Life-threatening complications of Henoch-Schönlein purpura: diffuse alveolar haemorrhage, venous thrombosis and bowel ischaemia

Abstract

Henoch-Schönlein purpura (HSP) is a common systemic vasculitis occurring in children. Making a diagnosis of HSP is often straightforward, managing its complications can be difficult. Diffuse alveolar haemorrhage (DAH), bowel ischaemia and venous thrombosis are rare complications of this disorder. We present a case of a 15-year-old teenage girl presenting with typical purpuric rash of HSP, developed DAH, bowel ischaemia and venous thrombosis. She was successfully treated with pulse methylprednisolone, intravenous Ig and intravenous cyclophosphamide.

Background

Henoch-Schönlein purpura (HSP) is a small-vessel vasculitis characterised by IgA deposition in the vessel wall. The classical tetrad is non-thrombocytopenic palpable purpura, arthritis/arthralgia, abdominal pain and renal involvement. Unlike many other systemic vasculitides, a majority of HSP are self-limiting. However, adults tend to develop a more severe disease with a higher incidence of diarrhoea, nephritis and pulmonary involvement.^{1 2} Pulmonary disease most commonly manifests as diffuse alveolar haemorrhage (DAH) and occasionally as usual interstitial pneumonia or interstitial fibrosis.² Subclinical lung function abnormalities have also been reported during the acute phase of HSP. However, these changes are not associated with subsequent development of lung disease.³ Often when patients develop DAH, clinicians are inclined towards antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Goodpasture’s syndrome and secondary vasculitis such as systemic lupus erythematosus (SLE). Here, we would like to highlight that HSP is an important cause of DAH.

Case presentation

Our patient is a previously healthy, 15-year-old girl, who presented with purpuric eruptions over bilateral lower limbs, which spread to the buttocks and upper limbs (figure 1). These rashes developed blisters which later became haemorrhagic necrotic skin lesions. She also had fever, rhinorrhoea and sore throat which started on the same day as the rash. There was no arthralgia, arthritis, gastrointestinal or respiratory symptoms at the time of presentation. A diagnosis of HSP was made based on the distribution of the rash. Skin biopsy of the rash showed leukocytoclastic vasculitis with IgA positive infiltrates over small vessel and perivascular area, which was consistent with HSP. She was started on systemic steroid for the extensive skin lesion (intravenous hydrocortisone 50 mg three times a day on day 8 of symptom onset then increased to intravenous hydrocortisone 100 mg three times a day on day 11 for persistent skin lesion). After 13 days from onset of symptoms, she developed sudden onset of pleuritic chest pain associated with haemoptysis and shortness of breath. An urgent chest X-ray (CXR) showed airspace opacities at the right middle zone (figure 2). CT of the thorax showed consolidation involving the right middle lobe as well as anterior segment of right upper lobe (figure 3). Urgent referral to our respiratory team was made for bronchoscopy which revealed multiple vasculitic changes over trachea and carina and blood oozing out from the right middle lobe lateral segment. She also had desaturation of oxygen concentration (from SPO₂ >95% to SPO₂≈ 90%), haemoglobin level dropped from 13.6 g/dL to 10.9 g/dL. Her new clinical symptoms, reduced in oxygen saturation, sudden drop in haemoglobin level, CXR, CT thorax and bronchoscopy findings were suggestive of DAH. The next day of developing DAH, she started to have left upper limb swelling. CT angiogram and venogram of bilateral upper limbs confirmed the thrombosis within the left distal basilic and cephalic veins. She was started on intravenous methylprednisolone (total 3 g was given) for DAH. However, commencing anticoagulant for the venous thrombosis posed a dilemma to us because of the recent DAH. Thus, anticoagulant treatment was deferred for 2 days until DAH halted, as evidenced by stable haemoglobin level (maintained above 10 g/dL), clearing CXR infiltrates, improving oxygenation and repeated bronchoscopy showed no active bleeding. Her left upper limb swelling resolved after 3 days of subcutaneous low molecular weight heparin. The next turn of events occurred on day 20 after initial symptom onset. She developed severe colicky, anginal type abdominal pain and bloody diarrhoea. Urgent CT of the abdomen revealed long segment ileal ischaemia (figure 4). She was given intravenous Ig 0.4 g/kg/day (total 2 g/kg). She was also kept nil by mouth to rest her bowel. Fortunately, her symptoms gradually improved without any surgical intervention.

Figure 1.

Pupuric rash with eruptions seen over the bilateral lower limbs of the patient. Ruptured blisters and haemorrhagic necrotic skin lesions seen on the dorsum of left foot.

Figure 2.

Chest radiographs showed right lung infiltrates (white arrow) during diffuse alveolar haemorrhage (A) and improvement post treatment (B). PA, postero-anterior.

Figure 3.

CT of thorax showed right middle lobe consolidation (red arrow) which represented diffuse alveolar haemorrhage (A) and improvement after treatment (B).

Figure 4.

CT of abdomen showed long segment thickened ileal wall (white arrows). (A) Showed coronal view, (B) showed transverse view.

Investigations

She presented with leucocytosis and thrombocytosis with a total white cell count and platelet 24.17×10³/μL and 556×10³/μL, respectively. Her haemoglobin was normal, 13.6 g/dL. Renal profile and liver functions tests were normal. Her inflammatory markers were elevated. Erythrocyte sedimentation rate (ESR) was 32 mm/ hour; C reactive protein was 14.5 mg/L. Serum Ig A level was normal; 2.28 g/L (0.54–3.6). Urinalysis showed 0.3 mg/L blood and 0.1 g/L protein. Otherwise, antinuclear antibody (ANA), extractable nuclear antigen (ENA), antidouble-stranded DNA (dsDNA), c and p ANCA, anticytomegalovirus IgM, antiEpstein-Barr virus IgM, anti hepatitis C, hepatitis B surface antigen and anti-HIV were all negative. Complement levels (C3/C4) were 1.26 g/L/ 0.330 g/L (normal). Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibody and anti-beta2 glycoprotein 1 antibody) were negative. Histopathology examination of the purpuric rash showed Ig A immune deposits around the wall of blood vessels, which is in parallel with the diagnosis of HSP. CXR and CT thorax showed infiltrates and consolidation during DAH and rapid resolution after intravenous methylprednisolone (figures 2 and 3). CT abdomen showed long segment ileum wall thickening with increased wall enhancement (figure 4).

Differential diagnosis

The differential diagnosis that we considered during the course of treating our patient were other causes of DAH such as ANCA associated systemic vasculitis (AASV) and SLE.

Both c-ANCA and p-ANCA were negative. Besides that, our patient had no oral or nasal inflammation, no granulomas or cavities on chest radiographs and no granulomas on skin biopsy to suggest granulomatosis with polyangiitis, microscopic polyangiitis or eosinophilic granulomatosis with polyangiitis. In addition, she had no history of bronchial asthma, neurological involvement to suggest AASV.

Absence of lupus features such as alopecia, oral ulcer, photosensitive rashes, arthritis, Raynaud’s phenomenon, sicca symptoms and negative serology testing (ANA, dsDNA, ENA) made the diagnosis of SLE less likely.

Hence, the diagnosis of HSP was made based on European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society endorsed consensus criteria⁴ (palpable purpuric rash not related to thrombocytopenia, skin biopsy predominant IgA deposition, generalised abdominal pain and proteinuria (UPCI >30 mg/mmol)) with rare sinister complications such as DAH and venous thrombosis.

Treatment

She received intravenous methylprednisolone (total 3 g) during DAH, followed by oral prednisolone 1 mg/kg/day. There was rapid improvement in her symptoms and infiltrates on her CXR after the intravenous methylprednisolone. Unfortunately, she developed bowel ischaemia after intravenous methylprednisolone therapy. She was given intravenous Ig (total 2 g/kg). Response to intravenous Ig was substantial, bowel ischaemia improved without surgical intervention. Subsequently, she was treated with intravenous cyclophosphamide (15 mg/kg/ dose 2 weekly for 3 cycles and 3weekly for three cycles).^{5 6}

Outcome and follow-up

The patient is under rheumatology clinic follow-up. She remains well 6 months from the time of initial presentation, our patient has completed six cycles of intravenous cyclophosphamide. Apart from the microscopic haematuria which is still persistent, all other symptoms have resolved completely and did not recur. The likely cause of her microscopic haematuria is IgA nephropathy. So far, no renal biopsy has been performed in view of proteinuria is less than 500 mg/day and creatinine is normal. She is being closely monitored for relapse. Besides that, she has completed 3 months of warfarin and there are no further episodes of thrombosis.

Discussion

HSP is characterised by deposition of IgA containing immune complexes and complement components within small vessel walls resulting in systemic leukocytoclastic angiitis. This process mainly affects small vessels of the skin, joints, gastrointestinal tract and more rarely, kidneys. The brain, lungs and scrotum may occasionally be involved. It is the most common vasculitis in children but it occurs less frequently in adults (13/million). HSP affects males more than females.^7–10

The most common and often the first symptom of HSP is palpable purpura (96%–100%). These purpuras can become blisters and necrotic haemorrhagic lesions especially in older patients. Other common manifestations are arthritis/ arthralgia (44%–74%), abdominal involvement (51%–69%), renal involvement (21%–54%) and intussusception (0.6%–2.3%). Some patients develop evidence of liver cell damage (15%), cholestasis (87%), neurologic (13.8%) and cardiac involvement (5.5%). Common laboratory abnormalities are raised ESR (57%), high IgA (37%) and proteinuria (42%).8 9 11 12

DAH is rare in HSP. The prevalence of DAH in HSP range from 0.8% to 5%. The median age for development of DAH in HSP is 16.5 years. DAH occurred variably after other organ involvement, ranging from 2 days to 18 years after the diagnosis of HSP. Sometimes it can present as the initial manifestation of HSP, even before cutaneous lesions appear. Most patients present with haemoptysis (75%), drop-in haemoglobin (74%) and chest infiltrates (94%). Pleural effusions were also observed (16.7%) and were often massive, requiring tube thoracostomy. Delayed diagnosis of DAH was reported as underutilisation of bronchoscopy (16.7%).^{12 13} This could result from a low index of suspicion due to the rarity of DAH in HSP.

Up to date, there are no established treatment guidelines for DAH in HSP. Various regimes of corticosteroids and immunosuppression have been used to treat and prevent recurrence of DAH. Chen et al suggested that steroid therapy should be used as first line treatment for patients without respiratory failure in view of significant adverse effects of immunosuppressant therapy. Cyclophosphamide pulse therapy should be considered if respiratory failure occurs.¹⁴ However, based on a literature review, most patients were already on steroids at the time of the DAH. In fact, 11% of the patients who developed DAH already received at least three doses of methylprednisolone, indicating that steroids alone are not sufficient in treating DAH. Furthermore, patients receiving pulse methylprednisolone alone had recurrence of DAH and pulse cyclophosphamide was successful in treating DAH among patients who failed pulse methylprednisolone therapy. Pulse methylprednisolone followed by cyclophosphamide for a median duration of 6 months was the most common treatment regimen.¹²

Although HSP generally has a good prognosis, in the event of DAH, mortality rates are high, ranging 27.8%–33%. Mortality rates among those who were untreated was 100%.¹⁴ Hence, a high index of suspicion of pulmonary haemorrhage is required despite the absence of overt clinical signs. HSP should be recognised as an important cause of DAH.

Another rare complication of HSP that occurred in our patient was venous thrombosis over the left upper limb. Arterial and venous thromboses in HSP are rare. To the best of our knowledge, there are only 11 cases of thrombosis related to HSP reported. Most of the cases involved venous thrombosis affecting the iliac, femoral, spermatic, penile, portal, superior mesenteric veins and sagittal sinuses. Arterial thromboses were reported less commonly; one case with tibial and fibular artery thrombosis and another one with right coronary artery thrombosis. Most of the patients responded well to steroids and anticoagulants, except for one case of a fatal necrotising vasculitis involving large and small intestine with portal vein thrombosis.^15–17 Raised factor VIII, homocysteine, lipoprotein A, von Willebrand factor and presence of antiphospholipid antibodies have all been linked to the prothrombotic state found in HSP. These factors together with the inflammatory state in HSP vasculitis increase the risk of thrombosis.^{15 17–19} In our case, we postulated that venous thrombosis of the left cephalic and basilic vein were related to HSP. Neither antiphospholipid syndrome screening nor other thrombosis risks were present.

Gastrointestinal manifestations are seen in 78.2% of adult HSP patients.²⁰ The main symptom is colicky abdominal pain, which can be very distressing. The use of steroids for abdominal pain in HSP is controversial. In a prospective, randomised, double blind trial, steroids were found to reduce the severity and duration of abdominal pain. The incidence of severe abdominal pain was twice as high in the placebo group compared with the prednisolone group.²¹ In another retrospective clinical analysis, steroids were shown to be helpful in preventing complications such as gastrointestinal bleeding and intussusception.²² In our case, despite a high-dose steroids, the patient still developed small bowel ischaemia, which is believed to be as a result of vasculitis induced thrombosis.²³ We postulated that this patient could be refractory to steroids and thus, intravenous Ig was given. This is supported by a retrospective study involving 12 children with gastrointestinal symptoms refractory to steroid, intravenous Ig was shown to be beneficial in improving symptoms.²⁴ Fortunately, our patient improved over the next few days with bowel rest, antibiotics and intravenous Ig.

Although HSP is always self-limiting, it should not be treated lightly as life-threatening complications, such as in this case, could occur. A high index of suspicion is necessary for early recognition of complications. More research in this area is imperative so that proper treatment guidelines can be developed.

Learning points.

• Henoch-Schönlein purpura (HSP) is always self-limiting, however, severe fatal complications may occur.

• HSP can be a cause of DAH.

• Early recognition of life-threatening complications, such as DAH and bowel ischaemia, is crucial in order to achieve a better outcome.