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Henoch-Schonlein Purpura
Updated: Mar 14, 2019
Author: Rajendra Bhimma, MBChB, MD, PhD, DCH (SA), FCP(Paeds)(SA), MMed(Natal); Chief Editor:
Craig B Langman, MD more...
OVERVIEW
Practice Essentials
Headache
Anorexia
Fever
Subsequently, symptoms develop, of which the following are the most common:
Rash (95-100% of cases), especially involving the legs; this is the hallmark of the disease
Abdominal pain and vomiting (35-85%)
Bloody stools
Because HSP can affect all organ systems, a full physical examination is indicated. Physical
findings in HSP may include the following:
Skin findings (usually the first sign of HSP) - Erythematous macular or urticarial lesions,
progressing to blanching papules and later to palpable purpura; typically symmetrical and
tend to be distributed in dependent body areas, such as the ankles and lower legs in older
children and adults and the back, buttocks, upper extremities, and upper thighs in young
children; hives, angioedema, and target lesions can also occur
Arthralgia is the presenting feature in as many as 25% of cases. Joints may be swollen,
tender, and painful. Warmth, erythema, and effusions are not typically associated with HSP.
The knees and ankles are most commonly affected. On rare occasions, symptoms involve the
fingers and wrists. Findings are transient but can occur again during active disease. The
joints are not permanently deformed.
Other findings - Vasculitis involving the myocardium or lungs; stenosing ureteritis, priapism,
penile edema, or orchitis; vasculitis involving the central nervous system (CNS) and
intracranial hemorrhage with confusion and convulsions; bilateral subperiosteal orbital
hematomas; adrenal hematomas; acute pancreatitis as the sole presenting feature (rare);
cystic changes of the ovaries
Diagnosis
The diagnosis of HSP, as revised by the Paediatric Rheumatology European Society (PRES) in 2008,
includes the following criteria: palpable purpura(mandatory criteria) in the presence of at least one
of the following (diffuse abdominal pain; any biopsy sample showing predominant IgA deposition;
arthritis or acute arthralgia in any joint; and renal involvement (any haematuria or proteinuria); and
IgA deposition in a biopsy sample in patients with atypical distribution of purpura. [83, 84]
No specific diagnostic laboratory test is available to assess for markers of HSP. The following
general laboratory tests may be helpful for excluding other diagnoses and evaluating renal
function:
Platelet count
Electrolytes
Plasma D-dimer
Serum IgA
Antistreptolysin O (ASO)
CH50
C3 and C4
Endoscopy
Renal biopsy (particularly when nephrotic syndrome persists and when renal function
deteriorates)
Management
Joint and soft tissue discomfort may be reduced by giving analgesics, such as the following:
Acetaminophen
Ibuprofen
Flurbiprofen
Ketoprofen
Naproxen
Substantial GI hemorrhage
Intrapulmonary hemorrhage
The beneficial effect of methylprednisolone pulses has been shown in patients receiving
combinations of multiple immunosuppressive drugs.
In HPS nephritis, a disease considered to be benign, long-term follow-up studies showed delayed
development of CKD in this population in the absence of rapidly progressive glomerulonephritis
when steroids and other immunosuppressants were used.
Other treatment regimens have included IV or oral steroids with or without any of the following:
Azathioprine
Cyclophosphamide
Cyclosporine
Dipyridamole
High-dose IV immunoglobulin G (IVIg)
Danazol
Fish oil
Surgical interventions that may be considered in specific circumstances include the following:
Kidney transplantation for severe renal disease that is resistant to medical therapy
Tonsillectomy together with corticosteroid pulse therapy for progressive HSP nephritis
Background
Henoch-Schönlein purpura (HSP; also referred to as Schönlein-Henoch purpura, anaphylactoid
purpura, or purpura rheumatica). It was first described more than 200 years ago by Heberdon in
two male children presenting with abdominal pain, purpuric rash, and arthralgia. [86] It is an acute
immunoglobulin A (IgA)–mediated disorder characterized by a generalized vasculitis involving the
small vessels of the skin, the gastrointestinal (GI) tract, the kidneys, the joints, and, rarely, the lungs
and the central nervous system (CNS). [1, 2, 3] It is a subset of necrotizing vasculitis characterized
by fibrinoid destruction of blood vessels and leukocytoclasis.
The prevalence of HSP peaks in children aged 3-10 years, but the condition is also seen in adults.
[4] It has been reported that 24 per 100 000 children younger than 17 years will develop HSP and
there is a strong ethic influence on the incidence of the disease with approximately 70/100,000
cases of children per year in Asia. [21] In the Northern hemisphere, the disease occurs mostly
between November and January. The male-to-female ratio is 1.5-2:1.
The dominant clinical features of HSP include cutaneous purpura, arthritis, abdominal pain, GI
bleeding, orchitis, and nephritis. In one half to two thirds of children, an upper respiratory tract
infection (URTI) precedes the clinical onset of HSP by 1-3 weeks. In general, patients with HSP
appear mildly ill. They often have a fever, with a temperature that usually does not exceed 38°C
(100.4°F).
HSP is typically an acute, self-limited illness, and treatment is primarily supportive. However, one
third of patients have 1 or more recurrences. In the majority of children, the outcome of HSP is
excellent. Symptoms and signs of the disease in children usually resolve within several days or
months. The most important organ determining long-term morbidity is kidney involvement. Up to
30-50% of children either have or will develop hematuria and/or proteinuria within 4-6 weeks of the
initial presentation. This is usually mild and self-limiting. However, approximately 20% of HSP
children with nephritis (7% of all HSP cases) will develop either a nephritis or nephrotic syndrome
[88, 89, 90, 91, 92, 93] .
Pathophysiology
IgA clearly plays a critical role in the immunopathogenesis of HSP, as evidenced by increased
serum IgA concentrations, IgA-containing circulating immune complexes, and IgA deposition in
vessel walls and renal mesangium. HSP is almost exclusively associated with abnormalities
involving IgA1, rather than IgA2. The predominance of IgA1 in HSP may be a consequence of
abnormal glycosylation of O-linked oligosaccharides unique to the hinge region of IgA1 molecules.
IgA aggregates or IgA complexes with complement deposited in target organs, resulting in
elaboration of inflammatory mediators, including vascular prostaglandins such as prostacyclin,
may play a central role in the pathogenesis of HSP vasculitis.
Some have speculated that an antigen stimulates the production of IgA, which, in turn, causes the
vasculitis. Allergens, such as foods, horse serum, insect bites, exposure to cold, and drugs (eg,
ampicillin, erythromycin, penicillin, quinidine, and quinine), may precipitate the illness. Infectious
causes include bacteria (eg, Haemophilus parainfluenzae, Mycoplasma, Legionella, Yersinia, Shigella,
or Salmonella) and viruses (eg, adenoviruses, Epstein-Barr virus [EBV], parvoviruses, or varicella-
zoster virus [VZV]). Vaccines such as those against cholera, measles, paratyphoid A and B, typhoid,
and yellow fever have also been implicated. Evidence supporting a direct role of herpesvirus,
retrovirus, or parvovirus infection in the pathogenesis of HSP is lacking.
Alterations in the production of interleukins (ILs) and growth factors may also play a pathogenetic
role. Tumor necrosis factor (TNF), IL-1, and IL-6 may mediate the inflammatory process present in
HSP. Transforming growth factor (TGF)–β is a recognized stimulant of IgA production. The
elevated levels of hepatocyte growth factor present during the acute phase of HSP may reflect
endothelial-cell damage or dysfunction. Increased levels of vascular endothelial growth factor
(VEGF) may at least partly induce these changes.
Cytokines have been implicated in the pathogenesis of HSP, and endothelins (ETs), which are
vasoconstrictor hormones produced by endothelial cells, may also have a role. levels of ET-1 are
substantially higher during the acute phase of the disease than during remission or in a control
group of children. However, ET-1 levels do not appear to be correlated with morbidity, severity of
disease, or acute-phase reactant response.
Although several lines of evidence suggest a genetic susceptibility to HSP, the fundamental basis
for this abnormality remains unclear. A functional correlation of the IL1RN-2 allele and IL-1ra
production in patients with IgA nephropathy and HSP nephritis (HSPN) has been described.
Therefore, gene polymorphism may contribute to the diversity of clinical responses to
inflammatory stimulation. The prevalence of the human parvovirus B19 component NS1 gene in
patients with HSP and hypersensitivity vasculitis is increased. Results support a role of human
leukocyte antigen (HLA)-B35 in the susceptibility to nephritis in unselected patients with HSP.
Researchers are currently investigating the importance of nitric oxide (NO) production in disease
activity. Inducible NO synthase polymorphism has been associated with susceptibility to HSP in
northwestern Spain. Aliyazicioglu et al have suggested that leptin and NO may play a role in the
immunoinflammatory process of HSP, especially in the acute phase. [5]
HSP that is likely due to montelukast has been noted in patients who present with subacute
intestinal obstruction.
Yilmaz et al examined 28 children with HSP and 79 healthy children to evaluate activities of protein
C, free-protein S, and antithrombin; resistance to activated protein C; and levels of fibrinogen. [6] D-
dimer, thrombin-antithrombin (TAT) complex, prothrombin fragment (PF)-1, PF-2, and von
Willebrand factor antigen (vWAg) and its activity (RiCof) were also investigated. The investigators
found that in patients with HSP, fibrinogen, D-dimer, TAT complex, PF-1, PF-2, vWAg, and RiCof
levels were significantly higher during the acute phase than during the recovery phase and were
significantly higher than those of control subjects. [6] The severity of disease was significantly
correlated with TAT, PF-1, PF-2, vWAg, and D-dimer levels. Higher levels of matrix metalloproteinase
(MMP)-9 levels in urine and serum appear to increase nephrologic severity in children with HSP.
Use of TNF-α blockers such as adalimumab may increase the risk of developing HSP.
HSP and IgA nephropathy appear to be related disorders. However, the precise relation between
them requires further definition. The question has been raised as to whether HSP and IgA
nephropathy are 2 aspects of a single disease entity or 2 distinct entities. The following
commonalities and differences have been noted:
IgA nephropathy almost exclusively involves young adults and typically affects only the
kidneys, whereas HSP affects mostly children and involves the skin and connective tissues,
GI tract, joints, and scrotum, as well as the kidneys. [3, 7, 8]
HPS nephritis is more benign in children than in adults with the latter tending to show a
chronic and relentless course similar to that of primary IgA nephropathy. [102, 62, 8]
In HSP nephritis, repeated and prolonged episodes of acute glomerular inflammation lead to
fibrous scars and hyperfiltration in the remaiing areas, resulting in chronic kidney disease that
may progress to end-stage kidney disease. Thus the number and severity of acute episodes
of HSP nephritis have a crucial role in the subsequent progression and loss of kidney
function. In IgA nephropathy initiation and progression to end-stage kidney disease occurs
slowly and often is asymptomatic with development of glomerulosclerosis and
tubulointerstitial fibrosis. [105]
IgA nephropathy has developed in patients with a history of HSP, and HSP and IgA
nephropathy have occurred in the same families; in a survey of 40 families in which 2 or more
members had IgA nephropathy, 5 presented with HSP. [9]
Patients with HSP who undergo renal transplantation develop IgA deposits in the graft.
Similar changes in the IgA system (ie, high IgA, IgA-1C, IgA1-IC, IgA-fibronectin aggregates,
aberrantly glycosylated IgA in the circulation) occur in both diseases. [10, 11, 12]
Cystic changes in the ovaries of a prepubertal girl with HSP have been recorded.
Overall, the data tend to support the view that HSP and IgA nephropathy are distinct diseases. [13]
Zhou et al examined 31 children aged 3-15 years with IgA nephropathy and 120 children aged 4-15
years with HSP, noting their clinical manifestations, blood biochemistries, serum immunology, and
follow-up data. [14] Renal pathologic findings on light microscopy, immunofluorescence study, and
electron microscopy were analyzed and compared between 31 children with IgA nephropathy and
32 children with HSP.
The age of onset was greater than 12 years in 25.8% of the children with IgA nephropathy but in
only 10% of those with HSP. [14] Clinical patterns of IgA nephropathy were similar to those of HSP,
but extrarenal manifestations were observed more often in patients with HSP.
All of the HSP patients had skin purpura, 59% had GI symptoms, and 47% had arthralgia.
Abdominal pain occurred in only 3.2% of children with IgA nephropathy. [14] In patients with IgA
nephrology and in patients with HSP, renal pathology revealed global sclerosis in 35.5% and 3.1%,
mesangial sclerosis in 41.9% and 6.3%, endothelial proliferation in 29% and 65.6%, and thin
basement-membrane nephropathy in 6.5% and 0%, respectively.
In HSP, electronically dense deposits in HSP were sparse, loose, and widely spread in the
glomerular mesangium, in the subendothelial area, and even in the intrabasement membranes,
whereas in IgA nephropathy, the deposits were dense, lumpy, and mostly limited to mesangium and
paramesangium. [14]
Immunoglobulin G (IgG) was found in glomerular immune deposits in 71.9% of patients with HSP
but in only 19.4% of patients with IgA nephropathy. [14] No IgG deposit was observed in 81.6% of
those with IgA nephropathy; most had IgA and immunoglobulin M (IgM) or C3 deposits.
Predominant IgG deposits were found in 12.5% of HSP patients, with relatively weak IgA deposits.
Moreover, 6.3% of HSP patients had linear IgG deposits in the glomerular capillary wall, a finding
that was not noted in patients with IgA nephropathy.
The rate of complete remission was 72.5% in patients with HSP at an average of 20 months’
follow-up; the corresponding rate was 19.4% in those with IgA nephropathy after 34 months’ follow-
up. [14] Moreover, 64.5% of patients with IgA nephropathy had consistent hematuria and proteinuria,
and 16.1% had active nephritides.
The important clinicopathologic differences Zhou et al found between HSP and IgA nephropathy
argue against the single-disease hypothesis.
Etiology
The etiology of HSP remains to be clearly defined but is thought to be multifactorial, with genetic,
environmental, and antigenic components. More than 75% of patients report antecedent URTI,
pharyngeal infection, or GI infection. Multiple bacterial and viral infectious agents have been
associated with the development of HSP, and cases also have been reported after drug ingestions
and vaccinations. [15]
Infections that may precede the development of HSP include the following:
Infectious Mononucleosis
Hepatitis
Mycoplasma infection
Campylobacter enteritis
Helicobacter pylori infection [16, 17, 18] (specifically noted in China [19] )
Yersinia infection
Shigella infection
Salmonella infection
Brucellosis
Legionella species
Parvovirus
Adenovirus
EBV infection
VZV infection
Rotavirus
Vaccinations that may precede the development of HSP include the following:
Measles
Yellow fever
Cholera
Drugs (eg, ampicillin, erythromycin, penicillin, quinidine, quinine, losartan, and cytarabine [20] )
Foods
Horse serum
Cold exposure
Insect bites
Epidemiology
United States statistics
In the United States, the prevalence of HSP is approximately 14-15 cases per 100,000 population in
children compared to 1-3 cases per 100,000 per year in adults. [98, 99, 100, 101]
International statistics
In the United Kingdom, the estimated annual incidence of HSP is 20.4 cases per 100,000
population. [21] In a Norwegian community hospital, the prevalence of Henoch-Schoenlein purpura
was 3.3 cases per 100,000 inhabitants. [22]
In a study that examined the renal biopsy results of 65 children younger than 18 years obtained by
the Clinical Hospital in the Croatian region of Dalmatia over a 10-year period (1995-2005), 10.8% of
glomerulonephritis cases were due to HSP. [23]
Nong et al reviewed the records of 107 Taiwanese pediatric patients diagnosed with HSP between
1991 and 2005 who had a mean age of 6.2 ± 2.5 years (range, 2-13 years); the male-to-female ratio
was 1:0.7. [24] The primary symptoms included the following:
Rashes (95.3%)
GI symptoms (72.0%)
Rashes (56.1%)
GI symptoms (35.5%)
From January 1983 to June 2004, Suehiro et al followed 4502 patients at the Pediatric
Rheumatology clinic in Brazil. [25] A diagnosis of HSP was made in 203 cases (4.5%); 5 patients
(0.1%) had acute hemorrhagic edema of infancy (AHEI). All patients with AHEI were male, and the
mean age at onset was 18 months (range, 8-21 months).
Age-related demographics
HSP primarily affects children; it may be seen in adults, but much less frequently. [2, 8] In the United
States, the prevalence peaks in children aged 5 years. Approximately 75% of cases occur in
children aged 2-11 years; HSP is rare in infants and young children. Older age at the onset of HSP is
associated with the development of chronic renal disease. [26] AHEI, a related but milder condition,
occurs in infants younger than 2 years. [27]
Ghrahani et al conducted a retrospective study in children with HSP in Hasan Sadikin Hospital from
2006 to 2011 to evaluate renal involvement in children with HSP. The authors reported that there
were 128 patients with an age range from 6 month to 15 years. Peak morbidity was between 5-10
years old. In most patients (71%) purpura was the first symptom. Seventy-one patients (44.5%) had
arthritis and 89 patients (69.5%) had abdominal pain, while renal involvement was in 28 patients
(21.8%). Gastrointestinal manifestations tend to manifest in patients less than 5 years old, while
renal involvement tend to manifest in age group 11-15 years old. The authors concluded that renal
involvement in children with HSP is more common in age group 11 to 15 years old. [28]
A study by Hennies et al that included data from 202 pediatric patients with Henoch-Schönlein
purpura nephritis reported that children older than 10 years of age had more insidious onset of
non-nephrotic proteinuria, impaired renal function, longer delay to biopsy, and more chronic
histopathological lesions than younger children. [29]
Sex-related demographics
HSP occurs more often in boys than in girls. In children, the male-to-female ratio is 1.5-2:1. In
adults, the male-to-female ratio is approximately 1:1.
Race-related demographics
In a study from Thailand, patients most commonly presented between the ages of 3 and 5 years.
[30] Frequency peaked from December to February. Organs involved included the skin (100%), GI
tract (74.5%), and kidneys (46.8%). Joints were also affected (42.6%). Renal involvement was
detected within the first 2 months in 16 patients (72.7%); however, it was delayed until 6 months
after diagnosis in 6 patients.
No risk factors for renal involvement could be identified in this study. [30] Mean follow-up time was
2.6 years (range, 1-5 years). Residual renal disease occurred in 6 (38%) of 16 patients, but none had
end-stage renal disease (ESRD).
In a study from China, a male predominance was observed in children but not in adults. [31]
Preceding infection was noted in 40.5% of children and 31.6% of adults; 8.3% of children and 13.2%
of adults were receiving medication at the onset of the disease.
The investigators found that abdominal pain was more common in children than adults (70.2% vs
28.9%), but renal involvement was more common and severe in adults than in children; this
involvement manifested as frequent hypertension and heavy proteinuria. [31] During acute attacks,
leukocytosis, thrombocytosis, and elevated serum C-reactive protein (CRP) levels were most
frequently observed in children, whereas elevated serum IgA and cryoglobulin levels were most
common in adults.
A study of 450 cases from Turkey showed that girls, patients with atypical presentations, and
patients undergoing early corticosteroid treatment had an increased risk of developing kidney
disease; relapses occurred more often in children treated with corticosteroids. [32]
Familial kindreds with HSP have been noted in Taiwanese aboriginal people. [33]
Prognosis
HSP is generally a benign disease with an excellent prognosis. Spontaneous resolution is usual:
Most patients experience complete resolution of symptoms within 8 weeks, and probably fewer
than 5% experience chronic symptoms. Initial attacks of HSP can last several months, and relapses
are possible. HSP is fatal only in the rarest of cases.
A clinical course with complete resolution of the disease usually occurs in patients with the
following:
No neurologic complications
Children younger than 3 years usually have a shorter, milder course than older patients do, as well
as fewer recurrences.
Recurrences occur in as many as 50% of patients within 6 weeks but can happen as late as 7 years
after the initial disease. A study by Calvo-Río et al indicated that in patients with HSP, the chance of
relapse is greater in those with GI and joint manifestations, with 72.3% of patients in the study with
abdominal pain relapsing, compared with 62.3% of those who did not, and 27.8% of patients with
joint manifestations relapsing, compared with 15.5% of those who did not. [34]
Although HSP generally resolves without permanent consequences, serious GI and renal
complications may occur, and the higher the number of recurrences, the higher the likelihood of
permanent renal damage. Potential GI complications include intussusception (usually ileoileal),
bowel infarction, bowel perforation, hydrops of the gallbladder, pancreatitis, and massive GI
bleeding.
Kidney damage related to HSP is the primary cause of morbidity and mortality. As many as 15% of
patients may have long-term renal insufficiency, but no more than 1-2% will have ESRD. As many as
20% of children who have HSP and are treated in specialized centers require hemodialysis. The
renal prognosis appears to be worse in adults than in children (in particular, those aged ≤6 years).
Bloody stools
Rash persistence
However, patients with a normal urinalysis at 6 months and without previous renal involvement
have not gone on to develop kidney problems. [35]
Pregnant women who had HSP during childhood appear to be at increased risk for developing
hypertension and proteinuria during pregnancy. [36]
Long-term prognosis of HSP nephritis is determined by the development of CKD which sometimes
is difficult to predict from the initial clinical and histological presentation. CKD can develop long-
term even after apparent complete recovery from HSP-nephritis. [84]
Patient Education
Patients should be informed that the disease is most likely to resolve with few residual adverse
effects but that relapses are possible. The clinician should explain that severe kidney involvement
is rare but that if it does occur, aggressive treatment may be required.
Clinical Presentation