Henoch-Schonlein Purpura in Children Hospitalized at a Tertiary Hospital during 2004-2015 in Korea: Epidemiology and Clinical Management

Henoch-Schonlein purpura (HSP) is the most common type of vasculitis in children [1, 2]. Patients with mild clinical symptoms respond well to conservative treatment, but steroids are often required to improve severe abdominal pain and joint symptoms [3, 4, 5]. Renal involvement is a well-known predictor of poor prognosis, but the rate of progression to chronic renal disease is lower in children than in adults [6, 7, 8, 9]. Hospitalization is often reserved for those cases complicated by severe abdominal or joint pain, and in those patients with proteinuria due to renal involvement. Most cases of HSP can be confidently diagnosed in the presence of the characteristic purpuric spots, but in cases that manifest as severe abdominal pain in the absence of purpura, obtaining a diagnosis can be difficult [10, 11]. The use of high dose steroids may be considered in HSP patients presenting with severe gastrointestinal (GI) symptoms (i.e., abdominal pain and hematochezia) or persistent proteinuria. If severe GI symptoms or nephrotic syndrome persist despite steroid treatment, then other treatment modalities such as intravenous immunoglobulin (IVIG), immunosuppressive drugs, or plasmapheresis may be used [12, 13, 14, 15, 16, 17]. In this study, we investigated the epidemiologic characteristics and clinical courses of children hospitalized with HSP at a tertiary hospital between 2004 and 2015.

We performed a retrospective review of the medical records of 240 children hospitalized with HSP (diagnosis code: D69.0) at Inje University Sanggye Paik Hospital between January 2004 and February 2015. Three children who were diagnosed at other hospitals before being transferred to Inje University Sanggye Paik Hospital were also included.

A total of 212 patients were included in this study after exclusion of 54 patients due to the passage of more than 1 month from initial diagnosis at another hospital (14 patients), incomplete medical records (13 patients) and 27 due to incorrect coding (27 patients). The study protocol was approved by the Institutional Review Board of the Inje University Sanggye Paik Hospital (SP IRB no. 16-02-005). Diagnosis of HSP was based on American College of Rheumatology Classification Criteria [18]. Recurrence of HSP was defined as the recurrence of symptoms more than 1 month after remission. The data for sex, age, year and month of onset, presence of symptoms (skin, joint, abdominal, renal, and other organs), recurrence of symptoms, results of renal biopsy, dosage and duration of steroid treatment, duration of steroid tapering, IVIG treatment, results of endoscopic exams or radiological exams: abdominal ultrasonography (USG), small bowel series (SBS), computed tomography (CT), and blood tests: white blood cell (WBC) count, platelet count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), were collected by review of medical records. The visual analog scale generally used to evaluate abdominal pain is not applicable for young children with HSP. In this study, abdominal pain was classified into three groups as follows: 1) Severe abdominal pain group: requiring radiological examination to exclude intussusception or appendicitis, confirmation of intussusception, complications requiring surgical or endoscopic intervention, gross hematuria or hematochezia; 2) Mild abdominal pain group: showing GI symptoms not meeting the criteria of the severe group; and 3) No abdominal pain group.

Renal involvement was classified as follows: 1) hematuria-5 red blood cells at high power light microscopy; 2) proteinuria-urine protein:creatinine (UP/UCr) >0.5 in children under 2 years of age, UP/UCr >0.2 in children over 2 years of age; 3) simultaneously meeting the criteria for 1) and 2); and 4) proteinuria over 40 mg/m²/hr or nephrotic range proteinuria (UP/UCr >2.0).

Analysis of steroid treatment was performed in 113 patients who were followed up over a one month period, after the exclusion of 14 patients without steroid treatment and 8 patients with extreme steroid-dosage (<0.5 mg/kg/day or >2.5 mg/kg/day). A total of 113 patients were divided into two groups based on their initial prednisolone dosage: 1) high-dose group (0.5 mg/kg/day-1.5 mg/kg/day), n=94 and 2) low-dose group (1.5 mg/kg/day-2.5 mg/kg/day), n=19. Statistical analysis was performed with SAS ver. 5.1 (SAS Institute, Cary, NC, USA) by chi-square test, Mann-Whitney test, one-way analysis of variances, logistic regression analysis, and Fisher's exact test.

HSP is the most common type of vasculitis in children. It is a form of leukocytoclastic vasculitis and is characterized by IgA-mediated injury. It has an incidence of 8-22/100,000 and is more prevalent in males [1, 2, 19, 20]. Although HSP could manifest in all age groups, including adults, it is most frequently diagnosed at 5-7 years of age [4, 19, 20, 21, 22, 23]. In this study that included children under 18 years of age, the average age at first diagnosis was 6.93 years, and this finding is consistent with previous studies. The frequency of diagnosis of HSP in this study was slightly decreased during 2008-2012 and subsequently increased after 2013, but this was not significant statistically. The peak incidence of HSP was in the winter (33.0%) and lowest in the summer (11.8%), which is in keeping with findings from previous studies [20, 23, 24].

Rostoker [2] reported that the incidence of skin rash, joint and GI symptoms and renal involvement in one group of patients was 100%, 70%, 66%, and 37%, respectively. In Northern Spain [6], these values were 100%, 63.1%, 64.5%, and 41.2%, respectively, and 100%, 45.3%, 34.4%, and 44.7%, respectively, in Turkey [25]. In this study, the incidence of skin rash, joint and GI symptoms and renal involvement was 98.6%, 69.8%, 75.0%, and 26.9%, respectively, reflecting a higher incidence of GI symptoms but lower incidence of renal involvement compared to those of other countries. In other Korean studies, Choi and Lee [23] reported that skin rash, joint and GI symptoms and renal involvement were 100%, 40.8%, 53.8%, and 18.9%, respectively. In the study by Kang et al. [26], these values were 100%, 55.4%, 56.3%, and 30.4%, respectively, and 93%, 52.4%, 71.4%, and 10.8%, respectively in the study by Hong and Yang [27]. In the present study, the incidence of GI and joint symptoms was relatively high compared to in other Korean studies, which might be due to regional factors and the fact that our study population was recruited from hospitalized patients.

The rate of renal involvement was relatively low in Korea compared to that of other countries. In a Japanese study, Nagamori et al. [28] reported that the renal involvement rate was 15%, which is similar with that of Korea. However, this number was quoted to be as high as 49% in another Japanese study and 31.9% in a recent Chinese study [24, 29]. These results suggest that the rate of renal involvement results from an association of multiple factors including ethnic, environmental, and access to medical services.

In the present study, joint symptoms were more frequently observed in younger children. This findings is consistent with the results of a recent Korean study and other studies comparing symptoms of HSP children with those of adults [6, 7, 9]. In HSP children without abdominal pain, joint pain was a major cause of hospitalization.

In this study, clinical manifestations were assessed by diving patients into two groups based on a reference age of 7 years. In previous studies that compared the clinical manifestations of HSP children with those of HSP adults, the rate of renal involvement was significantly higher in adults [6, 7, 9, 26]. In children, renal involvement and association with nephrotic syndrome was frequently observed in those over 10 years of age [8, 9]. Zhao et al. [24] proposed that age greater than 7 is a risk factor for renal involvement by multiple regression analysis. Rostoker [2] suggested that age greater than 5 is a risk factor for renal involvement, while other groups proposed that severe abdominal pain and age over 4 years are risk factors for renal involvement [29]. A recent Korean study stated that age of onset is a poor prognostic factor in HSPN patients [30]. It should be remembered that age of onset of HSP is the most important factor in evaluating prognosis, and thus it is essential to assess whether or not renal involvement is present in older children. In the present study, we found that only GI symptoms (p-value=0.033; OR, 2.701) and age (p-value<0.001) were significant factors associated with renal involvement, the latter of which increased the OR for renal involvement by 1.195 (1.083-1.318) for every 1 year increase in age. In this study, 7 years old (average age of total HSP patients: 6.93 years) was regarded as a reference age for grouping. We confirmed that the rate of renal involvement was significantly higher in older children, and occurred at the same rate in children aged between 6 years and 14 years. These findings suggest that the likelihood of renal involvement increases with age in children with HSP.

In this study, clinical manifestations were assessed by diving patients into two groups based on a reference age of 7 years. In previous studies that compared the clinical manifestations of HSP children with those of HSP adults, the rate of renal involvement was significantly higher in adults [6, 7, 9, 26]. In children, renal involvement and association with nephrotic syndrome was frequently observed in those over 10 years of age [8, 9]. Zhao et al. [24] proposed that age greater than 7 is a risk factor for renal involvement by multiple regression analysis. Rostoker [2] suggested that age greater than 5 is a risk factor for renal involvement, while other groups proposed that severe abdominal pain and age over 4 years are risk factors for renal involvement [B29]. A recent Korean study stated that age of onset is a poor prognostic factor in HSPN patients [30]. It should be remembered that age of onset of HSP is the most important factor in evaluating prognosis, and thus it is essential to assess whether or not renal involvement is present in older children. In the present study, we found that only GI symptoms (p-value=0.033; OR, 2.701) and age (p-value<0.001) were significant factors associated with renal involvement, the latter of which increased the OR for renal involvement by 1.195 (1.083-1.318) for every 1 year increase in age. In this study, 7 years old (average age of total HSP patients: 6.93 years) was regarded as a reference age for grouping. We confirmed that the rate of renal involvement was significantly higher in older children, and occurred at the same rate in children aged between 6 years and 14 years. These findings suggest that the likelihood of renal involvement increases with age in children with HSP.

It was initially thought that renal involvement was not usually present at the time of diagnosis. However, several researchers have recently reported that renal involvement is evident in 75-90% of children with HSP within 1 month of diagnosis [1, 2, 20, 31]. These findings were similar to our own, which showed that 90% of cases of renal involvement were manifest within 1 month of HSP onset.

In this study, there was an association between GI symptoms and scrotal involvement, but no significant association was observed between scrotal involvement and renal involvement. Wang et al. [32] reported an association between scrotal involvement, GI symptoms, raised D-dimer, and HSPN. Another recent study in Korea also showed that scrotal involvement was found only in patients with abdominal symptoms [33].

In this study, blood results on admission did not differ among groups. In patients with severe GI symptoms, the ESR was low, but this finding could not be explained rationally. In a previous study, Nagamori et al. [28] suggested that a scoring system comprising 6 laboratory tests (WBC, neutrophil count, albumin, D-dimer, coagulation factor XIII, and sodium) could be used for prognostic purposes. Recently, Hong and Yang [27] suggested a possible association between the grade of acute GI involvement, D-dimer, and fibrin degradation product. Wang et al. [32] reported that the occurrence of HSPN might be increased in patients with joint symptoms who showed an increased D-dimer. More studies are needed to investigate the use of laboratory values as markers of HSP severity and for prognostic purposes.

Characteristic purpura spots are observed in most patients with HSP, but in those cases where skin manifestations are delayed after GI symptoms or absent altogether, accurately diagnosing and thus treating HSP can be difficult [11, 33]. In this study, five patients complained of abdominal pain in the absence of purpura at admission (4 patients: no purpura after discharge, 1 patient: purpura 27 days after symptom onset). Focal thickening of the bowel wall in the duodenum and small bowel was observed in two patients by SBS and in one patient by abdominal USG. In one patient, treatment for HSP was started after finding a focal mucosal thickening and hematoma in the duodenum by gastrofiberscopy. These results suggest that non-invasive abdominal USG may be useful as a first line investigation to differentiate HSP from other GI diseases in patients with severe abdominal pain, and that SBS or gastrofiberscopy may be used selectively in patients who do not respond well to conservative treatment [11, 21, 34, 35, 36].

Steroid treatment should be considered in HSP patients with severe abdominal pain where possible differential diagnoses include intussusception or GI hemorrhage, and in cases of severe joint pain resulting in immobilization. Masarweh et al. [22] proposed the following HSP admission criteria: 1) scrotal pain and tenderness, 2) moderate abdominal pain, 3) GI hemorrhage, 4) proteinuria, 5) mobilization difficulty, and 6) multiple number of involved joints (>2). In this study, a total of 208 patients out of 212 were hospitalized due to severe GI and joint symptoms. Early steroid treatment could shorten the duration of extra-renal symptoms like severe abdominal pain [3, 4, 5], and lower the incidence of GI complications [21]. However, steroid treatment in HSP is not yet standardized, which explains the variable range of steroid dosage and treatment periods used in previous studies. Huber et al. [3] and Dudley et al. [37] reported that prednisolone treatment (2 mg/kg/day) for 1 week with subsequent dose reduction for 1 week did not show any significant difference in the incidence of renal and GI complications. In contrast, Ronkainen et al. [4] and Jauhola et al. [20] reported that prednisolone treatment (1 mg/kg/day) for 2 weeks with subsequent dose reduction for 2 weeks did improve renal and extra-renal symptoms in the short-term compared to placebo, but this finding did not significantly affect the patient's subsequent clinical course. In a recent Korean study, dexamethasone was given to HSP patients with severe abdominal pain until symptoms improved, and this was followed by a 2 week course of prednisolone (1 mg/kg/day) [38]. No difference in the rate of recurrence rate and persistence of nephritis was observed between the dexamethasone treated and untreated groups [38]. In another study, there was also no significant difference in treatment results after 4 weeks of follow-up between the hydrocortisone-treated and high dose methylprednisolone-treated groups [39]. According to most previous studies, steroid treatment does not affect the long-term prognosis of HSP [3, 20, 37, 40]. This finding is true even for different types and dosages of steroids [26, 38]. In this study, two groups classified according to the initial dose of steroid were compared, and we observed no significant difference in the rate of recurrence of HSP, renal involvement, and progression to nephrotic syndrome. However, this study is limited by the non-standardization of steroid treatment criteria, steroid type, and steroid dosage, as the results were based on a retrospective study performed by multiple clinicians over a long-term period. In this study, ESRD cases were not observed. However, relative underestimation of long-term prognosis in this study should be considered, because some patients transferred to other tertiary hospitals due to persistent elevation of creatinine or refractory severe GI symptoms, and thus could not be included in assessing the prognosis.

At present, there is no retrospective study that has investigated the long-term prognosis of HSP in Korea. There is an ongoing need for a prospective large-scale study to establish a standardized treatment protocol for HSP and accurately assess prognosis.

In children with HSP, the incidence of renal involvement and nephrotic syndrome is higher in those presenting at an older age, and in those patients with severe abdominal pain or GI hemorrhage. These patients should be carefully monitored to detect progression to HSPN. In children with severe abdominal pain, hematemesis, or hematochezia, performing a SBS or gastrofiberscopy could be helpful to differentiate cases of HSP without characteristic purpuric spots. In the future, more prospective and large-scaled studies are needed to set a definite treatment protocol based on long-term prognosis and clinical management.