From bloodjournal.hematologylibrary.org by guest on July 15, 2011. For personal use only.
2001 98: 2875-2877 doi:10.1182/blood.V98.9.2875a
Short-course corticosteroid−induced pulmonary and apparent cerebral aspergillosis in a patient with idiopathic thrombocytopenic purpura John Apostolidis, Marina Tsandekidi, Demitris Kousiafes, Maria Pagoni, Chrisanthi Mitsouli, Themis Karmiris, Maria Bakiri, Demitris Karakasis, Nikolaos Harhalakis and Emmanuel Nikiforakis
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To the editor: Factor V Leiden and intracranial hemorrhage The prevalence of factor V Leiden (FVL) in people of northern and central European descent suggests that FVL bestowed a survival advantage on those populations. In the study by Corral et al, the presence of FVL reduced the risk of spontaneous intracranial hemorrhage by 5-fold.1 Specifically, FVL protected against hemorrhagic transformation of ischemic events associated with artherosclerotic cerebrovascular disease in subjects with a mean age of 66.4 years. Although this finding is of interest, it seems unlikely that this advantage led to the persistence of FVL in European populations. There is no apparent survival advantage, biologically speaking, to protecting elders from hemorrhagic stroke. It is more plausible that this allele protected those of childbearing potential. Today, acquired hemorrhagic disease is uncommon in young people. However, it is likely that hemorrhagic disease of the newborn (HDN) was prevalent thousands of years ago, contributing significantly to neonatal mortality. HDN is caused by vitamin K deficiency, a common condition in neonates even today,2 and can result in life-threatening intracranial hemorrhage. Therefore, one could hypothesize that FVL is prevalent in certain populations because it lessens the severity of HDN. It is possible that clinically significant vitamin K deficiency was more common thousands of years ago because food sources rich in vitamin K were not available year-round and breast-feeding, which is a significant risk factor for HDN, was more common. The hemostatic system of the neonate is such that the presence of FVL could result in enhanced thrombin generation because of the limited capacity of both the antithrombin and the protein C pathways. Significant vitamin K deficiency could further enhance
this effect. In the neonate, levels of procoagulant and anticoagulant vitamin K–dependent proteins are low.3 In the healthy neonate, a balance is maintained, making bleeding and thrombotic complications uncommon. With worsening vitamin K deficiency, this balance is lost in favor of bleeding. The presence of factor V Leiden could prevent the loss of this fine balance by attenuating the protein C pathway. The study by Corral et al is important in that it lends evidence to the notion that there is benefit to having factor V Leiden. However, for a polymorphism associated with disease to persist in a population, the net effect must favor survival of those most likely to procreate. Nonetheless, the hypothesis that FVL protects against fatal intracranial hemorrhage in neonates with HDN would be difficult to prove; therefore, the elder population with cerebrovascular disease will have to suffice as an acceptable experimental model. J. Nathan Hagstrom
Correspondence: J. N. Hagstrom, Hematology-Oncology, Connecticut Children’s Medical Center, 282 Washington St, Hartford, CT
References 1.
Corral J, Iniesta JA, Gonza´lez-Conejero R, Villalo´n M, Vicente V. Polymorphisms of clotting factors modify the risk for primary intracranial hemorrhage. Blood. 2001;97:2979-2982.
2.
Bovill EG, Soll RF, Lynch M, et al. Vitamin K1 metabolism and the production of des-carboxy prothrombin and protein C in the term and premature neonate. Blood. 1993;81:77-83.
3.
Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood. 1987;70:165-172.
To the editor: Short-course corticosteroid–induced pulmonary and apparent cerebral aspergillosis in a patient with idiopathic thrombocytopenic purpura In a recent report on adults with idiopathic thrombocytopenic purpura (ITP), Portielje et al1 presented limited data on the morbidity and mortality attributed to the systemic effects of short-course corticosteroids in the context of initial treatment of ITP.2 Certain patients may be at high risk for unusual opportunistic infections. In this letter we present a patient with ITP and no occupational hazard or apparent underlying disease who, during the course of treatment with oral methylprednisolone (MP), developed invasive bilateral pulmonary aspergillosis and multiple intracerebral lesions, presumably due to aspergillosis. We believe that this is the first reported case of cerebral aspergillosis after short-course corticosteroid treatment in an otherwise immunocompetent host with ITP. A 52-year-old man was admitted to our department with asymptomatic severe thrombocytopenia (18 ⫻ 109/L), found on a routine full blood count (FBC). Clinical examination was unremarkable. Routine blood chemical values were normal, and tumor
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markers were negative. Serological tests for hepatitis B and C viruses, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, herpes zoster virus, and human immunodeficiency virus (HIV) were negative. The patient had no clinical or laboratory evidence of autoimmune or immunodeficiency syndromes. Findings on chest radiograph and computed tomography (CT) scans of the chest, abdomen, and pelvis were normal. A bone marrow smear revealed normal numbers of megakaryocytes in an otherwise normal bone marrow, while antiplatelet IgG and IgM antibodies were positive. Treatment was initiated with 1 mg/kg oral MP daily, and 3 days later the patient was discharged after a prompt recovery of the platelet (PTL) count (70 ⫻ 109/L). The patient was followed up at the outpatient clinic, and tapering of MP was initiated after 4 weeks of treatment, while corticosteroid-induced type 2 diabetes mellitus developed. Eight weeks later, while on 24 mg MP daily, the patient was readmitted, afebrile and with a 3-day history of fatigue and palpitation. The FBC revealed a normal hemoglobin level and
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white blood cell and platelet counts. A radiograph of the chest showed patchy, nodular consolidations in both lungs. MP was tapered to 16 mg every other day (and discontinued on the 14th day of hospital stay), while cotrimoxazole, ceftriaxone, clarythromycin, and fluconazole were administered. Repeat virology (including HIV) and immunological laboratory tests again excluded any underlying autoimmune or immunodeficiency syndromes. Culture specimens of blood, sputum, and urine were negative for microorganisms. A bone marrow smear was unremarkable. Microscopical examination of a stained specimen of sputum showed no acid-fast bacilli. A urine test for legionella antigen was negative. On the fifth day of hospital stay, the patient became febrile (39°C) and developed a bloodstained productive cough. A chest radiograph revealed an increase in the bilateral nodular and patchy consolidations, while a CT scan of the chest on the eighth day of hospital stay showed bilateral multifocal nodules with cavitation. Amphotericin 1.5 mg/kg IV and itraconazole 400 mg daily were initiated. On the 10th day of hospital stay, a bronchoscopy was performed and aspergillus fumigatus was isolated from bronchoalveolar lavage fluid samples. The patient showed no clinical or radiological improvement over the following days and was switched to liposomal amphotericin 5 mg/kg, while itraconazole was increased to 800 mg daily. The patient showed a slow but stable improvement and, on the 27th day of hospital stay, became afebrile. On the 30th day of hospital stay, the patient developed a brief Jacksonian-type seizure. Magnetic resonance imaging (MRI) of the brain disclosed multiple (19 in total) ring-shaped brain abscesses. T1- and T2weighted images showed low-intensity lesions containing highintensity areas and high-intensity lesions, respectively (Figure 1).
Figure 1. Axial contrast-enhanced T1-weighted MRI image of the brain at diagnosis. Multiple intraparenchymal lesions are detected, some with surrounding vasogenic edema. Characteristic ring-enhancing lesions are shown at the right inferior frontal gyrus and the corticomedullary junction of the left superior frontal gyrus.
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Figure 2. Axial contrast-enhanced T1-weighted MRI image of the brain 12 months after diagnosis. Complete disappearance of intracerebral lesions after treatment with oral itraconazole.
Cerebrospinal fluid (CSF) revealed a glucose level of 64 mg/dl (serum glucose 160 mg/dl), 2 cells/mm3, 15 RBC/mm3, and 55-mg/dl protein. Microscopic examination (gram staining, acidfast bacilli, fungi) and CSF cultures were sterile. Serum and CSF enzyme-linked immunosorbent assay antigen test for IgA, IgM, and IgG toxoplasma gondii antibodies and CSF latex agglutination tests for aspergillus and cryptococcus neoformans antigens were negative. The good condition of the patient and the small size of the intracerebral lesions (the largest, 19 mm in diameter) discouraged neurosurgeons from performing a stereotactic biopsy. Although central nervous system (CNS) toxoplasmosis was most unlikely, a 2-week trial of sulfadiazine and pyramethamine was initiated, and follow-up CT scans of the brain failed to show improvement in the lesions, ruling out CNS toxoplasmosis. We persisted with antifungal treatment, and the pulmonary lesions gradually improved while the brain lesions remained unchanged in number and size. On the 60th day of hospital stay, the patient was discharged with itraconazole 400 mg daily, in good condition and with marked improvement of pulmonary lesions but stable cerebral lesions. Over the next months, follow-up CT scans showed a slow improvement of the intracerebral lesions, while a 12-month follow-up MRI scan disclosed complete resolution of these lesions (Figure 2). The presenting features and the clinical course yielded an apparent diagnosis of cerebral aspergillosis. It is thought that vascular spread of aspergillosis is not a feature in immunocompetent patients. Immunosupression of a degree sufficient to permit the development of systemic disease in this patient was probably the result of the combination of two cofactors that compromised phagocytosis by macrophages and neutrophils: treatment with corticosteroids and hyperglycemia (a side effect often encountered in clinical practice). Although pneumonia due to aspergillosis in presumably immunocompetent hosts has received
From bloodjournal.hematologylibrary.org by guest on July 15, 2011. For personal use only. BLOOD, 1 NOVEMBER 2001 䡠 VOLUME 98, NUMBER 9
increased recognition over the years,3-4 this rare case of successfully treated cerebral aspergillosis suggests that short-course treatment with corticosteroids can exert deleterious systemic effects in certain patients with no evidence of autoimmune or immunodeficiency syndromes. John Apostolidis, Marina Tsandekidi, Demitris Kousiafes, Maria Pagoni, Chrisanthi Mitsouli, Themis Karmiris, Maria Bakiri, Demitris Karakasis, Nikolaos Harhalakis, and Emmanuel Nikiforakis
Correspondence: John Apostolidis, Department of Hematology and Lymphoma, Evangelismos Hospital, 43-45 Ipsilandou st, Athens 106 76, Greece; e-mail:
[email protected]
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References 1.
Portielje JEA, Westendorp RGJ, Kluin-Nelemans HC, and Brand A. Morbidity and mortality in adults with idiopathic thrombocytopenic purpura. Blood. 2001; 97:2549-2554.
2.
George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practical guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3-40.
3.
Karman GH, Griffin FM. Invasive pulmonary aspergillosis in nonimmunocompromised, nonneutropenic hosts. Rev Infect Dis. 1986;8:357-363.
4.
Clancy CJ, Nguyen MN. Acute community-aquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease. Chest. 1998;114:629-634.
To the editor: Interleukin-13 levels in serum from patients with Hodgkin disease and healthy volunteers The malignant Hodgkin and Reed-Sternberg (H/RS) cells of Hodgkin disease (HD) and the surrounding infiltrating cells are known to secrete several types of cytokines and chemokines, many of which have been implicated in the different clinical and histological presentations of HD.1-4 Most recently, interleukin-13 (IL-13) and IL-13 receptors have been shown to be expressed by cultured HD-derived cell lines and primary H/RS cells.5,6 Furthermore, IL-13 has been detected in the supernatants of cultured HD-derived cell lines, and neutralizing antibody to IL-13 has been shown to inhibit the growth of these cell lines in vitro,5 suggesting that H/RS cells may enhance their own survival by an IL-13 autocrine and paracrine cytokine loop.5 Because of the potential implication of these observations for treatment of HD, we examined IL-13 levels in serum samples from patients with newly diagnosed and relapsed HD and compared these levels with serum IL-13 levels in healthy volunteers. IL-13 levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit from Biosource International (Camarillo, CA) and were measured in duplicate using a -Quant plate reader equipped with KC4 software (Biotech Instruments, Winooski, VT). The sensitivity of this ELISA is less than 12 pg/mL. All experiments included a set of standard wells containing known quantities of recombinant human IL-13. Results are reported as the average value of duplicate measurements. Supernatants from 3 HD-derived cell lines that are known to secrete IL-13 (HD-LM-2, L-428, and KMH2) were used as positive controls.5 Supernatants from one additional HD-derived cell line (HD-MYZ) were used for comparison. The cell lines were obtained from the German Collection of Microorganisms and Cell Cultures (Department of Human and Animal Cell Cultures, Braunschweig, Germany).7 Cell lines were cultured (5 x 105/mL) in RPMI medium supplemented with penicillin (5%), streptomycin (5%), and heat-inactivated fetal calf serum (10%). Supernatants were collected after 24 hours in culture and immediately assayed for IL-13 levels by ELISA. Serum from 108 consecutive patients with newly diagnosed HD and from 31 patients with relapsed HD was studied. Serum from 40 healthy donors was used for comparison. All serum samples were obtained after proper consent was granted and were stored in a freezer at ⫺70°C until used. Consistent with a previously published report, the 3 IL-13– producing cell lines that we examined expressed a range of IL-13 levels, from 85 to 300 pg/mL5 (Figure 1). The HD-MYZ cells did not secrete IL-13. None of the 40 serum samples that were obtained
from healthy donors contained detectable levels of IL-13 (Figure 1). Subsequently, sera from 108 patients with newly diagnosed HD were examined. Of these patients, 70% had nodular sclerosis histology, and 36% had stage III or IV disease (Table 1). Thirty-one patients (28%) had B symptoms. Eleven (10%) of the 108 serum samples contained detectable levels of IL-13 (Figure 1). In all 11 cases, IL-13 levels were at least 30 pg/mL (range, 34 to 82 pg/mL). The 3 patients with the highest IL-13 levels had nodular sclerosis histology; 2 had stage IIA disease, and one had stage IIB disease. IL-13 levels did not correlate with gender, disease stage, histological subtype, disease bulk, or presence of extranodal involvement. This lack of correlation may simply be due to the small number of patients who were found to have elevated serum IL-13 levels. There was a trend for a higher percentage of patients with B symptoms to have elevated IL-13 levels (45.8% vs 26.8%), but this difference was not statistically significant (2 test). Of the 11 newly diagnosed patients who had elevated levels of IL-13, only one patient experienced disease progression, 4 months after completing therapy for stage IIB bulky mixed-cellularity disease. Interestingly, 2 of 12 patients with lymphocyte-predominant HD had elevated serum IL-13 levels. These data are in contrast with a previously published report that showed that IL-13 mRNA expression was limited to primary H/RS cells of the classic type.6 The source of IL-13 in the 2 patients with lymphocyte-predominant HD is not known (tissue blocks are not available to perform in situ hybridization of IL-13 mRNA), although the possibility of IL-13 being produced by the malignant cells cannot be ruled out. We also studied IL-13 levels in serum samples from 31 patients with relapsed HD. All samples were collected at the time of active
Figure 1. IL-13 levels in Hodgkin disease–derived cell lines and serum samples from patients with Hodgkin disease and healthy donors.
