blood hypereosinophilia ( he ) remains a frequent finding encountered in a daily clinical practice of different fields of medicine . under various conditions , eosinophils may produce and release a variety of biologically active substances which may invade target organ and lead to its dysfunction and/or damage . the harmful role of eosinophils results from their inflammatory , fibrotic and thrombotic properties .
the production and development of eosinophils are regulated by several cytokines , but the role of interleukin ( il)-5 was found to be essential .
it is secreted by activated t cells and to a lesser extent by mast cells and eosinophils themselves .
the underlying causes of he are diverse and can be broadly divided into primary ( clonal ) , secondary ( reactive ) , hereditary ( familial ) and idiopathic .
the term he should be used when blood eosinophilia is greater than 1.5    10/l on two occasions with a minimum of 1-month time interval , and/or tissue he is documented .
the contemporary definition of hypereosinophilic syndrome ( he s ) requires the presence of blood he and an end - organ damage that was proved to be eosinophilia related . as the characteristics of different he s variants are well - known , the outcome of patients with asymptomatic , unexplained and persistent he remains unclear .
herein , we present the clinical and laboratory characteristics of 40 consecutive patients with idiopathic blood he .
all patients included in the study met the criteria for blood he , and they were recruited from several hematologic centers in poland between 1994 and 2013 .
the reasons why the patients visited the primary care physician and performed full blood test were following : random blood investigation ( n  =  30 ) , abdominal pain ( n  =  2 ) , loss of weight ( n  =  2 ) , facial swelling ( n  =  1 ) , joint pain ( n  =  1 ) , bone pain ( n  =  1 ) , night sweats ( n  =  1 ) , diarrhea ( n  =  1 ) and dyspnoea ( n  =  1 ) .
all patients underwent the basic evaluations at the primary care level including all necessary tests in order to rule out the most common causes of blood he , but no abnormalities were detected .
originally reported complaints resolved spontaneously after 23  days without treatment , and they were found not to be he related . therefore , more detailed imaging and endoscopic studies were not recommended by a treating physician .
moreover , these symptoms did not re - appear in the long - term observation .
all patients were free of any symptoms . on admission a complete blood test with differential
the presence of infections caused by human immunodeficiency virus , cytomegalovirus , epstein - barr virus , hepatitis b virus , hepatitis c virus and toxocara was excluded using serological tests .
anti - nuclear antibodies as well as myeloperoxidase and proteinase 3 anti - neutrophil cytoplasmic antibodies were ruled out .
peripheral blood t - lymphocytes were determined by flow cytometry technique on epics - xl - mcl ( beckman - coulter , usa ) using monoclonal antibodies directed against t - cell surface antigens : cd2 , cd3 , cd4 , cd5 , cd7 , cd8 , t - cell receptor ( tcr )  and tcr , and no aberrant population ( including the most common cd3-cd4 + ) has been detected .
polymerase chain reaction ( pcr ) was negative for jak2v617f , bcr - abl and fip1l1-pdgfra molecular abnormalities .
blood tests with differential , biochemistry , electrocardiogram , echocardiography , chest x - ray and abdominal ultrasound were repeated every 3  months .
stool examination for ova and larvae was systematically repeated throughout the study period , and it remained negative .
the study was approved by local ethics committee by silesian medical university , katowice , poland .
twelve patients with at least moderate blood eosinophilia ( defined as greater than 3.0    10/l ) for more than 1-year duration were treated with corticosteroids to avoid end - organ damage . the starting cs dose varied between patients , and it was left to physician s discretion . a complete response ( cr ) was defined as a return of absolute eosinophil count ( aec ) to normal ranges ( < 0.7    10/l ) .
a maintenance dose was defined as the minimal effective cs dose needed for cr maintenance .
the response to cs was assessed daily during the first week , then weekly within the first month , and monthly thereafter .
forty patients ( 28 females and 12 males ) at a median age at diagnosis of 61  years ( range 1785 ) were included in this retrospective study .
a distant history of allergic skin reactions and helminth infections was present for five and four patients , respectively . before entering the study , all patients received tinidazole to prevent giardiasis with no effect on blood eosinophilia .
twenty - one patients ( 52  % ) had an increased white blood cell ( wbc ) count at diagnosis .
hemoglobin concentration < 12  g / dl and platelet count < 150    10/l were reported for nine and two patients , respectively .
an aec greater than 3.0    10/l was demonstrated for 17 ( 40  % ) patients .
65  % of studied patients had an increased serum ige levels , whereas only 2  % demonstrated an increased serum vitamin b12 levels .
a median bone marrow infiltration by eosinophils was 30.5  % ( range 1178.2 ) .
no patient had an aberrant t - cell population on flow cytometry , however , t helper ( th)/t suppressor ( ts ) ratio was found to be abnormal in eight patients .
cytogenetic studies revealed normal diploid karyotype in 30 patients , whereas no metaphases were obtained for the remaining 10 .
the median follow - up of the studied population was 55.2  months ( range 6.4231.4 ) .
patients characteristics are shown in table  1.table  1study group characteristicsparameterhe ( n)number of patients40gender : male / female12/28median age ( range ; years)61 ( 1785)wbc count ( 10/l)11.2 ( 5.570.1)wbc  >  10 ( 10/l)52  % hemoglobin ( g / dl)13.0 ( 8.719.1)hemoglobin < 12 ( g / dl)22  % platelet count ( 10/l)289 ( 68605)platelet count < 150 ( 10/l)2  % aec ( 10/l)4.2 ( 1.555.4)aec > 3    10/l42  % eosinophils in bone marrow ( % ) 30.5 ( 1178.2)serum ige ( iu / ml ) 
 528 ( 11.94,089)serum ige  >  n 
 67  % serum b12 vitamin ( pg / ml ) 
 333 ( 1491,431)serum b12  >  n 
 2  % 
 wbc white blood cell ,  aec absolute eosinophil count ,  normal ranges ( n ) : ige  <  100  iu / ml ; for vitamin b12 level : 1571,057  pg / ml study group characteristics 
 wbc white blood cell ,  aec absolute eosinophil count ,  normal ranges ( n ) : ige  <  100  iu / ml ; for vitamin b12 level : 1571,057  pg / ml twelve out of the 17 patients with at least moderate blood eosinophilia started the treatment with steroids whereas the remaining five refused the therapy . the starting cs dose varied between 5 and 60  mg daily , and the highest doses were reserved for patients with severe blood he .
all patients responded promptly to cs and remained in cr while receiving low doses of cs ( 20  mg / day to 5  mg every 2-day ) .
the attempts of treatment discontinuation while in cr failed , and the patients were left on a minimal effective cs dose .
no patient , who originally refused the therapy , received the follow - up treatment .
side effects of cs therapy were mild and included bone and joint pain and malaise .
twenty - seven patients who remained off therapy had a stable blood he , and no organ dysfunction was demonstrated during follow - up .
one female with no prior cs developed eosinophilia - related cardiac failure after 11  years of sustained blood he , and she was successfully treated with cs .
details of cs therapy are presented in table  2.table  2steroids for hypereosinophilia of undetermined significancenoaec ( x10/l ) at cs initiationserum ige ( iu / ml ) at cs initiationcs initial dose ( mg / day)cs maintenance dose ( mg / day)time to cr in days1.3.7311.9155 every 2-day<72.4.251,143.02010<73.3.551,033.01010/5 alternately144.31.119.46020145.3.1528.0205<76.3.82,550.0105<77.4.6543.055148.8.51,080.03010<79.7.94,089.03010<710.21.43,648.03010<711.15.8176.040101412.55.4361.0602014 
 aec absolute eosinophil count , cs corticosteroids , cr complete response steroids for hypereosinophilia of undetermined significance 
 aec absolute eosinophil count , cs corticosteroids , cr complete response
the term  hypereosinophilia of undetermined significance  ( heus ) previously known as idiopathic , benign eosinophilia , relates to patients who have a long - lasting , unexplained and asymptomatic blood he .
the pathogenesis and prognosis of such cases remain unknown , and its clinical implication is to be validated . by definition ,
moreover , these cases do not develop an eosinophilia - related organ dysfunction or damage .
there are lacking prospective studies involving this patient population , especially in regard to clinical and laboratory characteristics as well as long - term follow - up .
bearing all these issues in mind , this retrospective analysis was done . only single retrospective studies on a natural history of blood he have been published so far [ 6 , 7 ] . in fact , most reported patients had well - defined causes of he , and only a small minority of cases was actually idiopathic .
thus , regarding these two large reports , we focus on the patients with idiopathic blood he . unfortunately , both reports had many drawbacks resulting from their retrospective nature . a recently published report   recruited 33 patients with presumably heus , but in fact , the appropriate diagnostic work - up was performed in a minority of them , and it was restricted to some common investigations .
nevertheless , the presumably heus patients had aec greater than 5.0    10/l and an increased serum ige levels .
most patients were treated with steroids and achieved a long - term response , but the doses of cs were not provided .
the other retrospective study included 100 hospitalized patients with blood he , and 34  % of them had an unknown etiology despite an extensive panel of investigations .
conversely , only 3  % of the patients had unexplained he in a large study reported by lombardi et al .
however , one should keep in mind that all these studies were based on a chart review and they had many limitations resulting from its retrospective nature .
moreover , they did not provide the results of molecular studies ( e.g. , fip1l1-pdgfra ) .
there was also lacking data on the clinical outcome in a long - term follow - up .
nevertheless , the vast majority of detected blood eosinophilias was associated with allergic processes [ 7 , 8 ] .
kobayashi et al .   defined the threshold of blood he that may indicate the presence of he s and distinguished it from bronchial asthma .
it was demonstrated that aec greater than 2.052    10/l was strongly suggestive of he s , and this value was associated with a higher risk of organ damage .
however , one should keep in mind that the definition of he s provided by authors differed significantly from that used nowadays . in a very recent paper , chen et al .  
when they compared the laboratory data between heus and untreated he s subjects , they found no difference except for a higher serum ige and il-13 levels in the latter group . surprisingly , 50  % of heus patients had an aberrant t - cell population , but none of them developed clinical symptoms or organ damage .
only one patient from our study cohort developed he s , and it has been 11  years since blood he was detected . that was female with aec varied between 1.5    102.5    10/l during the whole follow - up , with a slightly increased serum ige level ( 146  iu / ml ; normal range < 100  iu / ml ) and an abnormal th / ts ratio ( 0.7 ) at heus diagnosis . at the time of he
namely , a study for t - cell receptor clonal rearrangement by pcr was performed , and it was found to be positive .
serum thymus and activation - regulated chemokine and interleukin ( il)-5 levels using commercially available elisa kits were also measured , and they were following : 178.7  pg / ml ( sensitivity > 7  pg / ml ) and 6.6 ( sensitivity > 1.08  pg / ml ) , respectively . taken together , the diagnosis of lymphocytic - hes was established .
despite the fact that blood aec was greater than 3.0    10/l in more than 40  % of study patients and serum ige levels exceeded normal ranges in almost 70  % of them , the organ involvements were not detected in subsequent imaging studies .
however , the median duration of follow - up for our patient population is less than 5  years .
older reports demonstrated that he s may develop after 89  years of sustained blood he .
currently , it is difficult to support the thesis that a benign idiopathic blood he is a smoldering form of he s . to confirm this hypothesis ,
the markers of eosinophil activity were measured in a patient with a long - standing blood he .
the test showed an impaired function of eosinophils , but it did not explain why and when they become deleterious to the organs .
there is no evidence that the introduction of cs , despite the lack of symptoms , will influence the natural history of these patients and prevent the he s development .
it should be highlighted that the treatment with cs for heus remains controversial , and currently , there is no data supporting this approach . in a daily clinical practice ,
the decision who and when should receive the treatment is left to the treating physician , e.g. , mayo group preference is to start the treatment when aec is considered too high , but this threshold is not established .
some authors recommend an aec greater than 2.0    10/l as an indication for treatment .
one should keep in mind that a sustained high blood he remains frustrating both for clinician and for a patient , but it should not justify a durable cs treatment .
it was due to a high number of circulating blood eosinophils and the risk of organ damage .
all treated patients responded to cs , and the dose was promptly reduced to maintain remission .
five patients were left on higher cs maintenance doses ( 1020  mg daily ) , and it was due to their very high blood he at diagnosis ( from 7.9    10 to 55.0    10/l ) .
in fact , the exposure to the higher cs dose was short , and therefore , the observed side effects were irrelevant .
the median duration of cs treatment is 8  weeks ( range 224  weeks ) .
a female patient who developed he s was free of cs until the cardiac failure occurred .
she responded to the treatment and remains in remission with normal cardiac function while still on cs .
every patient with heus requires the comprehensive evaluation to exclude various reactive and neoplastic eosinophilia - related conditions according to a contemporary consensus of multidisciplinary experts in the field of eosinophilia . an international prospective study with a larger patient population and a longer follow - up
the use of cs for heus patients should be individualized paying special attention to adverse drug reactions .
it seems reasonable to plan a randomized study in order to assess the benefit of cs in heus . 

 the term  hypereosinophilia of undetermined significance  ( heus ) previously known as idiopathic , benign eosinophilia relates to patients who have a long - lasting , unexplained and asymptomatic blood he . 
 these patients have not been studied so far in terms of demographic characteristics and clinical outcome . 
 the aim of this study was to present the clinical characteristics and outcome of heus patients . 
 this is a retrospective , single - center study of 40 patients with heus . 
 all patients underwent the basic and specialized evaluations in order to rule out the most common causes of blood he , but no abnormalities were detected . 
 twelve patients with at least moderate blood hypereosinophilia ( defined as greater than 3.0    109/l ) for more than 1-year duration were treated with corticosteroids ( cs ) to avoid end - organ damage . 
 twenty - one patients ( 52  % ) had an increased leukocyte count at diagnosis . 
 median blood eosinophilia was 4.2    109/l ( range 1.555.4 ) . 
 he  >  3.0    109/l was demonstrated in 17 patients . 
 65  % of studied population had an increased serum ige levels , whereas only 2  % demonstrated an increased serum vitamin b12 levels . 
 a median bone marrow infiltration by eosinophils was 30.5  % ( range 1178.2 ) . 
 all treated patients responded promptly to cs and remained in complete remission while receiving low doses of cs ( 20  mg / day to 5  mg every 2-day ) . 
 one patient developed hypereosinophilic syndrome ( he s ) after 11  years of follow - up . 
 further studies are needed to define risk factors of he s development . 
 the use of cs for heus patients is controversial and should be individualized . 
Introduction
Materials and methods
Treatment and response
Results
Discussion
Conclusions