Disseminated cryptococcal infection initially presenting as cryptococcal cellulitis in an HIV-negative patient on long-term steroids

Abstract

Cryptococcosis is an invasive fungal infection caused by encapsulated yeasts of the Cryptococcus species. Inoculation usually occurs by inhalation through the respiratory tract, where it can then spread haematogenously to various sites, such as the central nervous system or the skin, in susceptible patients. We present the case of a 68-year-old male patient on long-term steroids who presented with a right upper limb cellulitis not responding to antibiotics. This was subsequently diagnosed as cryptococcal cellulitis on an urgent skin biopsy. Wound swabs and blood cultures, which were initially negative, were repeated and confirmed the presence of disseminated cryptococcal disease. The patient’s neighbours kept racing pigeons and this was hypothesised as a potential source of infection.

Background

Cryptococcosis is an invasive fungal infection caused by encapsulated yeasts from the Cryptococcus species. Cryptococcus neoformans has a worldwide distribution and can be recovered from soil and pigeon excreta. Most people have been exposed to C. neoformans during childhood without causing infection.¹ Infection has been primarily associated with HIV-positive patients, and it is thought to be responsible for up to 200 000 deaths per year in this population alone through infection of the central nervous system,² although it is becoming increasingly prevalent in other immunocompromised patients.³

Case presentation

We present the case of a 68-year-old male patient with a 1-month history of cellulitis to his right upper limb following trauma which did not respond to oral antibiotics in the community. The patient was referred to the hospital when the cellulitis began to deteriorate with worsening swelling and erythema.

The patient’s background medical history was significant for severe chronic obstructive pulmonary disease (COPD) requiring frequent courses of oral prednisolone, Addison’s disease diagnosed 15 years prior and coeliac disease. The patient’s medications included fluticasone inhaler 250 μg twice per day, tiotropium bromide inhaler 2.5 μg once daily, theophylline 200 mg once daily, montelukast 10 mg once daily, hydrocortisone 15 mg in the morning and 5 mg at night, calcium carbonate and colecalciferol T once daily, azithromycin 500 mg three times a week, and lansoprazole 30 mg. He had no known drug allergies. His family history was significant for rheumatoid arthritis, ischaemic heart disease and prostate cancer. He was married and lived with his wife in a city house. He was an ex-smoker of 20 years with a 60 pack-year history. He was a retired businessman with an extensive travel history due to his work, having visited North America, South Africa, China, South-East Asia and throughout Europe. The patient did not keep any pets.

He was afebrile on admission. An examination of his right upper limb revealed diffuse erythema distally from his elbow, mainly involving the dorsal aspect of his right forearm with evidence of ulceration. A respiratory examination revealed a mild diffuse wheeze. Neurological, cardiovascular and gastrointestinal examinations were normal.

Investigations

Routine blood work showed a white cell count of 20.2×10⁹/L with a predominant neutrophilia. C reactive peptide was elevated at 116 mg/L, and the patient’s albumin was low at 17 g/L. A chest X-ray showed chest hyperinflation but no focal infiltrates.

The patient was initially treated with intravenous flucloxacillin, benzylpenicillin and oral clindamycin. Intravenous hydrocortisone was commenced as treatment for an exacerbation of COPD, as well as stress-dose steroids given the patient’s history of Addison’s disease. Further investigations demonstrated a positive antinuclear antibody (ANA) with a titre of 1:160, a negative antineutrophil cytoplasmic antibodies (ANCA), negative HIV test, negative blood cultures and wound swabs and normal immunoglobulins. Despite initial modest improvements on intravenous antibiotics, the patient developed worsening ulceration on day 10 of admission with significant deterioration of the wound (figure 1).

Figure 1.

Image of the dorsum of the affected arm on day 10 of admission.

The patient’s antimicrobial cover was broadened to piperacillin-tazobactam and clindamycin, while blood cultures were repeated, a wound swab was sent, and an urgent biopsy and MRI of the affected arm were organised. An MRI revealed soft tissue oedema with superficial cellulitis without evidence of a collection or underlying osteomyelitis.

Budding yeasts with thick capsules were seen on Periodic acid–Schiff (PAS) stain and mucicarmine staining was positive, (figure 2) suggesting the presence of C. neoformans (figure 3). These results were confirmed when C. neoformans was isolated from the patient’s wound swab and blood cultures on repeat testing, suggesting disseminated cryptococcal disease. On further questioning, it transpired that while the patient and his wife did not keep any pets, their next door neighbour kept and fed racing pigeons, which could have acted as the source of infection.

Figure 2.

Affected arm at the end of maintenance therapy.

Figure 3.

High-power view of subcutaneous soft tissue biopsy demonstrating ovoid fungi with positive mucicarmine staining.

Differential diagnosis

Differential diagnosis includes vasculitis, pyoderma gangrenosum, herpes, mycobacterial infection, histoplasmosis and blastomycosis.

Treatment

The patient received a 3-week induction course of intravenous liposomal amphotericin B 3–4 mg/kg once daily and oral flucytosine 25 mg/kg four times a day, followed by an 8-week consolidation course of oral fluconazole 800 mg once daily. He then received a 6-month maintenance course of oral fluconazole 200 mg once daily.

Outcome and follow-up

The patient was seen in clinic 1 year from his initial diagnosis and is well. His wound has significantly improved.

Discussion

Cryptococcal cellulitis is a relatively rare presentation of cryptococcal infection. Such infections usually present with painless papules that can subsequently ulcerate. The differential for such skin lesions includes blastomycosis, histoplasmosis and tuberculosis. Most skin and soft tissue manifestations occur in the setting of disseminated disease, which is apparent in 10%–15% of patients with disseminated cryptococcal disease.⁴ However, there exists in the literature some evidence to suggest that cutaneous cryptococcal infection can lead to disseminated infection among the immunocompromised.⁵ Cryptococcal infections are usually seen in HIV-positive patients but are also seen in HIV-negative patients,⁶ with case reports of infections occurring in solid organ transplant patients,⁷ patients with underlying conditions such as nephrotic syndrome⁸ and myelodysplastic syndrome,⁹ and in those on long-term steroids affecting cell-mediated immunity.¹⁰ Diagnosis is usually made on histopathological inspection or by culture, and in this instance skin biopsy was crucial in reaching a timely diagnosis. Serological testing can also be useful. Lumbar punctures are essential in cases of suspected cryptococcal meningitis to assess for the presence of cryptococcal infection in the cerebrospinal fluid (CSF) and for elevated opening pressures (and subsequent requirement for therapeutic lumbar puncture (LPs)). Treatment for mild to moderate disease consists of oral fluconazole, but treatment of disseminated disease or cryptococcal meningitis requires induction with liposomal amphotericin B and flucytosine, followed by consolidation and maintenance with prolonged courses of oral fluconazole. Unrecognised and untreated, cryptococcal disease is associated with high mortality rates in both HIV-positive and HIV-negative patients.¹¹

Learning points.

• Cryptococcal infection is most commonly seen in HIV-positive patients, but patients with impaired cell-mediated immunity, such as solid organ transplant recipients and those on long-term steroid therapy, are also susceptible.

• It is important to assess for the presence of disseminated cryptococcal disease in all cases of cryptococcal cellulitis.

• Consider a diagnosis of cryptococcal infection in HIV-negative immunosuppressed patients presenting with cellulitis not responding to antibiotics.