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Correspondence
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, González-Conejero R, Villalón 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
BLOOD, 1 NOVEMBER 2001 䡠 VOLUME 98, NUMBER 9
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
2875
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2876
CORRESPONDENCE
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.
BLOOD, 1 NOVEMBER 2001 䡠 VOLUME 98, NUMBER 9
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
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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]
CORRESPONDENCE
2877
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.
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2001 98: 2875-2877
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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