idiopathic hypereosinophilic syndrome ( he s ) is characterized by persistent or recurrent hypereosinophilia of unknown origin .
currently , we recognize that he s consists of the myeloproliferative form and the lymphocytic form ( t - cell - mediated disorders).1 recent identification of fip1l1-pdgfra fusion gene - positive he s , as a subgroup , has opened a door to innovative treatment using imatinib mesylate in patients with a subset of hes.2,3 however , treatment of other patients with a heterogeneous subgroup of gleich syndrome ( periodic angioedema and eosinophilia ) and other types of he s without known pathogenesis remains to be explored in future .
the causes of periodic oscillating hypereosinophilia411 are often obscure and need to be precisely diagnosed clinically and/or molecularly for the most effective therapy .
the patient reported here has shown significant periodic oscillating hypereosinophilia , which was shown to be fip1l1-pdgfra fusion gene - negative , and was suspected to have gleich syndrome , but not a version compatible with cases previously described .
our patient is considered to have a distinct subtype of he s in which we documented ( a ) the pattern of seasonal oscillation of eosinophilia over 6 years and ( b ) effective control of eosinophilia with a combination of cyclosporin a , suplatast tosilate , and a small dose of prednisolone .
a 29-year - old male patient with periodic oscillating hypereosinophilia was first diagnosed to have he s ( absolute eosinophil counts ( aec ) > 1500/l ) at age 21 . from age 21
to 26 years , he was treated for he s at a local hospital on and off with oral prednisolone , but details of the oscillating pattern were unknown .
since he was referred to us , his he s was found to be characterized by high levels of serum soluble il-2r ( up to 2700 u / ml ; normal < 518 u / ml ) , igm ( up to 1140 mg / dl ; normal < 190 mg / dl ) , tryptase ( 14.4 g / l , normal 2.19.0 g / l ) , and vitamin b12 ( 1400 pg / ml ; normal 233924 pg / ml ) .
serum levels of il-5 were elevated to 46.7 u / ml ( normal < 7.8 u / ml ) , but serum ige levels remained consistently within the normal range . at the time of referral , he was initially treated with prednisolone ( 30 mg / day ) alone , but did not attain a remission . the patient was found to have fip1l1-pdgfra fusion gene - negative ; however because there was no useful therapy available , he was treated with imatinib mesylate ( 100200 mg / day ) at age 26 , which was effective in reducing the aec and negating the oscillating pattern of he s temporarily for about 30 weeks.12 thereafter , the patient s oscillating hypereosinophilia became uncontrollable again . in order to determine the pathogenesis of
his he s and improve therapeutic measures , we performed flow cytometry analysis on his lymphocytes , which showed that the cd3cd4 + population , a subset described in cases of gleich syndrome,9 was increased , accounting for 5.7% of the total ( normal < 1.0% ) , but clonality studies on t cell receptors ( tcr ) showed no rearrangement bands for tcr - c - beta , -j - gamma , and j - delta1 genes ( data not shown ) . thus , we assumed that his he s could be defined as gleich syndrome9 ; however it was not clear if the seasonal periodic oscillation of aec was compatible with this syndrome .
in addition , we were aware that aec showed a good correlation with some serum biomarkers , which was not previously noted in patients with gleich syndrome . as first noted , such cyclic episodes were temporarily suppressed during the imatinib therapy.12 after the patient became refractory to imatinib , we were able to document the exact oscillating pattern closely over the past 6 years .
10,000/l ) two to three times a year , one in early spring ( february  march ) , another in fall ( september  october ) and another in between ( june ) in two of the 3 years from 2005 to 2007 ( figure 1a ) . among various biological markers , soluble il-2r (
r = 0.857 , p < 0.001 ) and serum igm ( r = 0.685 , p < 0.0025 ) values were closely associated with this eosinophilic oscillation ( figure 2 ) ; however , none of hemoglobin , platelet counts , igg , or iga levels were correlated with the oscillation in eosinophil levels . during the peak hypereosinophilic episodes , the patient showed soft tissue swellings on the face , forearms , and the lower legs , which could be a kind of angioedematous presentation , but
we searched for alternative therapeutic measures ; anti - il-5 therapy using humanized anti - il-5 monoclonal antibody13,14 was not available in japan . since cyclosporine a was proven beneficial in the treatment of hes15 and the suplatast tosilate , the th2 cytokine inhibitor , was reported effective for a patient with hypereosinophilia with a high level of serum il-516 as well as for a patient with eosinophilic gastroenteritis associated with elevated serum il-5 and sil-2r,17 we employed a combination of oral suplatast tosilate ( 300 mg / day ) combined with cyclosporine a ( 150 mg / day ) and prednisolone ( 1015 mg / day ) over the past 6 years . as seen in figure 1 , peak heights of aec reduced from 2005 to 2007 ( figure 1a ) , and further reduced yearly to 2010 in association with reduced incidence of the episodes ( figure 1b ) . since july 2010 ,
however , it was found that the cd3cd4 + population remained at a level similar to that prior to the initiation of treatment ( 6.7% of the total ) .
our observation explains the effectiveness of the combined therapy for this type of he s . as of october 2011 ,
in he s , xiao et al described a 54-year - old man who had periodic oscillations in eosinophils , wbc , platelet counts , and hb.4 cyclic oscillations in blood cell counts were also reported for an he s case by malcovati et al.5 in the case of xiao et al , the oscillatory cycle lasted approximately 2 months.4 in cases of gleich syndrome , eosinophilic cycles are known to occur every 35 weeks , ie , almost every month,8,9,11 and are related to the menstrual cycle in female patients.18 as shown in figure 1 , our case showed cyclic episodes occurring two to three times a year from 2005 to 2007 ; thereafter this cycle gradually became blunted over the next 3 years .
it seems that the episodic cycles in our case are distinct from previously described patients with he s . in gleich syndrome , episodic angioedema with eosinophilia
is associated with high serum il-5.611 although our case shows angioedematous soft tissue swelling at the peak heights of hypereosinophilic episodes , his clinical features are not associated with the high ige levels described by several authors,6,7,10 or with the itchy urticarial rash described by schiavino et al.7 in addition , the patient did not respond to prednisolone alone as previously reported.7,9,10 clonally proliferated helper t lymphocytes were also shown by several authors in cases of gleich syndrome.10,11 although we identified some increase in the cd3cd4 + subset in peripheral blood , no t cell clonality was shown in our case . the hematopoietic abnormalities in the cases of xiao et al and malcovati et al are thought to originate at the pluripotent stem cell levels.4,5 by contrast , periodic oscillations of eosinophils in gleich syndrome are thought to be regulated by t - cell expansion - associated il-5 release.10,11,19 distinct oscillations in the aec of our case , particularly in association with serum igm levels , appear to occur via a varied pathogenesis , which may represent a variant of gleich syndrome , although precise mechanism(s ) remain unknown .
so far no triggering factors have been identified to explain the seasonal hypereosinophilic episodes in our case . in a situation where no anti - il-5 antibody is available
, we have found that a combination of cyclosporin a , suplatast tosilate , and prednisolone is a good alternative approach in controlling the hypereosinophilic episodes , although suplatast tosilate is said to suppress ige , but not igg or igm production in vivo.20 over the past 6 years , the three drug combination slowly abolished aec oscillations in our case . how these drug combinations have acted to slowly alleviate his oscillating he s is unknown . since we found no decrease of cd3cd4 + subset with treatment , it was assumed that the inhibitory effect of the treatment including cyclosporin a was not through an effect on the cd3cd4 + subset .
the fact that the precise pathogenesis of oscillating hypereosinophilia is still unknown underscores that there is considerable heterogeneity in he s and/or in gleich syndrome .
 we report the treatment course of a 29-year - old man who has had unique oscillating fip1l1-pdgfra fusion gene - negative hypereosinophilic syndrome ( he s ) for nearly 6 years . 
 his periodic oscillating pattern of eosinophilia associated with angioedematous soft tissue swelling has shown two to three seasonal peaks ( > 15,000/l absolute eosinophil counts [ aec ] ) a year . 
 initially , the patient , who was thought to have distinct he s not compatible with previously described cases , did not respond to treatment except for a temporary response to imatinib mesylate . for 6 years , from 2005 to 2010 , he was treated with a combination of oral cyclosporine a , suplatast tosilate , and a small dose of prednisolone , which significantly reduced the peak heights of aec as well as blunting the oscillating patterns . 