29-Year-Old Woman With Fever and Bilateral Lower Extremity Lesions

Abstract

A 29-year-old woman with a history of obesity (body mass index, 39 kg/m2) and polycystic ovarian syndrome presented to her primary care physician in late spring for evaluation of fever (39.3°C), chills, and a boil on the inner thigh. She was otherwise healthy, had been feeling well, and was enjoying her weekly fishing excursions at several of the lakes in Minnesota until the day before the evaluation, when she had noted pain and induration on the medial aspect of her right upper thigh. She inserted a needle into this area, but no fluid was expressed. The pain progressed, and erythema was noted around the lesion. A similar phenomenon on the medial aspect of her left upper thigh developed; however, this was not punctured. She was given ibuprofen and ultimately directed to the emergency department for further evaluation of presumed abscesses. Physical examination revealed an area of erythema on the right thigh that blanched with palpation and surrounded a 4 × 2-cm hemorrhagic bulla. There was a similar 2-cm lesion on the left thigh also circumscribed by erythema. These regions were tender to palpation and firm, with no overt fluctuance. She was tachycardic (heart rate, 120 beats/min) but not febrile. Bilateral bedside ultrasonography revealed no focal fluid collection to suggest an abscess. A bilateral skin and soft tissue infection was diagnosed, and oral doxycycline was prescribed for treatment because the patient was allergic to sulfamethoxazole-trimethoprim. The following day, she returned to the emergency department because the pain and erythema had progressed. Physical examination supported progression of both the erythema and the large bullae, which now had central eschars but no underlying crepitus. Nikolsky sign (separation of the epidermis with a shearing force) was absent. The patient was afebrile and normotensive, but her pulse rate was 104 beats/min and respiratory rate was 22 breaths/min. Laboratory studies revealed the following (reference ranges provided parenthetically): hemoglobin, 12.3 g/dL (11.6-15.0 g/dL); white blood cell count, 22.9 × 109/L (3.4-9.6 × 109/L); platelets, 238 ×109/L (157-371 ×109/L); creatinine, 0.6 mg/dL (0.59-1.04 mg/dL); activated partial thromboplastin time, 28 seconds (25-37 seconds); sodium, 140 mmol/L (135-145 mmol/L); plasma lactate, 1.30 mmol/L (0.6-2.3 mmol/L); glucose, 97 mg/dL (70-140 mg/dL); C-reactive protein 209.0 mg/L (≤8.0 mg/L); and creatine kinase, 22 U/L (26-192 U/L).1.Based on the clinical scenario, which one of the following would be the best therapy to initiate?a.Incision and drainageb.Continue previously prescribed oral doxycyclinec.Intravenous ceftriaxoned.Intravenous clindamycine.Intravenous vancomycin plus piperacillin-tazobactam Skin and soft tissue infections are commonly encountered by clinicians in both the outpatient and inpatient settings. Appropriate coverage of the most likely pathogens is crucial to successful treatment. It should be noted that incision and drainage without antibiotics may often be the only treatment necessary for purulent abscesses smaller than 5 cm in the absence of signs of systemic infection. In this case, no purulence or focal fluid collection had been noted. Further oral antimicrobial therapy is inappropriate given the patient's systemic signs of infection and clinical progression despite previously prescribed doxycycline. Oral antibiotic therapy is appropriate for mild infections with classic cellulitis without purulence, with Streptococcus being the most common pathogen.1Stevens D.L. Bisno A.L. Chambers H.F. 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: 147-159Crossref PubMed Scopus (672) Google Scholar Conversely, infections with purulence or frank abscess should raise suspicion for methicillin-resistant Staphylococcus aureus (MRSA), and empiric coverage is advised. Although intravenous antibiotics such as ceftriaxone or clindamycin are the appropriate next step for moderate skin and soft tissue infections, this patient's bullae would suggest a deep soft tissue infection, raising the category to severe.1Stevens D.L. Bisno A.L. Chambers H.F. 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: 147-159Crossref PubMed Scopus (672) Google Scholar Of note, broadening coverage against MRSA is warranted not only in cases of penetrating trauma, evidence of MRSA infection elsewhere, nasal colonization, and injection drug use but also with associated systemic inflammatory response syndrome as exemplified in our patient. Vancomycin plus piperacillin-tazobactam would be the recommended empiric therapy for this patient, although there are several other antibiotic regimens that are also appropriate for severe skin and soft tissue infections. The patient was admitted to the hospital, and after blood was withdrawn for cultures, vancomycin and piperacillin-tazobactam was administered; the dermatology service was also consulted given the extent of the bullae. Local wound care and drainage of the large bulla without deroofing were advised, and a punch biopsy was obtained. The following day, there were an increased number of bullae with marked progression of the previous bulla (greater than 10 cm in length), skin ecchymosis, and erythema. Her fever persisted and pain progressed. She was transitioned to cefepime, metronidazole, and liposomal amphotericin B plus vancomycin on recommendation of the infectious disease service.2.Which one of the following is the most important next step in the care of this patient under this clinical context?a.Calculate the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) scoreb.Duplex ultrasonographyc.Initiate intravenous clindamycind.Computed tomography (CT)e.Superficial wound culture In the setting of rapid progression and systemic symptoms, a necrotizing soft tissue infection (NSTI) must be considered. While the definitive diagnosis of NSTI is established by surgery, diagnostic assistance may come from scoring systems and imaging.2Bonne S.L. Kadri S.S. Evaluation and management of necrotizing soft tissue infections.Infect Dis Clin North Am. 2017; 31: 497-511Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar The LRINEC score uses laboratory values (C-reactive protein concentration, white blood cell count, hemoglobin level, sodium value, creatinine concentration, and glucose level) from the time of admission to risk-stratify equivocal cases of early necrotizing infection.3Wong C.H. Khin L.W. Heng K.S. Tan K.C. Low C.O. The LRINEC (Laboratory Risk Indicator for Necrotizing Fasciitis) score: a tool for distinguishing necrotizing fasciitis from other soft tissue infections.Crit Care Med. 2004; 32: 1535-1541Crossref PubMed Scopus (883) Google Scholar This can be a helpful aid, although not sufficient for diagnosis and management alone, and prospective analysis of this scoring system has questioned its utility.2Bonne S.L. Kadri S.S. Evaluation and management of necrotizing soft tissue infections.Infect Dis Clin North Am. 2017; 31: 497-511Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Although duplex ultrasonography is effective in identifying thrombosis that may be complicated by phlebitis, the classic risk factors for phlebitis such as coagulation or endothelial dysfunction are absent in this patient, and given the clinical context, such evaluation is not warranted at this time. Of note, ultrasonography can be used to screen for NSTI, but the evidence to support its use is limited.2Bonne S.L. Kadri S.S. Evaluation and management of necrotizing soft tissue infections.Infect Dis Clin North Am. 2017; 31: 497-511Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar The established antibiotic regimen provides empiric treatment for a polymicrobial NSTI given the coverage against aerobes, anaerobes, and MRSA. When an NSTI is caused by group A streptococci, clindamycin suppresses streptococcal toxin and cytokine production. Because the infectious culprit is initially unknown, it is reasonable to include clindamycin with empiric NSTI coverage. However, in this clinical context, suspicion for NSTI is equivocal, and the most appropriate step is further risk stratification to determine if surgical intervention is required. Imaging modalities such as CT and magnetic resonance imaging can provide further insight by identifying features, such as gas, that are more specific for NSTI. The ease/speed of acquisition and preserved sensitivity of CT has made it the preferred imaging modality in practice, and in the current clinical context, it is the most appropriate next step.4Beaman F. Von Herrmann R. Kransdorf M. et al.Suspected osteomyelitis, septic arthritis, or soft tissue infection (excluding spine and diabetic foot). ACR Appropriateness Criteria® website.https://acsearch.acr.org/docs/3094201/Narrative/Date: 2016Date accessed: August 29, 2017Google Scholar There is no role for superficial wound culture in skin and soft tissue infections. Computed tomography of the thighs revealed prominent cutaneous and subcutaneous inflammatory changes, with fluid along the superficial myofascial plane but no tissue gas. The patient was taken to the operating room, and although there was no evidence of necrotizing fasciitis, the superficial skin was noted to be quite necrotic and was debrided. Within a few days, there appeared to be new areas of this necrosis along the wound edges. Deep tissue culture results remained negative for bacteria as well as fungi.3.At this time, which one of the following diagnoses is most likely?a.Pyoderma gangrenosumb.Bullous pemphigoidc.Tick-borne diseased.Ecthyma gangrenosume.Antiphospholipid syndrome An important observation is that the marked progression of cutaneous lesions throughout this case occurred first after incidental trauma to the skin (needle puncture at home) followed by iatrogenic trauma (punch biopsy and surgical debridement). This scenario is consistent with the phenomenon of pathergy, whereby minor trauma, including venipuncture, may lead to the development of new lesions or ulcers that are resistant to healing. The diagnosis of pyoderma gangrenosum should be strongly suspected in patients whose wounds are painful, rapidly expanding, unresponsive to antibiotics, and worsening with debridement, as in this case. Bullous pemphigoid is classically found in older adults, which makes this diagnoses less likely for this 29-year-old patient. Bullous pemphigoid may also present with pruritus and may be preceded by a new medication. Tick-borne diseases have several cutaneous manifestations and should be considered in regions with a high incidence of tick-borne disease and during months of peak transmission (late spring and summer). In early localized Lyme disease, erythema chronicum migrans classically demonstrates an expanding red lesion. However, the degree of pain experienced by our patient is not seen with erythema chronicum migrans. Ecthyma gangrenosum is a Pseudomonas-associated skin manifestation that may be rapidly progressive, but the lesions tend to be ulcerative, and the disease occurs most often in immunocompromised individuals. Antiphospholipid syndrome can lead to infarction of the skin, but with no history of thrombotic events or coagulation abnormalities, it is unlikely in this case. The pathology report from the punch biopsy identified epidermal spongiosis and exocytoses of neutrophils, papillary dermal edema, and diffuse dermal neutrophilic inflammation. These findings were most compatible with a diagnosis of pyoderma gangrenosum.4.Which one of the following is the most appropriate therapy to initiate at this point?a.Topical clobetasolb.Topical tacrolimusc.High-dose systemic corticosteroidsd.Infliximabe.Further surgical resection of lesions The treatment of pyoderma gangrenosum focuses on controlling inflammation and optimizing wound healing. Excellent wound care and dressings are the backbone of treatment in all cases. Medical therapy will depend on the severity of the lesions. For mild, superficial lesions, topical corticosteroids and topical calcineurin inhibitors like tacrolimus will often suffice and are associated with fewer adverse effects. However, with multiple large lesions that are rapidly progressive, as in this patient, systemic therapy is required to induce rapid remission. High-dose systemic corticosteroids (prednisone, 0.5-1 mg/kg per day, or methylprednisolone, up to 0.8 mg/kg per day) are highly effective in halting lesion progression, often in less than 2 to 3 days, and are thus considered first-line systemic therapy. Occasionally, a longer-term taper may be needed to maintain wound healing, necessitating the use of a glucocorticoid-sparing medication. Systemic cyclosporine is an alternative as well. Biologic agents such as infliximab are emerging as new treatment options for pyoderma gangrenosum but are generally reserved only for refractory cases given their toxicity. The role of surgical treatment in pyoderma gangrenosum is currently controversial because 25% to 50% of pyoderma lesions demonstrate pathergy and could worsen with surgical intervention.5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar, 6Miller J. Yentzer B.A. Clark A. Jorizzo J.L. Feldman S.R. Pyoderma gangrenosum: a review and update on new therapies.J Am Acad Dermatol. 2010; 62: 646-654Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar Surgical debridement and wound coverage via flaps, grafts, or bioengineered products may be indicated for coverage of at-risk deeper tissue elements (tendons, ligaments, muscle, vessels). Negative-pressure wound therapy can accelerate deep wound healing. A course of intravenous methylprednisolone, 80 mg daily, was initiated, which was transitioned to a prolonged oral prednisone taper after a week. The patient noted marked improvement in pain the day after corticosteroids were initiated, and the lesions appeared to stop progressing shortly after.5.Which one of the following would be the best test/procedure to obtain evidence of associated underlying conditions in this patient?a.Antitissue transglutaminase antibody testingb.Colonoscopyc.Hemoglobin A1c measurementd.Genetic testing/counselinge.Right upper quadrant ultrasonography Pyoderma gangrenosum is associated with an underlying systemic disease in more than 50% of patients, although rates as high as 78% have been reported.5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar The most commonly associated underlying conditions include inflammatory bowel disease (IBD) (14%-34%), inflammatory arthropathies (15%-25%), and hematologic disease or malignancy (IgA monoclonal gammopathy, myelodysplasia, acute myelogenous leukemia) (20%).5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar, 7Binus A.M. Quresh A.A. Li V.W. Winterfield L.S. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients.Br J Dermatol. 2011; 165: 1244-1250Crossref PubMed Scopus (236) Google Scholar Given this prevalence, a thorough work-up for underlying conditions should be undertaken in any patient newly diagnosed with pyoderma gangrenosum. Antitissue transglutaminase antibody testing should be obtained in patients presenting with dermatitis herpetiformis, characterized by pruritic papules or vesicles, because it is often associated with gluten sensitivity; however, no such link exists with pyoderma gangrenosum. Colonoscopy to evaluate for IBD should be pursued given its high prevalence in patients with pyoderma gangrenosum. There is no association between pyoderma gangrenosum and diabetes, although pyoderma lesions can be mistaken as diabetic ulcers. At this time, there is a limited role for genetic testing/counseling. Although familial cases of pyoderma gangrenosum have been reported, they are rare, and the most frequently associated syndromes do not require genetic analysis. Right upper quadrant ultrasonography is not needed because pyoderma is not associated with biliary disease but rather with IBD. It is also important to note that although pyoderma gangrenosum is usually diagnosed after the associated disease, it may also precede or be the presenting sign of an underlying disease. It also may or may not parallel the course of the underlying disease. The patient underwent an extensive investigation, including rheumatologic serologies, QuantiFERON-TB Gold testing, hepatitis B and C serologies, serum protein monoclonal electrophoresis and immunofixation, bone marrow biopsy, positron emission tomography-CT, and upper endoscopy, findings from all of which were unremarkable. However, a high level of vigilance moving forward is required because underlying diseases may manifest at any time following a pyoderma gangrenosum diagnosis. Pyoderma gangrenosum is a rare neutrophilic inflammatory dermatosis. The exact etiology and triggers for the condition are unknown but are suspected to be mediated by neutrophil dysregulation or an autoinflammatory disease process.8Braswell S.F. Kostopoulos T.C. Ortega-Loayza A.G. Pathophysiology of pyoderma gangrenosum (PG): an updated review.J Am Acad Dermatol. 2015; 73: 691-698Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Although commonly associated with a systemic disease or with rare familial syndromes, pyoderma gangrenosum may be distinct from a systemic process or even precede the development of the underlying associated condition. The diagnosis is challenging and often one of exclusion because no specific laboratory or histopathologic findings confirm the diagnosis.5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar However, several clinical features should raise clinicians' suspicion for this disorder. Pyoderma gangrenosum has 4 clinical variants based on morphologic features (ulcerative [classic], bullous, pustular, vegetative, and peristomal) and some site-specific locations (peristomal, genital, extracutaneous, postoperative wound). Although each subtype has unique clinical features, anatomic distributions, and associated diseases, the unifying theme in all cases is markedly painful lesions. The ulcerative subtype manifests as painful lesions, often with irregular violaceous and undermined borders, and is associated with systemic disease (ie, autoimmune or cancer). The bullous subtype is rapidly spreading, occurs most commonly on the face and upper extremities, and is most often associated with a myeloproliferative disorder. The pustular subtype is quite rare, occurs most commonly on the lower extremities and upper trunk, and is associated with IBD. The vegetative subtype tends to be solitary, responds quickly to topical treatment, and is not associated with a systemic disease. The violaceous ulcers seen in the peristomal subtype occur near stoma sites and are associated with IBD.5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar The diagnosis of pyoderma gangrenosum should be strongly suspected in patients whose wounds are painful, rapidly expanding, unresponsive to antibiotics, and worsening with debridement or trauma. Infection is always in the differential diagnosis and must be ruled out. Biopsy may reveal epidermal spongiosis, papillary dermal edema, and diffuse dermal neutrophilic inflammation, but these findings are nonspecific and not pathognomonic. Once pyoderma gangrenosum is suspected, the foundation for treatment is local wound care and controlling inflammation. The therapeutic strategy for controlling inflammation is largely based on the size and progression of the lesion. Topical calcineurin inhibitors or topical corticosteroids can be used for more mild lesions. For larger, rapidly progressive lesions, systemic corticosteroids or cyclosporine are considered first-line therapy. Although outcome data are limited, some reports have found that patients with idiopathic pyoderma gangrenosum fair better than those with associated systemic disease. Remission may take as long as 9 to 12 months, depending on the subtype, and, unfortunately, a recurrence rate up to 46% has been documented.5Ahronowitz I. Harp J. Shinkai K. Etiology and management of pyoderma gangrenosum: a comprehensive review.Am J Clin Dermatol. 2012; 13: 191-211Crossref PubMed Scopus (287) Google Scholar