REVIEW FOR THE GENERALIST :
Henoch-Schönlein purpura IN CHILDREN
Isabelle Koné-Paut*, Marseilles, France
Correspondence to:
Isabelle Kone-Paut,
Service de Pédiatrie, Hôpital NORD, chemin des Bourrelys, 13915 Marseille
cedex 20. FRANCE
TEL : +33
491968750
FAX :+33 491968748
E-mail : ikonepau@ap-hm.fr
Henoch-Schönlein purpura [HSP],
also known as anaphylactoid or allergic purpura, is a small vessels vasculitis
most frequent in children between 2 and 8 years with male predominance
[male:female 2:1]. The observation of cases in older children and young adults
is not unusual. In
HSP is a well-defined clinical entity that includes
palpable non-thrombocytopenic purpura, subcutaneous edema, crampy abdominal
pain, and arthralgia first described by Schönlein in 1837 and then
by Henoch in 1874. [3-4] Infiltration of IgA in the involved tissues is
classic. Four criteria for the diagnosis were selected by the American College
of Rheumatology in 1990: age less or equal to 20 years at disease onset,
palpable purpura, acute abdominal pain and biopsy showing granulocytes in the
walls of small arteries and venules. [5] The presence of 2 or more was
necessary to distinguish HSP from other vasculitis diseases. HSP may be
considered a primary disease or a secondary syndrome as the main clinical features
are occasionally associated with other inflammatory diseases such as familial
Mediterranean fever [FMF], polyarteritis nodosa [PAN] and Behçets disease. [6]
The course is relapsing but usually benign with most patients remaining an
outpatient. However, several serious visceral manifestations (and rarely renal)
may occasionally require hospitalization. [7]
Pathogenesis
The etiology
of HSP is unknown. Triggering factors, such as viral or bacterial infection or drug
exposure, are associated with the illness in 50% of cases. [8] Group A streptococcus is well known to be
associated with HSP [Allen DM, Diamond LK, Howell, DA.] Other reports of
infectious associations with HSP include
staphylococcal infections, various viruses (varicella, hepatitis,
rubella and rubeola, parvovirus), Mycoplasma pneumoniae, and some enteric
organisms. [9-15]
Several
genetic factors could influence the pathogenesis of this disease. For example,
an inherited glycosylation abnormality of IgA1 favors IgA deposition in small
vessels. Also, a partial complement C4 deficiency (especially C4B allele
deficiency) may also have a role [16-17]. Moreover, an increased frequency of
HSP in FMF patients or individuals carrying MEFV mutations suggests that the
MEFV gene may have a role in triggering neutrophils activation and
inflammation. [18]
The
pathogenetic disease mechanisms appear to be variable and do not yet fit into
any one coherent model. Many immunologic findings have been noted, the most important
being the role of IgA. Deposits of IgA are well known to be present in HSP
lesions in the skin, vessel walls, and renal mesangium suggesting that IgA
immune complexes are crucial to the disease pathology. Serum IgA can be
elevated in active HSP as well. HSP is associated with abnormalities of IgA1
and not IgA2. [19-21] Tumor necrosis factor-alpha levels are elevated in the
acute phase of the illness compared to the convalescent phase. [22] Apoptosis
was significantly increased in active HSP compared to when the HSP had
resolved. [23] IL-8, an endothelial interleukin, appears to be increased in the
sera of HSP children with active HSP, and may account for the perivascular
neutrophil infiltration and leucocytosis. [24] Serum nitric oxide and urinary nitrate
excretion were noted to be increased in HSP, suggesting a role for nitric
oxide. [25]
The pathogenesis of IgA nephritis
might be an increased production of abnormally glycosylated IgA1 which is not
sufficiently cleared by the liver, accumulating in the circulation and
depositing in the vessel walls and the glomerular mesangium. Indeed, the
characteristic finding on biopsy is IgA1 deposition forming crescents on
electronic microscopy in the glomerular mesangium. Other deposits contain
fibrinogen and complement C3. [26]
Clinical manifestations
The disease usually starts in
healthy children in winter after a mild upper respiratory tract infection or
after drug exposure. [27-28] Palpable vasculitic purpura (Figure 1) is the
predominant feature appearing usually below the waist and occasionally on the
face, over the extensor surface of the arms and over areas of pressure. Lesions
appear in-group and change from red to purple in a course of three to six days,
do not migrate, and sometimes ulcerate. The lesions appear to appear or worsen
around areas of pressure (belts, blood pressure cuffs).
Figure 1. The typical Henoch-Schönlein purpura rash
with palpable purpura on an older child’s lower extremities.
Other initial skin rashes of HSP may be
urticarial or macular but all skin lesions eventually become petechial,
purpuric, or ecchymotic over hours to days. Edema is commonly seen the
beginning of the disease and migrate over the periarticular area, the face
(Figure 2), the ears, the dorsum of hands and feet, and the external genitalia.
The edema is especially seen in children five years and younger who develop
HSP. Characteristic cutaneous findings are usually present at disease onset and
may come and go in different crops of rash over the duration of the initial HSP
episode. [29-30]
Figure 2.
Periorbital edema as commonly seen in young children with Henoch-Schönlein purpura
Occasionally, however, the rash is delayed by a few days which may delay
diagnosis and be problematic in the presence of severe abdominal pain. Children
may have abdominal surgery for an acute abdomen or appendicitis and then the
rash appears post-operatively. [3-4,19] There are some clinicians who believe
that the diagnosis of HSP can be made in a child when a characteristic
arthritis, GI involvement, and/or renal disease are present without the HSP
rash, though this contention is anecdotal and controversial.
Articular symptoms are present in 50-80% of
patients. These children may have painful swelling of and around large joints
(knees, ankles, elbows and wrists) with accompanying periarticular edema. [29-31]
Gastrointestinal manifestations are
the result of small vessel vasculitis producing parietal edema and hyperemia.
Mild to severe, diffuse or localized, crampy intermittent abdominal pain [bowel
angina] is classic for HSP and is seen in 2/3 of cases with occult hemorrhages.
[31] The enteropathy involves primarily the duodenum and the small intestine
with reddish mucosal thickening and petechiae at esogastroscopy. When severe
mesenteric vasculitis is present, it is clear that ulcerating lesions and
hematoma-like protrusions increase the risk for mesenteric infarction, massive
bleeding, and perforation which fortunately occur very infrequently (Figure 3).
[32-34] The parietal inflammation and mesenteric adenitis may favor bowel
ileo-ileal intussusception in 5% of cases; ileo-colic or ileocoecal ones are
unusual. The decision of surgical intervention is difficult in this very acute
situation when spontaneous reduction may also occur. [33-34] Hemorrhagic
pancreatitis, watery diarrhea and malabsorption are occasionally seen. [34-35]
Fistulae are a rare complication. [36]
Figure 3. Severe gastrointestinal vasculitis
in a child with Henoch-Schönlein purpura . The small intestinal loops are
edematous, inflamed, and hemorrhagic.
Renal manifestations are observed
in 20 to 50% of cases and are generally limited to isolated microscopic
hematuria (rarely macroscopic). [18,37] Severe involvement occurs in 10% of
patients and is suggested by flank pain, varying degrees of proteinuria, or
nephrotic syndrome. Hypertension and renal failure are exceptional (<1% of
HSP cases). Patients with nephrotic range proteinuria, elevated serum
creatinine, and with crescents on more than 50% of glomeruli have the worst
prognosis, even if remissions can be observed in these situations. The
prognosis of patients with isolated hematuria is usually good with spontaneous
remission. [39-41]
Unusual manifestations are
important to know because some of them may be life-threatening, e.g.,
neurologic involvement. Severe neurological manifestations occur occasionally
secondary to cerebral vasculitis and/or hemorrhage, hypertension or hydroelectrolytic
disorder present with headaches, seizures, and behavior changes. [42] Other
unusual involvements include optic neuritis, pulmonary and meningeal
hemorrhages, and pericarditis with tamponade, myocarditis, parotiditis, and
orchitis. [12,21,29-30] Also, involvement of the glans penis as well as
priaprism have been noted. (21,30). Antiphospholipid syndrome with clots
in children with HSP has been reported
as well. [43-45]
Clinical
criteria for diagnosis include (ACR criteria)
Laboratory investigations
The diagnosis of HSP is based on
clinical features. A few laboratory tests are necessary for routine evaluation
[21,30] and may show mild and non-specific inflammatory changes. The white
blood cell and platlet counts may be elevated, sedimentation rate mildly
increased [typically <50mm/h], C-reactive protein mildly elevated, and the
immunoglobulins may be increased, especially IgA. Unlike many other vasculitis
syndromes, the sedimentation rate and CRP may be normal and if elevated, are
often only mildly abnormal [21,30]. Circulating immune complexes containing IgA
and cryoglobulins may be present. [46-47] Antinuclear antibodies and rheumatoid
factor are absent. It is controversial whether IgA and IgG ANCA’s are present
in HSP. [48-49]
Several hemostatic alterations,
including high serum levels of Von Willebrand factor and decreased factor XIII
activity, probably reflect the magnitude of endothelial cell dysfunction and
alteration. Indeed, these parameters have been demonstrated to be modified in
correlation with disease activity and severity. [50]
Microscopic hematuria is often
present at the beginning of HSP but usually resolves in the first month to two
months after onset of the HSP. Only 2% of all HSP patients go on to nephrotic
range proteinuria or renal insufficiency. [38-41] It may be best to monitor for
urinalysis abnormalities for four to six months before referral to a
nephrologist unless the renal abnormalities progress significantly. Even if the
urinalyses during the acute HSP episode are normal, the pediatrician should
consider repeating a urinalysis approximately every two-three months for a year
after the HSP episode to detect the occasional delayed onset of nephritis.
[12,21,29-30]
In children with severe abdominal
pain, testing for blood in the stool may document gastrointestinal bleeding.
[21,30,32] Abdominal ultrasounds are very useful in detecting bowel vasculitis
(thumbprinting in the bowel wall) and screening for further complications of
the gastrointestinal involvement. Repeated exams are often needed for early
detection of bowel intussusception. [51-52] Contrast enema studies may diagnose
and treat intussusception that involves the large intestine. [32-33] Abdominal
computerized tomography may also be useful in difficult cases. [53] Scrotal
ultrasonography may be helpful in differentiating the orchitis of HSP from
testicular torsion. [54]
Renal
biopsy is required only in children with persistent or severe renal
abnormalities. Skin biopsy is rarely necessary in children, except if the diagnosis
is uncertain and the presentation atypical. The nephritis is usually focal and
segmental. Four subtypes of glomeruloparthy have been reported: mesangial,
focal, and segmental, with or without endocapillary proliferation or
extracapillary proliferation. [35]
Treatment
The treatment of HSP is mostly supportive due to the
self-limited nature of HSP in most children. Analgesics such as acetaminophen
can be used for pain relief. Non-steroidal antiinflammatory drugs are more
risky due to the concern of intestinal bleeding. Most children can be managed
at home by maintaining good hydration, treating with analgesics, and a careful,
bland diet. [21,29-30] It is important to educate the parents about the
relapsing, remitting nature of HSP. Otherwise, parents will possibly be
concerned with every change in the HSP disease course, such as each new crop of
rash, each change in the arthritis, each abdominal pain. Parents should be told
that the HSP may last from 10 days to 6 weeks and be very unpredictable, with crops
of rash coming intermittently, and with bouts of arthritis and GI problems
possible at any time [12,21,29-30].
If the child needs to be admitted to the hospital, it
is usually for severe, unremitting crampy abdominal pain, with or without
dehydration. The child is made NPO and given IV fluids. In a severe abdominal
crisis, prolonged NPO status may require early enteral nutrition. The
administration of antiulcerative agents may decrease intestinal bleeding
[21,29,32-34]. Though controversial, a short course [7 days] of intravenous
methyl-prednisolone or oral prednisone has been reported to be effective for
the control of severe GI and renal manifestations in mostly anecdoctal and
uncontrolled series. [32,55-58] In particular, use of corticosteroids for the
abdominal pain during hospitalizations has been shown to shorten hospital stays
[32] However, the advantage of this therapy compared to exclusive supportive
treatment has not been demonstrated. Though the numbers of patients were small
(20 per group), the one randomized study using oral prednisone in early HSP
failed to show any statistical differences in the incidence of gastrointestinal
or renal complications. [59] Moreover, the safety of steroïd treatment is not
guaranteed, especially because patients with HSP are at high risk of
gastrointestinal bleeding and secondary infections. If possible, the use of
morphine and other narcotic medications for pain relief should be avoided as
they may mask the evolution of significant GI complications. If these drugs
must be used, the clinician must perform a thorough abdominal follow-up
including repeated echography to rule out bowel intussusception or perforation.
There are several reports on the effectiveness of factor XIII infusion [15U/kg]
in cases of severe abdominal angina or bleeding resistant to steroid therapy
[60-61].
Renal
involvement that requires aggressive therapy is infrequent and represents less
than 2% of all children with HSP [37-41]. These children need to be managed in
specialized pediatric centers. The best treatment of the severe nephritis of
HSP with or without nephrotic range proteinuria has not been delineated by
evidence-based medical trials. If treatment is begun, the use of oral
prednisone or IV methylprednisolone in addition to immunosuppressive agents
such as azathioprine, cyclosporine, or cyclophosphamide is the classical
therapeutic approach [62-64] Urokinase has been used as an adjunct to the
corticosteroid or immunosuppressive therapy with some success.[65] Plasma
exchanges and immunoglobulin infusions have been tried in very exceptional
life-threatening forms of HSP. [66-67] Further clinical trials are necessary to
test the use of these different regimens for their safety and efficacy for HSP
renal involvement. Other therapies such as methotrexate, dapsone and
thalidomide are being currently utilized for their beneficial effects on
cutaneous, GI and articular manifestations of recurrent or chronic non-renal
HSP. [68-70]
Prognosis and outcome
HSP remains a benign disease in the majority of cases.
,The severity of clinical features varies widely between children. The observed
severity of the HSP may be affected by the referral bias: the pediatrician may
see the milder cases, and the specialist the more severe cases with unusual
manifestations. As noted earlier, the
usual duration is from 10 days to 6 weeks with frequent relapses during the
course. Late and repeated relapses up to
2 or more years after the onset of HSP have also been reported [12,21,29]. The morbidity of HSP is related to GI
and renal manifestations. An older age at onset, presence of severe abdominal
pain with intestinal bleeding, persistent purpura over 1 month, coagulation
factor XIII activity <80% and treatment with factor XIII concentrate have
been associated with a higher risk of severe renal involvement and significant
proteinuria. [18,41]
The occurrence of severe renal manifestation is about
2% of all patients with HSP, but among those with severe nephritis, 20% will
eventually require hemodialysis especially those with more than 80% of
glomeruli involved by crescents. Mortality is rare, but if it occurs is due to
diffuse vasculitis or secondary infection
[18,38-41]
Henoch Schönlein purpura as a manifestation of other diseases
HSP associated with Familial
Mediterranean Fever
HSP occurs in 5-10% of patients with Familial
Mediterranean Fever [FMF] and in some cases may be the initial manifestation of
the disease. HSP and FMF share common clinical features. In a recent study of
Gershoni-Baruch [71], 10% of
patients with HSP among a high risk population for FMF, were found with two
mutated MEFV alleles [genetic FMF]. This incidence exceeded the incidence of
this gene in a randomly selected cohort from the general Israeli population
(1-2%). The MEFV gene could be a link between HSP and FMF because its
corresponding protein, pyrin/marenostrin, presumably has a role in the down
regulation of neutrophil activation and apoptosis. To date, the consequence of
coexisting MEFV mutations and HSP is unknown in terms of prognosis and outcome,
especially for renal disease. [71]
Acute hemorrhagic edema of infancy, or Seidlmayer
disease, is a leukocytoclastic vasculitis proper of infants and children,
characterized by erythemous edema and purpuric lesions involving the face and
the extremities. The disease is self-limited without visceral involvement and
the course is benign. The acuteness of skin lesions contrast with the good
general condition of the patient. [72]
SUMMARY
HSP is a relatively common arthritis disease seen in a
typical pediatric practice in a developed country. It is generally easy to
recognize due to its impressive petechial and purpuric rash. The difficulty is
in helping the child and family through what is often an up and down,
relapsing, remitting course that most parents do not expect, and children and
parents do not enjoy. Treatment is supportive with only occasional use of
corticosteroids for the gastrointestinal complications. Vigilance is needed to
watch for significant GI and/or renal complications. Evidence-based medicine in
the pathogenesis and treatment of HSP remains limited and most treatment
remains conservative and experience-based.
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