Ulcerated lesions as a risk factor for Henoch-Schonlein purpura nephritis

Introduction

Henoch-Schonlein Purpura (HSP) is the commonest vasculitis in childhood with an incidence between 3-27 per 100,000 child population, with an increased prevalence in males.^1-2 It commonly presents between four and six years of age and is usually a self-limiting disease with rapid resolution of extra-renal symptoms. The long term prognosis correlates with renal involvement which involves about a third of cases. Chronic renal disease is estimated to occur in 1.8% of children and 10.4% of adults.⁴ Reports have shown a difference in presentation between childhood-onset and adolescent-onset HSP, with the latter having increased incidence of musculoskeletal symptoms and a marginally increased risk of progression to end-stage kidney disease.³Korean and Japanese individuals also seem to have a higher prevalence of HSP as compared to other races.⁴There are a number of rare complications that can be associated with HSP including orchitis, cerebral and cerebellar haemorrhage and pulmonary haemorrhage.

Microscopically, the condition is characterised by the deposition of IgA immune complexes in the organ vasculature, hence its new nomenclature in the Chapel Hill classification, IgA vasculitis.^4,5,6 Common viral infections often precede the condition as demonstrated by a higher incidence in the winter months. Predisposed individuals have abnormal glycosylation sites on IgA1 antibodies. Viral upper respiratory tract infections and gastrointestinal infections lead to increased production of these abnormal IgA1 antibodies and these are recognised by circulating anti-glycan antibodies, leading to the formation of the circulating immune complexes with deposition in the organ vasculature.⁷ Laboratory tests at presentation commonly show raised inflammatory markers and IgA levels and a variable degree of haematuria and/or proteinuria.⁸

Patients and Methods

The clinical notes of all patients aged less than 16 years (otherwise passed to adults) admitted with HSP to Mater Dei Hospital between January 2008 and January 2016 were reviewed. Data included demographics, clinical findings at presentation, laboratory test results and out-patient follow-up findings. All data was anonymised in a database.

We graded the severity of the rash as either mild, that is, a fine purpuric rash (Figure 1), or severe, that is, palpable purpura with or without ulcerated lesions (Figures 2 and 3).

Figure 1

Showing mild purpura

Figure 2

Showing more severe palpable purpura

Figure 3

showing severe purpura with blistering and ulcerated lesions

Blood tests were interpreted according to normal ranges for the patient’s age and sex. HSP nephritis was monitored using urine dipstick and formal urinalysis and microscopy.  Haematuria was defined as 1+ to 3+ on dipstick whilst proteinuria was defined as 1+ to 3+ or greater than 150mg/L on dipstick on three consecutive days. Proteinuria was quantified using the urine albumin: urine creatinine ratio. Nephrotic range proteinuria was defined as a 24hr urine protein of more than 40mg/m²/hr whilst nephritic-nephrotic syndrome was defined as more than 200 red blood cells on urine analysis and 24hr urine protein of more than 40mg/m²/hr and the presence of hypertension and/or biochemical findings of renal dysfunction. Blood pressure values were compared to age, sex and height-matched percentile values and hypertension was considered if the measured systolic and diastolic values exceeded the 95^th percentile according to the Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents.¹⁵Recurrence of HSP was considered if a patient who was symptom-free for at least a month presented with fresh signs and/or symptoms related to HSP.

Statistical analyses were performed using Microsoft Excel^® 2010. Fisher Exact test was used to study the relationship between the severity of the skin rash and the presence of HSP nephritis.

Results

Findings at presentation

96 children met the inclusion criteria. The male to female ratio was 1.35:1 with a mean age of 6.4 years (interquartile range 3.5 years). 65 cases (67.7%) presented in the months between September and March. A preceding infection, a mean of 2.8 weeks previously, was noted in 85 cases (88.5%), the majority being upper respiratory tract infections (82%).Table 1 summarises the clinical findings at first presentation.

95 children (99%) presented with the typical purpuric rash; one child presented with abdominal pain first, with the rash appearing within 3 days. Most children had a fine purpuric rash involving the lower limbs. 7 children (7.3%) presented with palpable purpura whilst another 7 children (7.3%) had ulcerated lesions. The mean age of children presenting with mild purpura was 6.9 ± 2.3 years whilst the mean age of children presenting with severe purpura was 5.4 ±1.38 years p=0.0202 (CI 0.2392 - 2.76).

35 children (36.5%) had evidence of renal involvement within the first week of presentation: 19 (19.8%) had proteinuria and 13 (13.5%) had haematuria. Three children (3.1%) had a combination of haematuria ± proteinuria and hypertension at presentation. The clinical findings of the latter are shown in Table 2.  

One child with nephritic-nephrotic presentation underwent a renal biopsy. The histological findings were consistent with IgA nephropathy.

Two patients experienced serious medical complications. One child developed nephrotic syndrome with heavy proteinuria and hypoalbuminaemia resulting in significant fluid overload with pulmonary oedema. Another patient developed severe abdominal pain and was found to have intussusception, requiring air reduction. Other rare complications such as orchitis, cerebral and cerebellar haemorrhage and pulmonary haemorrhage were not encountered in our study.

Findings on follow-up

93 children (96.9%) were followed-up in clinic at least once; the rest were lost to follow-up. 84 cases (87.5%) showed complete resolution of signs and symptoms within 2 months from presentation and were subsequently discharged by 6 months from the first presentation. Rash recurrence occurred in 12 cases (12.5%), with the majority (75%) of these recurrences occurring within 2 months from the initial presentation with no easily recognisable trigger.

Interestingly, two of the three patients presenting with nephritis and hypertension (Table 2) had a recurrence of HSP and this was associated with worsening of the kidney disease, as demonstrated in Table 3.

Table 4 and Table 5 represent a summary of the clinical findings that were observed in this study with Table 5 comparing the severity of the rash compared to the renal and extra-renal involvement.

Fisher Exact Test was used to correlate the severity of the rash with the incidence of renal involvement and this revealed a statistically significant association between the two; p=0.008, odds ratio is 0.21 (0.06-0.72) and a relative risk of 0.48 (0.39-0.59) with a severe, ulcerating rash more likely to be associated with nephritis. (Table 5) 

In children presenting with proteinuria and/or haematuria there was complete resolution in 47% of cases by 1 year and in 80% of cases by three years. Two cases developed proteinuria during follow-up rather than during the initial presentation with HSP. These occurred within the first four months from presentation and both required a follow-up of over one year for the proteinuria to disappear.

Discussion

This is the first study that characterises the course of HSP in the Maltese paediatric population. The prevalence of HSP is higher in males with a male to female ratio of 1.35:1 which is slightly less than that of 1.8:1 quoted in the literature.⁹ The mean age at presentation is similar to that quoted in the literature. The presenting feature of the disease is the ubiquitous rash with a variable distribution and severity. The majority of the cases (79%) had the typical HSP rash presenting in the lower limbs with only a minority having the upper limbs also affected, or having a generalised rash. Childhood HSP does tend to affect the lower limbs whilst adolescent or adult onset HSP tends to affect mainly the upper extremities more commonly for reasons unknown.³

Gastrointestinal involvement, joint involvement and age over 8 years have been shown to be independent risk factors for developing nephritis, increasing the risk 2-3 fold.^3,16 From our study, it is apparent that the severity of the skin rash is significantly associated with the development of nephritis (p=0.008). We also noted that younger children developed a more severe rash than their older counterparts (p=0.02).

HSP associated nephritis (HSN) occurs in about a third of cases and determines the long-term prognosis. At presentation, 36% of cases in our study showed a degree of proteinuria and/or haematuria to suggest HSN and this persisted for at least 1 year of follow-up in half of the cases. A minority (3.1%) had proteinuria, haematuria and hypertension and two cases required immunosuppressive medication and ACE inhibition. The importance of monitoring the urine for proteinuria/haematuria and the blood pressure cannot be overemphasised and recommendations for long-term follow-up have been put forward. HSN tends to develop within the first 4 weeks after the onset of HSP and at most, within the first 3 months.¹⁶The presence of nephritis at presentation increases the likelihood of developing chronic renal disease.¹⁶ A kidney biopsy may be warranted in selected cases  together with consideration of  immune suppressive therapy.¹¹ The use of ACE inhibitors and control of hypertension has been shown to be renoprotective.^12-13The use of corticosteroids and immunosuppressive therapy is mainly limited to cases with severe nephritis and should be considered after kidney biopsy and consideration of the updated Oxford classification score which is useful in predicting long-term outcomes of HSP nephritis.^13-14

HSP followed a mild course in the majority of the cases with complete recovery on follow-up. Most of these recoveries occurred in the first 3 months with the rash typically fading within the first 50 days. The recurrence rate was 12.5% and occurred within the first 2 months from the initial presentation but could take up to 5 months. No obvious trigger was identifiable for the recurrence in the majority of cases.

Conclusions

This study demonstrated that HSP in the Maltese paediatric population has similar presenting and long term clinical characteristics to that of other European populations.^9,10 A limitation of the study was that some mild cases of HSP presentations or relapses may have been treated in the community and would not have been included. Risk factors for developing nephritis are described as an older age at presentation (greater than 8 years), the presence of abdominal pain and recurrence of HSP. We have shown that increasing severity of the purpuric rash at presentation can also increase the likelihood of developing nephritis.

In most cases of HSP, the prognosis for complete remission is good and only a minority develop persistent renal disease requiring specialist management.

References

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