A man with skin rash and respiratory failure

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A 51-year-old man, a non-smoker and non-drinker, with history of pulmonary tuberculosis (TB), hypertension, hyperlipidemia and gout, was admitted for rash over his bilateral lower limbs for a few days (Figure 1). The rash was neither itchy nor tender. His complete blood picture including eosinophilic count, renal and function tests were grossly normal, but both ESR and CRP were elevated with 63mm/h (<20mm/h) and 30.9mg/L (<=8.2mg/L) respectively. Anti-nuclear Antibody (ANA) was negative and C3 and C4 level were normal. Anti-myeloperoxidase anti-neutrophilic cytoplasmic antibody (Anti-MPO ANCA) was positive with a level of 53 unit (<= 20 units). Urine protein creatinine ratio was 29 (<= 11mg/mmol Cr) and there was no dysmorphic red blood cell detected. His Chest X-ray (CXR) was completely clear.

Skin biopsy showed that the small vessels were infiltrated by neutrophils with fibrinoid necrosis, nuclear dusts and extravasated red blood cells. Scanty eosinophils were also seen. The larger vessels were not involved. Immunofluorescence studies with IgA, IgG, IgM, C3 and fibrinogen were all negative with no deposits in the vessels wall. The overall feature was compatible with leukocytoclastic vasculitis. A low dose of oral prednisolone 15 mg daily was started for the cutaneous small vessel vasculitis.

However, he had mild blood-stained sputum 3 days later. He was given Augmentin and intravenous hydrocortisone empirically. His serial CXR remained clear (Figure 2). However, he developed respiratory failure 3 days later and his new CXR reviewed extensive infiltrates bilaterally (Figure 3). He was intubated and transferred to the intensive care unit. Urgent computed tomography (CT) scan of the thorax showed diffuse airspace consolidations in both the lungs with batwings distribution (Figure 4). His hemoglobin level was dropped from 10.6 to 7.5 g/dL (13.5–17.3g/dL) at that time.

Questions

  1. What is the diagnosis?
  2. What is the management?

Answer

  1. ANCA positive vasculitis with pulmonary hemorrhage Causes of massive pulmonary hemorrhage include bronchiectasis, connective tissue diseases (GPA, MPA, SLE, catastrophic APLS, Goodpasture syndrome, Behcet’s disease), infection (necrotizing pneumonia, tuberculosis, fungal infection such as aspergillosis and dimorphic fungi, leptospirosis), disorders of coagulation (platelet dysfunction, clotting factor deficiency, DIC), bronchogenic carcinoma, rarely iatrogenic injury and bronchovascular fistula.This patient had rapid progression of lung infiltrates in the CXR with a sudden drop in the hemoglobin level. He had a positive result of anti-MPO ANCA, with leukocytoclastic vasculitis in skin. Sputum and endotracheal aspirates cultures were all negative. His platelet and clotting profile were normal. CT thorax did not detect any bronchogenic carcinoma or fungal infection, such as mycetoma. The diagnosis of ANCA-positive vasculitis with pulmonary hemorrhage is highly suggested.
  2. Pulmonary hemorrhage in ANCA-positive vasculitis is a rheumatological emergency because it can progress rapidly and carry high mortality. For patients with massive pulmonary hemorrhage, the immediate management should be active fluid resuscitation and airway protection by intubation. Sometimes, unilateral lung ventilation can be done if the bleeding site is confined unilaterally. Urgent bronchoscopy with intervention may be considered to identify the bleeding site if the pulmonary hemorrhage remains active and serious.[1] However, this measure is always futile as the bleeding is usually extensive, and multiple capillaries and areola are involved. Till now, adequate reports are not available to support the use of interventional bronchoscopy in managing ANCA associated pulmonary hemorrhage.Currently, EULAR guidelines recommend the use of glucocorticoids 1mg/kg/d and either cyclophosphamide or rituximab (level of evidence 1, grade of recommendation A; for GPA/MPA; 3 and C for EGRA) for inducing disease-remission in vasculitis related alveolar hemorrhage.[2]Intravenous pulse cyclophosphamide was as effective as oral cyclophosphamide, but with less adverse effects in the former, according to CYCLOPS trial.[3] Rituximab can be given, with a dose of 375 mg/m2 weekly for 4 weeks. It demonstrated a superior efficacy for relapsing diseases as compared to the cyclophosphamide in the RAVE study.[4]For maintenance therapy, EULAR suggests either azathioprine, methotrexate, MMF or rituximab. A maintenance regimen with rituximab (500 mg on days 0 and 14 and in months 6, 12 and 18) was shown to have a lower relapse rate at 28 months as compared to daily azathioprine (2 mg/kg/d for 12 months, followed by 1.5mg/kg/d for 6 months and then 1 mg/kg/d for 4 months), in the MAINRITSAN trial.[5] The RITAZAREM trial is currently under way (rituximab 1000 mg every 4 months for 5 doses compared to azathioprine 2 mg/kg/d) to investigate the safety and long term efficacy of high dose rituximab in treating vasculitis.[6]Plasma exchange can also be considered for the treatment of severe diffuse alveolar hemorrhage (level of evidence 3, grade of recommendation C). According to the data from the French vasculitis study group, 64 cases of alveolar hemorrhage, which include:30 cases admitted in ICU were all resolved with discontinuation of mechanical ventilation after a median time of 15 days of plasma exchange.[7]

References

  • [1]

    Lordan JL Gascoigne A Corris PA. The pulmonary physician in critical care: assessment and management of massive hemoptysis. Thorax. 2003;58:814–9. https://doi.org/10.1136/thorax.58.9.814

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  • [2]

    EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis 2016

  • [3]

    de Groot K Harper L Jayne DR Flores Suarez LF Gregorini G Gross WL et al.; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May;150(10):670–80. https://doi.org/10.7326/0003-4819-150-10-200905190-00004

    • Crossref
    • Export Citation
  • [4]

    Stone JH Merkel PA Splera R Set P Langford CA. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010 Jul 15;363(3):221-32

  • [5]

    Guillevin L Pagnoux C Karras A Khouatra C Aumaître O Cohen P et al.; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov;371(19):1771–80. https://doi.org/10.1056/NEJMoa1404231

    • Crossref
    • Export Citation
  • [6]

    Gopaluni S. Smith RM Lewin M McAlear CA Mynard K. Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trial 2017;18(1):112. https://doi.org/10.1186/s13063-.

    • Crossref
    • Export Citation
  • [7]

    de Luna G Chauveau D Aniort J Carron PL Gobert P Karras A et al.; French Vasculitis Study Group (FVSG). Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group. J Autoimmun. 2015 Dec;65:49–55. https://doi.org/10.1016/j.jaut.2015.08.003PMID:26330347

    • Crossref
    • Export Citation

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  • [1]

    Lordan JL Gascoigne A Corris PA. The pulmonary physician in critical care: assessment and management of massive hemoptysis. Thorax. 2003;58:814–9. https://doi.org/10.1136/thorax.58.9.814

    • Crossref
    • Export Citation
  • [2]

    EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis 2016

  • [3]

    de Groot K Harper L Jayne DR Flores Suarez LF Gregorini G Gross WL et al.; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May;150(10):670–80. https://doi.org/10.7326/0003-4819-150-10-200905190-00004

    • Crossref
    • Export Citation
  • [4]

    Stone JH Merkel PA Splera R Set P Langford CA. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010 Jul 15;363(3):221-32

  • [5]

    Guillevin L Pagnoux C Karras A Khouatra C Aumaître O Cohen P et al.; French Vasculitis Study Group. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov;371(19):1771–80. https://doi.org/10.1056/NEJMoa1404231

    • Crossref
    • Export Citation
  • [6]

    Gopaluni S. Smith RM Lewin M McAlear CA Mynard K. Rituximab versus azathioprine as therapy for maintenance of remission for anti-neutrophil cytoplasm antibody-associated vasculitis (RITAZAREM): study protocol for a randomized controlled trial. Trial 2017;18(1):112. https://doi.org/10.1186/s13063-.

    • Crossref
    • Export Citation
  • [7]

    de Luna G Chauveau D Aniort J Carron PL Gobert P Karras A et al.; French Vasculitis Study Group (FVSG). Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group. J Autoimmun. 2015 Dec;65:49–55. https://doi.org/10.1016/j.jaut.2015.08.003PMID:26330347

    • Crossref
    • Export Citation
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