Locoregional Multiple Nodular Panniculitis Induced by Pseudomonas aeruginosa Without Septicemia: Three Cases and Focus on Predisposing Factors

Importance  Pseudomonas aeruginosa–induced locoregional multiple nodular panniculitis without septicemia is an underreported condition, with only 3 cases reported to date. We report 3 new cases of P aeruginosa–induced multiple nodular panniculitis without septicemia and describe common features among all 6 cases, thus providing the first description, to our knowledge, of the natural history and potential predisposing factors for this entity.

Observations  Median age of the 6 patients was 74 years (range, 54-84 years). Patients had inflammatory nodules on a lower limb (n = 6) that were unilateral (n = 6) and had no fever (n = 5). Blood cultures were negative (n = 5). Skin biopsy specimens revealed panniculitis (n = 5), with skin cultures positive for P aeruginosa (n = 6). Skin nodules resolved with systemic antibiotics (n = 5). The comorbidities recorded were type 1 or 2 diabetes mellitus (n = 5), overweight (n = 3), and combined locoregional anatomical changes in the lower limbs (n = 5). Local skin injury, which constituted the portal entry, was present in all cases, especially leg ulcers (n = 3).

Conclusions and Relevance  We describe P aeruginosa–induced locoregional nodular panniculitis as a distinct entity. This should be investigated in elderly, diabetic, overweight patients with inflammatory nodules on a lower limb associated with locoregional anatomical changes and skin injury, with the optimal antibiotic regimen introduced as rapidly as possible.

Skin manifestations caused by Pseudomonas aeruginosa are classified as primary or secondary cutaneous lesions.^1-4 Primary cutaneous lesions (eg, pyoderma, intertrigo, and folliculitis) arise in previously healthy patients with predisposing factors such as maceration and skin damage, whereas secondary cutaneous lesions usually occur in immunosuppressed patients by blood dissemination of P aeruginosa in a context of bacteremia or septicemia. Such secondary cutaneous lesions include ecthyma gangrenosum, hemorrhagic vesicles and blisters, cellulitis, fasciitis, gangrene, and panniculitis.¹ Indeed, multiple nodular panniculitis classically constitutes a secondary cutaneous manifestation of P aeruginosa in a context of septicemia in immunosuppressed patients.^2-4 On the other hand, P aeruginosa–induced locoregional multiple nodular panniculitis without septicemia seems rare, and to our knowledge, only 3 cases have been reported.^5-7 The natural history and predisposing factors of this condition, therefore, have not been assessed. We report 3 new cases of P aeruginosa–induced multiple nodular panniculitis without septicemia and describe common features in the 6 cases, thus constituting the first description, to our knowledge, of the natural history and potential predisposing factors of this probably underdiagnosed entity.

A woman in her 80s was admitted for chronic leg ulcers related to venous insufficiency and chronic limb lymphedema. Her medical history included type 1 diabetes mellitus, chronic renal failure, and atrial fibrillation. She was treated with insulin, acetylsalicylic acid, fluindione, ramipril, atorvastatin, and bisoprolol hemifumarate. On admission, she had multiple ulcers on the right lateral malleolus and macerated interdigital intertrigo of both feet. She also had inflammatory nodules on the left thigh that had appeared 6 days before with no systemic symptoms (Figure 1A). Relevant clinical and paraclinical findings are reported in Table 1 and Table 2. In particular, there was no bacteremia or evidence of underlying immunosuppression. A skin biopsy specimen of a nodule showed neutrophilic panniculitis and no vasculitis (Figure 2A), and multisensitive P aeruginosa was isolated from a skin biopsy sample. Pseudomonas aeruginosa with the same antibiogram profile had been isolated from the ulcer on her contralateral limb 1 month earlier. No bacteriologic sampling of the interdigital intertrigo was performed. The nodules resolved rapidly after treatment with ciprofloxacin hydrochloride for 14 days.

A man in his 50s was referred for infiltrated and necrotic purpuric lesions of the legs that had appeared 10 days previously with progressive extension to the trunk. He had a medical history of obesity, type 1 diabetes mellitus, and dilated heart disease. His treatment consisted of insulin, furosemide, fluindione, bisoprolol, perindopril arginine, atorvastatin, and digoxin. Sildenafil citrate had been introduced 12 days before for pulmonary hypertension related to his heart condition. Clinical and histologic findings were consistent with leukocytoclastic cutaneous vasculitis (LCV). A systemic involvement was ruled out by clinical examination, laboratory tests (C-reactive protein, 10 mg/L [to convert to nanomoles per liter, multiply by 9.524]; complete blood count; and renal and liver function tests), and imaging (chest radiography and echocardiography). There was no evidence of an infectious process accounting for the LCV. Investigations (protein and immunoglobulin electrophoresis, autoimmune antibodies, cryoglobulinemia, and hepatitis B virus, hepatitis C virus, and human immunodeficiency virus serology) were unremarkable. Sildenafil was suspected and withdrawn. There was progressive resolution of the LCV with topical corticosteroids and colchicine. One month later, the patient developed inflammatory nodules on his left leg, where there remained some infracentimetric cutaneous ulcers secondary to the necrotic purpura. Relevant clinical and paraclinical findings are reported in Table 1 and Table 2. A skin biopsy specimen showed neutrophilic panniculitis (Figure 2B), and skin culture was positive for multisensitive P aeruginosa. The nodules rapidly resolved after treatment with ciprofloxacin for 15 days. He had no other flare-up of vasculitis during the following 6 months with colchicine.

A woman in her 70s was referred for a venous ulcer on the right leg lasting for 2 months. Her medical history included hypertrophic cardiomyopathy and high blood pressure. Her long-term treatment included atenolol. Six days after admission, she developed inflammatory nodules on the right limb (Figure 1B) with no systemic symptoms. Relevant clinical and paraclinical findings are reported in Table 1 and Table 2. Amoxicillin trihydrate–potassium clavulanic, 3 g/d, was introduced for the panniculitis after systematic blood cultures. Her condition rapidly worsened with confusion and ascites. Laboratory investigations revealed deterioration of hepatic function (prothrombin index, 35%; factor V, 47%; aspartate aminotransferase, 94 U/L [normal, <45]; alanine aminotransferase, 211 U/L [normal, <35]; total bilirubin, 2.16 mg/dL [normal, <25]; serum ammonia, 79.83 μg/dL [normal, <50]; and serum albumin, 2.4 g/dL) that led to the diagnosis of a chronic active hepatitis B virus infection (hepatitis B core antibody IgG positive, hepatitis B core antibody IgM negative, hepatitis B surface antigen positive, and hepatitis B virus DNA, 7 log copies/mL) (to convert aspartate aminotransferase and alanine aminotransferase to microkatals per liter, multiply by 0.01667 and 0.0167, respectively; total bilirubin and serum ammonia to micromoles per liter, multiply by 17.104 and 0.714, respectively; and serum albumin to grams per liter, multiply by 10). Results of abdominal ultrasonography were consistent with liver cirrhosis. Further bacteriologic sampling (cerebrospinal fluid, ascites, and blood cultures), performed during amoxicillin–clavulanic treatment, was negative. A biopsy specimen of a cutaneous nodule showed neutrophilic panniculitis and no vasculitis (Figure 2C), and culture was positive for multiresistant P aeruginosa. Ceftazidime pentahydrate and amikacin sulfate were started and the nodules had resolved when she died of grade IV hepatic encephalopathy 15 days later.

Nodular panniculitis due to P aeruginosaclassically constitutes manifestation of blood dissemination of the bacteria during septicemia in immunosuppressed patients.^2-4 We report 3 cases of P aeruginosa–induced locoregional panniculitis with no septicemia and discovered only 3 such cases reported in the literature,^5-7 making it probably an underdiagnosed and/or underreported condition. Interestingly, we found striking similarities among the previously reported cases and our 3 cases, allowing for a description of the natural history and the predisposing factors for this entity.

The clinical and paraclinical outcomes of the P aeruginosa infection in these 6 cases are summarized in Table 2. Multiple inflammatory nodules had developed out of the hospital (n = 3) or during hospitalization (n = 3). There was no fever or systemic signs (n = 5) or only a transient fever with no systemic signs (n = 1). Nodules were located unilaterally on a lower limb (n = 6). There was a high level of inflammatory syndrome (median C-reactive protein, 168 mg/L; range, 21-301 mg/L). Blood cultures were negative (n = 5) or had not been performed because of the absence of fever with a minor inflammatory syndrome (n = 1). There was no evidence of endocarditis on echocardiography (n = 5). Skin or pus cultures were positive for P aeruginosa (n = 6), most with a multisensitive profile (n = 4). Biopsy specimens revealed neutrophilic lobular (n = 3) or septal and lobular (n = 2) panniculitis, with extension to the deep dermis. In one patient, clinical features were consistent with panniculitis, whereas histopathologic findings and magnetic resonance imaging revealed abscesses.⁶ It remains unclear whether this patient had pseudomonal abscesses rather than panniculitis.

The anatomoclinical features of our cases distinguished them from ecthyma gangrenosum, another secondary cutaneous manifestation of P aeruginosa that has also been described with no septicemia,⁸ including in immunocompetent patients.⁹ There has been some controversy whether ecthyma gangrenosum without bacteremia represents a manifestation of initially undetectable bacteremia or a primary cutaneous infection.⁸ Our case series showed no evidence that panniculitis indicated initially undetectable bacteremia, based on the absence of systemic signs and the negativity of blood cultures drawn before administration of antibiotics.

Regarding the prognosis of the infectious process, skin nodules resolved under systemic antibiotics (n = 5) or with an additional surgical incision (n = 1), and no patients developed septicemia. All patients had been treated within 7 days after the onset of panniculitis, and it is unclear whether they would have developed septicemia without prompt therapy. We did not find any reports in the literature in which P aeruginosa–induced locoregional panniculitis turned into septicemia.

The overall prognosis of such panniculitis is more debatable. Pseudomonas aeruginosa bacteremia, irrespective of the cutaneous findings, is associated with mortality rates up to 39%.¹⁰ Patients developing ecthyma gangrenosum with no septicemia had a better prognosis than those with septicemia.⁸ Similarly, 1 death from septicemia was reported in the 17 previous cases of P aeruginosa panniculitis with septicemia,³ whereas none occurred in our case series. However, the patients in our series were older and had more comorbidities, and the outcome was fatal for 2, despite the absence of septicemia. These 2 patients developed the nodules in the hospital, with the intermediate-sensitive P aeruginosa possibly being acquired there. It is possible that the infectious process worsened organ failure; therefore, early diagnosis and treatment of such panniculitis should be recommended, especially in debilitated patients.

The predisposing factors for all reported cases of P aeruginosa–induced locoregional panniculitis are reported in Table 1. Median age was 74 years (range, 54-84 years). Frequent comorbidities were type 1 or 2 diabetes mellitus (n = 5), for which 4 patients received insulin therapy, and chronic heart disease (n = 5). Type 1 and 2 diabetes mellitus may represent a predisposing factor due to immunity impairment, although it was well controlled in 3 patients. Heart disease is usually not associated with a heightened risk of skin infections, although one study reported an increase in wound infections in patients receiving antihypertensives.¹¹ The high prevalence of chronic heart disease in this series may also be related to the high median age. Body mass index, when available (n = 4), indicated that most patients were overweight (n = 3), which is also related to an increased risk of infection.¹² Interestingly, most patients had combined locoregional anatomical changes in the lower limbs (venous insufficiency, n = 3; arterial insufficiency, n = 2; lymphedema, n = 1; and lipoedema, n = 1), consistent with risk factors previously described for limb erysipelas.¹² Similarly, a local skin injury was reported in all patients (homolateral leg ulcer, n = 3; ulcers secondary to LCV, n = 1; interdigital intertrigo, n = 1; and traumatic injury, n = 1). Pseudomonas aeruginosa with the same antibiogram profile had been isolated from cutaneous ulcers (n = 3), suggesting that long-term wound colonization may have favored skin infection. No bacteriologic results were available for the other 3 cases to confirm homolateral skin injury as the primary site of P aeruginosa infection. Although P aeruginosa has been isolated in 30% to 40% of leg ulcers,¹³ only some seem to develop panniculitis, suggesting that other predisposing factors are necessary for P aeruginosa–induced panniculitis. Insulin injections (n = 4) also may have constituted a breach of the cutaneous barrier and favored bacterial penetration, but the nodules were not located at the sites of insulin injections.

Unlike patients who develop panniculitis in the context of septicemia, those with P aeruginosa–induced locoregional panniculitis seem to have a relatively preserved immune condition. None of these patients had received systemic immunosuppressive therapy, but 1 patient had applied clobetasol for LCV for 1 month, which could have favored local infection. Immunity status had been investigated by γ-globulin count (n = 3), IgG count (n = 4), and human immunodeficiency virus serology (n = 4), but the results were unremarkable. Interestingly, total lymphocyte count was mostly decreased (n = 3) when performed (n = 4), with no further information on the lymphocyte subset analysis. When performed (n = 4), the serum albumin count was also mostly decreased (n = 3), possibly indicative of impaired nutritional status or related to the inflammatory syndrome.

The physiopathologic mechanism for such P aeruginosa–induced nodular panniculitis without bacteremia has to be distinguished from secondary skin lesions due to blood dissemination of P aeruginosa.^1,14 In our cases, unilateral, locoregionally distributed, multiple nodules upstream from a skin injury are consistent with lymphatic dissemination of the bacterium from a primary infectious site. Other organisms involved in locoregional panniculitis include bacteria (Streptococcus species, Staphylococcus aureus, and Mycobacterium species), fungi, and parasites,¹⁵ which may similarly spread from the inoculated source in a sporotrichoid pattern. However, bacterial panniculitis manifests as suppurative panniculitis, whereas granulomatous patterns are mostly reported with Mycobacterium species, fungi, and parasites.¹⁵

The overall systemic immunocompetent status of the 6 reported cases could explain the locoregional limitation of the infectious process. The general systemic predisposing factors appear to be advanced age, type 1 or 2 diabetes mellitus, chronic heart disease, and overweight. Local predisposing factors are anatomical changes, such as venous, arterial, or lymphatic insufficiency, and local skin injury, especially leg ulcers with P aeruginosa colonization.

Pseudomonas aeruginosa–induced nodular panniculitis is probably an underrecognized condition. It should be suspected in an elderly, diabetic, overweight patient with unilateral inflammatory nodules on a lower limb, even in the absence of fever, systemic symptoms, or immunosuppressive condition, and especially when combined with locoregional anatomical changes and concomitant skin injury, so that an optimal antibiotic regimen can be introduced as rapidly as possible.

Accepted for Publication: October 28, 2013.

Corresponding Author: Mahtab Samimi, MD, Department of Dermatology, Laboratory of Molecular Virology and Immunology, ISP 1282, INRA-University François Rabelais, Hospital of Tours, Tours, France (samimi.mahtab@yahoo.fr).

Published Online: March 26, 2014. doi:10.1001/jamadermatol.2013.9340.

Author Contributions: Drs Roriz and Samimi had access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Roriz, Maruani, Samimi.

Acquisition of data: Roriz, Maruani, Le Bidre, M.-C. Machet, Samimi.

Analysis and interpretation of data: Maruani, L. Machet, Samimi.

Drafting of the manuscript: Roriz, M.-C. Machet, Samimi.

Critical revision of the manuscript for important intellectual content: Maruani, Le Bidre, L. Machet, Samimi.

Administrative, technical, or material support: M.-C. Machet.

Study supervision: Maruani, L. Machet, Samimi.

Conflict of Interest Disclosures: None reported.