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A 30-year-old woman presented to a clinic in April 2019 noting swelling, itching, and reddened patches on her left foot. She said she had been having the symptoms periodically for the past 5 years, despite treatment with topical corticosteroids/antibiotic creams, along with oral antibiotics.

She became concerned 4 days earlier, however, when she developed mild diarrhea (3-5 watery bowel movements/day) and a somewhat elevated temperature (37.7ºC/99.9ºF).

She described a 5-year history of having itchy cellulitis-like eruptions unilaterally on her lower legs and feet, with swelling and fever up to 38ºC. The attacks typically lasted for 3-4 weeks before improving somewhat.

The most recent episode was about 3 months earlier, she said. She was treated with oral clindamycin (300 mg/6 h) and ciprofloxacin (500 mg/12 h) for 10 days, as well as prednisone (30 mg/day for 10 days), which was gradually tapered over the following month.

She had no joint pain or tenderness or changes in vision. Since her eyes were not red, dry, or painful, clinicians excluded the possibility of uveitis. The patient had no known allergies or hypersensitivity reactions to medications, metals, or arthropod bites and stings, had never smoked, and had not received any other medications.

Physical examination showed she was in good overall health. Her respiration rate was 15 breaths/minute, body temperature was 37.5ºC, blood pressure was 120/70 mmHg, and heart rate was 98 beats/minute. Clinicians noted generalized erythema with moderate swelling of her left lower foot.

Similarly, clinical examination of her heart, respiratory system, nervous system, and abdomen were all unremarkable.

Laboratory tests revealed:

• Mild anemia: (hemoglobin 11.6 g/dL)

• White blood cell count: 9,880/mm³ (eosinophils 3%)

• Erythrocyte sedimentation rate: 45 mm/hour

• C-reactive protein: 0.61 mg/dL

No peripheral eosinophilia had been reported in her previous cellulitis-like attacks.

Blood cultures showed no bacteria or fungi. Three stool sample cultures showed no evidence of ova or parasites, but all were positive for the C. difficile toxin transcranial Doppler A test.

The following were all found to be normal: serum protein electrophoresis, immunoglobulin E, antinuclear and antineutrophil cytoplasmic antibodies, cryoglobulins, hepatitis B surface antigen, HIV and HCV antibodies; a laboratory test for venereal disease was negative, and angiotensin converting enzyme was within normal levels.

Similarly, color Doppler ultrasound did not reveal any lower limb venous disease, and chest x-ray showed no obvious lung abnormalities or evidence of hilar lymphadenopathy. Clinicians thus determined that a fundus examination was not needed.

They considered numerous differential diagnoses, including infectious cellulitis, drug and foreign-body reactions, insect stings, lymphedema, eczema, panniculitis, thrombophlebitis, venous stasis dermatitis, gouty arthritis, carcinoma erysipeloides, familial Mediterranean fever, sarcoidosis, lupus erythematosus, Paget's disease, lymphoma, and Wells syndrome.

Clinicians then performed a skin biopsy, which revealed significant edema and subepidermal intraepithelial blister formation with numerous granulomatous eosinophils, but no evidence of nodular lymphocytic infiltration, vasculitis, or cancer.

Based on the presence of perivascular chronic inflammatory infiltrates with eosinophils and a few phagocytic histiocytes, the team diagnosed the patient with Wells syndrome.

Oral metronidazole (500 mg/8 h for 10 days) and probiotics were prescribed, which successfully treated the C. difficile infection. For the Wells syndrome, the team prescribed mometasone furoate cream (twice daily) for 2 weeks and levocetirizine (10 mg daily) for 1 month. Her symptoms resolved, and she has had no recurrences to date, the case authors reported.

Discussion

Clinicians presenting this of a woman with C. difficile infection with a background of Wells syndrome after 5 years of chronic recurrent cellulitis-like eruptions on her lower limbs emphasized the importance of making a correct diagnosis to avoid inappropriate treatment.

The authors noted that Wells syndrome is rare and that lack of awareness of it in Cyprus, Greece, where this case occurred, may explain why it had not been reported there previously.

The inflammatory dermatosis was defined as eosinophilic cellulitis by in 1979. Initial symptoms generally include tender or mildly itchy skin eruptions, often associated with a burning sensation and then swelling, and can include papular and nodular eruptions, annular plaques, vesicles, bullae, and urticaria.

The syndrome can be triggered by "inappropriate eosinophilic stimulation," which could be due to "arthropod bites and stings, medications, metals, as well as bacterial, viral, fungal, parasitic, and helminthic infections," the team wrote.

Wells syndrome has also occurred against a background of leukemia, lymphoma, myeloproliferative syndromes, solid tumors, and Churg-Strauss syndrome, and can overlap with hypereosinophilic syndrome. It is possible that the condition may occur due to a type IV hypersensitivity reaction, following exposure to various exogenous and endogenous stimuli, the authors theorized.

Regarding the histologic evolution, the syndrome typically begins with a dense infiltrate of degranulating eosinophils notable in the skin and observed in the outer skin and the dermis.

As in this patient, subepidermal eosinophilic blisters may develop, followed a few weeks later by "" associated with the intense focal eosinophilic degranulation and subsequent degeneration of collagen fibers.

As symptoms resolve in the final stage, the eosinophils gradually disappear and the surrounding histiocytes and giant cells form granulomas.

Although Wells syndrome is not harmful, it is marked by frequent recurrences that can persist for years, remitting spontaneously for 2 to 8 weeks at a time, the case authors noted.

A 2013 of 32 patients reported peripheral eosinophilia in 67% of the patients and leukocytosis in 41%. "Histopathological findings such as flame figures present in the majority of cases (96%), edema in the dermis, and infiltration of the dermis by eosinophils, which were present in all 32 cases, are considered to be the gold standard for diagnosis of Wells syndrome," those researchers stated, adding that vasculitis is not a feature of the condition.

The case authors noted that peripheral blood eosinophilia, reported in about 50% of cases during the acute stage of Wells syndrome, may occasionally be accompanied by joint pain and fever. The misdiagnosis of this patient was largely due to the nature of her past episodes, which presented with cellulitis-like lesions, the presence of fever, and the absence of peripheral eosinophilia.

The similarities between Wells syndrome and bacterial cellulitis may lead to unnecessary antibiotic treatment and hospitalizations, which can be harmful or even exacerbate the existing skin disease, the authors said.

Furthermore, they said, "inappropriate in the community can lead to the selection of resistant and multidrug-resistant bacteria, which is an evolving global threat to humanity." As this case demonstrates, antibiotic-induced alterations in gut microbiome can reduce colonization.

First-line treatment of Wells syndrome includes systemic and topical corticosteroids, the team said; additional options include antihistamines, azathioprine, cyclosporine, dapsone, minocycline, antimalarial medications, oral tacrolimus/topical tacrolimus, sulfasalazine, colchicine, tumor necrosis factor alpha inhibitors, interferon alpha, and psoralen and ultraviolet A therapy.

"Highly persistent recurrences should be managed with low-dose oral steroids, and any underlying conditions that may have caused Wells syndrome should be investigated for and treated," the authors emphasized.

Conclusion

They concluded that the case emphasizes the need for greater vigilance before making a final diagnosis of infectious cellulitis, excluding any dermatological diseases that may mimic infectious cellulitis. "This will prevent possible misdiagnosis, delay of appropriate treatment, future antibiotic-associated complications, and the evolution of antimicrobial-resistant microbes in the community," the team wrote. "Early suspicion of Wells syndrome is crucial to tailor further diagnostic strategies and provide appropriate therapy and care in this patient population."

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