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Mycobacterium marinum infections of the hand
Mycobacterium marinum infections of the hand Fifteen patients had culture proven Mycobacterium marinum infections of the hand; 11 had injured their hands while fishing in water around Long Island. No patient had type I lesions (verrucal), six patients had type II lesions (subcutaneous granulomas), and nine patients had type III lesions (deep). Histologic examination showed noncaseating granulomas in all cases. A specific defect in the patients' lymphocytes ability to respond to M. marinum antigens was identified. A combination of surgery and tetracycline provided effective treatment. Follow-up averaged 21/2 years. (J HAND SURG 1987; 12A:428-35.)
Lawrence C. Hurst, M.D., Peter C. Amadio, M.D., Marie A. Badalamente, Ph.D., Jerry L. Ellstein, M.D., and Raymond J. Dattwyler, M.D., Stony Brook, N.Y., and Rochester, Minn.
Mycobacterium marinum was first isolated in 1926 by J. D. Aronson. This mycobacterium was obtained from dead salt water fish at the Philadelphia Aquarium. I In 1942, Baker and Hagan4 described an atypical mycobacterium infection in the Mexican flat fish and named it Mycobacterium platypoecilus. 2 . 3 Linell and Norden 5 diagnosed the first human M. marinum infection. They called the new acid-fast bacillus, Mycobacterium balnei. 5 It is now known that these three organisms are identical, and the international code accepts M. marinum as the official name. 6 . 7 More than 75% of the reported cases of M. marinum infections involve the hand and upper extremity. All fifteen cases reported here involved the hand.
Materials and methods This work is a combined prospective and retrospective study of 15 patients with culture proven M. marinum infections. All patients were seen at the University From the Department of Orthopaedics, and the Department of Medicine, Division of Allergy/Rheumatology and Clinical Immunology, School of Medicine, Health Sciences Center, T-18, SUNYStony Brook, Stony Brook, N.Y., and the Department of Orthopaedics, Mayo Medical School, 200 First St., S.W., Rochester, Minn. Received for publication May 31, 1985; accepted in revised form Aug. 20, 1986. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Reprint requests: Lawrence C. Hurst, M.D., Department of Orthopaedics, School of Medicine, Health Sciences Center, T-18, SUNY-Stony Brook, Stony Brook, NY 11794.
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Hospital in Stony Brook, Long Island, New York between 1980 and 1986. Seven other patients with the presumptive diagnosis of M. marinum infection were also seen but were not included because results of cultures were negative. Tissue obtained at operation was sent for routine histological and microbiology studies. The histology was reviewed by the pathologist and by one of us (R. D.). Special stains for acid-fast bacilli and fungi were also done. Four patients also had tissue examined by electron microscopy. In all cases cultures for aerobic, anerobic, fungal, and M. tuberculosis were done on the excised tissues. In addition, tissue for culture was also incubated in Lowenstein-Jensen media at 30° C. Smooth orange colonies of acid-fast mycobacterium appeared on all cultures. In the dark, the colonies contained no pigment. Exposure to light resulted in the reappearance of orange pigmentation, thereby establishing the identity of these organisms as Runyon group I photochromogens. Several biochemical culture characteristics including nitrate reduction and pyrazinamidase tests were used to complete the identification. 8 Patients with culture proven M. marinum infections were included in the prospective immunological investigations. For these studies II of our 15 patients had 30 ml of venous blood drawn. The mononuclear cells were separated by a Ficoll-Hypaque density gradient, and lymphocyte cell cultures were set up using standard techniques for antigen stimulation (purified protein derivative [PPD Platy], tetanus toxoid, and Candida) and mitogens (concanavalin A [Con A], phytohemaggutinin [PHA], and pokeweed).
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Ten of our culture proven cases were also included in the Center for Disease Control's double blind prospective M. marinum skin test study (Protocol No. 538 bioassay study). Five intradermal tuberculin antigen inoculations were given to each patient. One inoculation contained 5 TV of PPD-T (M . tubercuLosis) and the other four inoculations contained PPD Platy (M. marinum) at doses of 0.009 fLg, 0.027 fLg, 0.081 fLg, and 0 .243 fLg. All skin tests were read by the same observer at 48 hours postinjection.
Results We treated 13 males and two females; the average age was 43 years (range 17 to 65). Symptoms were present for I to 36 months (average 7.7 months) before patients initial consultation . In half the patients the dominant hand was involved . In two patients the infection was present in both hands. There were 27 identifiable lesions in 14 patients, and the 15th patient had numerous diffuse lesions in both hands (Fig. I). The occupations of our patients were varied, but almost all participated in fishing for sport. Specifically 73% (Ill 15) of our patients had a history of antecedent trauma while fishing for bluefish (Pomatomus saLtatrix) in Long Island waters. Only two patients had no identifiable exposure to typical M . marinum sources. The most common complaint was painful swelling. Occasionally this symptom was associated with stiffness and numbness in the fingers. Three patients had "picked at" superficial skin lesions with a needle before the development of migratory subcutaneous swellings. Three patients had also received intralesional cortisone injections. Transient improvement occurred in two patients, but one was clearly worse after his injection. Additional medical history revealed one patient with leukopenia, three with intermittent carpal tunnel syndromes , one patient with spinal M. tubercuLosis (successfully treated by drug therapy and arthrodesis as an infant), and one patient allergic to tetracycline. Physical examination showed 29% of the patients had one or more subcutaneous masses and 57% had tenosynovitis, with 43% involving the extensors and 14% involving the flexor tendons. One patient had a ruptured extensor tendon, one had palpable axillary nodes, and one had carpal tunnel syndrome. None of the patients could be classified as type I (verrucal), although three patients may have changed type I lesions into type II lesions by self-treatment, six patients had type II lesions (subcutaneous granulomas), and nine patients had type III (deep) lesions. None of our patients had a typical sporotrichoid pattern, but four patients had fingertip lesions that spread to the wrist.
Fig. 1. Distribution of 27 lesions in 14 patients. Numerous diffuse lesions in patient 15 were not included. Twenty-one finger lesions (19 dorsal and 2 palmar). Six wrist lesions (5 dorsal and I palmar).
Laboratory and x-ray results All patients had normal white blood cell (WBC) counts and differentials, except one with chronic leukopenia (WBC, 26(0), which preceded her M. marinum infection. The average WBC was 6175 (range, 2600 to 92(0). Erythrocyte sedimentation rates were all normal (average, 3.6, range I to 7). Four patients had negative laboratory work-ups for rheumatologic disorders . All 15 patients had x-ray films of the hand, with the only positive finding being soft tissue swelling. None of the 15 patients had evidence of active tuberculosis on chest x-ray films. Two patients had findings consistent with old inactive peripheral granuloma.
Histology and microbiology The tissue from all 15 patients disclosed noncaseating granulomas shown on routine hematoxylin and eosin stains. Gram stains, special stains for acid-fast bacilli, and fungal stains were all negative . Electron microscopy was done in four cases. Extensive sectioning revealed an occasional bacillus that could not be distinguished from those seen in M. tubercuLosis (Fig. 2, A and B). All patients had positive M. marinum cultures. Cultures for aerobic and anerobic bacteria, fungi, and other mycobacterium were all negative. The M. marinum organisms from five of these cultures were tested for antibiotic sensitivities (Table I). In three patients the sensitivities to tetracycline were assessed. All five patients were treated with minocycline and had an excellent therapeutic response despite the sensitivity studies.
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Fig. 2. A, Mycobacterium marinum bacillus: Cell wall (CW) of bacillus (TB). (Original magnification x 36,000.) B, Granuloma reaction with ultrastructural evidence of organic material in and around macrophage activity nucleus (N). mitochondria (M), lysosomal material (L) suggests phagocytic activity. Irregular cell surface projections (arrows) are further evidence of phagocytic activity. (Original magnification x 10,000.)
Skin test results Using 12 mm of induration at 48 hours as the criteria for a positive reaction, seven of our ten patients with culture proven infections had positive skin tests with PPD Platy (M. marinum) at one or more of the four antigen inoculation doses given. The PPD-T (M . tu-
berculosis) skin tests were negative in ten patients. Five patients did not have skin tests.
Immunologic studies Eleven of our 15 patients with culture proven M. marinum infections were also part of a prospective im-
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~ EPIDEMIC ONLY _
o
EPIDEMICS. SERIES & CASES CASES OR SERIES
Fig. 3. Epidemics only: A = Orebro. Sweden (80 cases) and Vasteras, Sweden (60 cases). Epidemics, series, and case reports. B = U.S.A.: Colorado epidemic (290 cases largest epidemic), continental U.S.A. case reports and series (111 cases), and Hawaii (20 cases). C = England: Penarth epidemic (91 cases), and case reports (7). The epidemics that account for 511 of the 689 reported cases were all caused by swimming pool contamination. Cases or series only. D = Belgium (No. of cases not given). E = Holland (No. of cases not given). F = Denmark (I case). G = Czechosloakia (No. of cases not given). H = Israel (10 cases). I = Australia (16 cases). J = New Zealand (I case). K = Japan (2 castes). L = Hong Kong (5 cases). M = Canada (5 cases). Total number of cases reported in the English language literature is 689.
Table I. Sensitivity test results Patients Drug tested Tetracycline (Tetra) Minocycline (Mino) Isoniazide (INH) Aminosalicyclic Acid (PAS) Streptomycin Rifampin Ethambutol Drug used for treatment
s,
P S
2
3
R
R
P
Minocycline
5
S S S S S Minocycline
R R S S S Minocycline
S R R
Minocycline
4
S S S Minocycline
sensitive; p, partially sensitive; r. resistant.
munologic investigation. Only one of our II patients had a response in lymphocyte proliferative assays to M. marinum antigens. Nine of 14 healthy fishermen from Long Island, who were used as exposed controls, had a significant proliferative response to the same mycobacterium antigens. Five normal nonexposed controls, as expected, failed to react to the mycobacterium antigens (PPD Platy). The patients, the exposed controls, and the nonexposed controls all had a normal blastic response to other antigens and mitogens. Surgical procedures
These 15 patients had 31 separate operative procedures. There were 19 tenosynovectomies, two syno-
vectomies (thumb interphalangeal joints and long finger metacarpophalangeal joints), and ten subcutaneous mass excisions. One patient who had a tenosynovectomy also had simultaneous extensor tendon repair and another patient had a simultaneous carpal tunnel release. A third patient had three of his multiple small subcutaneous masses excised and then 4 months postoperatively one of the unexcised masses, which had not resolved with postoperative tetracycline therapy was excised. Tetracycline drug therapy was then continued for 2 more months. The end result was resolution of the infection. The excised tenosynovium was very hypertrophic, and the gross appearance were similar in appearance to
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_ _
D
EPIDEMICS SERIES OF CASES CASE REPORTS
Fig. 4. Distribution of cases in U.S.A.: A = New York (3)*, B = California (9), C = Hawaii (20), D = Louisiana (46), E = Colorado (epidemic = 290), F = Oregon (2), G = Missouri (1), H = Indiana (1), I = Idaho (1), J = Pennsylvania (1), K = Maryland (Chesapeake Bay and D.C.) (22), L = South Carolina (2), M = Florida (2). Total U.S.A. = 401 cases. *Medium shading to reflect additional cases reported in this article. Except for the Colorado epidemic in 1963 the majority of cases have come from the coastal areas of the United States.
giant cell tumors of tendon sheath but were less encapsulated and more adherent to the surrounding structures. An attempt was made to excise the well-defined subcutaneous mass completely. Multiple, small, ill-defined lesions were not excised. Except for the one mass (noted above), all the residual subcutaneous masses resolved with postoperative drug therapy without further surgery. Radical tenosynovectomies were not performed. The small amounts of residual involved tenosynovium that were left after limited tenosynovectomy, resolved with postoperative drug therapy. This approach appeared to minimize surgical morbidity. There were only two surgical complications. One wound hematoma, which resolved spontaneously, and one secondary infection caused by Staphlococcus epidermidis, which resolved after 10 days of additional cephalosporin therapy.
Drug therapy All patient's drug therapy was started immediately after their operations. Six patients received tetracycline, 500 mg, 4 times daily. Seven patients received minocycline, 100 mg, twice daily. One patient was treated with bactrim and erythromycin because he was allergic to tetracycline, and one patient received rifampin only. The patients received antibiotics for 2 to 6 months (mean, 4 months). One patient received rifampin for 12 months. Patients receiving tetracycline or minocycline had minimal side effects. Three patients had mild gas-
trointestinal symptoms, and a fourth patient had a rash, but these symptoms did not necessitate changes in drug therapy. A fifth patient experienced photophobia, which resolved when the tetracycline dose was lowered. None of the patients receiving minocycline complained of dizziness, a common side effect of that drug. 9 • 10 Follow-up Follow-up ranged from 7 months to 6 years (average, 2.5 years). Two patients had persistent symptoms and residual lesions after their operation and the start of tetracycline treatment. The first patient was only occasionally taking his minocycline and when he did, he was taking it with food. When this was corrected, his symptoms and residual lesions quickly resolved. The second patient had mUltiple subcutaneous lesions. Three lesions were initially excised. At 4 months one of several unexcised lesions had not resolved. With the excision of this mass and 2 additional months of tetracycline therapy symptoms resolved. At least three of our patients are known to have returned to sports fishing; however, so far none of these three has had recurrent infections despite their known recurrent exposure. Discussion On the basis of our review of the English-language literature it appears that M. marinum has a world-wide distribution (Fig. 3).2-5.6, II-57 Although the true inci-
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dence of this infection is not known, our observation is that many fish in Long Island Sound are infected. 58 . 59 This suggests that the low incidence of this infection in the Northeastern United States 8. 26. 31, 34 is underestimated (Fig, 4), The key to diagnosing this infection is a high index of suspicion, a thorough history, with emphasis on possible exposure to M, marinum sources, awareness that inoculation can occur as a result of seemingly trivial trauma, and obtaining tissue for culture and histological examination, Reported sources of M, marinum include contaminated swimming pools,5, 8·10. 39 contaminated fishing tanks/' 26, 38, 40 contaminated piers or boats, 19,36 brackish water,24-26 fish bites or injuries caused by fish fins or spines,12. 20. 33, 37, 49 and even laboratory accidents.29 There is no pathognomonic physical finding of aM. marinum infection. However, there are the following characteristic types: Type I, self-limited verrucallesion; type II, single or multiple subcutaneous granulomas, with or without ulceration; type III, deep infections involving tenosynovium, bursa, bones, or joints. 12 Type I verrucal lesions are probably self-limited but may be changed into more virulent type II lesions by attempted self-excision with needles, by intralesional cortisone injections, or by incomplete surgical excision that is not combined with appropriate drug therapy. The specific techniques for culturing M. marinum have been well described,5' 12, 32, 61 but the surgeon removing tissue that may contain mycobacterium organisms cannot expect to obtain positive laboratory cultures simply by asking for "TB cultures," The fastidious M. marinum organism requires Lowenstein-Jensen media and incubation at 30° C. Routine TB cultures incubated at 35° C to 37° C will frequently fail to grow M. marinum. On the basis of an analysis of the previously published cases and our data, we recommend the following treatment guidelines, In immunologically normal patients, with a single or a limited number of clinically diagnosed type I (verrucal) lesions that are not sporotrichoid, observation for 2 to 4 months seems appropriate. Patients should be instructed not to "pick at" their lesions, intralesional cortisone injections should not be given, and biopsies without postoperative antimicrobial therapy should not be done. If the clinical diagnosis is uncertain or the lesions do not resolve in 2 to 4 months, then a biopsy of at least one type I lesion should be performed, the tissue examined histologically, and cultured with sensitivity studies. Postoperatively, minocycline should be given for at least 2 months. 12, 16-18, 20, 24, 27, 54, 55 If the patient does not begin to respond within 2 to 4 weeks, then culture
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and sensitivity data should be reviewed. If the mycobacterium is resistent to minocycline, then antimicrobial therapy should be changed. Usually the marinum will be sensitive to ethambutol and rifampin. 2. 14, 15,21,28,31,36-38,58,63 If the patient is responding well, minocycline should be continued for 4 to 6 months even if the sensitivity data suggest resistance. If needed, ethambutol and rifampin should be given for 12 to 18 months, while watching for side effects. Ethambutol can cause ocular toxicity,31. 67 and rifampin can cause rash, abdominal distress, jaundice, liver dysfunction, tinnitus and vertigo, and flu-like immunologic reactions.36. 67 In type II (subcutaneous granuloma or sporotrichoid) lesions, the patient should have immediate excision of any well-defined masses, with appropriate studies on the excised tissues. Minocycline therapy should be started, and if the cultures are positive, it should be given for 2 to 6 months. If the cultures are negative and clinical diagnosis is supported by histological findings, then minocycline should also be given, because false negative cultures do occur. If at 2 to 4 months there are residual nonresponding masses and the organism is sensitive to minocycline, then the remaining lesion should be excised and the minocycline continued for an additional 2 months. If there are residual masses and the organism is resistent to minocycline, then the drug therapy should be changed according to the sensitivity data. After an additional 2 months of the new drugs, the need for additional surgery should be assessed. In type III (deep) infections the patient should have the appropriate tenosynovectomy, synovectomy, arthrodesis, or incision, and drainage of the infected bone or joint. The extent of the surgical therapy should be carefully considered to minimize surgical morbidity. Minocycline therapy should be started and continued for 4 to 6 months. Culture results and residual lesions should be managed in a manner similar to that outlined for type II lesions. If at 4 months there is residual infection, a limited, repeat biopsy should be done. Further appropriate drug therapy should be on the basis of the new culture and sensitivity data. Careful assessment of the overall situation should be undertaken before embarking on extensive secondary surgical procedures.
REFERENCES 1. Aronson JD. Spontaneous tuberculosis in salt water fish. J Infect Dis 1926;39:315-20. 2. Black H, Rush-Munro FM, Woods G. Mycobacterium marinum infections acquired from tropical fish tanks. Australas J Dennatol 1971;12:155-64.
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3. Jolly HW, Seabury JH. Infections with Mycobacterium marinum . Arch Dermatol Res 1972;106:32-6. 4. Baker JA, Hagan WA. Tuberculosis of Mexican platyfish (Platypoecilus Maculatus) . J Infect Dis 1942;70:248. 5. Linell F, Norden A. Mycobacterium balnei: new acidfast bacillus occurring in swimming pools and capable of producing skin lesions in humans . Acta Tuberc Scandinav (suppl) 1954;33: 1-84. 6. Reznikov M. Atypical mycobacteria their classification, identification, and etiological significance . Med J Aust 1970;2:553-7. 7. Schaefer WB, David CL. A bacteriologic and histopathologic study of skin granuloma due to Mycobacterium balnei. Am Rev Respir Dis 1962;84:1244-6. 8. Wagner RF, Tawil AB, Colletta AJ, Hurst LC , Yecies LD. Mycobacterium marinum tenosynovitis in a Long Island fisherman. N.Y.S.J. of Med 1981;81:1091-4. 9. Lockshin NA . Treatment of Mycobacterium marinum infections with minocycline. Arch Derm 1977; 113:987 . 10. Jacobson JA, Daniel B. Vestibular reactions associated with minocycline. Antibiol. Chemother 1975;8:453-6. II . Philpott JA , Woodburne R, Philpott as, Schaefer WB , Mollohan CS. Swimming pool granuloma . Arch Derm 1963;88: 158-62. 12 . Zettergren B, Malmgren B, Karth B. Nya ron betraffande simhallssjukdomen (Mycobacteriosis balnearea). Svenska lak tidning 1952;49:2936. 13. Thomas DT. Epidemiology swimming-pool granuloma. Br Med 1967; 1:437 . 14. Waddington E. An outbreak of swimming pool granuloma. Trans SI. John Hosp Derm Soc 1967;53:122. 15. Zeligman I. Mycobacterium marinum granuloma. Arch Derm 1972;106:26-31. 16. Williams CS, Riordan DC. Mycobacterium marinum (atypical acid-fast bacillus) infections of the hand. J Bone Joint Surg [Am] 1973;55: I 042-50. 17 . Bailey JP, Stevens SJ, Bell WM, Mealing HG, Loebl DH, Cook EH. Mycobacterium marinum infection. A fishy story. JAMA 1982;247:1314. 18. Hanke WC, Bergfeld WF, Schear H. Sporotricoid mycobacterium marinum skin infection treated with minocycline hydrochloride . Cleve Clin Q 1980;47:339-42. 19. Loria PR oMinocycline hydrochloride treatment for atypical acid-fast infection . Arch Derm 1976; 112:517-9. 20. Contorer P, Jones RN. Minocycline therapy of aquarium granuloma case reports and literature review. Cutis 1979;23:864-8. 21. Cott RE , Carter DM , Sail T. Cutaneous disease caused by atypical mycobacteria. Arch Derm 1967;95:259-68. 22 . Bernauer RD. Mycobacteria marinum infection an endemic condition in southwest Louisiana. Ortho Rev 1984;13:41-3. 23. Wolinsky E, Gomez F, Zimpfer F. Sporotrichoid Mycobacterium marinum infection treated with rifampinethambutol. Am Rev Respir Dis 1972;5:964-7. 24. Fisher DA, Lyss RS. Mycobacterium marinum infection . Arch Derm 1974;109:571.
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25 . Adams RM, RemingtonJS, SteinbergJ, SeibertJS. Tropical fish aquariums . JAMA 1970;211:457-61. 26. Dickey RF. Sporotrichoid mycobacteriosis caused by M. marinum (balnei). Arch Derm 1968;98:385-91. 27. Swift S, Cohen H. Granulomas of the skin due to Mycobacterium balnei after abrasions from a fish tank . N Engl J Med 1962;267: 28 . Barden GA. Mycobacterium marinum infection . Correspondence Newsletter 1984 1984-3; 1-3. 29. Van Dyke JJ, Lake KB. Chemotherapy for aquarium granuloma. JAMA 1975;233:1380-1. 30. Chappler RR, Hoke AW, Borchardt KA. Primary inoculation with Mycobacterium marinum. Arch Derm 1977; 113:380. 31. Cortez LM , Pankey GA. Mycobacterium marinum infections of the hand. J Bone Joint Surg lAm] 1973; 55:363-70. 32. Bodaness RS . SporotrichoidMycobacterium marinum infection in diabetes . NY State J Med 1978;78: 1935-6. 33. Winter FE, Runyon EH. Prepatellar bursitis caused by Mycobacterium marinum (balnei). J Bone Joint Surg [Am] 1965;47:375-9. 34. Gunther SF, Elliott RC, Brand RL, Adams JP. Experience with atypical mycobacterial infection in the deep structures of the hand . J HAND SURG 1977;2:90-6. 35. Gombert ME, Goldstein EJC, Corrado ML, Stein AJ, Butt KMH. Disseminated Mycobacterium marinum infection after renal transplantation. Ann Intern Med 1981 ;94:486-7. 36. Beyt BE, Ortbals DW, Santa Cruz OJ , Kobayshi GS, Eisen AZ, Medoff G. Cutaneous Mycobacteriosis: analysis of 34 cases with a new classification of the disease. Medicine 1981 ;60:95-109. 37. Belding RH, Hay EL, Thompson JD. Mycobacterium marinum infections of the hand: report of two cases in coastal South Carolina. J SC Med Assoc 1977;73:49-51 . 38. Chow SP, Stroebel AB, Lau JHK , Collins RI. Mycobacterium marinum infection of the hand involving deep structures. J HAND SURG 1983;8:568-72. 39. Engbaek HC, Thormann J, Vergmann B. Aquariumborne Mycobacterium marinum granulomas . Scand J Infect Dis 1980;12:74-8. 40. Even-Paz Z, Haas H, Sacks T, Rosenmann E. Mycobacterium marinum skin infections mimicking cutaneous leishmaniasis. Br J Dermatol 1976;94:435-42. 41. Brown J, Keirn M, Bryan LE. Infection of the skin by Mycobacterium marinum: Report of five cases. CMAJ 1977;117:912-4. 42. Lester TW. Drug-resistant and atypical mycobacterial disease . Arch Intern Med 1979; 139: 1399-40 I. 43 . Kirk J, Kaminski OW. Mycobacterium marinum infection. Australas J Dermatol 1976; 17: 111-6. 44 . Bauer F. Hueston J. A case of swimming pool granuloma in Australia. Australas J Dermatol 1966;8:241-5. 45. Turner T, Donald OF, Burry NJ , Kirk J, Reid JO . Mycobacterium marinum infection. Arch Derm 1975; 111:525.
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46. Yamamoto S. A case of multiple skin disease caused by Mycobacterium marinum. Jap J Denn 1970;80:142. 47. Saito H, Hironaka T, Nishikawa K, Fukuhara T. A case of Mycobacterium marinum infection of bucca-with special reference to the bacteriological investigations. Kekkaku 1972;47:309. 48. Keczkes K. Tropical fish tank granuloma. Br J Dennatol 1974;91:709. 49. Hay RL, McCarthy OR. Fish tank granuloma. Br Med J 1975;6:268. 50. Flowers DJ. Human infection due to Mycobacterium marinum after a dolphin bite. J Clin Pathol 1970;23: 475-7. 51. Barrow 01, Hewitt M. Skin infection with Mycobacterium marinum from a tropical fish tank. Br Med J 1971 ;29:505-6. 52. Mansson T, Brehmer-Andersson E, Wittbeck B, Grubb R. Aquarium-borne infection with Mycobacterium marinum. Acta Denn Venereol 1970;50:119-24. 53. Walker HH, Shinn MF, Higaki M, Ogata J. Some characteristics of "swimming pool" disease in Hawaii. Hawaii Med J 1962;21:403-9. 54. Gould WM, McMeekin Dr, Bright RD. Mycobacterium
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marinum (balnei) infection. Arch Denn 1968;97: 159-62. 55. Izumi AK, Hanke CW, Higaki M. Mycobacterium marinum infections treated with tetracycline. Arch Denn 1977;113: 1067-8. 56. Kim R. Tetracycline therapy for atypical mycobacterium granuloma. Arch Denn 1974;110:299-. 57. Black MM, Bykynt SJ. The successful treatment of tropical fish tank granuloma (Mycobacterium marinum) with co-trimoxazole. Br J Dennato 1977;97:689-92. 58. Nigrelli R, Vogel H. Spontaneous tuberculosis in fishes and in other cold-blooded vertebrates with special reference to mycobacterium fortuitum cruz from fish and human lesions. Zoologica 1963;48: 131. 59. Keating F. Imbedded and hard to see, fish spines can be a pain. Newsday 1980, Feb 1, p 99. 60. Torres JR, Sands M, Sanders Cv. In vitro sensitivity of Mycobacterium marinum to minocycline and doxycycline. Tubercle 1978;59:193-5. 61. Collins FM, Morrison NE, Montalbine V. Immune response to persistent mycobacterial infection in mice. Infect Immun 1978;20:430-8. 62. Bennett DR, ed. AMA drug evaluations. 5th ed. Chicago: AMA, 1984:1753-78.
Lawrence C. Hurst, M.D., Peter C. Amadio, M.D., Marie A. Badalamente, Ph.D., Jerry L. Ellstein, M.D., and Raymond J. Dattwyler, M.D., Stony Brook, N.Y., and Rochester, Minn.
Mycobacterium marinum was first isolated in 1926 by J. D. Aronson. This mycobacterium was obtained from dead salt water fish at the Philadelphia Aquarium. I In 1942, Baker and Hagan4 described an atypical mycobacterium infection in the Mexican flat fish and named it Mycobacterium platypoecilus. 2 . 3 Linell and Norden 5 diagnosed the first human M. marinum infection. They called the new acid-fast bacillus, Mycobacterium balnei. 5 It is now known that these three organisms are identical, and the international code accepts M. marinum as the official name. 6 . 7 More than 75% of the reported cases of M. marinum infections involve the hand and upper extremity. All fifteen cases reported here involved the hand.
Materials and methods This work is a combined prospective and retrospective study of 15 patients with culture proven M. marinum infections. All patients were seen at the University From the Department of Orthopaedics, and the Department of Medicine, Division of Allergy/Rheumatology and Clinical Immunology, School of Medicine, Health Sciences Center, T-18, SUNYStony Brook, Stony Brook, N.Y., and the Department of Orthopaedics, Mayo Medical School, 200 First St., S.W., Rochester, Minn. Received for publication May 31, 1985; accepted in revised form Aug. 20, 1986. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Reprint requests: Lawrence C. Hurst, M.D., Department of Orthopaedics, School of Medicine, Health Sciences Center, T-18, SUNY-Stony Brook, Stony Brook, NY 11794.
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Hospital in Stony Brook, Long Island, New York between 1980 and 1986. Seven other patients with the presumptive diagnosis of M. marinum infection were also seen but were not included because results of cultures were negative. Tissue obtained at operation was sent for routine histological and microbiology studies. The histology was reviewed by the pathologist and by one of us (R. D.). Special stains for acid-fast bacilli and fungi were also done. Four patients also had tissue examined by electron microscopy. In all cases cultures for aerobic, anerobic, fungal, and M. tuberculosis were done on the excised tissues. In addition, tissue for culture was also incubated in Lowenstein-Jensen media at 30° C. Smooth orange colonies of acid-fast mycobacterium appeared on all cultures. In the dark, the colonies contained no pigment. Exposure to light resulted in the reappearance of orange pigmentation, thereby establishing the identity of these organisms as Runyon group I photochromogens. Several biochemical culture characteristics including nitrate reduction and pyrazinamidase tests were used to complete the identification. 8 Patients with culture proven M. marinum infections were included in the prospective immunological investigations. For these studies II of our 15 patients had 30 ml of venous blood drawn. The mononuclear cells were separated by a Ficoll-Hypaque density gradient, and lymphocyte cell cultures were set up using standard techniques for antigen stimulation (purified protein derivative [PPD Platy], tetanus toxoid, and Candida) and mitogens (concanavalin A [Con A], phytohemaggutinin [PHA], and pokeweed).
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Ten of our culture proven cases were also included in the Center for Disease Control's double blind prospective M. marinum skin test study (Protocol No. 538 bioassay study). Five intradermal tuberculin antigen inoculations were given to each patient. One inoculation contained 5 TV of PPD-T (M . tubercuLosis) and the other four inoculations contained PPD Platy (M. marinum) at doses of 0.009 fLg, 0.027 fLg, 0.081 fLg, and 0 .243 fLg. All skin tests were read by the same observer at 48 hours postinjection.
Results We treated 13 males and two females; the average age was 43 years (range 17 to 65). Symptoms were present for I to 36 months (average 7.7 months) before patients initial consultation . In half the patients the dominant hand was involved . In two patients the infection was present in both hands. There were 27 identifiable lesions in 14 patients, and the 15th patient had numerous diffuse lesions in both hands (Fig. I). The occupations of our patients were varied, but almost all participated in fishing for sport. Specifically 73% (Ill 15) of our patients had a history of antecedent trauma while fishing for bluefish (Pomatomus saLtatrix) in Long Island waters. Only two patients had no identifiable exposure to typical M . marinum sources. The most common complaint was painful swelling. Occasionally this symptom was associated with stiffness and numbness in the fingers. Three patients had "picked at" superficial skin lesions with a needle before the development of migratory subcutaneous swellings. Three patients had also received intralesional cortisone injections. Transient improvement occurred in two patients, but one was clearly worse after his injection. Additional medical history revealed one patient with leukopenia, three with intermittent carpal tunnel syndromes , one patient with spinal M. tubercuLosis (successfully treated by drug therapy and arthrodesis as an infant), and one patient allergic to tetracycline. Physical examination showed 29% of the patients had one or more subcutaneous masses and 57% had tenosynovitis, with 43% involving the extensors and 14% involving the flexor tendons. One patient had a ruptured extensor tendon, one had palpable axillary nodes, and one had carpal tunnel syndrome. None of the patients could be classified as type I (verrucal), although three patients may have changed type I lesions into type II lesions by self-treatment, six patients had type II lesions (subcutaneous granulomas), and nine patients had type III (deep) lesions. None of our patients had a typical sporotrichoid pattern, but four patients had fingertip lesions that spread to the wrist.
Fig. 1. Distribution of 27 lesions in 14 patients. Numerous diffuse lesions in patient 15 were not included. Twenty-one finger lesions (19 dorsal and 2 palmar). Six wrist lesions (5 dorsal and I palmar).
Laboratory and x-ray results All patients had normal white blood cell (WBC) counts and differentials, except one with chronic leukopenia (WBC, 26(0), which preceded her M. marinum infection. The average WBC was 6175 (range, 2600 to 92(0). Erythrocyte sedimentation rates were all normal (average, 3.6, range I to 7). Four patients had negative laboratory work-ups for rheumatologic disorders . All 15 patients had x-ray films of the hand, with the only positive finding being soft tissue swelling. None of the 15 patients had evidence of active tuberculosis on chest x-ray films. Two patients had findings consistent with old inactive peripheral granuloma.
Histology and microbiology The tissue from all 15 patients disclosed noncaseating granulomas shown on routine hematoxylin and eosin stains. Gram stains, special stains for acid-fast bacilli, and fungal stains were all negative . Electron microscopy was done in four cases. Extensive sectioning revealed an occasional bacillus that could not be distinguished from those seen in M. tubercuLosis (Fig. 2, A and B). All patients had positive M. marinum cultures. Cultures for aerobic and anerobic bacteria, fungi, and other mycobacterium were all negative. The M. marinum organisms from five of these cultures were tested for antibiotic sensitivities (Table I). In three patients the sensitivities to tetracycline were assessed. All five patients were treated with minocycline and had an excellent therapeutic response despite the sensitivity studies.
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Fig. 2. A, Mycobacterium marinum bacillus: Cell wall (CW) of bacillus (TB). (Original magnification x 36,000.) B, Granuloma reaction with ultrastructural evidence of organic material in and around macrophage activity nucleus (N). mitochondria (M), lysosomal material (L) suggests phagocytic activity. Irregular cell surface projections (arrows) are further evidence of phagocytic activity. (Original magnification x 10,000.)
Skin test results Using 12 mm of induration at 48 hours as the criteria for a positive reaction, seven of our ten patients with culture proven infections had positive skin tests with PPD Platy (M. marinum) at one or more of the four antigen inoculation doses given. The PPD-T (M . tu-
berculosis) skin tests were negative in ten patients. Five patients did not have skin tests.
Immunologic studies Eleven of our 15 patients with culture proven M. marinum infections were also part of a prospective im-
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~ EPIDEMIC ONLY _
o
EPIDEMICS. SERIES & CASES CASES OR SERIES
Fig. 3. Epidemics only: A = Orebro. Sweden (80 cases) and Vasteras, Sweden (60 cases). Epidemics, series, and case reports. B = U.S.A.: Colorado epidemic (290 cases largest epidemic), continental U.S.A. case reports and series (111 cases), and Hawaii (20 cases). C = England: Penarth epidemic (91 cases), and case reports (7). The epidemics that account for 511 of the 689 reported cases were all caused by swimming pool contamination. Cases or series only. D = Belgium (No. of cases not given). E = Holland (No. of cases not given). F = Denmark (I case). G = Czechosloakia (No. of cases not given). H = Israel (10 cases). I = Australia (16 cases). J = New Zealand (I case). K = Japan (2 castes). L = Hong Kong (5 cases). M = Canada (5 cases). Total number of cases reported in the English language literature is 689.
Table I. Sensitivity test results Patients Drug tested Tetracycline (Tetra) Minocycline (Mino) Isoniazide (INH) Aminosalicyclic Acid (PAS) Streptomycin Rifampin Ethambutol Drug used for treatment
s,
P S
2
3
R
R
P
Minocycline
5
S S S S S Minocycline
R R S S S Minocycline
S R R
Minocycline
4
S S S Minocycline
sensitive; p, partially sensitive; r. resistant.
munologic investigation. Only one of our II patients had a response in lymphocyte proliferative assays to M. marinum antigens. Nine of 14 healthy fishermen from Long Island, who were used as exposed controls, had a significant proliferative response to the same mycobacterium antigens. Five normal nonexposed controls, as expected, failed to react to the mycobacterium antigens (PPD Platy). The patients, the exposed controls, and the nonexposed controls all had a normal blastic response to other antigens and mitogens. Surgical procedures
These 15 patients had 31 separate operative procedures. There were 19 tenosynovectomies, two syno-
vectomies (thumb interphalangeal joints and long finger metacarpophalangeal joints), and ten subcutaneous mass excisions. One patient who had a tenosynovectomy also had simultaneous extensor tendon repair and another patient had a simultaneous carpal tunnel release. A third patient had three of his multiple small subcutaneous masses excised and then 4 months postoperatively one of the unexcised masses, which had not resolved with postoperative tetracycline therapy was excised. Tetracycline drug therapy was then continued for 2 more months. The end result was resolution of the infection. The excised tenosynovium was very hypertrophic, and the gross appearance were similar in appearance to
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_ _
D
EPIDEMICS SERIES OF CASES CASE REPORTS
Fig. 4. Distribution of cases in U.S.A.: A = New York (3)*, B = California (9), C = Hawaii (20), D = Louisiana (46), E = Colorado (epidemic = 290), F = Oregon (2), G = Missouri (1), H = Indiana (1), I = Idaho (1), J = Pennsylvania (1), K = Maryland (Chesapeake Bay and D.C.) (22), L = South Carolina (2), M = Florida (2). Total U.S.A. = 401 cases. *Medium shading to reflect additional cases reported in this article. Except for the Colorado epidemic in 1963 the majority of cases have come from the coastal areas of the United States.
giant cell tumors of tendon sheath but were less encapsulated and more adherent to the surrounding structures. An attempt was made to excise the well-defined subcutaneous mass completely. Multiple, small, ill-defined lesions were not excised. Except for the one mass (noted above), all the residual subcutaneous masses resolved with postoperative drug therapy without further surgery. Radical tenosynovectomies were not performed. The small amounts of residual involved tenosynovium that were left after limited tenosynovectomy, resolved with postoperative drug therapy. This approach appeared to minimize surgical morbidity. There were only two surgical complications. One wound hematoma, which resolved spontaneously, and one secondary infection caused by Staphlococcus epidermidis, which resolved after 10 days of additional cephalosporin therapy.
Drug therapy All patient's drug therapy was started immediately after their operations. Six patients received tetracycline, 500 mg, 4 times daily. Seven patients received minocycline, 100 mg, twice daily. One patient was treated with bactrim and erythromycin because he was allergic to tetracycline, and one patient received rifampin only. The patients received antibiotics for 2 to 6 months (mean, 4 months). One patient received rifampin for 12 months. Patients receiving tetracycline or minocycline had minimal side effects. Three patients had mild gas-
trointestinal symptoms, and a fourth patient had a rash, but these symptoms did not necessitate changes in drug therapy. A fifth patient experienced photophobia, which resolved when the tetracycline dose was lowered. None of the patients receiving minocycline complained of dizziness, a common side effect of that drug. 9 • 10 Follow-up Follow-up ranged from 7 months to 6 years (average, 2.5 years). Two patients had persistent symptoms and residual lesions after their operation and the start of tetracycline treatment. The first patient was only occasionally taking his minocycline and when he did, he was taking it with food. When this was corrected, his symptoms and residual lesions quickly resolved. The second patient had mUltiple subcutaneous lesions. Three lesions were initially excised. At 4 months one of several unexcised lesions had not resolved. With the excision of this mass and 2 additional months of tetracycline therapy symptoms resolved. At least three of our patients are known to have returned to sports fishing; however, so far none of these three has had recurrent infections despite their known recurrent exposure. Discussion On the basis of our review of the English-language literature it appears that M. marinum has a world-wide distribution (Fig. 3).2-5.6, II-57 Although the true inci-
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dence of this infection is not known, our observation is that many fish in Long Island Sound are infected. 58 . 59 This suggests that the low incidence of this infection in the Northeastern United States 8. 26. 31, 34 is underestimated (Fig, 4), The key to diagnosing this infection is a high index of suspicion, a thorough history, with emphasis on possible exposure to M, marinum sources, awareness that inoculation can occur as a result of seemingly trivial trauma, and obtaining tissue for culture and histological examination, Reported sources of M, marinum include contaminated swimming pools,5, 8·10. 39 contaminated fishing tanks/' 26, 38, 40 contaminated piers or boats, 19,36 brackish water,24-26 fish bites or injuries caused by fish fins or spines,12. 20. 33, 37, 49 and even laboratory accidents.29 There is no pathognomonic physical finding of aM. marinum infection. However, there are the following characteristic types: Type I, self-limited verrucallesion; type II, single or multiple subcutaneous granulomas, with or without ulceration; type III, deep infections involving tenosynovium, bursa, bones, or joints. 12 Type I verrucal lesions are probably self-limited but may be changed into more virulent type II lesions by attempted self-excision with needles, by intralesional cortisone injections, or by incomplete surgical excision that is not combined with appropriate drug therapy. The specific techniques for culturing M. marinum have been well described,5' 12, 32, 61 but the surgeon removing tissue that may contain mycobacterium organisms cannot expect to obtain positive laboratory cultures simply by asking for "TB cultures," The fastidious M. marinum organism requires Lowenstein-Jensen media and incubation at 30° C. Routine TB cultures incubated at 35° C to 37° C will frequently fail to grow M. marinum. On the basis of an analysis of the previously published cases and our data, we recommend the following treatment guidelines, In immunologically normal patients, with a single or a limited number of clinically diagnosed type I (verrucal) lesions that are not sporotrichoid, observation for 2 to 4 months seems appropriate. Patients should be instructed not to "pick at" their lesions, intralesional cortisone injections should not be given, and biopsies without postoperative antimicrobial therapy should not be done. If the clinical diagnosis is uncertain or the lesions do not resolve in 2 to 4 months, then a biopsy of at least one type I lesion should be performed, the tissue examined histologically, and cultured with sensitivity studies. Postoperatively, minocycline should be given for at least 2 months. 12, 16-18, 20, 24, 27, 54, 55 If the patient does not begin to respond within 2 to 4 weeks, then culture
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and sensitivity data should be reviewed. If the mycobacterium is resistent to minocycline, then antimicrobial therapy should be changed. Usually the marinum will be sensitive to ethambutol and rifampin. 2. 14, 15,21,28,31,36-38,58,63 If the patient is responding well, minocycline should be continued for 4 to 6 months even if the sensitivity data suggest resistance. If needed, ethambutol and rifampin should be given for 12 to 18 months, while watching for side effects. Ethambutol can cause ocular toxicity,31. 67 and rifampin can cause rash, abdominal distress, jaundice, liver dysfunction, tinnitus and vertigo, and flu-like immunologic reactions.36. 67 In type II (subcutaneous granuloma or sporotrichoid) lesions, the patient should have immediate excision of any well-defined masses, with appropriate studies on the excised tissues. Minocycline therapy should be started, and if the cultures are positive, it should be given for 2 to 6 months. If the cultures are negative and clinical diagnosis is supported by histological findings, then minocycline should also be given, because false negative cultures do occur. If at 2 to 4 months there are residual nonresponding masses and the organism is sensitive to minocycline, then the remaining lesion should be excised and the minocycline continued for an additional 2 months. If there are residual masses and the organism is resistent to minocycline, then the drug therapy should be changed according to the sensitivity data. After an additional 2 months of the new drugs, the need for additional surgery should be assessed. In type III (deep) infections the patient should have the appropriate tenosynovectomy, synovectomy, arthrodesis, or incision, and drainage of the infected bone or joint. The extent of the surgical therapy should be carefully considered to minimize surgical morbidity. Minocycline therapy should be started and continued for 4 to 6 months. Culture results and residual lesions should be managed in a manner similar to that outlined for type II lesions. If at 4 months there is residual infection, a limited, repeat biopsy should be done. Further appropriate drug therapy should be on the basis of the new culture and sensitivity data. Careful assessment of the overall situation should be undertaken before embarking on extensive secondary surgical procedures.
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46. Yamamoto S. A case of multiple skin disease caused by Mycobacterium marinum. Jap J Denn 1970;80:142. 47. Saito H, Hironaka T, Nishikawa K, Fukuhara T. A case of Mycobacterium marinum infection of bucca-with special reference to the bacteriological investigations. Kekkaku 1972;47:309. 48. Keczkes K. Tropical fish tank granuloma. Br J Dennatol 1974;91:709. 49. Hay RL, McCarthy OR. Fish tank granuloma. Br Med J 1975;6:268. 50. Flowers DJ. Human infection due to Mycobacterium marinum after a dolphin bite. J Clin Pathol 1970;23: 475-7. 51. Barrow 01, Hewitt M. Skin infection with Mycobacterium marinum from a tropical fish tank. Br Med J 1971 ;29:505-6. 52. Mansson T, Brehmer-Andersson E, Wittbeck B, Grubb R. Aquarium-borne infection with Mycobacterium marinum. Acta Denn Venereol 1970;50:119-24. 53. Walker HH, Shinn MF, Higaki M, Ogata J. Some characteristics of "swimming pool" disease in Hawaii. Hawaii Med J 1962;21:403-9. 54. Gould WM, McMeekin Dr, Bright RD. Mycobacterium
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marinum (balnei) infection. Arch Denn 1968;97: 159-62. 55. Izumi AK, Hanke CW, Higaki M. Mycobacterium marinum infections treated with tetracycline. Arch Denn 1977;113: 1067-8. 56. Kim R. Tetracycline therapy for atypical mycobacterium granuloma. Arch Denn 1974;110:299-. 57. Black MM, Bykynt SJ. The successful treatment of tropical fish tank granuloma (Mycobacterium marinum) with co-trimoxazole. Br J Dennato 1977;97:689-92. 58. Nigrelli R, Vogel H. Spontaneous tuberculosis in fishes and in other cold-blooded vertebrates with special reference to mycobacterium fortuitum cruz from fish and human lesions. Zoologica 1963;48: 131. 59. Keating F. Imbedded and hard to see, fish spines can be a pain. Newsday 1980, Feb 1, p 99. 60. Torres JR, Sands M, Sanders Cv. In vitro sensitivity of Mycobacterium marinum to minocycline and doxycycline. Tubercle 1978;59:193-5. 61. Collins FM, Morrison NE, Montalbine V. Immune response to persistent mycobacterial infection in mice. Infect Immun 1978;20:430-8. 62. Bennett DR, ed. AMA drug evaluations. 5th ed. Chicago: AMA, 1984:1753-78.