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72-Year-Old Woman With Redness, Swelling, and Pain of the Forearms and Hands

Published:February 21, 2016DOI:https://doi.org/10.1016/j.mayocp.2015.12.004
      A 72-year-old woman from far eastern Kansas who had a history of psoriatic arthritis treated with methotrexate and infliximab presented to the Mayo Clinic Hospital, Saint Marys Campus emergency department for evaluation of redness, swelling, and pain of both forearms and hands of 10 weeks' duration. Psoriatic arthritis had been diagnosed 4 years earlier, and her disease had been under good control until 3 months previously. Six weeks before the current presentation, the patient's rheumatologist stopped her methotrexate, started prednisone at 20 mg/d (tapered to 2.5 mg/d), and increased the frequency of her infliximab infusions from every 6 weeks to every 4 weeks in the setting of worsening hand pain, swelling, and redness. Two weeks before presenting to the emergency department, redness, swelling, and induration of her forearms developed. Her right hand grew increasingly painful, and black skin discoloration developed over the right thumb pad.
      On presentation, her vital signs were notable for a heart rate of 116 beats/min and respirations of 25/min. Physical examination revealed diffuse edema of both forearms and hands with overlying erythematous, indurated plaques on the left forearm without palpable tenderness or crepitus. Marked swelling, induration, erythema, warmth, and scaling were noted on the thenar eminence and palmar metacarpophalangeal joint line of the right hand. There were 2 discrete areas of ulcerated black, dry, nonmalodorous skin on the right thumb pad. Laboratory studies yielded the following findings (reference ranges provided parenthetically): leukocytes, 10.5 × 109/L (3.5-10.5 × 109/L) with 54% neutrophils; plasma lactate, 3.3 mmol/L (0.6-2.3 mmol/L); and C-reactive protein, 128.2 mg/L (≤8.0 mg/L). Plain radiography of the hands revealed severe erosive osteoarthritis, chondrocalcinosis, and no subcutaneous gas.
      • 1.
        Which one of the following skin/skin structure infections (SSSIs) is the most likely primary process in this setting?
        • a.
          Necrotizing fasciitis (NF)
        • b.
          Gas gangrene
        • c.
          Ecthyma gangrenosum
        • d.
          Fungal or mycobacterial infection
        • e.
          Monomicrobial cellulitis
      An SSSI that is associated with clinical findings suggestive of tissue necrosis (black skin discoloration) may be caused by a variety of microbial pathogens and pathologic mechanisms. Necrotizing fasciitis may be caused by a monomicrobial infection due to a β-hemolytic streptococcus (type 2 NF) or a mixed infection (type 1 NF), and patients often present with septic parameters as seen in our patient. However, NF is rapidly progressive over hours to days rather than weeks. Gas gangrene is an infection associated with tissue death caused by gas-forming bacteria. These infections may be polymicrobial or due to Clostridium species and are less likely in this case because of the lack of subcutaneous crepitus. Ecthyma gangrenosum is an SSSI that may be caused by gram-negative bacteria such as Pseudomonas aeruginosa or Staphylococcus and is typically seen in patients with prolonged neutropenia, which was not present in our patient. Atypical microorganisms such as fungi or mycobacteria may cause necrotizing infections in immunocompromised patients such as those taking tumor necrosis factor α (TNF-α) inhibitors, and this is the most likely diagnosis in our patient. Monomicrobial cellulitis is most frequently caused by staphylococcal or streptococcal species but is not usually associated with progressive skin necrosis.
      The patient was a retired schoolteacher and had recently traveled to Texas. She lived on a farm that included chicken coops. She did not have a history of unpasteurized dairy consumption or other animal exposures. With multiple systemic inflammatory response syndrome criteria present, we initiated broad-spectrum antibacterial antibiotics because of concern about polymicrobial cellulitis in this immunocompromised patient.
      • 2.
        Given the patient's history of immunosuppression, she would be at greatest risk for which one of the following fungal infections?
        • a.
          Mucormyosis
        • b.
          Histoplasmosis
        • c.
          Blastomycosis
        • d.
          Coccidioidomycosis
        • e.
          Aspergillosis
      Although cutaneous mucormycosis may present with necrotic skin lesions, it is more commonly seen in patients with poorly controlled diabetes or chronic neutropenia. Histoplasmosis is an endemic mycosis caused by Histoplasma capsulatum, and disseminated histoplasmosis (DH) may present with joint pain, skin involvement, or tenosynovitis involving the wrists and hands. Patients taking TNF-α inhibitors are at increased risk for DH. Histoplasmosis is the most reasonable fungal consideration in an immunocompromised patient who lives in a Histoplasma-endemic region and is exposed to chicken coops. Blastomyces dermatitidis is an endemic dimorphic fungus found in the US Midwest that starts as a pulmonary infection following inhalation of spores and may lead to disseminated infection involving the skin, bones, or genitourinary system. Blastomyces dermatitidis skin lesions may present as necrotic lesions, skin ulcers, or exophytic lesions. Blastomycosis is not typically seen in immunocompromised patients, and our patient's travel history makes this infection unlikely. Disseminated coccidioidomycosis is more common in immunocompromised patients, but a lack of travel to the southwestern United States makes this diagnosis unlikely. Although disseminated aspergillosis may present with necrotic skin lesions, it is more common in patients with prolonged neutropenia, transplant recipients, or those receiving high-dose glucocorticoid therapy.
      Our patient experienced some improvement with the initiation of broad-spectrum antibacterial antibiotics, suggesting a secondary bacterial cellulitis. Results of screening serology for human immunodeficiency virus infection were negative. The patient's report of living on a farm that included chicken coops and residing in a Histoplasma-endemic area prompted us to consider the diagnosis of DH.
      • 3.
        Which one of the following is the most timely method to establish a diagnosis of DH in this patient?
        • a.
          Fungal blood cultures
        • b.
          Histoplasma serologies
        • c.
          Histoplasma urinary antigen measurement
        • d.
          Bone marrow examination
        • e.
          Skin biopsy
      Fungal blood cultures are specific but insensitive, and results may take several days. In this patient, fungal blood cultures were positive at 8 days. Histoplasma serologies are sensitive but may be nonspecific in a patient with substantial bird exposures. In our patient, fungal serologies were positive for H capsulatum by complement fixation (yeast and mycelial antibody titers of 1:32), and immunodiffusion studies were negative for Histoplasma H and M precipitating antibodies. Histoplasma H and M immunodiffusion studies are insensitive but are highly specific for active infection if both H and M precipitating antibodies are detected.
      • Connolly P.A.
      • Durkin M.M.
      • Lemonte A.M.
      • Hackett E.J.
      • Wheat L.J.
      Detection of histoplasma antigen by a quantitative enzyme immunoassay.
      Urinary Histoplasma antigen testing is specific if results are positive, but results were delayed in our patient because it was a send-out laboratory test (to MiraVista Diagnostics in Indianapolis, Indiana) at that time. An H capsulatum urinary antigen screen was later positive at 9.11 ng/mL (positive quantification range, 0.4-19 ng/mL). Bone marrow examination may be less sensitive than a skin biopsy in a patient with DH who presents with skin lesions. In patients who have skin rashes with plaques, necrotic skin lesions, and compromised immunity, it is crucial to obtain a skin biopsy to confirm the cause of infection and assess for possible fungal, mycobacterial, or Nocardia infection.
      A skin biopsy of both the right hand and arm in our patient revealed deep dermal granulomatous inflammation with numerous small yeast forms on fungal staining that were consistent in size and shape with H capsulatum, confirming a diagnosis of DH.
      • 4.
        For initial management of this patient's condition, which one of the following is the best option?
        • a.
          Oral ketoconazole
        • b.
          Oral itraconazole
        • c.
          Lipid formulation amphotericin B
        • d.
          Oral voriconazole
        • e.
          Oral fluconazole
      Ketoconazole is an antifungal agent that is no longer in common use in the United States. Oral itraconazole is the azole of choice for step-down therapy for DH, but it is not an appropriate initial treatment. A lipid formulation amphotericin B product is indicated for initial treatment of DH.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Voriconazole is the antifungal of choice for treatment of aspergillosis but is a second-line azole for the step-down treatment of histoplasmosis. Fluconazole is a second-line step-down azole therapy for histoplasmosis but is not an appropriate initial choice for DH.
      Once DH was diagnosed, we initiated daily intravenous lipid formulation amphotericin B (3 mg/kg). Pretreatment with acetaminophen and diphenhydramine was later added because our patient experienced infusion-related reactions that included fever, chills, paresthesias, tachycardia, tachypnea, abdominal pain, and hypertensive urgency.
      • Roden M.M.
      • Nelson L.D.
      • Knudsen T.A.
      • et al.
      Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics.
      The erythema and induration of the patient's hands and wrists improved following initiation of therapy. On the anticipated day of discharge, the patient experienced sudden onset of severe abdominal pain (rated 10 on a scale from 1 to 10) and was found to have a rigid abdomen with signs of peritoneal irritation on physical examination.
      • 5.
        Which one of the following is the most likely cause of the patient's severe abdominal pain?
        • a.
          Liposomal amphotericin B adverse effect
        • b.
          Severe constipation
        • c.
          Mesenteric ischemia
        • d.
          Acute pancreatitis
        • e.
          DH involving the gastrointestinal (GI) tract
      Lipid formulation amphotericin B infusions may be associated with moderate to severe abdominal pain in up to 20% of patients, but these symptoms typically resolve following completion of the infusion.
      • Roden M.M.
      • Nelson L.D.
      • Knudsen T.A.
      • et al.
      Triad of acute infusion-related reactions associated with liposomal amphotericin B: analysis of clinical and epidemiological characteristics.
      Amphotericin B is not routinely associated with constipation or signs of peritoneal irritation. The patient had no history of vascular disease–associated postprandial abdominal pain, so mesenteric ischemia was unlikely. Lipid formulation amphotericin B treatment is not associated with pancreatitis, nor did the patient have other risk factors for pancreatitis. The acute peritonitic abdominal pain was believed to most likely be due to GI tract involvement by histoplasmosis resulting in an intestinal perforation. Gastrointestinal tract involvement may cause clinical symptoms in 3% to 12% of patients with histoplasmosis.
      • Kahi C.J.
      • Wheat L.J.
      • Allen S.D.
      • Sarosi G.A.
      Gastrointestinal histoplasmosis.
      Plain abdominal radiography revealed markedly dilated loops of small bowel, prompting concern about possible free fluid in the abdomen. Abdominal computed tomography documented pneumatosis and free fluid in the abdomen without an identifiable area of perforation. Broad-spectrum antibacterials were initiated, and the patient underwent emergent surgery. Perforations of the ilium and jejunum were identified, and partial small-bowel resection was performed. Pathologic examination of the resected small bowel revealed numerous fungal yeast forms that were consistent with H capsulatum.
      The patient was transitioned to oral itraconazole after 2 weeks of intravenous lipid formulation amphotericin B therapy to complete a 12-month treatment course.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      The patient's TNF-α inhibitor therapy was withheld while she was being treated with antifungal therapy, and she was counseled to minimize acid-reducing therapies in order to maximize itraconazole absorption in the GI tract. If the patient's TNF-α inhibitor therapy is reinitiated at a later date, long-term itraconazole suppression should be considered following completion of the itraconazole treatment phase.
      Six months into her antifungal treatment course, the patient had development of a rash involving both forearms but remained asymptomatic off immunosuppressive therapies. Repeated skin biopsy revealed yeast forms that were consistent with H capsulatum, but culture results were negative. Her urinary Histoplasma antigen level was improved at 1.7 ng/mL. This condition was believed to be due to Histoplasma-associated immune reconstitution inflammatory syndrome (IRIS). Patients with TNF-α inhibitor–associated histoplasmosis are at risk for paradoxical worsening of their clinical condition—eg, IRIS—after cessation of TNF-α inhibitor therapy following initiation of antifungal therapy.
      • Hage C.A.
      • Bowyer S.
      • Tarvin S.E.
      • Helper D.
      • Kleiman M.B.
      • Wheat L.J.
      Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy.
      Although the optimal treatment of histoplasmosis-associated IRIS is unknown, our patient was treated with a brief course of prednisone.

      Discussion

      Histoplasmosis is the most common endemic dimorphic fungal infection in the midwestern and south central United States, with a hospitalization rate as high as 21 per 1,000,000 people in endemic areas and an estimated hospital mortality rate of 8%.
      • Chu J.H.
      • Feudtner C.
      • Heydon K.
      • Walsh T.J.
      • Zaoutis T.E.
      Hospitalizations for endemic mycoses: a population-based national study.
      Delayed diagnosis of DH may lead to mortality rates as high as 57%.
      • Hage C.A.
      • Bowyer S.
      • Tarvin S.E.
      • Helper D.
      • Kleiman M.B.
      • Wheat L.J.
      Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy.
      Most H capsulatum infections are asymptomatic and self-limited. Progressive DH occurs in approximately 1 in 2000 patients, many of whom are immunocompromised. A large single-center study of histoplasmosis that was performed at our medical center found that 59% of DH cases occurred in immunocompromised patients.
      • Assi M.A.
      • Sandid M.S.
      • Baddour L.M.
      • Roberts G.D.
      • Walker R.C.
      Systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients.
      Soil with bird or bat droppings is the classic reservoir of H capsulatum. Spelunking in caves with large populations of bats and exposure to pigeon droppings, chicken coops, and pet bird guano are recognized risk factors for acquisition of histoplasmosis. Histoplasmosis develops when Histoplasma microconidia are inhaled into the lungs and then grow into the H capsulatum yeast form, resulting in an often subclinical pneumonitis. Histoplasma capsulatum infection is controlled by cellular immunity. Macrophages laden with the organism spread to adjacent lymphatic channels and the reticuloendothelial system. Because of the integral role of cellular immunity for the control of histoplasmosis, patients with depleted T cells or those with T-cell dysfunction are at increased risk for DH. Tumor necrosis factor-α is an important inflammatory cytokine in macrophage activation, phagosome activation, and recruitment of neutrophils. Tumor necrosis factor-α inhibitors are used to treat inflammatory conditions such as rheumatoid arthritis and psoriatic arthritis. The risk of development of DH is increased in patients taking TNF-α inhibitors.
      • Hage C.A.
      • Bowyer S.
      • Tarvin S.E.
      • Helper D.
      • Kleiman M.B.
      • Wheat L.J.
      Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy.
      For example, infliximab therapy is associated with 16.7 cases of DH per 100,000 patients treated, with 78% of severe histoplasmosis cases occurring within 90 days of beginning infliximab therapy.
      • Wallis R.S.
      • Broder M.S.
      • Wong J.Y.
      • Hanson M.E.
      • Beenhouwer D.O.
      Granulomatous infectious diseases associated with tumor necrosis factor antagonists.
      Long-term methotrexate and glucocorticoid therapy are also independent risk factors for the development of DH.
      Clinical manifestations of pulmonary histoplasmosis include cough, dyspnea, or hemoptysis. Chest radiographic findings include chronic cavitary lesions, pleural thickening, calcified lymph nodes or granulomas, and, rarely, pleural effusions. Disseminated histoplasmosis has a highly variable presentation. Skin manifestations may be seen in 10% to 15% of patients and may present as papules, plaques, ulcers, vesicles, or generalized dermatitis. Uncommon dermatologic presentations of DH include panniculitis, cellulitis, necrotizing vasculitis, or exfoliative erythroderma. Patients may present with arthralgias or tenosynovitis. Gastrointestinal manifestations may include abdominal pain due to a perforated viscus or diarrhea.
      • Kahi C.J.
      • Wheat L.J.
      • Allen S.D.
      • Sarosi G.A.
      Gastrointestinal histoplasmosis.
      • Goodwin Jr., R.A.
      • Shapiro J.L.
      • Thurman G.H.
      • Thurman S.S.
      Des Prez RM. Disseminated histoplasmosis: clinical and pathologic correlations.
      Involvement of the adrenal glands may lead to adrenal insufficiency. Rare presentations may include testicular abscess or infective endocarditis. Patients with central nervous system involvement may present with headaches, meningismus, focal neurologic changes, or cranial nerve palsies.
      Culture of H capsulatum from tissue biopsies, ulcer swabs, blood, bone marrow, or bronchial material confirms the diagnosis of histoplasmosis. Urinary and serum antigen screening by enzyme immunoassy may be sensitive in the setting of disseminated infection but is less sensitive with milder forms of histoplasmosis.
      • Wheat L.J.
      Improvements in diagnosis of histoplasmosis.
      Urinary antigen screening can be up to 95% sensitive in immunocompromised patients.
      • Kauffman C.
      Diagnosis of histoplasmosis in immunosuppressed patients.
      Antibody testing by complement fixation (mycelial or yeast titers ≥1:8) and the presence of immunodiffusion H or M precipitin bands are 70% sensitive in immunocompromised patients and 90% sensitive in immunocompetent patients. Complement fixation titers of 1:8 or 1:16 may be seen in patients with previous infection. Histopathologic examination of biopsy material may reveal yeast forms that are 2 to 4 μm in size when stained with fungus-specific stains, but they may be confused with other organisms such as Cryptococcus neoformans or Pneumocystis jirovecii. Histoplasma capsulatum polymerase chain reaction assays are investigational and are not in wide clinical use.
      Untreated, DH may be fatal in 2 to 12 weeks, so aggressive treatment is indicated with an intravenous amphotericin analogue for 2 to 4 weeks and itraconazole step-down therapy for up to 12 months.
      • Wheat L.J.
      • Freifeld A.G.
      • Kleiman M.B.
      • et al.
      Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America.
      Itraconazole dosing is adjusted to a steady-state total itraconazole level of at least 1 to 2 μg/mL, although there are no published studies on therapeutic itraconazole levels. Other azoles such as voriconazole, fluconazole, and posaconazole have not been as well studied as itraconazole for the treatment of histoplasmosis.
      Some experts recommend that TNF-α inhibitors not be resumed in the setting of DH. In many patients, however, worsening of underlying inflammatory disease necessitates resumption of TNF-α inhibitor therapy. In a recent case series, 25 of 74 patients resumed TNF-α inhibitor therapy after a median duration of azole therapy of 12 months and had a 3.2% rate of DH recurrence (median follow-up, 32 months).
      • Vergidis P.
      • Avery R.K.
      • Wheat L.J.
      • et al.
      Histoplasmosis complicating tumor necrosis factor-α blocker therapy: a retrospective analysis of 98 cases.

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