Bullous and Necrotic Skin Lesions in a Cirrhotic Patient

The patient was a 79-year-old Hispanic man, a construction worker with a history of alcoholic liver cirrhosis (Child-Pugh score B) which was diagnosed clinically based on a history of heavy alcohol consumption and ultrasonographic findings consistent with liver cirrhosis (presence of nodular contour with coarsened echogenicity). No previous history of liver decompensations or related complications (eg, ascites, varices, or hepatic encephalopathy) had been documented. The patient also had history of chronic kidney disease (stage IV), chronic obstructive pulmonary disease, and compensated heart failure.

He presented with a 1-week history of pruritic rash, papules, and painful erythema, which rapidly evolved into hemorrhagic bullae involving the anterior aspect of his chest and spreading to his left arm and shoulder, the upper part of his back, and his neck. The patient denied abdominal pain, vomiting, or diarrhea, and no confusion, headache, or photophobia was noted. At presentation, his temperature was 98.2°F (36.7°C); pulse rate, 98/min; respirations, rate 20/min; blood pressure, 128/66 mm Hg; and oxygen saturation, 98% with room air. Physical examination findings were noteworthy for extensive skin necrosis and the presence of blisters and plaques (Figure 1). The patient denied skin trauma or injury, any recent consumption of raw oysters or undercooked seafood, or exposure to warm seawater. He did not have any recent infection, nor had he received any new medications, including antibiotics. He reported no history of recent travel or contact with animals reported, and had no indications of cancer or diabetes.

Figure 1.

Skin lesions on the anterior aspect of the patient’s chest and on his neck, left shoulder, and left arm, with extensive necrotic plaques and hemorrhagic bullae on an erythematous base.

Laboratory tests showed leukocytosis, with a white blood cell count of 27 500/μL (normal range, 4000–10 000/μL), 89.7% neutrophils (42%–66%), and a platelet count of 112 000/μL (150 000–350 000/μL). The patient had a creatinine clearance rate of 35 mL/min (normal, ≥60 mL/min), an international normalized ratio of 1.35 (0.85–1.17), and the following levels: glucose, 108 mg/dL (normal, 70–99 mg/dL); albumin, 2.1 g/dL (3.5–5.2 g/dL), alanine aminotransferase, 17 U/L (≤35 U/L), aspartate aminotransferase, 15 U/L (≤35 U/L), and total bilirubin, 0.6 mg/dL (≤1.2 mg/dL). Further testing revealed a ferritin level of 367 ng/mL (normal, 12–300 ng/mL) and a negative human immunodeficiency virus antibody test result.

Treatment was started with cefepime, vancomycin, and clindamycin for presumed necrotizing fasciitis, and the patient was transferred to our hospital for additional dermatological evaluation, with a presumptive diagnosis of Stevens-Johnson syndrome. A skin biopsy specimen was obtained from the anterior chest lesion, and a culture was performed. While we awaited the biopsy results, we continued empirical treatment with antibiotics and skin dressings. After 4 days of antibiotic therapy for presumed bacterial cellulitis, the patient’s rash continued to worsen, with progressive erythema and further skin necrosis.

What is your diagnosis?

Diagnosis: Necrotizing skin infection due to Cryptococcus neoformans.

The differential diagnosis of acute bullous and necrotic skin lesions is broad and includes infectious versus noninfectious causes. Stevens-Johnson syndrome, toxic epidermal necrolysis, and bullous skin diseases are of concern. Bullous cellulitis can be caused by infection with Staphylococcus aureus, group A Streptococcus, Aeromonas hydrophila, Photobacterium damsela, or Erysipelothrix rhusiopathiae, as well as clostridial infections, such as Clostridium perfringens and Clostridium septicum infection. Moreover, in cirrhotic patients, Vibrio vulnificus and Vibrio parahaemolyticus infection should be considered highly possible in the differential diagnosis.

Histopathological testing of a skin biopsy specimen showed suppurative inflammation with separation of tissue in the upper reticular dermis filled with neutrophils and numerous narrow base budding yeasts. Hematoxylin-eosin stain showed yeasts with narrow bases and surrounding halos. Mucicarmine stain revealed yeast cell walls with capsular material suggestive of Cryptococcus spp., and Grocott-Gomori methenamine silver stain showed yeast organisms present within multinucleated giant cells (Figure 2).

Figure 2.

Histopathological appearance of skin lesions demonstrating suppurative inflammation with infiltration of neutrophils. A, Hematoxylin-eosin stain revealing yeasts with narrow base and surrounding clearing (arrow) (original magnification ×40). B, Mucicarmine stain showing yeast cell wall with capsular material (arrow) (original magnification ×10). C, Grocott-Gomori methenamine silver stain showing yeast organisms within multinucleated giant cells (arrow) (original magnification ×10).

Culture from the skin biopsy specimen yielded Cryptococcus neoformans (confirmed by means of matrix-assisted laser desorption ionization–time of flight), and the result of a test for cryptococcal antigen in serum was positive (titer, 1:640). Further microbiological analyses excluded other infectious causes that could lead to hemorrhagic bullae, including herpes simplex virus and varicella zoster virus. Results of fungal blood culture were negative. Given the concern of disseminated cryptococcal disease, chest and head computed tomographic scans were obtained, yielding normal results. Lumbar puncture indicated a normal opening pressure. Cerebrospinal fluid analyses revealed that normal cell counts and glucose and protein levels and negative Cryptococcus antigen and culture results.

C. neoformans is an encapsulated yeast that usually affects immunocompromised hosts and commonly presents as a meningoencephalitic disease and/or pulmonary infection. It is an ubiquitous organism that is frequently found in soil contaminated with pigeon droppings, and it can be found in decaying wood and vegetables [1]. It is characterized by 4 serotypes, with serotype D (C. neoformans, var. neoformans) being the most common. Although cutaneous cryptococcal infection mainly occurs in the setting of disseminated cryptococcosis, a primary cutaneous cryptoccocosis (PCC) has also been described secondary to direct skin inoculation [1].

Patients with PCC have baseline characteristics that differ from those of secondary cutaneous cryptococcosis. Indeed, they tend to be older, with a male-female ratio of 1:1. Patients affected with serotype D have high-risk exposure activities resulting in skin injuries and dermal inoculation [1]. Skin infection usually presents as solitary lesions, cellulitislike dermatitis, ulcerations, or localized whitlow, in contrast to cutaneous lesions secondary to disseminated cryptococcosis, which are scattered and may mimic Molluscum contagiosum [1]. Interestingly, cirrhotic patients have abnormal neutrophil phagocytosis and intracellular killing activities that predispose them to cryptococcal infection [2]. Cases of cryptococcal cellulitis have been described in the literature, mainly among patients with solid organ transplants [3] and liver cirrhosis [4].

Our patient had compensated liver cirrhosis and presented with severe necrotizing hemorrhagic cutaneous infection that mimicked Stevens-Johnson syndrome. He received fluconazole (600 mg/d, adjusted to his creatinine clearance rate), and his skin lesions showed remarkable improvement after 1 week of treatment (Figure 3). Unfortunately, his hospital course was complicated by a bowel obstruction secondary to incarcerated hernia that resulted in respiratory failure and aspiration pneumonia and progressed to his death.

Figure 3.

Appearance of cryptococcal skin lesions on the chest and left arm after 7 days of antifungal therapy.

The treatment is not standardized and the Infectious Disease Society of America recommends induction therapy with amphotericin B or high-dose fluconazole for patients without human immunodeficiency virus and without transplants who have non–central nervous system infection, followed by maintenance therapy with fluconazole for 6–12 months [5]. PCC has a better prognosis than secondary cutaneous cryptococcosis [1]. The diagnosis of PCC can be challenging, and clinicians should maintain a high index of suspicion for necrotizing cryptococcal skin infection among patients with liver cirrhosis presenting with progressive cellulitis despite antibiotic therapy.

Notes

Financial support. C. A. A. is supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant K24-AI114818).

Potential conflicts of interest. C. A. A. has received grant support from MeMed Diagnostics, Merck, and Entasis Pharmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.