© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Transplant Infectious Disease, ISSN 1398-2273
Case report
Cutaneous legionellosis: case report and review of the medical literature L.J. Padrnos, J.E. Blair, S. Kusne, D.J. DiCaudo, J.R. Mikhael. Cutaneous legionellosis: case report and review of the medical literature. Transpl Infect Dis 2014: 16: 307–314. All rights reserved Abstract: Discrete nodules developed on the leg of a 27-year-old immunosuppressed woman after an allogeneic stem cell transplant. Biopsy and culture grew Legionella pneumophila serogroup 8. On day 7 of azithromycin treatment, respiratory distress and abnormal liver transaminases developed, and the patient died on day 14. Review of the medical literature identified 19 reports of Legionella species-associated skin or soft tissue infections (total of 20 patients, 13 with confirmed infection). Manifestations of the 13 confirmed cases included erythematous macular rash (n = 7), erythema after thoracentesis (n = 1), abscess formation (n = 4), respiratory symptoms (n = 6), and abnormal chest radiographs (n = 8). Six required surgical exploration and d ebridement, and 7 were immunocompromised. Rash and respiratory infection improved with antibiotics in 10, but 3 died. Immunosuppression may predispose transplant recipients to Legionella infections. Diagnostic biopsies may facilitate appropriate treatment.
L.J. Padrnos1, J.E. Blair2, S. Kusne2, D.J. DiCaudo3, J.R. Mikhael4 1
Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA, 2Division of Infectious Diseases, Mayo Clinic, Scottsdale, Arizona, USA, 3 Department of Dermatology and Division of Anatomic Pathology, Mayo Clinic, Scottsdale, Arizona, USA, 4 Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona, USA Key words: cutaneous infection; Legionella; legionellosis; Legionella pneumophila Correspondence to: Janis E. Blair, MD, Division of Infectious Diseases, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA Tel: 480 342 0337 Fax: 480 342 0689 E-mail: [email protected]
Received 23 May 2013, revised 25 September 2013, 30 October 2013, accepted for publication 12 November 2013 DOI: 10.1111/tid.12201 Transpl Infect Dis 2014: 16: 307–314
Legionella species was first documented in 1976 after an outbreak of fatal respiratory illness (1). Of more than 50 species and serogroups (2, 3), the most common pathogenic species is Legionella pneumophila serogroup 1 (3). With the evolution of more sensitive diagnostic testing methods, legionellosis is increasingly recognized as a cause of pneumonia: its US incidence increased 217% from 2000 (n = 1110) to 2009 (n = 3522) (4, 5). Extrapulmonary legionellosis is rare, but reported sites include pericarditis (6), septic arthritis (7), and cutaneous infections (8, 9). We report a case of cutaneous legionellosis and summarize the relevant English-language medical literature. Our aim was to raise awareness of this rare entity and summarize its various manifestations.
Case report Pre–B-cell acute lymphoblastic leukemia (Philadelphia chromosome–negative with complex cytogenetics) was diagnosed in a 27-year-old woman in May 2008, for which she received induction and intensification chemotherapy. After treatment for a second and third relapse, she underwent allogeneic double-cord blood stem cell transplantation (SCT) (4/6 matched) in March 2011. Post transplantation, she had restrictive lung disease, graft-versus-host disease of skin (stage 3, April 2011) and bowel (grade 4, May 2011), and corticosteroid-associated myopathy. On post-SCT (pSCT) day 172, she was hospitalized for back and leg pain, diffuse erythema, and 3 distinct, well-marginated, firm, indurated, 2-cm subcutaneous masses on the
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posterior left thigh. Although she had no cough or dyspnea, chest radiographs revealed bibasilar abnormalities consistent with atelectasis or consolidation. Her medications included tacrolimus (1 mg, twice daily, oral), mycophenolate mofetil (1 g, twice daily), budesonide (3 mg, 3 times daily), and prednisone (15 mg daily). She was treated empirically with voriconazole, meropenem, and vancomycin, and then with ampicillin-sulbactam and clindamycin. Biopsy of the skin lesion (pSCT day 175) revealed “mixed deep dermal inflammation” suggestive of infection, but no microorganisms were observed on stained specimens. Caspofungin was added to her treatment regimen. Despite improvement of the rash, the patient became agitated and required intubation for airway protection (pSCT day 179). Ceftriaxone and acyclovir were empirically added. Of note, she had a history of levofloxacin allergy, and all fluoroquinolones were avoided. Stains and cultures of specimens from bronchoalveolar lavage and sputum were negative for fungi, Pneumocystis, mycobacteria, Nocardia species, Legionella species, herpesvirus, and varicella. Polymerase chain reaction (PCR) was negative for Coccidioides species. She was extubated (pSCT day 182). Antibiotics were reduced to piperacillin and tazobactam, and erythema improved. However, new subcutaneous nodules developed on her leg, and a biopsy (pSCT day 188) showed “subcutaneous neutrophilic microabscesses.” Ten days later, the skin biopsy culture grew L. pneumophila serogroup 8, which was then confirmed with DNA sequencing. Urinary Legionella antigen remained negative. She was prescribed azithromycin (pSCT day 198) and transitioned to inpatient rehabilitation (pSCT day 200). However, on pSCT day 207, she was rehospitalized with an unrelated infection (severe adenoviral hepatitis). Following a family conference, she began comfortonly measures and died on pSCT day 210. There was no known association between the patient’s cutaneous Legionella and the systemic illness that led to her death.
Review of the literature We searched the English-language literature from inception through December 2012 on PubMed and Ovid MEDLINE using the terms: “Legionella,” “Legionella longbeachae,” “Legionella pneumophila,” “Legionnaires’ disease,” “legionellosis” combined with “cutaneous,” “skin disease,” “skin manifestation,” and “soft tissue” or “exanthem.” Retrieved articles were
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reviewed to identify additional cases of Legionella skin and soft tissue infection. We included confirmed cutaneous legionellosis only if skin or associated structures were culture- or PCRpositive for Legionella species. Possible cutaneous legionellosis was defined as confirmed respiratory infection (positive for Legionella species by culture, PCR, or direct fluorescent antibody stain) accompanied by skin abnormalities suggestive of skin or soft tissue infection. Cases of possible cutaneous legionellosis were tabulated but not included in the primary analysis. The Mayo Clinic Institutional Review Board reviewed and approved this study.
Results We identified 19 additional reports of cutaneous legionellosis ([n = 20] 12 confirmed; 7 possible). Table 1 summarizes the treatment of the 13 patients with confirmed cutaneous legionellosis (10–21, and the current report [CR]); Table 2 (8, 9, 22–24) summarizes treatment of the 7 with possible cutaneous legionellosis.
Skin findings The skin manifestations of cutaneous Legionella infection are varied and include erythematous macular (12, 13, 18–20), nodular (18, CR), and vesicular (17) eruptions. One patient had rapidly expanding erythema after thoracentesis (14). Abscesses were identified in 4 individuals: 2 receiving high-dose corticosteroids (10, 12) and 2 with hematologic abnormalities (immunoglobulin A gammopathy [15] and chronic lymphocytic leukemia [21]). One patient had a purulent open wound at a previous surgical site (11).
Diagnostic studies Direct culture or immunofluorescent stain of abnormal skin and soft tissue (10–20, CR) identified L. pneumophila in 7 cases (10, 11, 14, 17, 19, 20, CR); Legionella micdadei in 3 cases (12, 13, 16); and Legionella cincinnatiensis (15) and Legionella maceachernii (18) in 1 case each. L. pneumophila findings included serogroups 1 (19), 3 (10), 4 (11), 5 (20), and 8 (CR). In addition, PCR identified Legionella feeleii in papular lesions (21). Of 13 confirmed cases, 6 had skin biopsies. Punch biopsies identified hemorrhage and necrosis suggestive of cellulitis or vasculitis in 1 case (12), inflammation and necrosis in another (21), and short acid-fast bacilli
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63/F
68/F
65/F
9 (18)
10 (19)
66/M
5 (14)
8 (17)
39/F
4 (13)
9/F
62/F
3 (12)
7 (16)
71/M
2 (11)
73/F
46/F
1 (10)
6 (15)
Age, years/ Gender
Patient no. (Reference)
Leg induration and erythema
Erythematous nodules on right hand
Cutaneous bullae on chest
Posterior neck abscess
Recurrent soft tissue abscesses
Erythema near thoracentesis site
Erythema on left hand with pustule
Erythema, abscess
Purulent left hip incision
Perirectal abscess
Skin manifestations
Idiopathic thrombocytopenic purpura; interstitial lung disease, chronic corticosteroid use (unknown dose)
Polymyalgia rheumatica; prednisone; methotrexate
Trauma, cardiothoracic surgery, intubation
NR
Nephritic syndrome; IgA gammopathy
Follicular lymphoma
Renal transplant; azathioprine (unreported dose); methylprednisone (unreported dose)
Glomerulonephritis; prednisone (20 mg/d); cyclophosphamide (125 mg/d)
Septic arthritis
Glomerulonephritis; prednisone (80 mg/d)
Medical history
Hypoxia; worsening, diffuse groundglass opacities
NR
Increased respiratory secretions; bilateral pneumonia
NR
NR
Dry cough, pleural effusion
Pleural effusion
Bilateral pneumonia
NR
Dry cough; left lobe nodule
Pulmonary focus
Confirmed cutaneous legionellosis documented by skin or soft tissue analysis (n = 13)
Skin biopsy: L. pneumophila DFA: L. pneumophila serogroup 1
Vancomycin (2 days), cefepime and azithromycin (36 h)
Levofloxacin (12 weeks)
Cefazolin (6 days), then imipenem/cilastatin and tobramycin (24 h)
Postmortem chest wall culture: L. pneumophila
Pustular fluid DFA: Legionella DFA: Legionella maceachernii
Clarithromycin (duration unknown)
bridement; clarithromycin De and rifampin (14 weeks)
bridement; erythromycin De (3 weeks)
bridement (3 times); De forearm amputation; erythromycin and rifampin (6 weeks)
Erythromycin (IV, then oral; 6 weeks)
Erythromycin (IV, unknown duration)
Incision and drainage; erythromycin, rifampin, chloramphenicol (4 weeks)
Treatment (duration)
Bartonella PCR sample: L. micdadei
DNA sequence analysis: Legionella cincinnatiensis
Operative tissue culture: L. pneumophila DFA: L. pneumophila
Surgical culture: L. micdadei DFA: L. micdadei
DFA: Legionella micdadei Abscess culture: L. micdadei
DFA: L. pneumophila serogroup 4
Abscess aspiration culture: Legionella pneumophila DFA stain: L. pneumophila serogroup 3
Microbiology and pathology
Death
Erythema resolved, nodules persisted
Death
Abscess resolved
Abscess resolved
Infection resolved
Infection resolved
Abscess resolved
Wound healed
Abscess resolved
Outcome
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within mononuclear cells in a third (13). One punch biopsy demonstrated dermal suppurative neutrophilic and granulomatous inflammation (18). A postmortem skin biopsy on a patient with culture-proven relapsed Legionella cellulitis demonstrated dermal neutrophilic and lymphocytic infiltration (19). The outcome of 1 biopsy was not described (20).
Concurrent pulmonary infection Six of 13 patients had concurrent respiratory symptoms and abnormal chest imaging consistent with pulmonary infection (10, 14, 17, 19, 20, CR). Chest radiographs showed bilateral patchy infiltrates (17, 20), unilateral effusions (14, CR), and nodules (10, CR). Three of the 6 patients with pulmonary symptoms had non-productive cough (10, 14, 20). Two had chest radiographic abnormalities without respiratory symptoms: 1 patient had pulmonary infiltrates (12) and another had pleural effusion (13). One patient with underlying interstitial lung disease had worsening diffuse ground-glass opacities on computed tomograms (19). Five patients had no respiratory symptoms or abnormal chest images (11, 15, 16, 18, 21).
Immunosuppression Seven patients were immunosuppressed (10, 12, 13, 18, 19, CR). Two received anti-rejection therapy for solid organ transplantation (13, 20); 4 received corticosteroids for glomerulonephritis (10), progressive glomerulonephritis secondary to vasculitis (also treated with cyclophosphamide) (12), polymyalgia rheumatica (also treated with methotrexate; doses for either medication were not available in the report) (18), and idiopathic thrombocytopenia and arthritis (19). Our patient received high-dose corticosteroids, tacrolimus, and mycophenolate after SCT and graft-versus-host disease.
Treatment and clinical course
Table 1
F, female; /d, per day; DFA, direct fluorescence antibody; M, male; NR, not reported; h, hours; IV, intravenous; IgA, immunoglobulin A; PCR, polymerase chain reaction; CR, current report.
Death Right leg wound culture: L. pneumophila serotype 8, confirmed with DNA sequencing Hematopoietic stem cell transplant; prednisone; tacrolimus; mycophenolate mofetil 27/F 13 (CR)
Erythematous, subcutaneous masses right leg
Hypoxia, left nodular lesion, pleural effusion
bridement, amoxicillinDe clavulanate and levofloxacin (unknown duration) PCR: Legionella feeleii Chronic lymphocytic leukemia 66/F 12 (21)
Papular lesion with cellulitis and abscess
NR
Azithromycin (14 days, of 21-day prescribed therapy)
Unclear
Improved bridement (4 times); De tigecycline and moxifloxacin (100 days) Ulcer biopsy: L. pneumophila serotype 5 and Candida albicans Dry cough, bilateral pneumonia Liver transplant; pyoderma gangrenosum, methylprednisolone (20 mg/ d), tacrolimus, mycophenolate mofetil (1 g) 48/M 11 (20)
Enlargement of chronic leg ulcer
Microbiology and pathology Age, years/ Gender Patient no. (Reference)
Table 1 Continued
Skin manifestations
Medical history
Pulmonary focus
Treatment (duration)
Outcome
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Manifestations of cutaneous legionellosis resolved in 9 patients with antimicrobial therapy (10–16, 18, 20). In the case of cutaneous Legionella nodules, erythema improved with antibiotic treatment, although the nodules persisted (18). One report did not disclose the outcome of the subcutaneous infection (21). Three died while hospitalized (17, 19, CR). Nine of the 13 patients received macrolide therapy. Seven of those 9 received erythromycin (n = 5) (10–14)
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38/M
46/M
67/M
69/M
48/F
32/F
64/M
1 (22)
2 (23)
3 (24)
4 (24)
5 (8)
6 (8)
7 (9)
Erythema, focal blisters on chest
Erythematous lesions on chest and limbs
Erythematous rash on trunk and limbs
Maculopapular rash on trunk and limbs
Maculopapular rash on trunk and limbs
Erythema on pretibial surfaces
Petechial rash on palate and body
Presenting skin manifestations
Fever, upper abdominal pain
Fever, diarrhea, dry cough
Dry cough, flaccid quadriplegia
Fever; renal and respiratory failure
Fever; renal and respiratory failure
Febrile, dry cough, diarrhea
Confusion, dry cough, myalgia
Associated symptoms
Chronic alcohol abuse; B-cell chronic lymphatic leukemia
NR
NR
NR
NR
Chronic renal failure; renal transplant
NR
Medical history
BAL and serum ELISA: L. pneumophila
Urinary antigen: Legionella
Urinary antigen: Legionella
Sputum culture: L. pneumophila serotype 1 Sputum DFA: Legionella
Sputum culture: Legionella pneumophila serotype 1 Sputum DFA: Legionella
Sputum culture: Legionella Lung aspirate DFA: Legionella Legionella titers 1:128 on day 6; 1:2048 on day 19
Serology: Legionella titer 1:256
Diagnostic test
Blister biopsy negative
NR
NR
Skin biopsy negative
Skin biopsy negative
NR
NR
Microbiology and pathology
Meropenem and cotrimoxazole
Clarithromycin, imipenem, and ciprofloxacin
Clarithromycin, imipenem, and ciprofloxacin
Erythromycin and rifampin
Erythromycin (IV)
Erythromycin
Erythromycin
Treatment
Multisystem organ failure
Improved
Improved
Multisystem organ failure
Sudden MI; death
Improved
Improved
Outcome
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Table 2
M, male; NR, not reported; DFA, direct fluorescence antibody; IV, intravenous; MI, myocardial infarction; F, female; BAL, bronchoalveolar lavage; ELISA, enzyme-linked immunoassay.
Age, years/ Gender
Patient no. (Reference)
Possible cutaneous legionellosis in 7 patients without confirmation by skin or soft tissue analysis
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or clarithromycin (n = 2) (15, 16), and 4 of those 7 required incision and drainage (10), d ebridement (13– 15), or amputation (13) to clear progressive cutaneous disease. Three of the 4 in whom surgical interventions were indicated also received rifampin (10, 13, 15). Ultimately, all 7 of the patients given erythromycin or clarithromycin survived. The 2 remaining macrolidetreated patients received azithromycin (1 also received cefepime and vancomycin); both died, one after just 1 day of azithromycin treatment (19), and the other is the patient reported here (CR), who died from an unrelated comorbid condition. The third patient in the literature who died had a necrotizing Legionella chest wall infection that was treated with broad-spectrum antibiotics, but none with anti-Legionella activity (17). The remaining 3 cases with confirmed cutaneous Legionella all received fluoroquinolones (levofloxacin [n = 2]; moxifloxacin [n = 1]) (18, 20, 21). Two of the 3 patients required d ebridements (Table 1) (20, 21). Of these 3 patients, 2 survived, 1 with monotherapy (18), and the other with co-administration of tigecycline, reduction in immunosuppression, and 4 d ebridements (20). The outcome of the third fluoroquinolone-treated patient was not reported (21).
Discussion Legionella is a fastidious aerobic gram-negative bacillus. Associated with water environments, it may be traced to man-made water-collecting systems (e.g., air conditioners, hot tubs) (3). Most Legionella pneumonias are caused by L. pneumophila serogroup 1. Legionella species do not grow on routine bacterial media (25); charcoal-containing yeast extract media are required and incubation for 2–5 days (26). Cultures require several days and can detect non-L. pneumophila species. Legionella urinary antigen detects only L. pneumophila serogroup 1. Ten of 13 cutaneous Legionella cases in this report were caused by either nonserogroup 1 L. pneumophila species or non-pneumophila species. Therefore, specific assays and cultures were required for diagnosis, and tests such as Legionella urinary antigen would not have been adequate for diagnostic purposes. Legionella skin infections are uncommon, and the addition of our case brings the published total to 13 patients with culture-proven infection, as identified in our review of the literature. Infections were diagnosed by skin or ulcer biopsy, abscess drainage material, or surgically d ebrided tissue. Nearly half had concurrent respiratory infections, and the cutaneous infection was presumably a result of hematogenous spread from
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lungs (10, 20, 25). One patient received hydrotherapy in a tank subsequently found to be contaminated with the same L. pneumophila species cultured from his surgical wound (11). For those cases with no proven pulmonary infection, the mechanism of cutaneous infection may be direct inoculation via contaminated water. However, no other cases in our series had a proven water source. Treatment of extrapulmonary legionellosis is generally acknowledged to be similar to that of Legionella pneumonia (27), although little is known about optimal management of cutaneous legionellosis in particular. Clinical and animal studies have shown that both macrolides and fluoroquinolones are effective for Legionella pneumonia, but no head-to-head trials have been conducted. Retrospective studies of Legionella pneumonia suggest that fluoroquinolones are associated with more rapid defervescence and shorter hospital stays, but mortality rates are similar for both groups of agents (28). Higher doses of fluoroquinolones at the outset of treatment are recommended for optimal outcome (27). Respiratory fluoroquinolones do not interact with cyclosporine and tacrolimus and so are preferred in transplant recipients. The newer macrolides (azithromycin and clarithromycin) demonstrate high intracellular activity and fewer medication-induced adverse effects than erythromycin. Doxycycline and tigecycline have been noted as alternative therapeutic agents (27). In our review, for the 2 cases in which azithromycin was used to treat cutaneous legionellosis, the soft tissue infection appeared to improve but both patients died of multiorgan failure (19, CR). Whether this result was caused by delayed recognition and treatment or insufficient treatment duration is unknown, but mortality appeared to be related to a concurrent morbid illness in both patients’ situations. The optimal treatment duration for cutaneous legionellosis has not been established. Most patients with Legionella pneumonia are successfully treated in 1 week (7–10 days [29]) to 2 weeks (10–14 days [25]). Treatment is initially intravenous and then oral after 3–5 days, if the patient is hemodynamically stable (29). Immunocompromised patients with cutaneous legionellosis may require 3 weeks of treatment (25); however, duration of treatment is difficult to state with certainty because our case series was small and not all reports indicated the duration of antibiotics. Six of 13 (46.1%) patients in our analysis were treated for at least 4 weeks; all 6 survived (10, 12, 13, 15, 18, 20), although 1 had persistent skin nodules (18). Three patients in this series had fatal illness. Two of the 3 died before provision (or adequate duration) of
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treatment. One patient died 7 days after a traumatic motor vehicle accident; she required cardiothoracic surgery, and necrotizing soft-tissue Legionella infection developed afterward (the organism, in hindsight, was resistant to the antibiotic used) (17). One patient died 1 day after azithromycin initiation, despite improvement in cellulitis (19), and our patient died because of another comorbid illness, despite improvement in the cutaneous legionellosis. Although all 3 patients received no more than 2 weeks of Legionella-specific antibiotics, given the circumstances, we hesitate to call these situations failures of specific treatments. Patients with cutaneous legionellosis may require d ebridement; such intervention was performed in 5 of the 13 patients in our series (13–15, 20, 21). The majority of patients with confirmed cutaneous legionellosis in this report (9 of 13) presented for medical attention with the Legionella infection in progress. Therefore, very few were potentially hospital-acquired infections (12, 13, 15, 16, 18–21, CR). Because the individual reports did not disclose information regarding an epidemiologic investigation for hospital acquisition, and because some community-acquired infections have been misclassified as hospital-acquired (30, 31), it is unclear whether any of these cases were nosocomial in origin. Immunosuppression, particularly cellular immune dysfunction, confers increased risk for extrapulmonary Legionella infections (32). Scerpella et al. (6) identified pericarditis caused by L. pneumophila serogroup 1 in an immunocompromised bone marrow transplant patient. Another patient with systemic lupus erythematous-like disease had recurrent septic arthritis caused by Legionella species (7). Among our 13 confirmed cases, more than half (7 of 13 [54%]) received corticosteroids (20– 80 mg/day). Three patients were recipients of solid organ (n = 2) or hematopoietic SCT (n = 1) transplants. We identified 7 patients with possible cutaneous legionellosis documented in published reports (Table 2). They primarily had skin abnormalities associated with pulmonary Legionella infection. In 4 patients, the legionellosis was identified by culture or direct fluorescent antibody stain of infected respiratory secretions, and the concurrent skin eruption resolved with Legionella-active antimicrobials (9, 23, 24). In 2 patients with skin eruptions, diagnosis of the pulmonary process was made by positive urinary antigen only (8). Four of the 7 patients had a dry cough; 6 had chest imaging that revealed pulmonary infiltrates (4 bilateral). The 7 cases of possible cutaneous legionellosis had various skin manifestations resembling those of the 13 confirmed cases. However, they differed in several respects: (i) immunosuppression was less common
(1 renal transplant recipient [23] and 1 patient with pre–B-cell leukemia [9]); and (ii) the mortality rate appeared higher (3/7 [43%]) than that for confirmed cases (3/13 [23%]) but was not significantly different (P = 0.61). Deaths in patients with possible cutaneous legionellosis resulted from myocardial infarction (n = 1) (24) or multiorgan failure (n = 2) (9, 24). Study limitations include the small sample size of confirmed cutaneous legionellosis, which possibly restricted characterization of the most common skin manifestations. Finally, the lack of completely reported information in prior case reports precluded extrapolation of details, especially related to dosage or duration of antibiotic treatment. Cutaneous legionellosis is uncommon, but because it requires specific diagnostic cultures and tests for proper identification and treatment, Legionella species should be considered in the differential diagnosis of skin lesions that fail to respond to empiric treatment, especially in immunocompromised patients.
Acknowledgements: Author contributions: L.J.P. Concept/design, data collection and analysis, drafting the article, critical revision, and approval of the article. J.E.B.: Data analysis, critical revision, and approval of the article. S.K.: Concept/design and approval of the article. D.J.D.: Approval of the article. J.R.M.: Concept/design and approval of the article. Conflicts of interest: None.
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Case report
Cutaneous legionellosis: case report and review of the medical literature L.J. Padrnos, J.E. Blair, S. Kusne, D.J. DiCaudo, J.R. Mikhael. Cutaneous legionellosis: case report and review of the medical literature. Transpl Infect Dis 2014: 16: 307–314. All rights reserved Abstract: Discrete nodules developed on the leg of a 27-year-old immunosuppressed woman after an allogeneic stem cell transplant. Biopsy and culture grew Legionella pneumophila serogroup 8. On day 7 of azithromycin treatment, respiratory distress and abnormal liver transaminases developed, and the patient died on day 14. Review of the medical literature identified 19 reports of Legionella species-associated skin or soft tissue infections (total of 20 patients, 13 with confirmed infection). Manifestations of the 13 confirmed cases included erythematous macular rash (n = 7), erythema after thoracentesis (n = 1), abscess formation (n = 4), respiratory symptoms (n = 6), and abnormal chest radiographs (n = 8). Six required surgical exploration and d ebridement, and 7 were immunocompromised. Rash and respiratory infection improved with antibiotics in 10, but 3 died. Immunosuppression may predispose transplant recipients to Legionella infections. Diagnostic biopsies may facilitate appropriate treatment.
L.J. Padrnos1, J.E. Blair2, S. Kusne2, D.J. DiCaudo3, J.R. Mikhael4 1
Department of Internal Medicine, Mayo Clinic, Scottsdale, Arizona, USA, 2Division of Infectious Diseases, Mayo Clinic, Scottsdale, Arizona, USA, 3 Department of Dermatology and Division of Anatomic Pathology, Mayo Clinic, Scottsdale, Arizona, USA, 4 Division of Hematology and Oncology, Mayo Clinic, Scottsdale, Arizona, USA Key words: cutaneous infection; Legionella; legionellosis; Legionella pneumophila Correspondence to: Janis E. Blair, MD, Division of Infectious Diseases, Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA Tel: 480 342 0337 Fax: 480 342 0689 E-mail: [email protected]
Received 23 May 2013, revised 25 September 2013, 30 October 2013, accepted for publication 12 November 2013 DOI: 10.1111/tid.12201 Transpl Infect Dis 2014: 16: 307–314
Legionella species was first documented in 1976 after an outbreak of fatal respiratory illness (1). Of more than 50 species and serogroups (2, 3), the most common pathogenic species is Legionella pneumophila serogroup 1 (3). With the evolution of more sensitive diagnostic testing methods, legionellosis is increasingly recognized as a cause of pneumonia: its US incidence increased 217% from 2000 (n = 1110) to 2009 (n = 3522) (4, 5). Extrapulmonary legionellosis is rare, but reported sites include pericarditis (6), septic arthritis (7), and cutaneous infections (8, 9). We report a case of cutaneous legionellosis and summarize the relevant English-language medical literature. Our aim was to raise awareness of this rare entity and summarize its various manifestations.
Case report Pre–B-cell acute lymphoblastic leukemia (Philadelphia chromosome–negative with complex cytogenetics) was diagnosed in a 27-year-old woman in May 2008, for which she received induction and intensification chemotherapy. After treatment for a second and third relapse, she underwent allogeneic double-cord blood stem cell transplantation (SCT) (4/6 matched) in March 2011. Post transplantation, she had restrictive lung disease, graft-versus-host disease of skin (stage 3, April 2011) and bowel (grade 4, May 2011), and corticosteroid-associated myopathy. On post-SCT (pSCT) day 172, she was hospitalized for back and leg pain, diffuse erythema, and 3 distinct, well-marginated, firm, indurated, 2-cm subcutaneous masses on the
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posterior left thigh. Although she had no cough or dyspnea, chest radiographs revealed bibasilar abnormalities consistent with atelectasis or consolidation. Her medications included tacrolimus (1 mg, twice daily, oral), mycophenolate mofetil (1 g, twice daily), budesonide (3 mg, 3 times daily), and prednisone (15 mg daily). She was treated empirically with voriconazole, meropenem, and vancomycin, and then with ampicillin-sulbactam and clindamycin. Biopsy of the skin lesion (pSCT day 175) revealed “mixed deep dermal inflammation” suggestive of infection, but no microorganisms were observed on stained specimens. Caspofungin was added to her treatment regimen. Despite improvement of the rash, the patient became agitated and required intubation for airway protection (pSCT day 179). Ceftriaxone and acyclovir were empirically added. Of note, she had a history of levofloxacin allergy, and all fluoroquinolones were avoided. Stains and cultures of specimens from bronchoalveolar lavage and sputum were negative for fungi, Pneumocystis, mycobacteria, Nocardia species, Legionella species, herpesvirus, and varicella. Polymerase chain reaction (PCR) was negative for Coccidioides species. She was extubated (pSCT day 182). Antibiotics were reduced to piperacillin and tazobactam, and erythema improved. However, new subcutaneous nodules developed on her leg, and a biopsy (pSCT day 188) showed “subcutaneous neutrophilic microabscesses.” Ten days later, the skin biopsy culture grew L. pneumophila serogroup 8, which was then confirmed with DNA sequencing. Urinary Legionella antigen remained negative. She was prescribed azithromycin (pSCT day 198) and transitioned to inpatient rehabilitation (pSCT day 200). However, on pSCT day 207, she was rehospitalized with an unrelated infection (severe adenoviral hepatitis). Following a family conference, she began comfortonly measures and died on pSCT day 210. There was no known association between the patient’s cutaneous Legionella and the systemic illness that led to her death.
Review of the literature We searched the English-language literature from inception through December 2012 on PubMed and Ovid MEDLINE using the terms: “Legionella,” “Legionella longbeachae,” “Legionella pneumophila,” “Legionnaires’ disease,” “legionellosis” combined with “cutaneous,” “skin disease,” “skin manifestation,” and “soft tissue” or “exanthem.” Retrieved articles were
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reviewed to identify additional cases of Legionella skin and soft tissue infection. We included confirmed cutaneous legionellosis only if skin or associated structures were culture- or PCRpositive for Legionella species. Possible cutaneous legionellosis was defined as confirmed respiratory infection (positive for Legionella species by culture, PCR, or direct fluorescent antibody stain) accompanied by skin abnormalities suggestive of skin or soft tissue infection. Cases of possible cutaneous legionellosis were tabulated but not included in the primary analysis. The Mayo Clinic Institutional Review Board reviewed and approved this study.
Results We identified 19 additional reports of cutaneous legionellosis ([n = 20] 12 confirmed; 7 possible). Table 1 summarizes the treatment of the 13 patients with confirmed cutaneous legionellosis (10–21, and the current report [CR]); Table 2 (8, 9, 22–24) summarizes treatment of the 7 with possible cutaneous legionellosis.
Skin findings The skin manifestations of cutaneous Legionella infection are varied and include erythematous macular (12, 13, 18–20), nodular (18, CR), and vesicular (17) eruptions. One patient had rapidly expanding erythema after thoracentesis (14). Abscesses were identified in 4 individuals: 2 receiving high-dose corticosteroids (10, 12) and 2 with hematologic abnormalities (immunoglobulin A gammopathy [15] and chronic lymphocytic leukemia [21]). One patient had a purulent open wound at a previous surgical site (11).
Diagnostic studies Direct culture or immunofluorescent stain of abnormal skin and soft tissue (10–20, CR) identified L. pneumophila in 7 cases (10, 11, 14, 17, 19, 20, CR); Legionella micdadei in 3 cases (12, 13, 16); and Legionella cincinnatiensis (15) and Legionella maceachernii (18) in 1 case each. L. pneumophila findings included serogroups 1 (19), 3 (10), 4 (11), 5 (20), and 8 (CR). In addition, PCR identified Legionella feeleii in papular lesions (21). Of 13 confirmed cases, 6 had skin biopsies. Punch biopsies identified hemorrhage and necrosis suggestive of cellulitis or vasculitis in 1 case (12), inflammation and necrosis in another (21), and short acid-fast bacilli
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63/F
68/F
65/F
9 (18)
10 (19)
66/M
5 (14)
8 (17)
39/F
4 (13)
9/F
62/F
3 (12)
7 (16)
71/M
2 (11)
73/F
46/F
1 (10)
6 (15)
Age, years/ Gender
Patient no. (Reference)
Leg induration and erythema
Erythematous nodules on right hand
Cutaneous bullae on chest
Posterior neck abscess
Recurrent soft tissue abscesses
Erythema near thoracentesis site
Erythema on left hand with pustule
Erythema, abscess
Purulent left hip incision
Perirectal abscess
Skin manifestations
Idiopathic thrombocytopenic purpura; interstitial lung disease, chronic corticosteroid use (unknown dose)
Polymyalgia rheumatica; prednisone; methotrexate
Trauma, cardiothoracic surgery, intubation
NR
Nephritic syndrome; IgA gammopathy
Follicular lymphoma
Renal transplant; azathioprine (unreported dose); methylprednisone (unreported dose)
Glomerulonephritis; prednisone (20 mg/d); cyclophosphamide (125 mg/d)
Septic arthritis
Glomerulonephritis; prednisone (80 mg/d)
Medical history
Hypoxia; worsening, diffuse groundglass opacities
NR
Increased respiratory secretions; bilateral pneumonia
NR
NR
Dry cough, pleural effusion
Pleural effusion
Bilateral pneumonia
NR
Dry cough; left lobe nodule
Pulmonary focus
Confirmed cutaneous legionellosis documented by skin or soft tissue analysis (n = 13)
Skin biopsy: L. pneumophila DFA: L. pneumophila serogroup 1
Vancomycin (2 days), cefepime and azithromycin (36 h)
Levofloxacin (12 weeks)
Cefazolin (6 days), then imipenem/cilastatin and tobramycin (24 h)
Postmortem chest wall culture: L. pneumophila
Pustular fluid DFA: Legionella DFA: Legionella maceachernii
Clarithromycin (duration unknown)
bridement; clarithromycin De and rifampin (14 weeks)
bridement; erythromycin De (3 weeks)
bridement (3 times); De forearm amputation; erythromycin and rifampin (6 weeks)
Erythromycin (IV, then oral; 6 weeks)
Erythromycin (IV, unknown duration)
Incision and drainage; erythromycin, rifampin, chloramphenicol (4 weeks)
Treatment (duration)
Bartonella PCR sample: L. micdadei
DNA sequence analysis: Legionella cincinnatiensis
Operative tissue culture: L. pneumophila DFA: L. pneumophila
Surgical culture: L. micdadei DFA: L. micdadei
DFA: Legionella micdadei Abscess culture: L. micdadei
DFA: L. pneumophila serogroup 4
Abscess aspiration culture: Legionella pneumophila DFA stain: L. pneumophila serogroup 3
Microbiology and pathology
Death
Erythema resolved, nodules persisted
Death
Abscess resolved
Abscess resolved
Infection resolved
Infection resolved
Abscess resolved
Wound healed
Abscess resolved
Outcome
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within mononuclear cells in a third (13). One punch biopsy demonstrated dermal suppurative neutrophilic and granulomatous inflammation (18). A postmortem skin biopsy on a patient with culture-proven relapsed Legionella cellulitis demonstrated dermal neutrophilic and lymphocytic infiltration (19). The outcome of 1 biopsy was not described (20).
Concurrent pulmonary infection Six of 13 patients had concurrent respiratory symptoms and abnormal chest imaging consistent with pulmonary infection (10, 14, 17, 19, 20, CR). Chest radiographs showed bilateral patchy infiltrates (17, 20), unilateral effusions (14, CR), and nodules (10, CR). Three of the 6 patients with pulmonary symptoms had non-productive cough (10, 14, 20). Two had chest radiographic abnormalities without respiratory symptoms: 1 patient had pulmonary infiltrates (12) and another had pleural effusion (13). One patient with underlying interstitial lung disease had worsening diffuse ground-glass opacities on computed tomograms (19). Five patients had no respiratory symptoms or abnormal chest images (11, 15, 16, 18, 21).
Immunosuppression Seven patients were immunosuppressed (10, 12, 13, 18, 19, CR). Two received anti-rejection therapy for solid organ transplantation (13, 20); 4 received corticosteroids for glomerulonephritis (10), progressive glomerulonephritis secondary to vasculitis (also treated with cyclophosphamide) (12), polymyalgia rheumatica (also treated with methotrexate; doses for either medication were not available in the report) (18), and idiopathic thrombocytopenia and arthritis (19). Our patient received high-dose corticosteroids, tacrolimus, and mycophenolate after SCT and graft-versus-host disease.
Treatment and clinical course
Table 1
F, female; /d, per day; DFA, direct fluorescence antibody; M, male; NR, not reported; h, hours; IV, intravenous; IgA, immunoglobulin A; PCR, polymerase chain reaction; CR, current report.
Death Right leg wound culture: L. pneumophila serotype 8, confirmed with DNA sequencing Hematopoietic stem cell transplant; prednisone; tacrolimus; mycophenolate mofetil 27/F 13 (CR)
Erythematous, subcutaneous masses right leg
Hypoxia, left nodular lesion, pleural effusion
bridement, amoxicillinDe clavulanate and levofloxacin (unknown duration) PCR: Legionella feeleii Chronic lymphocytic leukemia 66/F 12 (21)
Papular lesion with cellulitis and abscess
NR
Azithromycin (14 days, of 21-day prescribed therapy)
Unclear
Improved bridement (4 times); De tigecycline and moxifloxacin (100 days) Ulcer biopsy: L. pneumophila serotype 5 and Candida albicans Dry cough, bilateral pneumonia Liver transplant; pyoderma gangrenosum, methylprednisolone (20 mg/ d), tacrolimus, mycophenolate mofetil (1 g) 48/M 11 (20)
Enlargement of chronic leg ulcer
Microbiology and pathology Age, years/ Gender Patient no. (Reference)
Table 1 Continued
Skin manifestations
Medical history
Pulmonary focus
Treatment (duration)
Outcome
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Manifestations of cutaneous legionellosis resolved in 9 patients with antimicrobial therapy (10–16, 18, 20). In the case of cutaneous Legionella nodules, erythema improved with antibiotic treatment, although the nodules persisted (18). One report did not disclose the outcome of the subcutaneous infection (21). Three died while hospitalized (17, 19, CR). Nine of the 13 patients received macrolide therapy. Seven of those 9 received erythromycin (n = 5) (10–14)
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38/M
46/M
67/M
69/M
48/F
32/F
64/M
1 (22)
2 (23)
3 (24)
4 (24)
5 (8)
6 (8)
7 (9)
Erythema, focal blisters on chest
Erythematous lesions on chest and limbs
Erythematous rash on trunk and limbs
Maculopapular rash on trunk and limbs
Maculopapular rash on trunk and limbs
Erythema on pretibial surfaces
Petechial rash on palate and body
Presenting skin manifestations
Fever, upper abdominal pain
Fever, diarrhea, dry cough
Dry cough, flaccid quadriplegia
Fever; renal and respiratory failure
Fever; renal and respiratory failure
Febrile, dry cough, diarrhea
Confusion, dry cough, myalgia
Associated symptoms
Chronic alcohol abuse; B-cell chronic lymphatic leukemia
NR
NR
NR
NR
Chronic renal failure; renal transplant
NR
Medical history
BAL and serum ELISA: L. pneumophila
Urinary antigen: Legionella
Urinary antigen: Legionella
Sputum culture: L. pneumophila serotype 1 Sputum DFA: Legionella
Sputum culture: Legionella pneumophila serotype 1 Sputum DFA: Legionella
Sputum culture: Legionella Lung aspirate DFA: Legionella Legionella titers 1:128 on day 6; 1:2048 on day 19
Serology: Legionella titer 1:256
Diagnostic test
Blister biopsy negative
NR
NR
Skin biopsy negative
Skin biopsy negative
NR
NR
Microbiology and pathology
Meropenem and cotrimoxazole
Clarithromycin, imipenem, and ciprofloxacin
Clarithromycin, imipenem, and ciprofloxacin
Erythromycin and rifampin
Erythromycin (IV)
Erythromycin
Erythromycin
Treatment
Multisystem organ failure
Improved
Improved
Multisystem organ failure
Sudden MI; death
Improved
Improved
Outcome
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Table 2
M, male; NR, not reported; DFA, direct fluorescence antibody; IV, intravenous; MI, myocardial infarction; F, female; BAL, bronchoalveolar lavage; ELISA, enzyme-linked immunoassay.
Age, years/ Gender
Patient no. (Reference)
Possible cutaneous legionellosis in 7 patients without confirmation by skin or soft tissue analysis
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or clarithromycin (n = 2) (15, 16), and 4 of those 7 required incision and drainage (10), d ebridement (13– 15), or amputation (13) to clear progressive cutaneous disease. Three of the 4 in whom surgical interventions were indicated also received rifampin (10, 13, 15). Ultimately, all 7 of the patients given erythromycin or clarithromycin survived. The 2 remaining macrolidetreated patients received azithromycin (1 also received cefepime and vancomycin); both died, one after just 1 day of azithromycin treatment (19), and the other is the patient reported here (CR), who died from an unrelated comorbid condition. The third patient in the literature who died had a necrotizing Legionella chest wall infection that was treated with broad-spectrum antibiotics, but none with anti-Legionella activity (17). The remaining 3 cases with confirmed cutaneous Legionella all received fluoroquinolones (levofloxacin [n = 2]; moxifloxacin [n = 1]) (18, 20, 21). Two of the 3 patients required d ebridements (Table 1) (20, 21). Of these 3 patients, 2 survived, 1 with monotherapy (18), and the other with co-administration of tigecycline, reduction in immunosuppression, and 4 d ebridements (20). The outcome of the third fluoroquinolone-treated patient was not reported (21).
Discussion Legionella is a fastidious aerobic gram-negative bacillus. Associated with water environments, it may be traced to man-made water-collecting systems (e.g., air conditioners, hot tubs) (3). Most Legionella pneumonias are caused by L. pneumophila serogroup 1. Legionella species do not grow on routine bacterial media (25); charcoal-containing yeast extract media are required and incubation for 2–5 days (26). Cultures require several days and can detect non-L. pneumophila species. Legionella urinary antigen detects only L. pneumophila serogroup 1. Ten of 13 cutaneous Legionella cases in this report were caused by either nonserogroup 1 L. pneumophila species or non-pneumophila species. Therefore, specific assays and cultures were required for diagnosis, and tests such as Legionella urinary antigen would not have been adequate for diagnostic purposes. Legionella skin infections are uncommon, and the addition of our case brings the published total to 13 patients with culture-proven infection, as identified in our review of the literature. Infections were diagnosed by skin or ulcer biopsy, abscess drainage material, or surgically d ebrided tissue. Nearly half had concurrent respiratory infections, and the cutaneous infection was presumably a result of hematogenous spread from
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lungs (10, 20, 25). One patient received hydrotherapy in a tank subsequently found to be contaminated with the same L. pneumophila species cultured from his surgical wound (11). For those cases with no proven pulmonary infection, the mechanism of cutaneous infection may be direct inoculation via contaminated water. However, no other cases in our series had a proven water source. Treatment of extrapulmonary legionellosis is generally acknowledged to be similar to that of Legionella pneumonia (27), although little is known about optimal management of cutaneous legionellosis in particular. Clinical and animal studies have shown that both macrolides and fluoroquinolones are effective for Legionella pneumonia, but no head-to-head trials have been conducted. Retrospective studies of Legionella pneumonia suggest that fluoroquinolones are associated with more rapid defervescence and shorter hospital stays, but mortality rates are similar for both groups of agents (28). Higher doses of fluoroquinolones at the outset of treatment are recommended for optimal outcome (27). Respiratory fluoroquinolones do not interact with cyclosporine and tacrolimus and so are preferred in transplant recipients. The newer macrolides (azithromycin and clarithromycin) demonstrate high intracellular activity and fewer medication-induced adverse effects than erythromycin. Doxycycline and tigecycline have been noted as alternative therapeutic agents (27). In our review, for the 2 cases in which azithromycin was used to treat cutaneous legionellosis, the soft tissue infection appeared to improve but both patients died of multiorgan failure (19, CR). Whether this result was caused by delayed recognition and treatment or insufficient treatment duration is unknown, but mortality appeared to be related to a concurrent morbid illness in both patients’ situations. The optimal treatment duration for cutaneous legionellosis has not been established. Most patients with Legionella pneumonia are successfully treated in 1 week (7–10 days [29]) to 2 weeks (10–14 days [25]). Treatment is initially intravenous and then oral after 3–5 days, if the patient is hemodynamically stable (29). Immunocompromised patients with cutaneous legionellosis may require 3 weeks of treatment (25); however, duration of treatment is difficult to state with certainty because our case series was small and not all reports indicated the duration of antibiotics. Six of 13 (46.1%) patients in our analysis were treated for at least 4 weeks; all 6 survived (10, 12, 13, 15, 18, 20), although 1 had persistent skin nodules (18). Three patients in this series had fatal illness. Two of the 3 died before provision (or adequate duration) of
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treatment. One patient died 7 days after a traumatic motor vehicle accident; she required cardiothoracic surgery, and necrotizing soft-tissue Legionella infection developed afterward (the organism, in hindsight, was resistant to the antibiotic used) (17). One patient died 1 day after azithromycin initiation, despite improvement in cellulitis (19), and our patient died because of another comorbid illness, despite improvement in the cutaneous legionellosis. Although all 3 patients received no more than 2 weeks of Legionella-specific antibiotics, given the circumstances, we hesitate to call these situations failures of specific treatments. Patients with cutaneous legionellosis may require d ebridement; such intervention was performed in 5 of the 13 patients in our series (13–15, 20, 21). The majority of patients with confirmed cutaneous legionellosis in this report (9 of 13) presented for medical attention with the Legionella infection in progress. Therefore, very few were potentially hospital-acquired infections (12, 13, 15, 16, 18–21, CR). Because the individual reports did not disclose information regarding an epidemiologic investigation for hospital acquisition, and because some community-acquired infections have been misclassified as hospital-acquired (30, 31), it is unclear whether any of these cases were nosocomial in origin. Immunosuppression, particularly cellular immune dysfunction, confers increased risk for extrapulmonary Legionella infections (32). Scerpella et al. (6) identified pericarditis caused by L. pneumophila serogroup 1 in an immunocompromised bone marrow transplant patient. Another patient with systemic lupus erythematous-like disease had recurrent septic arthritis caused by Legionella species (7). Among our 13 confirmed cases, more than half (7 of 13 [54%]) received corticosteroids (20– 80 mg/day). Three patients were recipients of solid organ (n = 2) or hematopoietic SCT (n = 1) transplants. We identified 7 patients with possible cutaneous legionellosis documented in published reports (Table 2). They primarily had skin abnormalities associated with pulmonary Legionella infection. In 4 patients, the legionellosis was identified by culture or direct fluorescent antibody stain of infected respiratory secretions, and the concurrent skin eruption resolved with Legionella-active antimicrobials (9, 23, 24). In 2 patients with skin eruptions, diagnosis of the pulmonary process was made by positive urinary antigen only (8). Four of the 7 patients had a dry cough; 6 had chest imaging that revealed pulmonary infiltrates (4 bilateral). The 7 cases of possible cutaneous legionellosis had various skin manifestations resembling those of the 13 confirmed cases. However, they differed in several respects: (i) immunosuppression was less common
(1 renal transplant recipient [23] and 1 patient with pre–B-cell leukemia [9]); and (ii) the mortality rate appeared higher (3/7 [43%]) than that for confirmed cases (3/13 [23%]) but was not significantly different (P = 0.61). Deaths in patients with possible cutaneous legionellosis resulted from myocardial infarction (n = 1) (24) or multiorgan failure (n = 2) (9, 24). Study limitations include the small sample size of confirmed cutaneous legionellosis, which possibly restricted characterization of the most common skin manifestations. Finally, the lack of completely reported information in prior case reports precluded extrapolation of details, especially related to dosage or duration of antibiotic treatment. Cutaneous legionellosis is uncommon, but because it requires specific diagnostic cultures and tests for proper identification and treatment, Legionella species should be considered in the differential diagnosis of skin lesions that fail to respond to empiric treatment, especially in immunocompromised patients.
Acknowledgements: Author contributions: L.J.P. Concept/design, data collection and analysis, drafting the article, critical revision, and approval of the article. J.E.B.: Data analysis, critical revision, and approval of the article. S.K.: Concept/design and approval of the article. D.J.D.: Approval of the article. J.R.M.: Concept/design and approval of the article. Conflicts of interest: None.
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