Multiple Skin Lesions in an HIV-Positive Man

BACKGROUND
A 41-year-old man presents with fever, malaise, and a 20-lb weight loss over the past 3 months. The patient also has intermittent headaches, coughing with occasional hemoptysis, and multiple chronic skin lesions. The lesions initially appeared as hyperpigmented scaly plaques on his lower back (see Image 1). They have enlarged over the last year, spreading to his arms, nose (see Images 2-3), and penis (see Image 4). The lesions are not itchy or painful. Over the last few weeks, the lesions on the patient’s nose and penis have begun to ulcerate and produce a bloody, purulent discharge.

{mosimage}The patient was diagnosed with HIV infection 13 years ago. He denies having any chest discomfort, shortness of breath, nausea, or diarrhea. He has not traveled recently and has not had any contact with people who were sick. He has not spent any time in environments where the risk of tuberculosis is high (eg, prison, shelters). On physical examination, the patient is afebrile with a blood pressure of 116/58 mm Hg and a heart rate of 92 bpm. His respiratory rate is 14 breaths/min, and his oxygen saturation while breathing room air is 96%.
On his nose is a crusted, indurated plaque with irregular borders and central ulceration that produces thick, blood-tinged, suppurative discharge (see Image 3). A nontender oval-shaped crusted plaque with superficial ulceration is located on his penis at the base of the glans (see Image 4). Numerous skin-colored umbilicated papules, of about 3-6 mm and with central hemorrhagic crusts, are scattered irregularly on his arms and face (see Image 2). A diffuse, hyperpigmented lichenification of the skin is noted on his back, with many small areas of superficial ulceration (see Image 1).
No retinal lesions are noted on funduscopic examination. No frank nuchal rigidity is present; however, the patient expresses moderate discomfort with neck flexion. The lungs are clear to auscultation with no rales, rhonchi, or wheezing; the cardiac examination is normal. The remainder of the physical examination yields unremarkable results.
The patient is transferred to the adjoining emergency department (ED) and, because infectious meningitis is suspected, is placed in respiratory isolation. A lumbar puncture reveals an opening pressure of 22 cm H2O. A cerebrospinal fluid (CSF) sample is sent for laboratory evaluation and shows a WBC count of 450/mm33 (0.450 X 109/L) with a mononuclear predominance, a mildly elevated protein level, and a slightly decreased glucose concentration. India ink staining reveals the presence of fungi.

What is the etiology of the patient’s symptoms? Are all of the lesions from the same disease process?

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C neoformans var. neoformans exists in high concentrations in pigeon feces, and it can subsist in soil contaminated by pigeon feces for as long as 2 years. The organism grows as a round or oval yeast cell surrounded by a polysaccharide capsule composed of mannose, xylose, and glucuronic acid. It may be single or may have a budding daughter cell. Cell sizes vary widely and range from 3.5-8 µm in diameter.
Cryptococcus is primarily transmitted by means of respiratory exposure to environmental sources. Person-to-person transmission has not been documented. The host response to cryptococcal infection includes both cellular and humoral immune components, with an early reaction by natural killer cells, T lymphocytes, and macrophages. Antibody-dependent cell-mediated mechanisms may be involved. After the organism is inhaled, alveolar macrophages ingest the yeast. The encapsulated organisms resist phagocytosis with several mechanisms, such as the antiphagocytic properties of the polysaccharide capsule, which block recognition of the yeast by phagocytes. The capsule may also have immunosuppressive qualities that inhibit the migration of leukocytes to the area of fungal replication. In addition, the organism does not produce endotoxins or exotoxins.
As a result of these factors, cryptococcal infection typically does not cause clinically significant necrosis or organ dysfunction until late in the course of the disease. Tissue injury occurs primarily from the expanding fungal burden itself and is characteristically not associated with extensive inflammation or fibrosis. Lesions often consist of a cystic cluster of yeast with little to no surrounding inflammatory response.
Biopsies of tissue thought to contain Cryptococcus may be stained with several reagents, including mucicarmine (which preferentially stains mucopolysaccharides in the capsule), Fontana-Masson ammoniac silver stain (to detect melanin precursors in the cell wall of the yeast), and periodic acid–Schiff stain (PAS). India ink, which outlines the organisms in negative contrast, can also be used to identify yeast cells in fluids or macerated tissue samples.
Meningitis and meningoencephalitis are the most common manifestations of cryptococcal disease and are usually subacute or chronic in nature. Cryptococcal infection of the central nervous system (CNS) is lethal without appropriate therapy; however, mortality may occur anywhere from 2 weeks to several years after the onset of symptoms. The most common symptoms are headache and altered mental status. Other symptoms include nausea and vomiting, fever, meningismus, blurred vision or photophobia, hearing deficits, seizures, ataxia, aphasia, and choreoathetoid-type movements.
Overt pulmonary infection is the second most common clinical manifestation of disseminated cryptococcosis. This infection is characterized by fever, malaise, cough with scant sputum, pleuritic pain, and hemoptysis (which is uncommon). Although all cryptococcal diseases are likely to originate from a pulmonary infection, most of these infections are initially asymptomatic. Among HIV-positive patients with pulmonary cryptococcal infection, only 5-25% present with cough and dyspnea.1 Other pulmonary manifestations are poorly defined mass lesions, pulmonary nodules, and, rarely, pleural effusion. In severe cases, acute respiratory distress syndrome may develop.
After the lungs and the CNS, the next most commonly involved organs or tissues in disseminated cryptococcosis are the skin, prostate, and medullary cavity. Cutaneous manifestations occur in 10-15% of patients and appear as papules, pustules, nodules, ulcers, or draining sinuses.2 Rarely, patients may present with myocarditis, hepatitis, chorioretinitis, peritonitis, renal abscess, prostatitis, myositis, and adrenal infection.
As previously stated, skin involvement is observed in approximately 10-15% of patients with C neoformans infection. Isolated skin lesions may occur in immunocompetent patients; however, skin involvement in immunosuppressed patients indicates disseminated disease. The differential diagnosis of skin lesions in immunocompromised individuals includes basal cell carcinoma, syphilis, tuberculosis, bacterial or fungal abscess, blastomycosis, and infection with molluscum contagiosum. Umbilicated papules in patients with AIDS may resemble molluscum contagiosum.
Cutaneous cryptococcal infection is confirmed with biopsy and cultures. On diagnosis, disseminated cryptococcosis is presumed to be present, and the patient is treated with systemic antifungal therapy. Assessment of disseminated cryptococcal disease consists of cultures of the urine, blood, and sputum, as well as a lumbar puncture with appropriate evaluation of the CSF, including an India ink stain and fungal culture. In addition, a latex agglutination test should be performed to detect cryptococcal polysaccharide in the blood serum and the CSF. Detection of cryptococcal antibodies is of little utility because low concentrations may be present in healthy people.
In this case, cryptococcal meningitis was diagnosed, and the patient was given intravenous amphotericin B at 0.7 mg/kg/day and flucytosine at 100 mg/kg/day. Skin biopsy of the lesion on the nose revealed 5- to 8-µm, PAS-positive, encapsulated yeast consistent with C neoformans. Biopsy of the other skin lesions also revealed C neoformans. Culture of the penile lesion revealed coinfection with herpes simplex in addition to cryptococcal disease. The lesions on the patient’s back were tested with potassium hydroxide (KOH) and were positive for dermatophytes (tinea corporis) with follicular involvement (Majocchi granuloma). The surprising concomitant infections were thought to reflect the patient’s profound underlying immunosuppression. CSF bacterial cultures were negative. Bronchoalveolar lavage samples from bronchoscopy were negative for Pneumocystis jiroveci (previously Pneumocystis carinii) but positive for budding yeast consistent with C neoformans.