Henoch-Schönlein purpura (HSP), also known as anaphylactic purpura,
nonthrombocytopenic purpura, rheumatic purpura or allergic purpura, is the most
common type of vasculitis in the pediatric age group.
It is characterized by cutaneous, articular, gastrointestinal and renal involvement,
while orchitis, vasculitis of the central nervous system (CNS) and pulmonary hemorrhage
are rare findings.
The most characteristic clinical manifestation, and one which is found in all
patients, is non-thrombocytopenic palpable purpura, symmetrically located and
with a preference for the lower limbs and buttocks.
damage is the principal prognostic determinant in HSP, affecting between 10 and
50% of patients.
The most common renal alterations are transitory hematuria and proteinuria, commonly
with duration of less than 1 month.
Of those children who do continue to suffer from these urinary sediment alterations
beyond the first month of the disease, around 30% exhibit complete recovery by
the third month, rarely progressing with persistent hematuria and/or proteinuria
or nephritic or nephrotic syndromes.
While prognosis is habitually favorable, patients with nephritis may progress
to renal insufficiency.
is a scarcity of studies of pediatric HSP patients employing multivariate analysis
models that have evaluated the initial prognostic factors associated with renal
and those that do exist generally investigate oriental populations.
Furthermore, these studies do not describe other initial alterations of this disease,
such as orchitis, CNS vasculitis and pulmonary hemorrhage.
This being so,
the objectives of this study were to evaluate renal involvement in patients with
HSP and to identify initial factors, assessed during the first 3 months, that
are predictive of nephritis, based on demographic data, clinical characteristics,
laboratory test results and the treatment given to these patients.
The medical records of all 189 children and adolescents who were seen during
a 21-year period (January, 1983 to December, 2003) and were diagnosed with HSP
were retrospectively analyzed in accordance with a clinical and laboratory protocol.
All of these patients met the American College of Rheumatology classification
criteria for a diagnosis of HSP: the presence of two or more of four criteria
in patients with palpable purpura (Table 1).
All of these patients were seen at the Children’s Institute (ICr –
Instituto da Criança) part of the Hospital das Clínicas (HC), affiliated
to the Faculdade de Medicina, Universidade de São Paulo (FMUSP). At our University
Hospital, all patients with HSP seen at the infirmary and emergency room, irrespective
of disease severity and manifestations, were promptly assessed by the physicians
at the Rheumatology and/or Pediatric Nephrology Departments of the ICr-HC-FMUSP,
and were followed-up at these departments’ clinics. This study was approved
by the Research Ethics Committee at the HC-FMUSP.
Criteria for Henoch-Schönlein purpura classification
protocol covered evaluation of demographic data, clinical manifestations, laboratory
findings and HSP treatments, such as cutaneous, articular and gastrointestinal
involvement, orchitis, CNS involvement, pulmonary hemorrhage, elevated serum IgA,
treatment with corticosteroids, immunosuppressive drugs or intravenous gammaglobulin.
to other studies in the medical literature,
HSP renal involvement or nephritis can be defined as the presence of one or more
of the following alterations: hematuria (> 5 red blood cells per microscopic
field), proteinuria (> 0.1 g/m2/day),
renal insufficiency (creatinine clearance > 80 mL/min/1.73m2), nephrotic
syndrome (edema, serum albumin > 2.5 g/L and proteinuria > 1 g/m2/day).
Kidney biopsies were indicated, in particular for patients with renal insufficiency
or nephrotic syndrome. Histology results were assessed according to the International
Study of Kidney Disease in Children, and classified into one of six subtypes:
grade I (normal, or discrete alterations), grade II (proliferative mesangial glomerulonephritis),
grade III (proliferative mesangial glomerulonephritis with crescents in less than
50% of glomeruli), grade IV (proliferative mesangial glomerulonephritis with crescents
in 50 to 75% of glomeruli), grade V (proliferative mesangial glomerulonephritis
with crescents more than 75% of glomeruli) and grade VI (membranoproliferative
In order to identify initial prognostic factors (present
within the first 3 months of the disease) associated with renal involvement (initial
or progressive), patients were divided into two groups: with or without nephritis.
The two groups were then compared on the basis of the following initial variables:
demographic data (sex and age at disease onset), clinical characteristics (persistent
palpable purpura lasting for more than 1 month after disease onset, arthritis,
abdominal pain, gastrointestinal bleeding, orchitis, CNS involvement or pulmonary
hemorrhage), elevated serum IgA during the first month of the disease (> 255
mg/dL), use of corticosteroids, immunosuppressors or intravenous gammaglobulin.
pain was defined as mild (pain improves with paracetamol) or severe (abdominal
angina, with diffuse abdominal pain that make eating impossible
and/or gastrointestinal bleeding).
Patients with severe abdominal pain either did not tolerate or did not respond
to paracetamol. Abdominal or testicular with Doppler ultrasound was employed to
confirm diagnoses of intussusception or orchitis, respectively. This is important
for ruling out orchitis secondary to vasculitis of the spermatic cord, which is
rarely observed in HSP.
employed during the first 3 months of HSP, were indicated for treatment of severe
gastrointestinal involvement (severe abdominal pain and/or intestinal bleeding),
orchitis or nephritis (nephrotic syndrome and/or renal insufficiency). Prednisone
or prednisolone were administered at a dosage of 2 mg/kg/day for 1 week and later
reduction between 3 and 4 weeks or pulse therapy with methylprednisolone at a
dosage of 30 mg/kg/day (maximum of 1 g/day for 3 days), followed by prednisone
or prednisolone as described above. Immunosuppressors, particularly intravenous
pulse therapy with cyclophosphamide (0.5 to 1 g/m2/month) during the
first 3 months of HSP, were indicated for patients with renal insufficiency or
nephrotic syndrome who did not respond to pulse therapy with methylprednisolone.
Intravenous gammaglobulin (2 g/kg/in a single dose) was administered during the
first 3 months of HSP to patients with severe gastrointestinal involvement (severe
abdominal pain and/or intestinal bleeding) who did not respond to pulse therapy
statistical analysis was carried out using Fisher’s exact test and the chi-square
test to compare demographic data, clinical characteristics, serum IgA levels and
treatment between the two study groups (with or without nephritis). Student’s
t test for independent samples was used to compare mean age at onset. Multivariate
analysis employed backward stepwise logistic regression. Independent variables
that had statistical significance of 5%, or close to this figure, after univariate
analysis were chosen for the multivariate analysis. In the regression model the
dependent variable was presence of nephritis, and independent variables were persistent
purpura, abdominal pain, severe abdominal pain and gastrointestinal bleeding.
For all statistical tests the level of significance was defined as 5%.
total of 189 patients with HSP were treated during the 21-year period, and of
these 142 patients were included in the study as their medical records provided
The principal clinical characteristics, laboratory tests
and treatment of these patients with HSP are listed in Table 2. Forty-six percent
of these 142 patients were male, 100% had palpable purpura, 28% persistent palpable
purpura during the first month of the disease, 69% had arthritis, 62% abdominal
pain, 49% nephritis, 32% severe abdominal pain, 10% gastrointestinal bleeding,
9% orchitis (painful, acute scrotal edema associated with palpable purpuric lesions),
and one patient (0.7%) suffered a cerebral vascular accident due to vasculitis
of the CNS. None of the patients suffered pulmonary hemorrhage. Elevated serum
IgA levels occurred in 43% (Table 2).
Clinical characteristics, laboratory tests and treatment of 142 patients with
Forty-six patients (32%) were given corticosteroids
during the first 3 months of their HSP, which were indicated for severe gastrointestinal
involvement in isolation in 38 cases (31%), severe gastrointestinal involvement
associated with orchitis in six (9%), abdominal invagination, nephrotic syndrome,
acute renal insufficiency and cerebral vascular accident due to vasculitis of
the CNS in one case (0.7%) and for nephrotic syndrome with acute renal insufficiency
in another (0.7%). These two patients (1.4%) with nephrotic syndrome and renal
insufficiency (renal biopsy showing grade IV glomerulonephritis) required pulse
therapy with intravenous cyclophosphamide, and two others (1.4%) with intestinal
bleeding were given intravenous gammaglobulin.
All 70 patients with nephritis
had isolated hematuria or proteinuria (31 and 7%, respectively) or both (11%),
two had nephrotic syndrome (1%) and two had renal insufficiency (1%) (Table 2).
Nephritis occurred during the first 3 months of the disease in 69.98% of these
70 patients, and just one patient (2%) developed late-onset nephritis (acute renal
insufficiency, hematuria and proteinuria, with renal biopsy demonstrating grade
III glomerulonephritis) after 3 years’ follow-up.
Table 3 contains
the univariate analysis of prognostic factors associated with renal involvement
in HSP. Patients with nephritis exhibited a significantly greater frequency of
intense abdominal pains, gastrointestinal bleeding and corticosteroid use compared
with the patients with no renal involvement (43 vs. 21%, p = 0.004, OR = 1.62,
95%CI 1.18-2.21; 16 vs. 5%, p = 0.049, OR = 1.57, 95%CI 1.10-2.26; and 44 vs.
21%, p = 0.0012, OR = 1.75, 95%CI 1.28-2.40, respectively) (Table 3). There was
also an increased tendency for patients with abdominal pain to develop nephritis
than for patients without this manifestation (70 vs. 54%, p = 0.059).
Univariate analysis of prognostic factors in 142 patients associated with renal
involvement in Henoch-Schönlein purpura
Nevertheless, there was
no statistical difference between patients with and without nephritis in terms
of male sex (50 vs. 43%, p = 0.5), age at onset of HSP above 4 or 7 years (83
vs. 71%, p = 0.311; 43 vs. 36%, p = 0.6, respectively), mean ± standard deviation
of age at disease onset (6.7±2.9 vs. 6.1±3.0 years, p = 0.247), persistent
purpura during the first month of the disease, arthritis, orchitis and CNS vasculitis
(33 vs. 24%, p = 0.2; 66 vs. 72%, p = 0.469; 11 vs. 6%, p = 0.676; 1 vs. 0%, p
= 0.493, respectively), elevated serum IgA (14 vs. 29%, p = 0.809) or treatment
with immunosuppressors or intravenous gammaglobulin (1 vs. 0%, p=0.493; 1 vs.
0%, p = 0.493, respectively) (Table 3).
The only variable independently
associated with nephritis according to the multivariate analysis logistic regression
model was presence of severe abdominal pain (p < 0.012; OR = 2.593; 95%CI 1.234-5.452;
Nagelkerke’s R2 = 0.061) (Table 4).
Multivariate analysis by logistic regression of prognostic factors in 142 patients
associated with renal involvement in Henoch-Schönlein purpura
damage is the principal determinant of prognosis in HSP and occurs in between
10 and 50% of cases, predominantly among preschool children and schoolchildren
with mean age of disease onset of 6 years,
in common with our study. The majority of these children develop nephritis during
the first 3 weeks of the disease,
and it is uncommon for an initial renal injury to appear after other clinical
manifestations have disappeared, as can be observed in 98% of our patients.
remaining manifestations of HSP identified in the present study were similar to
those found in the medical literature: palpable purpura (100%), persistent palpable
purpura during the first month of the disease (22 to 62%), arthritis (50 to 74%),
abdominal pain (55 to 72%), severe abdominal pain (15 to 60%), gastrointestinal
bleeding (8.8 to 24%) and orchitis (2 to 32%).
In contrast, CNS involvement with cerebral vasculitis has rarely been described,
as was observed in just one of our patients.
One feature of this study population
is that all patients with HSP seen at our Hospital, even those presenting with
mild forms of the disease, were invariably treated by the Rheumatology and/or
Pediatric Nephrology departments. These patients were seen at the various clinics
and the emergency room concomitantly by general pediatricians and specialists
(rheumatologists and/or pediatric nephrologists).
Just four studies have
assessed initial risk factors for nephritis of HSP using univariate and multivariate
analysis models, and three of these were undertaken in oriental countries (Japan
and Korea). In these studies nephritis occurred in between 21 and 49% of cases,
which is comparable with our study.
Kaku et al.
found evidence that abdominal pains of severe intensity, persistent purpura, age
over 7 years and reduced serum coagulation factor XIII levels were initial risk
factors associated with HSP nephritis. Sano et al.
assessed 134 patients with HSP and used univariate analysis to determine that
significant abdominal pain, persistent purpura and treatment with corticosteroids
were most associated with nephritis of HSP. The third study, undertaken by Rigante
demonstrated that the presence of persistent purpura (> 1 month) and severe
abdominal pain at the start of the HSP clinical picture were also associated with
increased kidney damage on univariate analysis. A second analysis, employing logistic
regression, revealed that persistent purpura was the only factor that remained
associated with nephritis of HSP and that it also increased the chances of recurrent
kidney disease. In a recent study, Shin. et al.
evaluated 94 patients with HSP and also found evidence that the presence of persistent
purpura and intense abdominal pains at disease onset had a significant relationship
with renal involvement.
In our paper it has been demonstrated that by univariate
analysis severe abdominal pain, gastrointestinal bleeding and use of corticosteroids
were factors associated with nephritis. However, when a logistic regression model
was constructed, it was revealed that only severe abdominal pain were an independent
variable with significance for predicting nephritis. Nevertheless, it is worth
pointing out that significant abdominal pain was practically the only factor associated
with nephritis in common with all the other studies.
the definition of severe abdominal pain adopted here was similar to that of other
studies in the literature,
and all of the patients presenting this manifestation required corticosteroids,
emphasizing the severity of this development.
There is considerable disagreement
in published literature with relation to early introduction of corticosteroids
and reduced frequency of nephritis in HSP.
Mollica et al.,
in a prospective, randomized study, found that early introduction of 1 mg/kg/day
of prednisone for 2 weeks reduced the incidence of nephritis. Similarly, Kaku
demonstrated that treatment with corticosteroids reduced the risk of nephritis,
with a low relative risk of 0.36. However, other authors have failed to demonstrated
any reduction in the course of HSP nephritis with early introduction of corticosteroids.
Other randomized and placebo-controlled trials have also found that the use of
prednisone at the start of HSP does not avert kidney damage.
In our patients sample it was demonstrated that use of corticosteroids was associated
with greater renal involvement, since these patients exhibited a greater frequency
of severe gastrointestinal involvement and required these medications. These were
habitually introduced during the first month of the disease and were predominantly
indicated to control significant gastrointestinal manifestations, such as intermittent
and severe abdominal pain in colic, and bleeding and intussusception.
have also been carried out of early laboratory markers associated with nephritis
of HSP. Elevated serum IgA levels can be observed in 20 to 50% of patients with
HSP, during the first 3 months of the disease, tending to normalize later.
Rheumatoid factor IgA (RF-IgA) can be detected in around 50% of cases, without
correlation with severity or duration of the disease.
Similarly, some authors have reported that the presence of circulating IgA-immune
IgG perinuclear antineutrophil cytoplasmic antibodies and IgA antineutrophil cytoplasmic
antibodies (IgG P-ANCA and IgA ANCA, respectively)
are associated with increased renal involvement during the acute phase of the
disease. Notwithstanding, our results did not demonstrate any association between
serum IgA levels and the occurrence of nephritis. Furthermore, other authors suggest
that serum IgD levels are elevated in patients with HSP who do not have nephritis
and low in those patients who do; with no correlation with serum IgA levels.
etiopathogenesis of HSP remains unknown. It is, however, known that a combination
of several factors, in genetically predisposed patients, favor the alterations
to immunoregulatory mechanisms that are responsible for the manifestations of
and that different populations are likely to differ, which could possibly explain
the higher prevalence rates in oriental countries. More recently, attempts have
been made to predict nephritis by means of genetic polymorphism studies.
In a study carried out by Yi et al.,
the presence of a polymorphism in the PAX2 gene (a gene which is involved in renal
maturation) was not associated with the occurrence of HSP, but did increase genetic
susceptibility to nephritis. Additionally, a study conducted by Ozkaya et al.
demonstrated that a polymorphism of the renin-angiotensin system gene was associated
with a 3.5 times greater risk of nephritis.
Further studies are needed to
identify the genetic markers for HSP, in order to predict which patients will
develop severe nephritis and would benefit from immunosuppressive treatment with
a reduced frequency of adverse events (pharmacogenetics).
with HSP, particularly those with renal involvement, should be monitored indefinitely
with renal function and urinary sediment tests. Ronkainen et al.
studied adults after 26 years’ follow-up of HSP and found evidence of delayed
nephritis development in pregnancy, even among patients who had not initially
presented with nephritis or developed it while in the pediatric age group.
conclusion, renal involvement occurred in 70 (49%) of our patients, with 69 98%
developing it within the first 3 months of the disease. The presence of severe
abdominal pain, gastrointestinal bleeding and use of corticosteroids were associated
with renal involvement in HSP by a univariate statistical analysis. However, after
multivariate analysis, only severe abdominal pain remained as the only initial
factor associated with the occurrence of HSP nephritis. This being so, those patients
with HSP who exhibit gastrointestinal symptoms during the first 3 months should
be rigorously monitored, due to the increased risk of renal involvement.
study was supported by the Conselho Nacional de Desenvolvimento Científico
e Tecnológico – CNPQ (grant number 302469/2005-2 awarded to CAAS).