A rare trigger for macrophage activation syndrome
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Rheumatol Int (2011) 31:405–407 DOI 10.1007/s00296-009-1204-0 123 CASE REPORT A rare trigger for macrophage activation syndrome Shikhar Agarwal · Jayavani Moodley · Gati Ajani Goel · Karl S. Theil · Syed S. Mahmood · Richard S. Lang Received: 3 July 2009 / Accepted: 13 September 2009 / Published online: 16 October 2009 © Springer-Verlag 2009 Abstract Macrophage activation syndrome (MAS) is a disorder characterized by increased activation of mononu- clear cells leading to phagocytosis of blood cell precursors in the bone marrow. We describe a case of MAS triggered by disseminated histoplasmosis occurring in a patient with Still’s disease on long-term treatment with adalimumab. Keywords Macrophage activation syndrome · Histoplasma · Hemophagocytosis Case report A 21-year-old Caucasian male with a history of Still’s dis- ease diagnosed 2 years prior presented with fevers to 105 ° F, constitutional symptoms, headache, and migratory joint pains. He had been treated with intermittent courses of prednisone, methotrexate, and anakinra. For the past 1 year he was maintained in remission on adalimumab alone. Examination revealed an erythematous macular rash of the trunk, marked scleral icterus, and hepatomegaly. Laboratory data on admission were signiWcant for hematocrit 44%, white blood cell count (WBC) 5.09 £ 10 9 / L, platelet count 76 £ 10 9 /L, bilirubin 5.2 mg/dL, AST 361 U/L, ALT 526 U/L, alkaline phosphatase 374 U/L, cre- atinine 1.01 mg/dL, erythrocyte sedimentation rate 5 mm/h, hypocomplementemia (C3 60 mg/dL, C4 10 mg/dL), Lac- tate dehydrogenase 4,807 U/L and elevated ferritin 13,800 ng/mL, triglycerides 342 mg/dL, and d-dimer 18,400 ng/mL. A diagnosis of MAS was considered and bone marrow (BM) aspiration and biopsy undertaken. Hospital course was complicated by unremitting fevers, increasing dyspnea, profound pancytopenia (nadir hemato- crit 19%, WBC 3 £ 10 9 /L, platelets 12 £ 10 9 /L) and wors- ening liver function (peak total bilirubin 19.3 mg/dL, AST 1050 U/L, ALT 530 U/L, alkaline phosphatase 470 U/L). A computed tomographic scan of his chest revealed diVuse nodules in both lung Welds producing hazy ground glass opaciWcation. An infectious disease work-up revealed posi- tive antibody titers for Histoplasma capsulatum at 1:128 (N < 1:8) and a positive Histoplasma urinary antigen. Gene probe analysis was positive for H. capsulatum DNA. Sub- sequent bronchoalveolar lavage demonstrated yeast forms, consistent with histoplasmosis. MAS was conWrmed by BM aspirate (Fig. 1) and biopsy (Fig. 2), which demonstrated macrophages with hemophag- ocytosis with and without intracellular budding yeast forms, morphologically compatible with H. capsulatum infection. The patient was treated with intravenous ampho- tericin B (4 mg/kg/day) for disseminated histoplasmosis, and subcutaneous anakinra (100 mg/day), and high dose steroids for MAS. He demonstrated steady recovery on this regimen and was discharged home in stable condition 3 weeks later. S. Agarwal · J. Moodley · G. Ajani Goel Department of Internal Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected] K. S. Theil Department of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA S. S. Mahmood School of Medicine, Case Western Reserve University, Cleveland, OH, USA R. S. Lang (&) Department of Preventive Medicine, Cleveland Clinic Foundation, Desk A-11, 9500 Euclid Avenue, Cleveland, OH 44195, USA e-mail: [email protected]
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Transcript of A rare trigger for macrophage activation syndrome
Rheumatol Int (2011) 31:405–407
DOI 10.1007/s00296-009-1204-0CASE REPORT
A rare trigger for macrophage activation syndrome
Shikhar Agarwal · Jayavani Moodley · Gati Ajani Goel · Karl S. Theil · Syed S. Mahmood · Richard S. Lang
Received: 3 July 2009 / Accepted: 13 September 2009 / Published online: 16 October 2009© Springer-Verlag 2009
Abstract Macrophage activation syndrome (MAS) is adisorder characterized by increased activation of mononu-clear cells leading to phagocytosis of blood cell precursorsin the bone marrow. We describe a case of MAS triggeredby disseminated histoplasmosis occurring in a patient withStill’s disease on long-term treatment with adalimumab.
Keywords Macrophage activation syndrome · Histoplasma · Hemophagocytosis
Case report
A 21-year-old Caucasian male with a history of Still’s dis-ease diagnosed 2 years prior presented with fevers to 105°F,constitutional symptoms, headache, and migratory jointpains. He had been treated with intermittent courses ofprednisone, methotrexate, and anakinra. For the past 1 yearhe was maintained in remission on adalimumab alone.
Examination revealed an erythematous macular rash of thetrunk, marked scleral icterus, and hepatomegaly.
Laboratory data on admission were signiWcant forhematocrit 44%, white blood cell count (WBC) 5.09 £ 109/L, platelet count 76 £ 109/L, bilirubin 5.2 mg/dL, AST361 U/L, ALT 526 U/L, alkaline phosphatase 374 U/L, cre-atinine 1.01 mg/dL, erythrocyte sedimentation rate 5 mm/h,hypocomplementemia (C3 60 mg/dL, C4 10 mg/dL), Lac-tate dehydrogenase 4,807 U/L and elevated ferritin13,800 ng/mL, triglycerides 342 mg/dL, and d-dimer18,400 ng/mL. A diagnosis of MAS was considered andbone marrow (BM) aspiration and biopsy undertaken.
Hospital course was complicated by unremitting fevers,increasing dyspnea, profound pancytopenia (nadir hemato-crit 19%, WBC 3 £ 109/L, platelets 12 £ 109/L) and wors-ening liver function (peak total bilirubin 19.3 mg/dL, AST1050 U/L, ALT 530 U/L, alkaline phosphatase 470 U/L). Acomputed tomographic scan of his chest revealed diVusenodules in both lung Welds producing hazy ground glassopaciWcation. An infectious disease work-up revealed posi-tive antibody titers for Histoplasma capsulatum at 1:128 (N< 1:8) and a positive Histoplasma urinary antigen. Geneprobe analysis was positive for H. capsulatum DNA. Sub-sequent bronchoalveolar lavage demonstrated yeast forms,consistent with histoplasmosis.
MAS was conWrmed by BM aspirate (Fig. 1) and biopsy(Fig. 2), which demonstrated macrophages with hemophag-ocytosis with and without intracellular budding yeastforms, morphologically compatible with H. capsulatuminfection. The patient was treated with intravenous ampho-tericin B (4 mg/kg/day) for disseminated histoplasmosis,and subcutaneous anakinra (100 mg/day), and high dosesteroids for MAS. He demonstrated steady recovery on thisregimen and was discharged home in stable condition3 weeks later.
S. Agarwal · J. Moodley · G. Ajani GoelDepartment of Internal Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USAe-mail: [email protected]
K. S. TheilDepartment of Clinical Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA
S. S. MahmoodSchool of Medicine, Case Western Reserve University, Cleveland, OH, USA
R. S. Lang (&)Department of Preventive Medicine, Cleveland Clinic Foundation, Desk A-11, 9500 Euclid Avenue, Cleveland, OH 44195, USAe-mail: [email protected]
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406 Rheumatol Int (2011) 31:405–407
Discussion
MAS or hemophagocytic syndrome is a severe and poten-tially life-threatening complication of systemic juvenilerheumatoid arthritis, systemic lupus erythematosus (SLE),and other rheumatic diseases [1]. MAS is believed to be animmunologically mediated reactive disorder of mononu-clear cells, characterized by exaggerated activation of
macrophages leading to phagocytosis of erythrocyticprecursors (hemophagocytosis) [2] and multiorgan dysfunc-tion. Although MAS is considered a rare complication ofStill’s disease, the syndrome may be under-diagnosedbecause of failure to recognize the clinical constellation, andthe necessity of BM examination to make the diagnosis [2].
Recognition of MAS is often challenging because it maymimic the clinical features of the patient’s underlying diseaseor be confused with an infectious complication. Non-remittinghigh fevers, hepatosplenomegaly, lymphadenopathy, and cen-tral nervous dysfunction [3] are characteristic features associ-ated with MAS. Laboratory features include pancytopenia,coagulopathy, hypoWbrinogenemia, elevated liver enzymes,and hypertriglyceridemia [4]. The characteristic Wndingsinclude high levels of lactate dehydrogenase and markedlyelevated ferritin derived from the phagocytic macrophages.
Although the cause of MAS remains unknown, triggerssuch as infections (e.g., Epstein-Barr virus, adenovirus,dengue, leishmania, histoplasma [5]), and drugs (e.g., aspi-rin, phenytoin, methotrexate, inXiximab, etanercept) havebeen implicated. Less than ten reported cases of MAS inthe setting of disseminated histoplasmosis [5] have beendescribed, the majority of which occurred in HIV-infectedindividuals. Prompt diagnosis of MAS is essential becauseearly treatment favors a better outcome. MAS is usuallytreated by eradication of triggers, immunosuppressive ther-apy and/or administration of intravenous immune globu-lins. Despite treatment, MAS is associated with a highmortality rate (approximately 50%) [6].
Fig. 1 Macrophages with hemophagocytosis and rare small intracellular budding yeast compatible with Histoplasma capsulatum (arrows) were iden-tiWed in bone marrow aspirate smear (Wright–Giemsa)
Fig. 2 Left panel bone marrow biopsy showed macrophages withhemophagocytosis (blue arrows) (Hematoxylin–eosin stain). Rightpanel small budding yeast compatible with Histoplasma capsulatum(black arrows) were present (Gomori methamine silver stain)
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Rheumatol Int (2011) 31:405–407 407
Conclusions
• MAS or hemophagocytic syndrome is a rare complica-tion seen with rheumatic diseases, especially rheumaticdiseases.
• MAS is an immunologically mediated reactive disorderof mononuclear cells, characterized by exaggerated acti-vation of macrophages leading to phagocytosis of bloodcell precursors.
• MAS is characterized by multiorgan dysfunction withsymptoms mimicking a Still’s Xare. Subtle diVerencesinclude non-remitting high fevers, hepatosplenomegaly,lymphadenopathy and central nervous dysfunction withlaboratory features including pancytopenia, coagulopa-thy, hypertriglyceridemia, and hyperferrritinemia.
• MAS is characteristically associated with an identiWabletrigger like drugs or infection.
• Histoplasma capsulatum has been identiWed as a raretrigger for MAS.
References
1. Kuzmanova SI (2005) The macrophage activation syndrome: a newentity, a potentially fatal complication of rheumatic disorders. FoliaMed (Plovdiv) 47(1):21–25
2. Ravelli A (2002) Macrophage activation syndrome. Curr OpinRheumatol 14(5):548–552
3. Rumbach L, Berger E, Tatu L et al (1997) Transient multiple cranialnerve involvement as a Wrst sign of macrophage activation syn-drome. J Neurol Neurosurg Psychiatry 62(3):292–293
4. Lambotte O, Cacoub P, Costedoat N, Le Moel G, Amoura Z, PietteJC (2003) High ferritin and low glycosylated ferritin may also be amarker of excessive macrophage activation. J Rheumatol30(5):1027–1028
5. Sanchez A, Celaya AK, Victorio A (2007) Histoplasmosis-associat-ed hemophagocytic syndrome: a case report. AIDS Read17(10):496–499
6. Pinto L, Kagalwala F, Singh S, Balakrishnan C, Prabhu SV,Khodaiji S (2007) Macrophage activation syndrome: experiencefrom a tertiary referral centre. J Assoc Physicians India 55:185–187
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