ARTICLE
Proximal white subungual onychomycosis (PWSO) is a rare form of nail
infection that occurs almost exclusively in immunocompromised patients.
This variant of onychomycosis is caused by Trichophyton rubrum
in 95% of all cases.
PWSO, extremely rare in HIV negative patients, was first described in
a patient with AIDS [1] and was later found in more than 80% of patients
with HIV infection affected by onychomycosis [2]. In this report we describe
a case of PWSO in a patient affected by a defect of polymorphonuclear
chemotaxis. Until now, there are no reports in the literature about the
association between ungual parasitism and alterations of leucocyte functions
in HIV-negative patients.
Case report
In June 1989 a 17-year-old woman, without risk factors for HIV infection,
was seen because of a recurrent furunculosis of the bottom and total-proximal
leukonychia localized at almost all the toe-nails and at some finger-nails
(Fig. 1). Deep scraping
of the white patches and potassium hydroxide preparation from this material
showed numerous hyphae. The cultural examination on Sabouraud glucose
agar with and without chloramphenicol revealed colonies of Trichophyton
rubrum. A complete recovery with negative results in the mycological
examinations was obtained after a 2-month therapy with fluconazole 50
mg a day. In February 1992 the patient reported the appearance, in recent
months, of irregular white patches in the proximal portion of the same
toe-nails. The mycological examinations revealed a nail infection by Trichophyton
rubrum. We decided to treat the patient with itraconazole 200 mg daily
for 2 months with complete resolution of the clinical and mycological
picture. Two years later, the patient returned to our observation because
of the reappearance, for over 6 months, of the PWSO. Again the onychomycosis
concerned almost all the toe-nails. The patient was treated with fluconazole
100 mg daily for 40 days with recovery. In February 1995, there was a
new appearance of the PWSO localized to the big toe-nail of the left foot.
Moreover, during the six years of our observation an unmodified picture
of the recurrent furunculosis of the bottom and the thighs persisted.
The repeated cultural examinations showed Staphylococcus
aureus as the isolated agent of the lesions on the bottom, so the
patient was treated with local and systemic antibiotic. Then the patient
was admitted to the day hospital to look for a cause for her immunodeficiency.
In fact, the patient showed no risk factors for HIV infection and she
had not been treated with immunosuppressive drugs, but she presented recurrent
infections typical of the immunocompromised host. The laboratory examinations
were performed; they included: routine investigations, erythrocyte sedimentation,
C reactive protein, rheumatoid factor, complement fractions (C3 and C4),
Rose-Waaler, Immunoglobulins, Antinuclear antibodies, hepatitis serology,
peripheral CD4+ and CD8+ cell counts. The results
were normal or negative. The investigation of HIV antibodies in serum,
and both ELISA and Western blot results were negative. A chest X-ray and
abdominal ultrasound showed no abnormalities. Finally, granulocyte functions
were studied. Polymorphonuclear leukocytes (PMN) were purified from heparinized
venous blood by Lymphoprep gradient (Nyegaard, Oslo, Norway) centrifugation
[3]. Chemotaxis was evaluated by a modified Boyden-chamber assay using
blind well chambers and 3 µm micropore filters (Millipore) as previously
described [3]. The chemoattractants include: zymosan-treated autologous
or AB serum (ZTS; 1mg zymosan/ml serum for 30 min at 37° C) and 10
8 M N-formyl-methionyl-leucyl-phenylalanine (FMLP, Sigma, USA).
Results were expressed as the number of PMN migrating through the entire
thickness of the filter/high power field(hpf).
The phagocytic capacity of PMN was evaluated using candida albicans
as the particle for uptake in the presence of autologous serum [3]. The
PMN oxidative metabolism was evaluated with a luminol-amplified chemiluminescence
assay in resting conditions and after stimulation with phorbol-myristate-acetate
(PMA, 50 ng/ml) [3].
In these functional evaluations, the patient's PMN showed normal phagocytosis
and oxidative metabolism (data not shown), while a significant defect
was observed in their chemotaxic activity (Table
I). At the present time the treatment of polymorphonuclear chemotaxis
defect is based on the use of vitamin C, in order to prevent recurrences
of infections. Nevertheless, this treatment gives different results. Our
patient refused any treatment and didn't come back for checking.
Discussion
The proximal white subungual onychomycosis (PWSO) is a rare form of
nail infections caused in 95% of cases by Trichophyton rubrum.
The fungus is believed to penetrate through the horny layer of the proximal
nail fold and subsequently invade the cells of the ungual matrix and the
deeper portions of the nail plate [4-6]. Initially leukonychia in the
lunula region appears; later, in long-standing disease, with nail growth,
the whitening of the proximal portion may involve the entire nail.
PWSO, extremely rare in HIV negative patients, was first described in
a patient with AIDS [1] and later found in more that 80% of the patients
with HIV infection affected by onychomycosis [2]. Today, PWSO is considered
to be a clinical sign of AIDS and in known cases of HIV positive serology,
it can suggest the onset of the disease [7-9]. Moreover, PWSO has been
described in two patients who received immunosuppressive therapy after
a kidney transplant [10, 11] and recently in a patient affected by systemic
lupus erythematosus (SLE), treated with systemic steroid therapy [12].
In this report we described a case of PWSO in a patient affected by
a defect of polymorphonuclear chemotaxis. Until now, there are no reports
in the literature about the association between ungual parasitism and
alterations of the leucocyte functions in HIV-negative patients.
Chemotactic disorders of polymorphonuclear leucocytes (PMN), congenital
or acquired, have commonly been classified in cellular defects (caused
by intrinsic cellular defects such as disorders of cell adherence, deformability,
cytoskeleton, etc.) and humoral defects (due to alterations of complement
fractions, mainly C3 and C5) [13] (Table
II).
The results of PMN functional tests on our patient
showed a normal chemotactic activity of the serum, suggesting a cellular
defect. Moreover, the laboratory investigations excluded immunological
defects (e.g. AIDS, immunoglobulin deficiency, abnormalities of
the complement fractions) and systemic diseases associated with a chemotactic
defect (leukemia, lymphoma, SLE, rheumatoid arthritis, etc). The association
between PWSO and chemotaxis impairment is not, probably, a casual event.
The determinant role of the altered polymorphonuclear activation in the
rising of mycotic infections, in the absence of other conditions of immunosuppression,
is suggested by the repeated recurrencies which followed complete recovery
and by the negative results of mycological examinations after systemic
therapy. We emphasize that every recurrence was always characterized by
the early involvement of the proximal portion of the ungual lamina by
Tr. rubrum. It is well know that this fungus usually causes a distal
subungual infection of the big toe-nail in non-immunocompromised patients.
The different parasitism of ungual laminas by Tr. rubrum in our
patient and the contemporaneous involvement of the finger-nails suggest
that the PMN can play an important role in the defense mechanisms of the
host during some types of dermatophytosis. Such mechanisms have not yet
been completely identified in onychomycosis. It is commonly thought that
the processes of cell-mediated immunity have great importance in the host
defense mechanisms during fungal infections [3, 14, 15]. We suppose that
the PMN can also play a decisive role in preventing proximal nail fold
infection caused by mycotic agents. Furthermore, the involvement of PMN
has been confirmed by an important polymorphonuclear activation during
dermatophytosis induced experimentally on guinea pigs [16]. In fact, it
is demonstrated that Tr. rubrum can produce a chemotactic low weight
molecular factor and can stimulate the synthesis of chemotactic seric
factor C5a [17]. We also notice that significant defects of chemotaxis
have been described in patients affected by AIDS [18] in whom the proximal
mycotic leukonychia represents the most frequent variant of onychomycosis.
In conclusion, we draw attention to the importance of recognizing this
variant of onychomycosis, which, though rare and not incapacitating, must
be considered clinically as a marker of immunological alterations. For
this reason we suggest carrying out HIV tests on all patients coming with
PWSO and, if the tests are negative, we recommend investigating the immunological
condition of the patients with PMN functional tests (chemotaxis).
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