Abstract
A 58-year-old female following an allogeneic stem cell transplant (alloSCT) presented with tender subcutaneous nodule in the axillary and inguinal regions. One of the nodules was biopsied and cultured. The patient was diagnosed with Pseudomonas aeruginosa (P. aeruginosa) panniculitis. Blood cultures were negative for P. aeruginosa. The patient responded to 4 weeks of imipenem-cilastatin and gentamicin treatment but relapsed immediately after the discontinuation of antibiotic treatment with a change in the susceptibility of P. aeruginosa to antibiotics. The patient received piperacillin-tazobactam and aztreonam with no recurrence for nine months. Differential diagnosis of subcutaneous nodules can be difficult in an alloSCT setting. P. aeruginosa should be kept in mind, and the biopsy and culture of a nodule should be obtained without delay. Blood cultures can be negative. Despite long term antibiotic treatment, relapse can occur.
Introduction
Systemic infection caused by Pseudomonas aeruginosa (P. aeruginosa) is common in patients undergoing allogeneic stem cell transplant (alloSCT). Early posttransplant, these patients are immunosuppressed due to severe neutropenia, graft-versus-host disease (GVHD), and GVHD prophylaxis and treatment. These patients also experience severe gastrointestinal tract (GIT) mucositis resulting from conditioning regimens composed of high dose chemotherapy and/or radiotherapy. P. aeruginosa colonized in the GIT can readily cause bacteremia through the damaged GIT mucosa, which causes high mortality (up to 35.8%) in alloSCT patients (Hakki et al. 2007).
P. aeruginosa can infrequently cause primary or secondary skin and soft tissue infections (Silvestre and Betlloch, 1999). Primary skin infections can occur if the intact skin barrier is damaged as in burns, trauma, surgery or dermatitis. Healthy individuals can also have primary skin infection due to high moisture conditions like ear infections of swimmers, toe webs of athletes, perianal region, under diapers in infants, and skin of whirlpool and hot tub users. Secondary P. aeruginosa skin infections can be associated with sepsis. Secondary skin infections can manifest as hemorrhagic vesicles, bullae, ecthyma gangrenosum, deep abcesses, cellulites, nodules or gangrenous cellulites.
We report a patient who developed P. aeruginosa panniculitis, an inflammation of subcutaneous fat underlying the epidermis of the skin, three months posttranplant without bacteremia while receiving immunosuppressive drugs for the treatment of acute GVHD.
Case Report
A 58-year-old African-American female initially presented in 2002 with microcytic anemia, thrombocytosis, and hepatosplenomegaly. Agnogenic myeloid metaplasia with myelofibrobosis was diagnosed by a bone marrow aspirate and biopsy. The patient's disease remained stable until March of 2006 with no treatment when she presented with worsening anemia and myeloblasts in the peripheral smear. An alloSCT was considered from a HLA-identical sibling because of disease progression. The patient received a preparative regimen composed of fludarabine 25 mg/m2 daily for four days and melphalan 70 mg/m2 daily for two days in May 2006. On day +12, the patient developed erythematosus, maculopapular rash in the chest, trunk, and both extremities and diarrhea despite receiving tacrolimus and mycophenolate mofetil for GVHD prophylaxis. A colon biopsy confirmed acute GVHD. Methylprednisone at a dose of 1 mg/kg/day was initiated and increased to 2 mg/kg/day due to thrombocytopenia, decreased appetite, and skin rash. Neutrophil engraftment and platelet recovery occurred on day +18 and +61, respectively. The patient achieved a 100% donor chimerism. On day +51, cytomegalovirus (CMV) antigen became positive, and preemptive therapy was initiated with ganciclovir 5 mg/kg twice a day. On day +90, the patient noted emergence of multiple painful subcutaneous nodules in both axillae and left inguinal region (Fig. 1) when the patient was on fluconazole and pentamidine for antifungal and Pneumocystis jirovici prophylaxis and ganciclovir for maintenance treatment of CMV antigen-emia. Immunosuppression drugs consisted of tacrolimus 2 mg bid, mycophenolate mofetil 1 gm in the morning and 500 mg in the evening, and prednisone 20 mg daily at the time of admission. Review of systems was negative for fever and chills, but positive for decreased appetite, weight loss, dry mouth, and dry eyes for 2 months, all being secondary symptoms of mucocutaneous chronic GVHD. Physical exam revealed normal vital signs, improving skin rash without any sclerodermatous changes, splenomegaly, and multiple subcutaneous nodules in the range of 3 × 4 cm to 1 × 1 cm in diameter. The nodules were tender, mobile, and firm. A complete blood count (CBC) showed the following: white blood count (WBC) of 1.7 × 10 9 /L, hemoglobin (Hb) of 10.6 mg/dL, and platelet count of 129 × 10 9 /L. Liver function tests were within normal limits. Epstein-Barr virus (EBV) DNA was negative in the blood. Blood cultures grew Enterococcus faecalis (E. faecalis). The largest nodule was biopsied and cultured. A histological exam of the nodule revealed septal panniculitis, and the cultures grew P. aeruginosa. The patient was empirically started on imipenem-cilastatin (500 mg IV three times a day), gentamicin (5 mg/kg IV daily) and vancomycin (1000 mg IV twice a day). P. aeruginosa was sensitive to imipenem-cilastatin (MIC ≤ 1) and piperacillin/tazobactam (MIC = 64/4), intermediate sensitive to aztreonam (MIC = 16) and cefepime (MIC = 16), and resistant to gentamicin (MIC > 8), levofloxacin (MIC > 4), and piperacillin (MIC > 64). Gentamicin was discontinued based on this report. The patient remained on vancomycin for a total of 2 weeks and imipenem-cilastatin for a total of 4 weeks, with complete resolution of nodules after 3 weeks of treatment. Blood cultures remained negative. Two days after completion of imipenem-cilastatin, the patient presented again with new, multiple subcutaneous nodules associated with fever (38.9 °C) and chills. The multiple-confluent subcutaneous nodules were in the same regions but larger than their original presentation. Blood cultures were negative. IgG level was 745 mg/dL. Cultures from one of the nodules once again grew P. aeruginosa again. The antibiotic susceptibility showed a decreased sensitivity to imipenem-cilastatin and meropenem (MIC = 8, intermediate) and increased sensitivity to azotreonam (MIC = 8, sensitive), susceptibility to piperacillin/tazobactam remained unchanged at second occurrence. The patient was started on piperacillin/tazobactam and azotreonam, and given IVIG dosed at 500 mg/kg for 4 days. Between hospital admissions, immunosuppression drugs were tapered (tacrolimus 1.5 mg bid, mycophenolate mofetil 500 mg bid, and prednisone 10 mg daily) in an effort to reduce the risk of recurrent infection. The patient became clinically stable and afebrile after two days, and the nodules completely resolved after five days. Antibiotic treatment was continued for 4 weeks. An investigation of the source of her recurring infection led to us to culture the patient's hand creams, deodorant, and soap bars; however, no source was identified. The patient has had no recurrence of these nodules for nine months.
Subcutaneous nodules in the right axilla.
Discussion
P. aeruginosa associated subcutaneous nodules has been reported in 16 patients (12 male and 4 female) (Watanakunakorn, 1998; Bourelly and Grossman, 1998; Berger et al. 1995; Reed et al. 1976; Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989; Schlossberg, 1980; Llistosella et al. 1984; Aleman et al. 1999). The patients’ age ranged from 3 months to 74 years old. Similar to our patient, most of these patients (11 patients) were immunocompromised (Watanakunakorn, 1998; Bourelly and Grossman, 1998; Berger et al. 1995; Reed et al. 1976; Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989). Of these 11 patients, four had malignancies, four had AIDS, one had aplastic anemia, one had congenital agammaglobulinemia, one had renal and heart transplant (Watanakunakorn, 1998; Bourelly and Grossman, 1998; Berger et al. 1995; Reed et al. 1976; Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989).
P.aeruginosa subcutaneous nodules were secondary to Pseudomonas bacteremia in the majority of these patients (75%, 12 out of 16 patients) (Watanakunakorn, 1998; Bourelly and Grossman, 1998; Reed et al. 1976; Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989; Schlossberg 1980; Llistosella et al. 1984). The source of septicemia was reported in eight patients: pneumonia in two, infective endocarditis in one, appendiceal abscess in one, pyomyositis in one, recurrent prostatitis in one, maxillary sinusitis in one, and arthritis in one (Watanakunakorn, 1998; Bourelly and Grossman, 1998; Reed et al. 1976; Korten et al. 1992; Bagel and Grossman, 1986; Schlossberg, 1980; Llistosella et al. 1984). In our patient, P. aeruginosa colonization in the GIT was likely due to prior long-term hospitalizations and long-term non-Pseudomonas prophylactic antibiotic use. When the nodules appeared, P. aeruginosa bacteremia could have occurred through the GIT mucosa damaged by gut GVHD. In fact, the patient's blood cultures grew E. faecalis, indicating that the GIT mucosa barrier was damaged. However, neither at first presentation nor at relapse did blood cultures grow P. aeruginosa. Although unlikely, concurrent local P. aeruginosa infections in multiple sites could be the cause of P. aeruginosa panniculitis instead of systemic infection. In particular, the patient had no fever or hypotension at the first presentation. Considering the nodules were in the inguinal and axillary regions, contamination through hot tub or personal used items could have resulted in the colonization of P. aeruginosa concurrently in these multiple moist sites. The broken skin barrier due to skin GVHD might have been responsible for penetration of P. aeruginosa into the subcutaneous tissue and then for panniculitis. The patient's personally used items were cultured, all of which were negative.
Biopsy of one of the nodules is vital for diagnosis in these immunocompromised patients because early diagnosis and thus early appropriate treatment that leads to lower mortality rate (Micek et al. 2005). Nodular lesions can present an infection, including Staphylococcus aureus, bacillary angiomatosis, mycobacterial infection, acanthamebiasis, protothecosis, and variety of deep mycoses. Nodular lesions can also present EBV-associated lymphoproliferative disorder or extramedullary hematopoiesis in patients with myelofibrosis posttransplant. EBV DNA was negative, and the biopsy of a nodule showed panniculitis in the patient. Panniculitis can be caused by infection, lymphoproliferative disorders, collagenous tissue disorders, pancreatitis, cold, or trauma. Repeated cultures yielded P. aeruginosa in the patient. In the literature, out of the 16 patients with subcutaneous nodules, eight underwent a biopsy (Bourelly and Grossman, 1998; Berger et al. 1995; Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989; Llistosella et al. 1984; Aleman et al. 1999) and five were diagnosed with panniculitis (Korten et al. 1992; Bagel and Grossman, 1986; Patterson et al. 1989; Llistosella et al. 1984; Aleman et al. 1999).
Treatment of P. aeruginosa panniculitis can be very difficult in immunocompromised patients. Two out of the 10 patients died (Watanakunakorn, 1998; Reed et al. 1976). The role of surgery in the treatment of P. aeruginosa panniculitis is controversial (Reed et al. 1976; Korten, 1992). Six patients were treated by antibiotics plus surgical drainage while the remainder did not have any surgical intervention (Reed et al. 1976; Aleman et al. 1999). Our patient was treated with antibiotic only at initial presentation and relapse. Changing susceptibility of P. aeruginosa to antibiotics can occur and represent a challenge in the treatment. At the time of relapse, in addition to changing antibiotics, intravenous immunoglobulin (IVIG) was administered, and the dose of steroids was decrease. Among 16 patients, only one with congenital agammaglobulinemia received IVIG and survived (Reed et al. 1976). The significance of IVIG administration and decreasing steroid dose on the positive outcome is unknown in this patient. It was shown that the use of high dose steroids was significantly associated with higher mortality however hypogammaglobulinemia and neutropenia were not (Hakki et al. 2007). In our patient, tapering immunosuppressive therapy might have contributed to resolution of infection. Of interest, concurrent infection with a microorganism decreased survival significantly in the same study (Hakki et al. 2007). Our patient had E. faecalis bacteremia with the recurrence of P. aeruginosa panniculitis.
In conclusion, Pseudomonas panniculitis should be considered in alloSCT recipients who develop subcutaneous-tender nodules. Emergent histopathological and microbiolgical examination of the nodules is vital for differential diagnosis because delayed treatment would increase mortality rate. Blood cultures may be negative. Treatment may require long-term antibiotic treatment. Recurrence is possible, and the cultures and antibiotic susceptibility should be repeated.
Potential Conflicts of Interest
All authors claim no conflicts of interest.
Footnotes
Acknowledgements
None.