ARTICLE
Cryptococcus neoformans has been known as a source of human infection
for more than 90 years [1]; however, the number of cryptococcosis cases
has considerably increased since the outbreak of HIV infection. Cryptococcosis
is most frequently found in HIV-positive subjects, as it affects about
2-10% of AIDS patients [2, 3]. Of these, more than 15% are located in
Africa [4], even though new anti-retroviral therapies are noticeably modifying
the epidemiology of AIDS-related opportunistic infections. The initial
phase of cryptococcal infection usually involves the respiratory tract
and causes, in the immunocompetent subject, a benign, localized infection,
which is often asymptomatic and tending to spontaneous resolution. In
the immunocompromised patient, the pulmonary involvement gives rise to
scarce and aspecific symptoms only, making its recognition difficult;
in addition, in these patients, fungi tend to spread from the respiratory
tract, invading the bloodstream, and colonizing other organs, chiefly
resulting in meningoencephalitis and sepsis [3, 5]. Systemic dissemination
is a characteristic of the terminal phases of cryptococcal sepsis, but
it can also affect subjects with a prevalent CNS involvement, who display
neurological as well as organ failure symptoms. In particular, the cutaneous
localization usually occurs in the terminal phases of lethally disseminated
infections.
Cases of primary cutaneous cryptococcosis have rarely been described
[1], especially if AIDS patients are excluded; reports of such an infection
in immunocompetent subjects are even rarer [6, 7]. We describe a case
of primary cutaneous cryptococcosis (clinically, microbiologically and
histologically diagnosed) in a patient whose immunological competence
showed no sign of alteration.
Case report
G.B., a 76-year-old man living in Northern Italy, suffering from by
prostatic hyperplasia, was admitted to our Dermatology Clinic with painless,
ulcerated lesions (duration: 45 days) with a sero-purulent exudation,
surrounded by an erythematous halo and localized at the second, third,
fourth and fifth fingers of the right hand (Figs.
1 and 2).
One month after the eruption of the first ones, similar lesions arose
on the right elbow (Fig. 3);
the entire forearm's aspect was oedematous. The patient was not feverish
and, at clinical examination, there were no palpable lymph-nodes. The
patient denied having recently had any traumatic lesion of his right limb;
when questioned about his life conditions, and in particular about any
contact with animals, he stated that he kept some poultry, but that he
had neither pigeons nor cage-birds.
Laboratory tests, X-rays of the chest and superior right limb and the
HIV test were negative; a cutaneous swab, a cutaneous biopsy and serological
examinations were additionally performed.
In particular, both the serological and the cultural examination for
Cryptococcus neoformans were carried out, as the patient presented
symptoms which were highly suspect for a cryptococcal infection.
The determination of the level of the Cryptococcus
neoformans capsule polysaccharide antigen in the serum and urine specimens
of the patient gave a result of 1/512 and 1/64, respectively; it is important
to remark that the prostatic infection is particularly interesting, as
this organ is a "reservoir" of the cryptococcal infection, and responsible
for relapses [8, 9]. Serological examinations were carried out by a highly
sensitive and specific latex test (Latex-Crypto Antigen Detection System-Immuno-Mycologics,
Inc.) [10].
The cultural examination of a fragment of the cutaneous biopsy was performed
by seeding the specimen on Sabouraud Dextrose Agar (SAB-OXOID) medium,
with the addition of chloramphenicol (CAF-OXOID). After incubation of
the culture at 37° C for 72 hrs, a yeast-like fungus could be isolated;
its identification was based on biochemical tests of standard absorption
in suitable strips (ID 32 C bio Merieux) containing substrates of dehydrated
carbon. Their evaluation after an incubation of 24-48 hrs at 30°
C, both direct (optical) and automatic (ATB analyzer) confirmed the identification
of Cryptococcus.
The cultural examination of the cutaneous swab and a culture for Mycobacteria
on the biopsy gave negative results.
The histological examination showed a heavy inflammatory infiltrate
containing PAS + micro-organisms (Fig.
4).
A systemic attack therapy was started at once, with fluconazole 400
mg/day for 10 days; after this period, there was a remarkable clinical
improvement of the lesions, and the patient was discharged with a maintenance
therapy (fluconazole 200 mg/day). After one month, the cutaneous lesions
were further reduced, but, although a complete series of laboratory and
clinical examinations was scheduled, the patient repeatedly refused any
other re-evaluation, and he was lost from follow-up.
Discussion
The existence of primary cutaneous cryptococcosis as a distinct clinical
entity has long been debated; indeed, in the 70's it was considered as
"a sentinel of disseminated disease" [11], simply the first phase of an
infection doomed to spread systemically, associated with a poor prognosis.
In the same period, the prevailing opinion was reinforced by Noble and
Fajardo [12], who, reviewing five cases of cutaneous cryptococcosis, denied
the existence of cutaneous cryptococcal infection without previous, concurrent
or future systemic involvement. However, after a few years, the first
detailed report of primary cutaneous Cryptococcus was made: the
patient was a renal transplant recipient undergoing immunosuppressive
therapy [1]; after the outbreak of HIV infection, it became clear that
an altered immunological status is an important factor for developing
this disease.
In fact, Cryptococcus neoformans infection
usually affects subjects with an impaired cell-mediated immune response
(e.g. HIV-infected patients), defined by high antigenic levels
and aspecific symptoms, and, in this subset of patients, it is characterized
by a striking tendency to systemic dissemination [13, 14] with a poor
prognosis.
In addition, in our case the patient had a normal cell-mediated immunity
(CD4 = 939, in absolute number) and non-elevated antigenic levels (less
than 1/1,024, considering the minimal dilution at which sera from immunocompromised
patients are usually positive for Cryptococcus antigen in acute
infection) [CC's personal observations, data not published].
In the past few years, some reports of primary cutaneous Cryptococcus
neoformans infection in HIV negative patients have been published
(Table I). As summarized
in Table I, risk factors
include exposure to pigeons, which was not relevant in our patient's case.
A long-term follow-up of the patient is necessary, as the risk of systemic
spread of the infection is present [15]. Keeping in mind that the monthly
laboratory control of the Cryptococcus neoformans circulating antigen
level in serum and urine specimens of the patient constitutes a constant
check on the efficacy of the therapy; whenever an increase of the antigenic
level occurs, a cultural examination should also be performed, so as to
prevent possible relapses.
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