ARTICLE
The pathogenesis of erythema induratum (EI) and its relationship to
tuberculosis (TB) are still poorly understood, and while there is no doubt
that for some of EI such a relationship exists, there are good reasons
to doubt it in others. The tuberculous etiology of EI is largely circumstantial
and not always convincing. Active TB is found only rarely in EI patients
[1]. We herein report a case of EI in which concurrent active TB of the
axillary lymph nodes could be proved. At the same time we highlight the
IFN-gamma release of specific T cells in order to determine whether or
not the formation of EI is associated with IFN-gamma.
Case report
In October 1997 a 57-year-old woman presented with recurrent crops of
painful red nodules on her legs over the previous 6 months. She was otherwise
in good health. She had no past history, family history or contact history
of TB. Physical examination revealed multiple erythematous nodules of
varying sizes on the anterior and posterior aspects of the lower legs.
There was no ulceration and no lymphadenopathy was palpable. Tests regarding
a diagnosis of TB showed a normal chest X-ray. At 48 hrs, the purified
protein derivative (PPD) skin test produced a 35 x 23 mm area of induration.
The erythrocyte sedimentation rate was 66 mm/hr. A biopsy specimen of
a skin nodule of her leg revealed a granulomatous panniculitis with vasculitis.
Epithelioid cell granulomas with multinucleated giant cells including
Langhans type were seen. Small and medium-size blood vessels were affected.
Caseation necrosis was not observed. Staining for acid-fast bacilli was
negative. These findings were consistent with EI. Since no evidence of
active TB was obtained at that time, initial therapy was started with
a nonsteroidal anti-inflammatory agent.
In December 1998 several tender nodular lesions recurred on her legs
and arms, and then gradually spread to her buttocks and face. A second
biopsy of the subcutaneous nodule from her face showed a similar histological
picture to that of the first biopsy specimen from the leg. Staining for
acid-fast bacilli was negative.
During a follow-up, in March 1999 the patient
developed an enlargement of the right axillary lymph nodes. An MR imaging
appearance of the chest showed no remarkable changes in her hilar lymph
nodes or associated pulmonary lesions. An excisional biopsy of one of
the enlarged axillary lymph nodes revealed numerous granulomatous lesions
with epitheloid cells and Langhans giant cells and massive coagulative
caseation necrosis. Staining for acid-fast bacilli was negative. Based
on the characteristic histological features of the lymph nodes, tuberculosis
was diagnosed. Treatment with rifampicin and isoniazid was started and
continued for 6 months. Both skin nodular lesions and residual lymph nodes
effectively responded to the antituberculous therapy.
The patient's peripheral blood mononuclear cell (PBMC), suspended with
RPMI medium with 10% AB human serum (1 x 106/ml), was cultured
with or without PPD (2 mug/ml) for 72 hrs. Cell-free supernatants were
collected and the activities of IFN-gamma in the culture supernatants
were measured with an EIA test kit (Medgenix, Brussels, Belgium). When
PBMC were incubated with PPD, a very high level of IFN-gamma (45.9 IU/ml)
was detected, in contrast to that (0.4 IU/ml) obtained from incubation
without PPD. PBMC from the patient showed a high proliferative response
to PPD (stimulation index; 19.5), by measuring the tritiated thymidine
uptake. Positive control samples were done by stimulation with lymphocytes
mitogen phytohemagglutinin (stimulation index; 41.0). These results indicate
that IFN-gamma was released by PPD-specific T cells from the patient with
EI.
Discussion
In close agreement with previous studies [2], our findings illustrate
that patients with EI may have a markedly enhanced T cell response to
PPD as shown in vivo by skin testing and in vitro by a lymphocyte
proliferation assay. However, little information is yet available concerning
the cytokines participating in the formation of EI. A number of cytokines
such as IFN-gamma, are associated with the granuloma formation of TB [3].
IFN-gamma plays a role in the effector phase of the delayed-type hypersensitivity
(DTH) reaction. It has been reported that mycobacterium tuberculosis (MT)
DNA can be detected using PCR from skin lesions of EI [4-7] while MT may
not be detected by culture. In our patient in vitro IFN-gamma release
studies indicate the possibility that PPD-specific T cells, capable of
producing IFN-gamma, are likely to be involved in the formation of EI
as a type of DTH response to MT antigens at the site of skin lesions.
It is quite clear today that EI has a multifactorial
etiology and TB can be considered to be one of several possible causes.
Although active TB is rarely found in EI patients, it has been reported
in the lungs, lymph nodes, endometrium, and kidney [8, 9]. Several authors
have stressed the high incidence of lymph node involvement [10, 11]. We
herein reported EI in a woman with active TB of the axillary lymph nodes.
The association between EI and active TB in peripheral lymph nodes has
been previously reported [10-13], with the cervical lymph nodes most frequently
involved by TB. The axillary site of lymph node involvement is rare [11].
TB is still a very important infectious disease world-wide and a recent
resurgence of TB has been observed in Japan. We believe that, as a result
of this case, the potential tuberculous origin of EI should be re-emphasized
while the finding of EI should prompt a careful search for the pulmonary
or extrapulmonary involvement of a tuberculous infection.
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