ARTICLE
Auteur(s) : Markus Streit1,
Lorenz M Böhlen1, Thomas Hunziker1, Stefan
Zimmerli2, Gion G Tscharner1, Helga
Nievergelt1, Thomas Bodmer2, Lasse R
Braathen1
1Department of Dermatology, Inselspital, University
of Bern, 3010 Bern, Switzerland
2Institute for Infectious Diseases, Inselspital,
University of Bern, 3010 Bern, Switzerland
accepté le 20 Avril 2005
A typical i.e. non-tuberculous mycobacteria comprise a heterogenous
group of acid-fast bacilli. The epithet “atypical” originates from
the initial belief that these organisms were unusual strains of M.
tuberculosis; however these organisms differ from M. tuberculosis
in their clinical spectrum, cultural characteristics and
susceptibility to antimycobacterial drugs [1]. Atypical
mycobacteria are found in water and soil, on plants and in feces of
healthy animals. Usually they are not pathogenic for
immunocompetent humans, but some of these bacteria can lead to
infection after trauma when bacteria enter the skin and induce
lesions resembling panniculitis. The increasing prevalence of
infections with atypical mycobacteria observed recently is partly
due to the rising prevalence of immunocompromised patients. These
patients – in contrast to the immunocompetent ones – often present
widespread infection with multiple cutaneous and subcutaneous
nodules [1].Mycobacterium marinum is an atypical mycobacterium
which has a worldwide distribution, lives freely in fresh or salt
water and preferentially infects skin tissue. In immunocompetent
hosts it may cause a single nodule or plaque or clustered lesions
that appear on the extremities and may be crusted, ulcerated or
verrucous [2]. A sporotrichoid spread along the lymphatics may be
observed [3]. Disseminated cutaneous lesions and more invasive
infections have been described in immunocompromised patients,
systemic lesions, however, are extraordinarily rare [4].
Case report
An 87-year-old Swiss woman – the wife of a former general
practitioner – had been treated with systemic corticosteroids for
more than twenty years because of polymyalgia rheumatica, diagnosed
in 1980. Systemic corticosteroids were dosed according to the blood
sedimentation rate and in the last years were at 6 mg oral
deflazacort daily. Following the implantation of an aortic valve
prosthesis (St. Jude Medical number 23) in 1990 for severe aortic
stenosis and moderate aortic insufficiency, the patient was
anticoagulated with phenprocoumon. Otherwise she had been in good
health until May 2001 when she noticed a tender painful red nodule
on her right forearm and a painful swelling of the right wrist. The
clinical aspect of the skin lesion was suggestive for erythema
nodosum accompanied by oligoarthritis of the right wrist. Histology
revealed non-specific inflammation of the dermis and subcutaneous
tissue without vasculitis and with mostly septal involvement. Blood
sedimentation rate was 40 mm/1. hour. Complete WBC, C-reactive
protein, conventional chest X-ray and abdominal sonography were
within normal limits. Assuming an increased activity of the
rheumatological disease, the steroid dose was increased to
40 mg prednisone daily and rofecoxib was added. With this
treatment the arthritis of the wrist resolved and the erythema
nodosum-like lesion on the forearm became less indurated. 6 months
later, methotrexate was introduced (weekly subcutaneous injections
at a dosage of 15 mg) because of relapsing arthritis of the right
wrist. One week later, the patient was hospitalized with
gastro-intestinal bleeding from a duodenal ulcer. High doses of
omeprazole and blood transfusions successfully healed the ulcer. No
other skin lesions were detected at this time, but there was a
relevant elevation of transaminases of unknown cause. At home again
the general condition of the patient worsened. She complained of
severe arthralgias of both ankles and wrists without any clinical
sign of arthritis. The erythematous nodule on the right forearm
grew larger and new, identical lesions developed on all limbs. The
patient was readmitted to the local hospital with a fever of
39.2 °C. Elevated values were measured for leucocytes (27.8
G/L, with 87% neutrophils), blood sedimentation rate (75 mm/1.
hour), C-reactive protein (227 mg/L), lactic acid dehydrogenase
(1189 U/L), ALAT/ASAT (74/95 U/l) and alcaline phosphatase (147
U/L). A skin biopsy revealed lobular panniculitis with formation of
neutrophilic abscesses, but without vasculitis. Levels of
alpha1-antitrypsin, antinuclear antibodies including subsets (i.e.
anti-ds-DNA-, -Sm-, -RNP-, -SS-A-, -SS-B-, -Histon-antibodies), c-
and p-ANCA and rheuma factor were normal. Repeated blood cultures
were sterile. By transesophageal echocardiography the heart valves
were free of vegetations. CT-scan and ultrasonography disclosed no
significant pathology of the abdominal organs. A “culture-negative”
endocarditis of the prosthetic valve was suspected. But neither
empiric therapy with intravenous cefepime, ofloxacin and
fluconazole, nor increased doses of prednisone up to 200 mg daily
could improve the general condition. Increasing fever, rapidly
spreading skin lesions and a deterioration of the general condition
led to the referral to the University Department of Dermatology.
On admission, the critically ill somnolent patient presented
with fever up to 40 °C, tachycardia (112/min) and hypotension
(112/64 mmHg). Multiple haemorrhagic and necrotic nodules that were
partly ulcerated and crusted covered her arms and legs (( figure 1 )A and B),
the trunk, and her face. Interestingly, there were no cutaneous
lesions on her back and on dorsal aspects of the extremities, i.e.
the parts of the body on which the patient was lying.
Cultures of the lesions were negative for Herpes simplex virus
and Cytomegalovirus. Serology was negative for Rickettsia conorii
and R. mooseri, Borrelia burgdorferi, Treponema pallidum, HIV,
Hepatitis B and C and Toxoplasma gondii. Skin biopsies again
revealed superficial and deep nodular suppurative dermatitis and
mixed septal and lobular panniculitis. There was no granulomatous
reaction and there were no epitheloid cells or giant cells or signs
of vasculitis. However, very high numbers of acid-fast bacilli were
detected by Ziehl-Neelsen stain (( figure 2 )). Cultures of
skin biopsies, peripheral blood, and urine samples grew
Mycobacterium marinum. Biopsies of liver and bone marrow were not
performed because of the risk of bleeding complications under
anticoagulation. The final diagnosis was disseminated cutaneous and
bacteremic infection with Mycobacterium marinum.
Suspecting immunological panniculitis, at admission high-dose
intravenous immunoglobulines (IVIG) were administered for two days,
which decreased the fever and reversed the hypotension. When
acid-fast bacilli were found, a tuberculostatic therapy with
rifampicin 600 mg qd, isoniazid 250 mg qd, pyrazinamid
1,500 mg qd and ethambutol 1,300 mg qd was started. This
treatment was changed to clarithromycin 500 mg bid and ethambutol
1,200 mg qd when nucleic acid amplification tests were
negative for the Mycobacterium tuberculosis-complex and when
possibly drug-induced pancytopenia developed (which was suspected
to be of medicamentous origin, in first line rifampicin).
Corticosteroid dosage was lowered without relapse of polymyalgia
rheumatica. The patient’s general condition improved slowly. She
remained afebrile, her pancytopenia resolved very slowly, and
liver-function tests returned to near-normal levels within three
months. A transient severe hypoproteinemia with anasarca was
treated with albumine infusions and intravenous colloid-osmotic
substances and resolved completely. After installation of the
antimycobacterial treatment no new skin lesions developed, the size
of the nodules decreased significantly and most of the exulcerated
lesions reepithelialized. However, a skin biopsy taken three months
later revealed numerous acid-fast bacilli. After 4 months, new
papulo-vesiculous skin lesions appeared on the neck and legs, and
the C-reactive protein increased. A biopsy of a new lesion was
again positive for acid-fast bacilli. When doxycycline 200 mg
daily was added to her regimen, the C-reactive protein normalized
and no new skin lesions occurred. Treatment has been continued
until today and will be administered for at least 6 months.
Discussion
Mycobacterium marinum was first isolated in 1926 from salt water
fish that had died in the Philadelphia aquarium [5]. In fresh water
the organism platyfish can cause tuberculosis but it was not
recognized as a cause of human disease until 1951 when Norden and
Linnel isolated the organism from granulomatous skin lesions [6].
Infection arises when traumatized skin comes into contact with
infected water in swimming pools, aquariums, oceans or lakes.
In most cases the source of infection can not be identified. In
a literature review of 652 cases of M. marinum infection [7] the
source of exposure was not documented in 72% of the cases. Known
sources of exposure are most often associated with aquariums (i.e.
50% in the study mentioned above, 84% in a French survey [8]).
Today, due to improvement in water-disinfection, swimming
pool-associated infections account for only 2.6-4.4% of cases.
Other sources of infection include fish or shellfish injuries as
well as salt- or freshwater contact [7]. Therefore the key
information in the patient’s history concerns occupational or
recreational contact with fish and water in the presence of a
trauma at the site of infection. The only potential source of
exposure in our patient was a visit to a public open-air whirlpool,
which might have presented ideal temperatures for the growth of M.
marinum.
Mycobacterium marinum grows optimally at 30 to 32 °C and
poorly, or not at all, at 37 °C [9]. Therefore, infection is
usually limited to the peripheral, cooler parts of the body, mainly
to the skin of hands and fingers: In a series of 38 patients,
infectious lesions were localized on the fingers in 25%, in 10%
each on hands and wrists and in 5% on the forearms [2]. The upper
limbs were the site of infection in 60 of 63 patients in another
study [8]. Clinically, plaques and nodules predominate [2].
Papules, ulcers and a sporotrichoid distribution are only found in
a small percentage. The infectious process may rarely spread to
deeper structures to involve tenosynoviae, bursae, bones or joints
[8, 10]. The infection is termed disseminated if multiple
metastatic cutaneous lesions occur on the contralateral side of the
body with or without bacteremia and/or involvement of deep
structures such as bones, joints, lungs and intra-abdominal organs
[4].
To our knowledge only 19 cases of disseminated infection –
including the present report – have been published [4, 11-27]. In
immunocompetent patients, disseminated M. marinum infection is rare
[13, 19, 24]. The majority of the cases arose in immunocompromised
patients, most often in patients with an immunosuppressive therapy
[14], notably systemic corticosteroids [4, 11, 12, 16, 18, 26, 27].
Our patient had been on long-term therapy with systemic
corticosteroids when she was infected and when the infection
disseminated, methotrexate was added to the steroids.
There are also reports of disseminated M. marinum infection
associated with AIDS [22, 25, 28], but AIDS does not seem to
influence prevalence [1].
The incubation period for cutaneous M. marinum infection is
commonly reported to range from 2 to 6 weeks. In a literature
review Jernigan and Farr [7] found evidence that the incubation
period may last longer than 9 months (the 75th
percentile of the incubation period according to their data at 30
days, the 90th percentile at 60 days). Given that the
erythema nodosum-like lesion on the forearm was the first clinical
manifestation of M. marinum infection, symptoms in our patient
occurred 9 months before diagnosis. Ziehl-Neelsen staining of the
initial biopsy disclosed no acid-fast bacteria, which may not be
surprising. In localized disease only 9 [29] to 13% [2] of skin
biopsies are microscopically positive. The very high numbers of
mycobacteria found in biopsies at the time of readmission may only
be seen in disseminated disease [4], especially in immunosuppressed
patients [30].
The histological manifestations of M. marinum infection are
variable and depend on the age of the lesion [31]. Although
non-caseating granuloma formation is a common histological feature
of M. marinum infection [2], the complete absence of both
epitheloid cells and multinuclear giant cells is not unusual in
acute lesions.
Minocycline (100 mg bid), doxycycline (100 mg bid),
trimethoprim-sulfamethoxazole (160/800 mg bid), rifampicin
(600 mg qd), clarithromycin (500 mg bid), and
ciprofloxacin are recommended drugs for the treatment of localized
M. marinum infections [1, 31]. Hyperthermic treatment which
prevents growth of M. marinum is another therapeutic option in
localized infections [18, 32] as well as excision, curettage or
cryotherapy. Some lesions heal spontaneously within 3 months to 3
years [33].
In extensive disease, monotherapy should be avoided [4]. In the
rare cases of disseminated disease, combination therapy with more
than 3 agents was most often used [4]. The combination of
clarithromycin and ethambutol led to a dramatic initial improvement
in our patient but new skin lesions developed after 3 months and
doxycycline was added to the regimen. The high doses of
immunoglobulins initially administered in our patient also seemed
to be beneficial. In a recent case report immunoglobulins in
combination with streptomycin were used successfully [11]. The role
of immunoglobulins, however, is difficult to assess and the
mechanism of action remains unclear.
Conclusion
This case highlights some aspects of Mycobacterium marinum
infection. Clinical diagnosis may be difficult. Painful
erythematous nodules on the skin of the extremities are indicative
of infectious panniculitis. Atypical mycobacteria can cause
panniculitis and these pathogens should be considered even if the
acid-fast stain is negative. Furthermore, laboratories which do not
routinely culture skin biopsies at 28 °C-32 °C must be
alerted to the suspicion of a M. marinum infection to ensure
correct culturing of specimens. The patient’s history may give the
right clues and one should inquire about skin lesions associated
with water or fish contact that may have occurred many months
before the onset of symptoms. Finally, our case demonstrates that
M. marinum infection can present as a life threatening illness in
immunocompromised patients.
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