Henoch-Schönlein Purpura in Children from Northwestern Spain

Abstract

Introduction Abbreviations used in this article: ACR, American College of Rheumatology, CI, confidence interval, ESR, erythrocyte sedimentation rate, HSP, Henoch-Schönlein purpura, ICAM-1, intercellular adhesion molecule-1, IgA, immunoglobulin A, URT, upper respiratory tract Henoch-Schönlein purpura (HSP) is a systemic vasculitis characterized by purpuric skin lesions unrelated to any underlying coagulopathy, gastrointestinal manifestations, arthritis, and renal involvement (25,51). Infiltration of small blood vessels with polymorphonuclear leukocytes and the presence of leukocytoclasia are typical pathologic findings in this vasculitis. In addition, immunofluorescence staining of tissues usually discloses the presence of immunoglobulin A (IgA)-dominant immune deposits in the wall of the small vessels and in the renal glomeruli (21,30). Henoch-Schönlein purpura is mainly a childhood disease: it is the most common type of vasculitis in children and an infrequent condition in adults (26). The first description of this syndrome was given by Heberden (27), who reported a child with joint pain and painful subcutaneous edema, abdominal pain, vomiting, bloody stools and urine, and “bloody points” over the skin of his legs. However, the names of Schönlein and Henoch are most commonly used as the designation of the syndrome. Initially, Schönlein (52) described the association between arthralgia and purpuric cutaneous lesions in a child using the term “purpura rheumatica.” Some years later, his pupil Henoch (28) described a syndrome of purpura, severe abdominal colic, and melena. A few years later, Henoch referred to nephritis as a complication of this syndrome (29). As recently pointed out by Stone (56), there has been a relative paucity of clinical and epidemiologic studies on HSP in children over the past few years (50). Of note, the long-term morbidity and mortality of HSP are predominantly attributable to renal involvement. In some studies HSP in children has been reported to account for 5%–15% of patients entering end-stage renal failure (10,37). Most of these studies were done on series of selected patient populations with kidney dysfunction attended in reference centers. Two unselected series (33,55), however, suggested a good prognosis for HSP nephritis in children—a more optimistic outcome than most published series based on more selected groups of patients. To investigate this syndrome further, we examined the incidence, clinical spectrum, and prognosis of HSP in an unselected population of children diagnosed at the single reference hospital for a defined population in northwestern Spain over a 20-year period. Special interest was focused on the outcome of these patients and, in particular, on the risk factors implicated in the development of permanent renal damage. Patients and Methods A retrospective study of the case records of all patients diagnosed with primary cutaneous vasculitis in the Division of Pediatrics of the Hospital Xeral-Calde (Lugo, Spain) from January 1980 through December 1999 was undertaken. In Lugo patients aged 14 years and younger are seen at the Pediatrics Division. The Hospital Xeral-Calde is the only referral center for a mixed urban (40%) and rural population of almost 250,000 people living in the Lugo region of northwestern Spain. The main characteristics of the Lugo population have been reported previously (18,19,23,24). The population is relatively static, has its own regional language, and is considered to be descended from Celtic origin (15). During the past 2 decades the population has barely changed, and migratory flows have been relatively low. Inclusion criteria Classification criteria have been proved to be useful in epidemiologic studies of HSP (50,57). The American College of Rheumatology (ACR) criteria and those proposed by Michel et al do not require a biopsy, and IgA deposits were not examined in those studies (39,40). In Lugo, patients with primary cutaneous vasculitis were classified as having either HSP or hypersensitivity vasculitis following the criteria put forward by Michel et al (39). Patients were classified as having HSP if they met 3 or more of the following criteria: 1) palpable purpura, 2) bowel angina, 3) gastrointestinal bleeding, 4) hematuria (macroscopic or microhematuria), 5) aged ≤20 years at the onset of disease, and 6) absence of previous history of medications before the onset of the vasculitis. Patients who fulfilled fewer than 3 criteria were classified as having hypersensitivity vasculitis and therefore were excluded from this study. In children from Lugo, a diagnosis of cutaneous vasculitis was considered in most cases without skin biopsy if they had typical nonthrombocytopenic symmetric palpable purpura involving the lower extremities. For the diagnosis of primary cutaneous vasculitis in children other conditions, such as connective-tissue diseases and infections, in particular meningitis, also had to be excluded (4). Clinical definitions As reported in former studies on adults with primary cutaneous vasculitis (8,18,20,24), drug-intake history and upper respiratory tract (URT) infections before the onset of the vasculitis were considered precipitating events. These events were considered to be present if there was a close temporal relationship (less than 7 days) between the start of drug intake and the onset of HSP or if there was a URT infection shortly before the onset of disease that might explain the occurrence of this condition. A URT infection in children was considered if a cold, influenza, or pharyngitis was observed within the week before the onset of cutaneous vasculitis. We defined the clinical features as follows: Nephritis (renal involvement) was defined as the presence of any renal event that happened over the whole course of the disease. It was defined as previously reported (8,18,20,24,45,49) : 1) “Mild nephropathy” if hematuria (≥5 red blood cells/high power microscopic field) and/or proteinuria (>300 mg/24 hours), without nephrotic range, was present, 2) “Severe nephropathy” if nephrotic syndrome (that is, >40 mg/m 2 body surface per hour or >50 mg/kg per day or >2 g/day proteinuria with plasma albumin ≤25 g/L), with or without edema and/or acute nephritic syndrome (that is, hematuria with at least 2 of the following: hypertension, elevated plasma urea or creatinine, and oliguria) was present, 3) “Renal insufficiency” if the plasma creatinine concentration was more than 125% the upper limit of normal, 4) “Renal sequelae” were considered to be present if at last follow-up (at least 1 year) a patient had any of the renal complications described above. However, a patient who had proteinuria, hematuria, or renal insufficiency during the course of the disease and at last follow-up did not have any abnormality in the urine and had normal renal function was not classified as having renal sequelae. Therefore, the “renal sequelae” group was patients who had permanent renal involvement at last follow-up (20). Joint manifestations: if patients complained of well-defined arthralgia, or if synovitis was observed on examination (18). manifestations: 1) abdominal pain that or bowel usually bloody 2) gastrointestinal or for blood in the 1) lower than 2) blood than 3 3) erythrocyte sedimentation if were than 4) as normal of IgA on the of the a child was considered to have IgA if the IgA was the normal for at the of if a patient diagnosed with HSP and for at least 1 a of skin lesions or other systemic complications Clinical and at the of diagnosis of the patients with HSP were from clinical records to a and in a In to on the following were and of of disease, to diagnosis from the onset of precipitating events clinical of skin and renal from the onset of to the development of renal manifestations, elevated ESR, IgA and creatinine presence of hematuria, proteinuria, nephrotic renal and of and/or and To follow-up and renal between and December patients classified as having HSP were by to the hospital for patients who to to the hospital for were examined by a and a Clinical history for and blood and blood and urine were patients with than 1 follow-up who did not the hospital for were excluded from the of the follow-up of the disease. and renal were only examined in those children with at least 1 For populations with and were from the and and the 1999 populations were by To investigate if there were in the incidence, the of cases was with the of cases by a were by the using the population as the was to the it a We the for the whole and for the and using the of cases with HSP in as the and the population of as the The for the whole was as the for the 20-year by The for the 2 and were as the for by for HSP were reported as cases for population aged 14 years and younger in confidence were a were described as and and as and were using the To we the the was than the with was The for renal was by We a than some not be in a were and were was defined as were with the College January 1980 and December children were classified as having features of children with HSP The main epidemiologic characteristics of patients with HSP are in The at the onset of was the of was not more commonly in and In of cases a history of URT infection before the onset of the vasculitis was in particular or was observed in of the patients. In most patients were diagnosed within the first week the onset of and factors in children with Henoch-Schönlein cases of HSP more commonly between the of and years In in the onset of disease was more common between the of 3 and 7 in the of cases by between and were not of cases of Henoch-Schönlein purpura by and at the onset of 2 the by is of were observed in and however, in the of HSP in children was by during the of study. is per aged 14 years and for the 20-year was people aged 14 years and younger The during the was people aged 14 years and younger and during the the was people aged 14 years and younger The for the population aged 14 years and younger by and are in 2 and During the there was a in the of children with a was mainly to the in the of patients with HSP seen at the in particular during the for children with HSP in Lugo, Spain per aged 14 years and younger for the for children with HSP in Lugo, Spain per aged 14 years and younger for the and features In of children skin lesions were not the of the disease pain was the the onset of purpura by in patients and/or was the only in cases In these cases joint before the onset of purpura by in 2 children abdominal and joint were the 3 before the onset of skin In the patients palpable purpura or with abdominal and/or was the features of the disease in children with features children nonthrombocytopenic palpable purpura during the course of the disease. In all cases the purpuric lesions on the and lower extremities. The upper and were commonly the typical purpuric other skin more or were observed in patients. In all however, palpable purpura was the cutaneous Joint manifestations, in particular arthritis, were common during the course of the they were observed in of In most cases joint involvement was an involving and or and, upper In the in the series of patients with are children abdominal bleeding, was by the presence of bloody stools in in of the children A the presence of vasculitis in 2 in addition, 1 patient had a were observed in children within the first 3 the onset of Nephritis in the course of the disease 1 of the patients with renal had hematuria, microscopic in of cases and hematuria in the children of the patients with hematuria also had proteinuria without hematuria was observed in only 1 a clinical of renal involvement was in most cases patients of the patients with nephritis severe of nephrotic syndrome within the first 3 the onset of disease. 2 patients were and had acute renal insufficiency with of creatinine during the course of the disease These 2 patients also nephrotic syndrome within the first 3 the onset of disease. 3 patients had involvement and 1 patient skin most cases mg/kg per day as was in to gastrointestinal or severe renal A and a were also with and to severe clinical features in children with of in children with findings in children with from onset of to development of nephritis in of patients had at the of almost of patients had an elevated however, was observed in only were however, they were in a few patients with severe gastrointestinal A infection was by in of patients. IgA concentration was to be in of the children in it was was present in more than of patients Of note, and with IgA deposits was in the cases in renal biopsy was of children with HSP had at least 1 the of those patients with HSP in children from Lugo was acute and a few a follow-up of 7 of patients had hematuria with proteinuria, of had renal In this those 2 patients who had renal insufficiency in the course of the disease also had were observed in in those who renal of children with HSP and a follow-up of at least 1 and clinical between children with and without renal in at disease onset were were not with the onset of the vasculitis in any in a history of URT infections or before the onset of disease was not with a was a to from the onset of the of diagnosis at the in the group of patients who renal renal involvement) in those without renal between children with HSP with and without renal at last follow-up (at least 1 hematuria at the onset of disease or renal within the first 3 the onset of of vasculitis were more common in the group of patients with renal sequelae. Of note, the presence of nephrotic syndrome during the course of the disease was with permanent renal involvement (renal of the vasculitis were more common in children with renal Clinical and between children with HSP with and without renal at last follow-up (at least 1 To the of onset was with disease and children were in 3 and to the at the onset of vasculitis. epidemiologic or clinical were the of severe gastrointestinal and the of patients who nephritis was in these 3 groups not To investigate the of disease onset was with a characterized by a of and, the presence of permanent renal those patients who had at least 1 follow-up were also by We that the at the onset of HSP was not with a outcome in of permanent renal in outcome by in children with HSP and a follow-up of at least 1 for renal As in the Methods to the clinical with renal a was undertaken. on the presence of nephrotic syndrome during the first 3 the onset of was the for renal sequelae. most children who this complication had renal involvement at the of the present study The for renal in patients who had nephrotic syndrome was this and as all patients who had nephrotic we the following of of of and this of patients with a follow-up of at least 1 were classified for the risk of renal sequelae. In the for nephrotic syndrome as of renal is of the presence of nephrotic syndrome during the course of disease as of renal in children with HSP and a follow-up of at least 1 for nephrotic syndrome as a of renal In a former we the of the systemic in adults from northwestern Spain In the present we have focused on the of HSP in children in the In to on the and the clinical of of this syndrome in we examined the outcome of unselected children with this that is, the of renal sequelae. We also for a for renal involvement. HSP from to of cases are seen in children the disease is observed predominantly in children between the of 2 and and the of onset is years (50). In with former in the present study only of children were years or at the onset of and the was Most series have described a in with a of to of more than In northwestern however, there was a of with a of to of The of HSP in children between and per In northwestern Spain the of HSP in the population aged 14 years and younger during the of study was to the reported before in other The of HSP Some have an of cases in and of the cases in and in the in of an in the of the disease. infections, in particular those from URT, were reported as a precipitating event in at least of the cases reported in some series In children from Lugo, a history of URT infection before the onset of disease was in more than of the the URT infections, pharyngitis or and have been implicated in the development of the disease. of infection such as the skin have been considered In a a of infection in of the patients with HSP and only in the group was observed In HSP, the most is the and A and and have also been implicated in the development of HSP with a lower than in hypersensitivity medications have been considered to be precipitating factors for the development of HSP in children IgA has been to an in the of HSP immune deposits small vessels are observed in this syndrome. In this the of HSP is based on the presence of IgA deposits However, few children with clinical features of HSP the absence of these a diagnosis to be based on the In as in other series from the Lugo region did not skin on children with typical purpuric palpable purpura involving the lower (4). For these criteria were used in the present study. In to the typical purpuric involving mainly and gastrointestinal complications have been described in to of the series pain is by or purpura to and of blood and edema to of the bowel and the In addition, and have been reported in to and of the As in acute is is however, severe cases to and complications such as and have been reported As with gastrointestinal joint the development of palpable purpura by in to of patients with HSP The between the onset of joint and the occurrence of cutaneous lesions seen in Lugo was the as that reported by et al During the course of the disease, joint usually in more than of As in former studies in the patients from Lugo arthralgia or arthritis, involving mainly the of the lower and with edema, was and permanent were not as hematuria either or in association with proteinuria, the most of occurrence has been reported in of the cases complication is lower in children younger than 2 years and in However, renal involvement be more common as of have been described in the of patients without As previously reported in the present study renal involvement within the first 3 the onset of disease. of hematuria be observed in association with of skin do of hematuria a other of HSP have been As observed in 2 patients in the present the most severe clinical is that of mixed nephritic and nephrotic with hematuria, hypertension, and renal insufficiency with severe proteinuria and The long-term morbidity and mortality of HSP are almost to renal involvement. However, of the previous series that reported a relatively of renal failure in children and adults were based on selected patient usually to referral of kidney dysfunction In this based on an unselected population of children and adults with HSP, et al reported a more severe clinical syndrome with a of renal involvement in adults than the outcome in was with a in most patients. Henoch-Schönlein purpura is a disease. The of the disease is however, in children and of the disease are not The of from series to In the present were seen in almost of the patients with more than 1 and they were more common in those patients who renal sequelae. As series are of the previous series were based on selected patient However, as in the present in 1999 reported the clinical of HSP in children from a region in in the also using the criteria for to the clinical features of HSP in the Lugo region of with those from the In series the at the onset of disease was in and in and the disease was more common in and The only between the series was a lower of in however, was not In series the of IgA was of the main clinical features of HSP in 2 of the have recently observed an association with HSP in northwestern Spain (4). However, patients with severe gastrointestinal or renal did not have any association other than the underlying association with the in patients with HSP from Lugo the intercellular adhesion was not with the development of the of at have been with the to severe gastrointestinal complications A of for who children with HSP is to the risk of permanent characterized by renal sequelae. present group is in studies to implicated in the development of this a clinical of few studies have to this et al observed that the presence of proteinuria and hematuria at the onset of disease was with to renal et al observed that a failure to a creatinine of more than per at 3 years the onset of HSP to end-stage renal In an unselected series of children with HSP, et al reported of for at least 1 in almost of patients. However, a follow-up of only and of the children had to end-stage renal failure or disease, In unselected series of children with HSP, et al observed of renal involvement in of patients. A examination at an of years the onset of disease a good prognosis in that series with mortality lower than and long-term morbidity of only These 2 unselected series a good prognosis for HSP nephritis in It is based on a follow-up of more than years in children with HSP et al observed that the of the clinical with the children with the most severe clinical had the In almost of the children who had nephritic nephrotic or at the onset of disease long-term of renal in of who had proteinuria and/or was observed during the in the absence of previous renal disease. to et al suggested that HSP nephritis in children long-term during on the of HSP by the for in et al also the outcome with the of the on the renal in et al the relationship between the of renal involvement in children with HSP and observed renal involvement in of children a of between 3 and from the onset of disease. at onset of more than 7 the presence of proteinuria, and a of the risk of renal these observed that severe abdominal purpura, and of the risk of renal involvement in HSP with than In the of the risk of These that patients with risk factors for renal involvement be with to renal and studies are to the of for renal involvement in In et al in an unselected population in children and adults with HSP were described a risk of renal in those patients with previous In series of children a history of drug intake shortly before onset of disease was not with a risk of renal sequelae. Of note, in series of adults with HSP, permanent renal involvement was present in of patients (20). The presence of hematuria at disease onset and the of renal during the course of the disease were of the development of renal in These with other such as onset in at disease or of the disease, to the development of renal in most of patients (20). In the present hematuria and proteinuria during the first 3 the onset of the vasculitis and during the course of the disease were also more common in patients with renal nephrotic syndrome was the for renal sequelae. most children who this complication on during the course of the disease had renal involvement at the of the study. In HSP is a common to a URT In children from northwestern Spain HSP is a and some children permanent renal involvement. the for close follow-up studies in unselected patients from other are for of the and outcome of this syndrome. Henoch-Schönlein purpura (HSP) is a systemic vasculitis characterized by purpuric skin lesions unrelated to any underlying coagulopathy, gastrointestinal manifestations, arthritis, and renal involvement. It is the most common type of vasculitis in children and an infrequent condition in The long-term morbidity and mortality of HSP are predominantly attributable to renal involvement. Most studies of renal outcome were done on series of selected patient populations with kidney dysfunction attended in reference centers. has been a relative paucity of clinical and epidemiologic studies on HSP in children over the past few To investigate this syndrome further, we examined the incidence, clinical spectrum, and and, in particular, the risk factors implicated in the development of permanent renal in an unselected population of children diagnosed with HSP at the single reference hospital for a defined population in northwestern Spain over a 20-year period. children were classified as having The at the onset of was more commonly in and A history of upper respiratory infection before the onset of the vasculitis was not The for the 20-year was people aged 14 years and pain and/or joint the onset of purpura in of the children nonthrombocytopenic palpable purpura during the course of the disease. involving the lower was seen in of patients. in and renal in of children within the first 3 the onset of 1 of the patients with renal had hematuria, with proteinuria in of of the cases were for at least 1 a follow-up of 7 of the patients had hematuria with however, of had renal at the onset of disease or renal within the first 3 the onset of of the vasculitis and were more common in the group of patients with renal sequelae. Of note, the presence of nephrotic syndrome during the course of the disease was with permanent renal involvement (renal however, the at the onset of disease was not with a disease and the for renal was the presence of nephrotic syndrome during the first 3 the onset of The for renal in patients who had nephrotic syndrome was this of patients with a follow-up of at least 1 were classified for the risk of renal sequelae. In in northwestern HSP is a and some in particular those who nephrotic permanent renal involvement. follow-up studies in unselected patients from other are for of the and outcome of this syndrome. We are to the of the Pediatrics Division of the Hospital Lugo, Spain. We are in to and for in the and diagnosis of the patients with cutaneous vasculitis. the are for the given by and from the of the Hospital