6). – Anticoagulation. – Inferior vena cava filter if anticoagulation is contraindicated or if anticoagulation fails.

An Emergency Medicine-Focused Review of Cellulitis Mimics

Table 4. Mimics of Cellulitis

– Anti-MRSA antibiotics if found on the face, with coverage for Streptococcus species as well. – Penicillin or cephalosporin sufficient for the lower extremity.

– Incision and drainage from the lateral approach (5). – If no overlaying inflammation, incision and drainage without antibiotics may be appropriate. – If overlaying inflammation, antibiotics are required. – Cover for MRSA and Streptococcus species. – Amoxicillin-clavulanate if concern for anaerobic bacteria (traumatic injury). – Broad-spectrum antibiotics and place splint. – Consultation with hand surgeon for open irrigation and debridement.

(Continued)

479

Clinical Condition Flexor tenosynovitis

Gouty arthritis (4,21)

Necrotizing soft tissue infection

Orbital cellulitis (5)

Phlegmasia Cerulea Dolens

Diagnosis – Misdiagnosis leads to adhesions, tendon vascular compromise, necrosis with loss of finger function, and potential loss of hand function. – Most commonly after penetrating trauma. Next most common is blunt trauma. – Risk factors for amputation: > 45 years of age, diabetes mellitus, peripheral vascular disease, renal failure, subcutaneous purulence, ischemic changes (20). – Kanavel’s signs in order of frequency: fusiform swelling (97%), pain with passive extension (72%), digit held in flexion (69%), tenderness to flexor sheath (64%) (20). – Staphylococcus (most commonly), Gram negatives, anaerobes. – Precipitation of crystals in the joint with neutrophil migration leading to inflammation due to vasodilation in the surrounding area. – Redness, swelling, pain, and edema spread past the joint space into surrounding tissue. – Peak intensity of gout attack is 6-12 h, vs. cellulitis, which develops over days. – High risk of developing septic arthritis. – Mortality rate of 70–100% if untreated. – Symptoms include pain out of proportion (Likelihood Ratio 4.5), redness extending beyond the margins (LR 3.1), fluctuance (LR 5.0), diarrhea (LR 6.0), hypotension (LR 8.0), recent surgery (LR 7.0), bullae (LR 8.0), necrotic skin (LR 30.0), altered mental status (LR 3.3) (22). – LRINEC score does not possess adequate sensitivity to rule out diagnosis (43.2%; 95% CI 32.5–54.6%) (23). – Ultrasound and CT can assist with diagnosis. – Ultrasound may demonstrate subcutaneous thickening, air, and fascial fluid (STAFF) or, alternatively, hypoechoic fluid tracking along the deep fascial layer with air present in the soft tissue (24,25). – CT is the most sensitive modality to evaluate for soft-tissue gas and is able to show the degree of soft tissue involved (26). – Erythema and swelling of the periorbital soft tissue with infection deep to orbital septum. – Pain with extraocular movement, proptosis, chemosis, and poor visual acuity. – Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus species, and anaerobes. – CT orbits should be obtained. – Intraocular pressure should be monitored. – Complications include vision loss, meningitis, brain abscess, cavernous sinus thrombosis, frontal bone osteomyelitis. – Infection of the lateral nail fold, usually due to minor trauma to the nail. – Pain, tenderness, and swelling of one of the lateral folds of the nail. – Literally means ‘‘edema, blue, painful’’ and presents with triad of leg swelling, acute ischemic pain, and discoloration. – Large obstructing thrombosis leading to low flow state.

Treatment – – – –

Initial management: immobilization, elevation. Initial antibiotics: vancomycin with clindamycin or ceftriaxone. Consultation with hand surgeon. If diagnosed in early stages, can be managed nonoperatively with intravenous antibiotics.

– Arthrocentesis may assist if concern for septic arthritis as exemplified by fever, first episode, or different joint involvement from prior episode. – NSAIDs and Colchicine can be utilized. – Continue urate-lowering medication, but do not initiate during an acute attack. – Steroids such as prednisone if patient has contraindications to NSAIDS and colchicine. – Initial management: resuscitation, broad spectrum antibiotics, and immediate surgical consultation. – Definitive treatment: emergent irrigation and debridement in the operating room. – Antibiotics include vancomycin, plus piperacillin-tazobactam or a carbapenem, plus clindamycin (anti-toxin effect) (6). – Alterative antibiotic regimen: vancomycin plus ceftriaxone and metronidazole (6).

– Antibiotics. – Lateral canthotomy may be indicated if intraocular pressures are > 40 mm Hg. – Consult ophthalmology for possible operative drainage.

– Drain by lifting nail fold with needle or number 11 blade. – If pus below the nail, then remove nail, being careful not to damage the nail bed. – If no pus to drain, treat with warm soaks, elevation, and antibiotics. – Initial management: absolute bed rest, leg elevation, fluids, and i.v. heparin (27).

G. Blumberg et al.

Paronychia (5)

480

Table 4. Continued

Septic joint (32)

Toxic shock syndrome (TSS)

Dermal hypersensitivity (39)

Calciphylaxis (40,41)

– Septic prepatellar bursitis treatment can range from oral antibiotics to surgery. – Most patients will respond nonoperatively with dicloxacillin or clindamycin. – Septic olecranon bursitis treated by drainage and systemic antibiotics. – Nafcillin or oxacillin or cefazolin for MSSA. – Vancomycin for MRSA. – Consultation with orthopedic surgery (5). – Disposition depends on clinical presentation, age, risk factors (history of arthritis, prior septic arthritis, history of joint surgery, ESRD, diabetes, cancer, immunosuppression, i.v. drug use), presence of fever, synovial fluid white blood cell count, crystals, and gram stain (34,35). – Most patients require admission.

– Clindamycin or linezolid to decrease toxin production (36,37). – Consultation with surgeon to obtain source control: abscess, surgical wound, foreign body, necrotizing fasciitis. – Intravenous IgG may be needed as patients often do not have antibodies to target toxin produced by bacteria. – No study has statistically proven a decrease in mortality with IVIG (38).

– Treatment requires H1 and H2 antagonists. Prednisone 40 mg may be required for severe symptoms. – Other immunosuppressant medications are second-line for nonresponders. – Biopsies are warranted for definitive diagnose. – Appears similar to cellulitis and necrotizing fasciitis, and antibiotics are warranted. – Treatment requires consultation with dermatology, as options include corticosteroids, bisphosphonates, vitamin D, and sodium thiosulfate.

481

– In-hospital mortality rates are as high as 15% (33). – Approximately 50% of cases of septic joint involve the knee (33). – Risk factors include osteoarthritis, rheumatoid arthritis, pseudogout, gout, Charcot arthropathy, intravenous drug use, diabetes mellitus, HIV, age > 80 years. – Monoarticular joint that is erythematous, swollen, and exquisitely painful on passive and active range of motion. – Arthrocentesis is required for diagnosis: 50,000 WBC/mm3 was only 61% (95% CI 48–75%) sensitive in one study, and MRSA infections may result in synovial fluid with WBC count < 20,000 (34,35). – Risks of arthrocentesis: iatrogenic infection 0.1% in immunocompetent and 0.5% in immunosuppressed. – Frequently young and otherwise healthy individuals. – Staphylococcal TSS associated 50% with menstrual-related (tampons) and 50% with non-menstrual-related (soft tissue infections, sinusitis, sinus packing, pneumonia). Presents with gastroenteritislike symptoms, viral/influenza-like illness. – Streptococcal TSS due to soft tissue infection (cellulitis, necrotizing fasciitis, surgical wound, myositis). – Present with local signs of infection or a mixed picture of local and influenza-like illness/gastrointestinal symptoms. – Diffuse erythema of the skin and strawberry tongue often transient or subtle. – Progress to septic shock that is refractory to standard treatments. – Allergic reaction in the dermis, appears similar to cellulitis with redness on the trunk and extremities. – More commonly pruritic, rather than painful. – Lesion are red papules that coalesce into plaques. – Etiologies include insect bite, drug reaction, and viral illness. – May be multifocal and recurrent. – Patients often have end-stage renal disease, obesity, diabetes, liver disease, hypercoagulable states, or warfarin use. – More common in Caucasians and females, with lower extremities more commonly affected. – This appears red and is usually painful. – Prognosis can be severe, with mortality that reaches 60% if proximal. – Condition relapses and remits. – Disease due to calcium deposition in blood vessels of the dermis and fat.

– Interventional radiology or vascular surgery catheter-directed thrombolysis (28).

An Emergency Medicine-Focused Review of Cellulitis Mimics

Septic bursitis

– Mortality 25–40%, amputation rate 20–50% (27). – Risk factors include malignancy and oral contraception. – Ultrasound is fast and reliable for diagnosing extensive DVT, though CT or MR venography are gold standard for diagnosis to show extent of thrombus. – Infection of bursa from direct inoculation by trauma, infection of nearby tissue, or hematogenous spread. – Most common location is prepatellar followed by olecranon (29). – Diagnosed by ultrasound or aspiration of bursal fluid: > 1000 cells/uL, neutrophil predominance, Gram stain shows no growth in 50% (30). – Only 40–44% patients will develop a fever (31). – Palpation of the site reveals fluctuance.

(Continued)

MSSA = methicillin-susceptible Staphylococcus aureus; SIRS = systemic inflammatory response syndrome; MRSA = methicillin-resistant Staphylococcus aureus; CI = confidence interval; DVT = deep vein thrombosis; NSAID = nonsteroidal anti-inflammatory rug; LR = Likelihood Ratio; LRINEC = Laboratory Risk Indicator for NECrotizing fasciitis scoring system; CT = computed tomography; MR = magnetic resonance; MSSA = methicillin-susceptible Staphylococcus aureus; ESRD = end-stage renal disease; HIV = human immunodeficiency virus; WBC = white blood cell; IVIG = intravenous immunoglobulin.

Inflammation of the subcutaneous fat, commonly on lower extremities Usually associated with chronic venous insufficiency. The acute form includes a tender, erythematous indurated plaque. Subacute and chronic forms are nontender and hyperpigmented. Diffusion of capillary contents (fibrinogen) into the dermis results in a woody texture. Lipodermatosclerosis (42)

Clinical Condition

Table 4. Continued

– – – – –

Diagnosis

– Acute form with tenderness appears similar to cellulitis and erysipelas. – Management includes dermatology consultation and prednisone daily.

G. Blumberg et al.

Treatment

482

injury may help predict which bacteria should be suspected. For example, patients with skin and soft tissue infection from a contaminated puncture wound may have both Gram-negative and anaerobic bacteria as an infectious source. b. Examination: In the physical examination, the location of inflammation is highly important. If inflammation spans a joint, higher suspicion should be raised for cellulitis mimics. Special attention should also be taken when skin and soft tissue infections involve the hand. Severe pain or tenderness or necrosis is concerning for necrotizing fasciitis. Extensive involvement of the body, such as patients with skin lesions affecting over 10% of the body surface area or those with mucosal involvement, require further evaluation and treatment, as these are red flags for more severe conditions. 3. Laboratory Assessment: Depending on the severity of illness of the patient, diagnostic studies may or may not be required. Well-appearing patients without abnormal vital signs with typical cellulitis do not need laboratory evaluation. This is in contrast to the patient presenting in extremis from sepsis. Complete blood count, electrolytes, lactic acid, blood cultures, urinalysis, urine culture, and other laboratory orders to further elucidate the causes of sepsis are warranted in the patient with concerning examination or hemodynamic instability. 4. Differentiation: With information at this point from the history, physical examination, and diagnostic studies, the provider can likely begin to separate cellulitis from its mimics. However, diagnostic imaging may be useful in these settings to separate benign disease from pathology with high morbidity and mortality. This includes ultrasound, radiographs, or computed tomography. 5. Disposition: After the data have been collected, including history, physical examination, and imaging studies, management and disposition are key. Of patients admitted with a cellulitis diagnosis, 30% are misdiagnosed (1,3,7,8). If there is concern for a cellulitis mimic, emergent irrigation and debridement in the operating room vs. admission with appropriate medical management may be required, depending on the specific condition, such as necrotizing fasciitis. Ultimately, the approach to the patient with cellulitis or a cellulitis mimic is similar to patients with other chief complaints. The role of an emergency physician is to rule out life- and limb-threatening disease. By utilizing the patient’s history, physical examination, and imaging studies, differentiation of cellulitis from its mimics is possible.

An Emergency Medicine-Focused Review of Cellulitis Mimics

CONCLUSIONS Cellulitis presents similarly to disease processes that result in inflammation of the skin. There are many mimics of cellulitis. The most important aspect in managing these patients is to consider other life-threatening diseases. Duration and location is often essential to making the correct diagnosis and not missing an emergent condition. Inflammation of the hand can be due to closed fist injury or flexor tenosynovitis. If a joint is involved, septic bursa or septic joint should be considered. Necrotizing fasciitis must always be included in the differential diagnosis of cellulitis. Surgical intervention may be warranted in necrotizing fasciitis, septic arthritis, phlegmasia cerulea dolens, flexor tenosynovitis, fight bite, or orbital cellulitis. REFERENCES 1. Weng QY, Raff AB, Cohen JM, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol 2017;153:141–6. 2. Healthcare Cost and Utilization Project (HCUP). Nationwide Inpatient Sample (NIS) most frequent conditions in US hospitals. September 2013 edn. Available at: http://www.hcup-us.ahrq.gov. foyer.swmed.edu/nisoverview.jsp2011. Accessed January 14, 2017. 3. Raff AB, Kroshinsky D. Cellulitis: a review. JAMA 2016;316:325–37. 4. Hirschmann JV, Raugi GJ. Lower limb cellulitis and its mimics: part I. Lower limb cellulitis. J Am Acad Dermatol 2012;67:163.e1– 16312. quiz 75–6. 5. Tintinalli JE, Stapczynski JS, Ma OJ, et al. Tintinalli’s emergency medicine a comprehensive study guide. New York; Chicago; San Francisco: McGraw-Hill Education; 2016. 6. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59:e10–52. 7. Davis JP, Osterholm MT, Helms CM, et al. Tri-state toxic-shock syndrome study. II. Clinical and laboratory findings. J Infect Dis 1982;145:441–8. 8. Levell NJ, Wingfield CG, Garioch JJ. Severe lower limb cellulitis is best diagnosed by dermatologists and managed with shared care between primary and secondary care. Br J Dermatol 2011;164:1326–8. 9. Hook EW 3rd. Acute cellulitis. Arch Dermatol 1987;123:460–1. 10. Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 1999;318:1591–4. 11. Krasagakis K, Valachis A, Maniatakis P, et al. Analysis of epidemiology, clinical features and management of erysipelas. Int J Dermatol 2010;49:1012–7. 12. Lazzarini L, Conti E, Tositti G, et al. Erysipelas and cellulitis: clinical and microbiological spectrum in an Italian tertiary care hospital. J Infect 2005;51:383–9. 13. Marx J, Walls R, Adams J, et al., eds. Rosen’s emergency medicine concepts and clinical practice. 7th edn. Philadelphia, PA: Mosby Elsevier; 2010. 14. Stevens DL. Infections of the Skin, Muscles, and Soft Tissues. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e New York, NY: McGraw-Hill; 2014. Available at: http://accessmedicine.mhmedical. com/content.aspx?bookid=1130§ionid=79733782. Accessed February 09, 2017. 15. Sattar H. Fundamentals of pathology: medical course and step 1 review. Chicago: Pathoma LLC; 2013. 16. Bjo¨rnsdo´ttir S, Gottfredsson M, Tho´risdo´ttir AS, et al. Risk factors for acute cellulitis of the lower limb: a prospective case-control study. Clin Infect Dis 2005;41:1416–22.

483 17. Karppelin M, Siljander T, Vuopio-Varkila J, et al. Factors predisposing to acute and recurrent bacterial non-necrotizing cellulitis in hospitalized patients: a prospective case-control study. Clin Microbiol Infect 2010;16:729–34. 18. Halpern J, Holder R, Langford NJ. Ethnicity and other risk factors for acute lower limb cellulitis: a U.K.-based prospective casecontrol study. Br J Dermatol 2008;158:1288–92. 19. Goodacre S, Sutton AJ, Sampson FC. Meta-analysis: the value of clinical assessment in the diagnosis of deep venous thrombosis. Ann Intern Med 2005;143:129–39. 20. Pang HN, Teoh LC, Yam AK, et al. Factors affecting the prognosis of pyogenic flexor tenosynovitis. J Bone Joint Surg Am 2007;89:1742–8. 21. Hirschmann JV, Raugi GJ. Lower limb cellulitis and its mimics: part II. Conditions that simulate lower limb cellulitis. J Am Acad Dermatol 2012;67:177.e1–9. quiz 185–6. 22. Alayed KA, Tan C, Daneman N. Red flags for necrotizing fasciitis: a case control study. Int J Infect Dis 2015;36:15–20. 23. Al-Hindawi A, McGhee J, Lockey J, et al. Validation of the laboratory risk indicator for necrotising fasciitis scoring system (LRINEC) in a Northern European population. J Plast Reconstr Aesthet Surg 2017;70:141–3. 24. Castleberg E, Jenson N, Dinh VA. Diagnosis of necrotizing faciitis with bedside ultrasound: the STAFF Exam. West J Emerg Med 2014;15:111–3. 25. Thom C, Warlaumont M. A necrotizing fasciitis fake out on pointof-care iltrasound-watch the shadow. J Emerg Med 2017;52:523–6. 26. Chaudhry AA, Baker KS, Gould ES, et al. Necrotizing fasciitis and its mimics: what radiologists need to know. AJR Am J Roentgenol 2015;204:128–39. 27. Chinsakchai K, Ten Duis K, Moll FL, de Borst GJ. Trends in management of phlegmasia cerulea dolens. Vasc Endovascular Surg 2011;45:5–14. 28. Geroulakos G, Hossain J, Tran T. Economy-class syndrome presenting as phlegmasia caerulea dolens. Eur J Vasc Endovasc Surg 2000; 20:102–4. 29. Aaron DL, Patel A, Kayiaros S, et al. Four common types of bursitis: diagnosis and management. J Am Acad Orthop Surg 2011;19:359–67. 30. Wasserman AR, Melville LD, Birkhahn RH. Septic bursitis: a case report and primer for the emergency clinician. J Emerg Med 2009; 37:269–72. 31. Ho G Jr, Tice AD, Kaplan SR. Septic bursitis in the prepatellar and olecranon bursae: an analysis of 25 cases. Ann Intern Med 1978;89:21–7. 32. Esterhai JL Jr, Gelb I. Adult septic arthritis. Orthop Clin North Am 1991;22:503–14. 33. Carpenter CR, Schuur JD, Everett WW, et al. Evidence-based diagnostics: adult septic arthritis. Acad Emerg Med 2011;18:781–96. 34. McGillicuddy DC, Shah KH, Friedberg RP, et al. How sensitive is the synovial fluid white blood cell count in diagnosing septic arthritis? Am J Emerg Med 2007;25:749–52. 35. Frazee BW, Fee C, Lambert L. How common is MRSA in adult septic arthritis? Ann Emerg Med 2009;54:695–700. 36. Linner A, Darenberg J, Sjolin J, et al. Clinical efficacy of polyspecific intravenous immunoglobulin therapy in patients with streptococcal toxic shock syndrome: a comparative observational study. Clin Infect Dis 2014;59:851–7. 37. Coyle EA, Cha R, Rybak MJ. Influences of linezolid, penicillin, and clindamycin, alone and in combination, on streptococcal pyrogenic exotoxin a release. Antimicrob Agents Chemother 2003;47:1752–5. 38. Darenberg J, Ihendyane N, Sjolin J, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003;37:333–40. 39. Kossard S, Hamann I, Wilkinson B. Defining urticarial dermatitis: a subset of dermal hypersensitivity reaction pattern. Arch Dermatol 2006;142(1):29–34. 40. Zhou Q, Neubauer J, Kern JS, Grotz W, Walz G, Huber TB. Calciphylaxis. Lancet 2014;22(9922):1067. 41. Weenig RH, Sewell LD, Davis MD, McCarthy JT, Pittelkow MR. Calciphylaxis: natural history, risk factor analysis, and outcome. J Am Acad Dermatol 2007;56(4):569–79. 42. Walsh SN, Santa Cruz DJ. Lipodermatosclerosis: a clinicopathological study of 25 cases. J Am Acad Dermatol 2010;62:1005.

484

G. Blumberg et al.

ARTICLE SUMMARY 1. Why is this topic important? With every passing year, the rate of admission for cellulitis continues to climb. Of those admitted, 30% are incorrectly diagnosed. Fortunately, most cellulitis mimics are benign. However, many have high rates of morbidity and mortality requiring rapid diagnosis and treatment. It is essential for emergency physicians to differentiate between cellulitis and its mimics. 2. What does this review attempt to show? This review evaluates cellulitis pathophysiology, risk factors of cellulitis, how to manage cellulitis, mimics of cellulitis, and an approach to management for cellulitis mimics. 3. What are the key findings? The current Infectious Disease Society of America defines cellulitis as diffuse, superficial spreading skin infection with the exclusion of cutaneous inflammation with collections of pus. However, nearly all skin and soft tissue infections present with similar findings: erythema, induration, swelling, pain. As a result, cellulitis and its mimics are difficult to differentiate. Cellulitis mimics include septic bursitis, septic joint, deep vein thrombosis, phlegmasia cerulea dolens, necrotizing fasciitis, flexor tenosynovitis, fight bite (closed fist injury), orbital cellulitis, toxic shock syndrome, erysipelas, abscess, felon, paronychia, and gouty arthritis. A combination of history, physical examination, and adjunctive studies may assist providers in diagnosing cellulitis mimics and targeting treatment. 4. How is patient care impacted? This evaluation of cellulitis and cellulitis mimics evaluates cellulitis pathophysiology, risk factors, and management, as well as a review of the cellulitis mimics and an approach to the management of cellulitis and cellulitis mimics.