Seizures, renal failure and acute respiratory failure: not your typical case of Henoch-Schonlein purpura

Abstract

A 30-year-old Caucasian woman with no prior medical history presented with pedal oedema, arthralgias and abdominal pain with diarrhoea, following a respiratory infection. She had mild abdominal tenderness along with a purpuric rash on the extremities and was anaemic. Following initial workup for anaemia and rash, her condition deteriorated with renal impairment, respiratory failure and seizures necessitating ventilatory support, dialysis and steroids. Serologies were negative, and skin biopsy showed leucocytoclastic vasculitis without vascular IgA deposition, and renal biopsy showed subendothelial, mesangial deposits of IgA with C3 indicative of Henoch-Schonlein purpura (HSP). She was treated with steroids, haemodialysis and on 6-month follow-up recovered renal function. We present the case to illustrate that HSP, though rare in adults, can present with multiorgan failure, with renal, pulmonary and central nervous system involvement, and the need for early diagnosis and prompt treatment for rapid clinical recovery.

Background

Henoch-Schonlein purpura (HSP) is an autoimmune, granulomatous, small vessel systemic vasculitis with a prominent cutaneous component and can involve multiple organ systems.¹ The clinical course is generally benign with complete recovery within weeks to months. HSP is characterised by a combination of four findings: non-thrombocytopenic palpable purpura, gastrointestinal (GI) and renal involvement, arthralgia with or without arthritis and rarely the involvement of other organ systems including the central nervous system (CNS), genitourinary tract and lungs.^2–4 HSP is rare in the adult population, among whom incidence varies between 3.4 and 14.3 per million.⁵ We present a 30-year-old previously healthy Caucasian woman presented with purpuric rash, crampy abdominal pain, diffuse joint pains and her course complicated with seizures, acute respiratory distress syndrome (ARDS) and rapidly progressive glomerulonephritis (RPGN) requiring haemodialysis (HD). Following a colonoscopy, skin and renal biopsy, the clinical presentation and pathological findings were consistent with HSP, a primary childhood vasculitis.

Case presentation

A 30-year-old Caucasian woman with no prior medical history presented to an outside facility with extremities swelling, joint pains and crampy diffuse abdominal pain with a loose stool for 4 days. One week before the presentation, she reported an episode of upper respiratory tract infection. On presentation, she was afebrile, distressed with abdominal pain and had a purpuric, non-blanchable rash on the extremities (figure 1). Her abdomen was mildly tender on palpation. Laboratory workup showed, low haemoglobin of 84 g/L (reference: 129–166 g/L), high white cell count of 19.4×10⁹ /L (reference: 4.1–10.9 ×10⁹/L) with no bandaemia and a normal chemistry panel with a serum creatinine of 0.69 mg/dL. Urine analysis (UA) and the pregnancy test were negative. Coagulation studies were normal. CT of abdomen and pelvis revealed small bowel wall thickening with mesenteric lymphadenopathy. A colonoscopy showed scarring of the ileocaecal valve and ulcerations in transverse colon and was biopsied. Over the next 5 days, the patient’s renal function rapidly deteriorated and developed proteinuria and microscopic haematuria on UA. Given clinical deterioration, the patient was transferred to our institution. A dermatology consult was requested. Additional testing was done for anti-neutrophil antibody (ANA), anti-ds DNA, Anti-Neutrophil cytoplasmic antibody (ANCA), anti-Smith, anti-Ribonucleoprotein (anti-RNP), rheumatoid factor, complement 3 and 4 (C3, C4), hepatitis serologies, haemolysis screen, which were all normal. Echocardiogram showed normal ejection fraction and an absence of endocarditis. Given rapid deterioration, a biopsy from the skin and kidney was obtained, and the patient was started on empiric high-dose corticosteroids. At this point, the patient developed dyspnoea and seizures requiring ventilatory support.

Figure 1.

Purpuric, non-blanchable rash located on her lower (left dorsum of the foot) and upper extremities (right hand).

Further work included a CT head, which was benign. MRI of the brain was indicative of non-specific foci of signal abnormality in the white matter. Electroencephalogram (EEG) was significant for triphasic waves suggestive of metabolic imbalance. Imaging was indicative of bilateral diffuse ground-glass opacities with moderate bilateral pleural effusions. Further testing with the respiratory viral panel, monospot, and blood and stool cultures was negative. Anti-streptolysin O (ASO) titer was at 508 IU (reference: 0–200 IU). Twenty-four-hour urine protein was 1.5 g.

As the renal function deteriorated, the patient was started on HD and continued steroids. She was started on plasmapheresis (therapeutic plasmapheresis) empirically given high clinical suspicion for the pulmonary-renal syndrome. Bronchoscopy was not performed by the pulmonary team given absence of haemoptysis or bloody endotracheal lavage or aspirations.

An initial colonic biopsy was inconclusive. Skin biopsy showed leucocytoclastic vasculitis without vascular IgA deposition (figure 2). Renal biopsy on light microscopy (figure 3) showed diffuse cellular proliferation and exudation of inflammatory cells. Subendothelial deposits in glomerular capillaries and widespread interstitial oedema were observed. However, no vasculitic changes were evident. Immunofluorescence microscopy (figure 4) demonstrated widespread to diffuse mesangial and subendothelial glomerular basement membrane (GBM) deposits of IgA along with C3, kappa and lambda light chains. C1Q was trace and C4 negative. Glomerulus on electron microscopy (figure 5) significantly expanded with subendothelial deposits, fibrin thrombi in several capillary loops. No subepithelial deposits seen, and epithelial foot processes were intact. Mesangial regions contained electron-dense deposits and inflammatory cells. Mesangial cells were swollen and somewhat hypertrophied. Overall, the findings were indicative of severe diffuse glomerulonephritis with the pattern of electron dense deposits consistent with HSP. Patient’s clinical condition progressively improved over the next few days and was extubated successfully, but remained dialysis dependent. She was discharged home on a 3-month course of oral prednisone.

Figure 2.

Skin biopsy—leucocytoclastic vasculitis without vascular IgA deposition.

Figure 3.

Renal biopsy: light microscopy—diffuse cellular proliferation and exudation of inflammatory cells. Subendothelial deposits in glomerular capillaries and widespread interstitial oedema.

Figure 4.

Renal biopsy: immunofluorescence microscopy—subendothelial and mesangial deposits of IgA.

Figure 5.

Renal biopsy: electron microscopy—glomeruli expanded with subendothelial deposits, fibrin thrombi in several capillary loops.

Investigations

• Colonoscopy with biopsy.

• Skin and renal biopsy.

• CT of the abdomen, chest and head.

• MRI of the brain.

• EEG.

Differential diagnosis

Her presentation and initial workup pointed to a possible systemic vasculitis versus infection-related acute GI disease in the absence of renal impairment and negative UA. Following colonoscopy and a skin biopsy, her clinical condition deteriorated with new clinical laboratory findings, and the differential was broadened to include systemic vasculitis-mediated RPGN from ANCA, anti-GBM, cryoglobulinemic vasculitis, IgA nephritis, HSP, systemic lupus erythaematosus with renal, CNS involvement and drug-mediated vasculitis.⁶

Treatment

• High-dose intravenous and oral steroids.

• HD.

• Anti-seizure medications.

• Ventilatory support.

Outcome and follow-up

The patient had a rapid clinical recovery with the administration of the high-dose steroids and remained dialysis dependent. She was discharged to a local rehabilitation centre. During her 6-month clinic follow-up, she remained asymptomatic with renal recovery and dialysis independent.

Discussion

The annual incidence of HSP ranges from 6.3 to 70.3 per 100 000 in children less than 17 years of age. Incidence peaks between four and 6 years, as 90% of cases are seen before ten years of age. HSP is rare in adults with incidence between 3.4 and 14.3 per million. As HSP is known to be self-limited, the true incidence may be under-reported.⁴ The clinical course is generally benign with complete recovery taking place within several weeks or months. The aetiology of HSP has not been elucidated, but the condition is thought to be associated with preceding bacterial, viral or parasitic infections. Other potential causes include medications, malignancies (prostate cancer, non-small cell lung cancer, oesophageal, breast, gastric and haematological malignancies), vaccinations (measles, mumps and rubella, pneumococcal, influenza, meningococcal and hepatitis B), alpha-1-antitrypsin deficiency and familial Mediterranean fever.^{2 7} The pathophysiology of HSP revolves around the formation of antigen and antibody complexes, mostly IgA (specifically IgA1), which is generated secondary to bacterial and viral infections, drug reactions, vaccinations and a variety of autoimmune mechanisms.⁸ Bacterial infections linked to HSP include group A beta-hemolytic Streptococci, Staphylococcus aureus, Helicobacter pyloriand Mycoplasma. Viral aetiologies include hepatitis A, B and E, herpes simplex, human parvovirus B19, and varicella, adenovirus, Cytomegalovirus (CMV) and HIV. Toxocara Canis is a parasitic infection linked to HSP.^{2 8} Peru et al found an increased frequency of human leucocyte antigen (HLA) HLA-A2, A11 and B55 alleles in paediatric HSP patients and miscarrying of HLA-A1, B49 and B50 were found to be risk factors for HSP.⁹ The history of recent upper respiratory infection coupled with an elevated ASO titer in the present case points to Streptococcus as the most likely causal factor in precipitating HSP. ASO titers are often evaluated and are elevated in cases of HSP. In one study performed by Motoyama et al., ASO titers were elevated in 23% of cases of HSP.¹⁰ Of note, as in the present case, serum complement levels are often normal in cases of HSP.¹¹

HSP is characterised by a combination of four findings: non-thrombocytopenic palpable purpura, GI and renal involvement, arthritis or arthralgias and rarely the involvement of other organ systems including the CNS, genitourinary tractand lungs.^{3 4} Involvement of the skin is the most prevalent clinical manifestation, though some patients present with involvement of additional organ systems, as was seen in the present case. In 2010, the European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society proposed criteria for the diagnosis and included, apart from the above, the need for leucocytoclastic vasculitis with IgA deposits on the skin or renal biopsy.¹²

Cutaneous findings include the characteristic non-thrombocytopenic rash which tends to begin as an erythaematous rash. It may then evolve into macular wheels and subsequently into non-blanching palpable purpura with petechiae and ecchymoses. The presenting cutaneous symptom is palpable purpura in 50% of instances, which appear in clusters and may last up to 10 days. The lesions are characteristically symmetrical and tend to involve dependent areas such as the lower extremities and buttocks. Lesions can, however, be seen in the upper extremities, trunk and face. Regarding the histopathology of these lesions, leucocytoclastic vasculitischaracterised by neutrophilic infiltration and nuclear fragmentation involving the upper and middle layers are seen. IgA deposition can be visualised on immunofluorescence. Nonpitting oedema can be observed in the extremities, back and scalp.¹³ While histopathologic findings of the skin biopsy in the present case were inconclusive, the clinical appearance and distribution of lesions in the absence of thrombocytopaenia was concerning for systemic vasculitis.

Colicky abdominal pain enervated by eating is the most common GI symptom reported in HSP. The symptoms are caused by mesenteric vasculitis. Intussusception, massive GI bleeding,¹⁴ perforation of the intestines, ischaemic necrosis of the bowel wall, acute acalculous cholecystitis, haemorrhagic ascites with serositis, biliary cirrhosis or pancreatitis can be seen, though less commonly. Skin findings usually precede GI manifestations. The duodenum is more commonly involved in the small intestine, while the rectum and ileum are more commonly implicated on colonoscopy.^{3 13} In the present case, GI involvement of HSP manifested as crampy diffuse abdominal pain, loose stool and colonoscopy showed scarring of the ileocaecal valve and ulcerations in the transverse colon.

HSP involvement of the joints is noted in as much as two-thirds of cases and can be the presenting symptom in about one-fourth of patients. Characteristically, nondestructive, nonmigratory polyarthralgias occur symmetrically and are generally above the knees and ankles.¹³ In the present case, limb swelling and polyarthralgias were components of the presenting symptomatology, as joint involvement of HSP is more commonly seen in adults than in children.¹³

Severe renal involvement is one of the greater threats to morbidity and mortality in cases of HSP. HSP-related vasculitis can lead to chronic renal failure.¹⁵ The most prevalent renal manifestation is haematuria, which can be microscopic or gross. While the majority of cases of HSP nephritis are self-limited, about 5% of cases evolve into chronic end-stage renal disease at 5 years.¹³ One major feature seen in HSP-associated glomerulonephritis is granular deposition of IgA,¹² as was observed in the present case. The renal histological findings in HSP are identical to those in IgA nephropathy, suggesting that the two disorders may have similar pathogenesis. While the pathogenesis of HSP nephritis has yet to be fully unveiled, recent studies have shown that high levels of galactose-deficient IgA1 (Gd-IgA1) has been found in children with HSP nephritis, and not in HSP-afflicted patients who did not have nephritis. Gd-IgA1 is recognised by anti-glycan antibodies, subsequently leading to the development of large molecular immune complexes and their deposition in renal mesangium may contribute to glomerular inflammation.¹⁶ The persistence of proteinuria and haematuria is predictive of the development of end-stage renal disease. Renal involvement arises within 3 months of cutaneous findings in majority of patients.¹³ In the present case, the acute development of significant proteinuria and acute renal failure coupled with non-thrombocytopenic purpura further increased concern for systemic vasculitis, and a renal biopsy was performed to evaluate for intrinsic renal disease.

Renal biopsy is a key study for the diagnosis of HSP-associated nephritis.¹⁷ Characteristically, the glomerular lesion pointing to HSP is focal and segmental proliferative glomerulonephritis.¹⁸ Granular mesangial IgA is often accompanied by C3 on immunofluorescence in cases of HSP. Electron microscopy reveals the presence of electron-dense deposits in the mesangium, where the matrix therein is characteristically somewhat expanded in a subendothelial position, and commonly in a subepithelial position.¹⁸ In the present case, renal biopsy was concerning for diffuse and endocapillary proliferative glomerulonephritis with severe IgA and C3 deposition. Electron microscopy of two glomeruli was that of diffuse glomerulonephritis with the pattern of electron dense deposits consistent with HSP, confirming the diagnosis.

Although pulmonary involvement of HSP is rare, it can have a significant effect on morbidity and mortality.¹⁹ In the present case, bilateral diffuse ground-glass opacities with scattered interlobular septal thickening were noted on CT scan of the thorax, in addition to patchy right upper and middle lobe opacities. ARDS, pulmonary oedema, pneumonia and diffuse alveolar haemorrhage were on the differential for this pulmonary process. In the setting of glomerulonephritis and palpable purpura pointing to a diagnosis of systemic vasculitis, and in the absence of any sign of pulmonary infection, the pulmonary vasculature may have been involved in the vasculitic processes affecting the skin, kidneys and brain. Therefore, diffuse alveolar haemorrhage was a concern given this clinical picture. As diffuse pulmonary haemorrhage is a very rare occurrence in the setting of HSP,¹⁹ ARDS was a more likely cause of the pulmonary findings in this case possibly from aspiration. It is possible that the HSP involvement of the nervous system may be underestimated.²⁰ While significant neurologic manifestations including paresis, coma, seizures or encephalopathy are not commonly seen, mild cerebral involvement such as headaches may have a prevalence of as much as one-third of HSP cases.²¹Some mechanisms have been proposed for the development of neurologic involvement in HSP and may be secondary to metabolic disorders and hypertension, especially in the setting of renal failure.²² Cerebral infarction or ischaemia resulting from intracranial vasculitis may cause generalised or focal deficits of the CNS. The neuropathy which may take place during HSP results from intraneural haemorrhage or ischaemia caused by vasculitis of the vasa nervousum.²³ In the present case, a seizure may have been secondary to intracranial vasculitis, as the patient had no history of seizure or head trauma.

In summary, this patient presented with purpuric rash, abdominal pain, myalgias and had seizures, rapid decline in renal function, haematuria and proteinuria raising concern for systemic vasculitis. In addition, she developed acute respiratory failure with ground-glass opacities on CT chest representing ARDS, though diffuse alveolar haemorrhage was not excluded. She was found to have a upper respiratory infection (URI) induced HSP confirmed by renal biopsy, complicated with seizures and RPGN necessitating HD. Fortunately, the patient responded well to high-dose corticosteroid therapy, ventilatory support and HD.

Though rare, HSP can develop in adults, can have a complicated course and multiorgan failure, including severe renal, pulmonary and CNS involvement, as was seen in our case. There may be a discrepancy in long-term outcome when comparing children and adults, as one study showed complete recovery in 94% of children, while 89% of adults showed total resolution of disease.²⁴ One long-term study of 250 adults with HSP complicated by renal involvement showed that, on a median follow-up of 15 years, 11% of the patients were dialysis dependent, while 13% had severe renal failure (<30 mL/min/1.73mt² of creatinine clearance).¹⁴

Unfortunately, recurrence of HSP is seen in one-third of patients, with an even greater chance of recurrence in those with nephritis on the first outbreak of HSP.²⁵ While the diagnosis of HSP is made clinically, patients with atypical presentation, as our patient, may need a biopsy of the skin lesions in conjunction with a renal biopsy for confirmation. Although in the majority of cases, HSP is self-limited, rarely, disease course may be prolonged and complicated, which is seen more commonly in adults than in children.¹⁴ Early recognition, especially outside the typical age group, and appropriate, timely intervention are extremely crucial to manage the disease and limit organ damage.

Learning points.

• Henoch-Schonlein purpura (HSP), though rare in adults, can have a complicated course with multiorgan failure.

• HSP in adults is associated with infections, medications and malignancies though can present with no inciting event.

• HSP is characterised by a combination of non-thrombocytopenic palpable purpura, gastrointestinal and renal involvement, arthritis or arthralgias and rarely the involvement of other organ systems.

• The diagnosis is based on clinical presentation; it can be confirmed with skin and renal biopsy showing leucocytoclastic vasculitis and the IgA deposits.

• Treatment is supportive with a combination of steroids, analgesics, intravenous hydration, though severe presentations need ventilatory support and renal replacement therapy.