ECMO and the Antisynthetase Syndrome
The Antisynthetase Syndromes are a rare group of autoimmune conditions related to polymyositis and dermatomyositis, with features including fever, myositis, arthritis, Raynaud’s phenomenon, “mechanic’s hands” and interstitial lung disease. They are diagnosed by the presence of antisynthetase antibodies, most commonly anti-Jo-1 (60-80%) but also anti-PL-7, anti-PL-12, anti-EJ, anti-ZO and others. These target tRNA synthetases that are involved in DNA replication. Further investigations including HRCT or MRI, EMG, muscle or lung biopsies and pulmonary function testing can all help clarify the diagnosis and guide treatment.
Once diagnosis is confirmed, immunosuppressive therapy can begin. Typically, corticosteroids are used, often orally, but occasionally intravenously in severe cases. Other immunosuppressants such as cyclosporin may also be used. The new anti-CD20 monoclonal antibody therapy Rituximab has proven to be of significant benefit in patients whose interstitial lung disease has proved refractory to standard immunosuppression, leading to improvements in both clinical condition and radiological appearance.
Patients in whom the disease is limited to muscle involvement generally have a good prognosis and respond well to immunosuppressive therapy. Unfortunately, if there is lung involvement (present in 60% of cases), prognosis is significantly poorer, with a 10-year survival rate of 70-80% in those with anti-Jo-1 antibodies.
Case Report 1:
Our first case is a 47-year-old previously fit and well man diagnosed with multilobar community-acquired pneumonia and treated accordingly. He deteriorated into Type 2 respiratory failure, necessitating invasive ventilation. Despite maximal conventional treatment hypoxia worsened and he was referred and accepted for ECMO on day 5 from hospital presentation. He was stabilised on ECMO support via a right internal jugular 31F dual lumen Avalon Elite cannula, achieving flows of 4.5-5l/min prior to transfer to his local ECMO centre. Percutaneous dilatational tracheostomy was performed on day 9. Oxygenation issues persisted during ECMO support necessitating FiO2 0.5-0.6 to achieve PaO2 > 6kPa, the use of prone positioning and the addition of a second oxygenator in parallel to the ECMO circuit.
Despite an improvement in inflammatory markers with broad spectrum antimicrobial treatment his gas exchange parameters and compliance failed to improve. Extensive microbiological investigations were essentially normal.
Chest x-rays demonstrated severe bilateral consolidation (Fig 1) and a CT Chest on day 10 showed extensive consolidation with ground glass opacities affecting 70% of the pulmonary parenchyma, with pulmonary hypertension and right heart strain (Fig 2). A trial of methylprednisolone (500mg/day for 3 days followed by a 14-day tapering regime) to treat presumed ARDS with failure to progress was commenced on day 13. From day 16 onwards he demonstrated persistent improvement in oxygenation allowing successfully weaning from ECMO support on day 28.
Unfortunately, 48 hours post ECMO decannulation he deteriorated, requiring FiO2 up to 0.8 and peak inspiration pressures of 30-34cmH2O to achieve adequate gas exchange. Immunological testing yielded negative serology for ANCA, ANA, anti-GBM, anti-dsDNA with normal immunoglobulin and complement profiles but on day 32 a standard Extractable Nuclear Antigen (ENA) panel revealed the presence of anti-Jo antibodies, leading to a diagnosis of Antisynthetase Syndrome. Steroid therapy was recommenced at 60mg prednisone and Rituximab administered on day 33. There was a rapid and dramatic improvement in oxygenation and compliance in following days and although critical care acquired weakness slowed his respiratory weaning, tracheostomy decannulation was successfully achieved on day 48 and he was transferred to the ward for ongoing rehabilitation on day 49.
At 6-month follow-up, imaging demonstrated bilateral peripheral and mainly lower zone interstitial shadowing consistent with a degree of pulmonary fibrosis but he reported much improved exercise tolerance, being able to cycle 2-3km and back at work part-time.
Case Report 2:
The second case is a 39-year-old woman with insulin dependent diabetes who presented to her local hospital with a seven-day history of productive cough and pyrexia. She was diagnosed with community acquired pneumonia and treated accordingly. Three days after admission her condition deteriorated, with increased oxygen requirements and she was intubated and ventilated, and also needed CVVH for an acute kidney injury. As she was requiring a very high FiO2 to maintain an acceptable PaO2, she was referred and accepted for ECMO support. Veno-venous ECMO was initiated at her local hospital via a 19F multi-stage drainage cannula in her femoral vein with 17F return cannula in her right internal jugular vein and she was transferred to her local ECMO centre on day 4. Flows were maintained at 3.0-3.5l/min and she was weaned to ‘rest ventilator settings’ (FiO2 0.3-0.4, BIPAP 20/10cmH2O). She underwent percutaneous dilatational tracheostomy on day 9. She initially responded well to treatment and was successfully weaned off ECMO support by day 10. Unfortunately, oxygen requirements increased over subsequent days and despite numerous measures including proning and inhaled nitric oxide, her respiratory function worsened. She was therefore placed back on ECMO via a 27F dual lumen cannula in her right internal jugular vein on day 18, achieving similar ECMO and ventilator settings.
Microbiological testing revealed pneumococcus in the original sputum sample, but all other microbiological tests were returned as negative, including PCR for respiratory viruses and atypical pneumonia screen. She failed to improve when treated with various antimicrobial regimens. Radiological investigation showed widespread lung field shadowing on chest x-ray (Fig 3) and multiple CT scans demonstrated frank bilateral lung consolidation with areas of necrosis (Fig 4). Immunological tests yielded negative serology for rheumatoid factor, ANCA, anti-dsDNA, anti-ENA and anti-GBM, with a normal immunoglobulin and complement profiles although a weakly positive ANA was detected. An extended ENA panel revealed the presence of anti-PL-12 antibodies, diagnostic of the Antisynthetase Syndrome. She was given 3 days of pulsed methyl-prednisolone followed by maintenance steroids, and was treated with Rituximab on day 24 with rapid and dramatic improvement in gas exchange and compliance; twenty-four hours later, she was successfully weaned off ECMO.
Within a week, her FiO2 was 0.35, and she was spontaneously breathing via a tracheostomy mask. Her critical care recovery was complicated by on-going need for renal replacement therapy, a prolonged ileus and critical care acquired weakness. She was transferred back to her local hospital on day 50 to continue rehabilitation. At six month follow-up, her main symptom was myalgia with no reported breathlessness, CXR demonstrated some bronchiectasis in mid lung fields with no evidence of extensive pulmonary fibrosis and pulmonary function tests were within normal limits. She had regained independent renal function.
Despite both these patients presenting with a common cause of Severe Acute Respiratory Failure, standard ICU treatment for pneumonia failed to deliver any improvement. When this occurs, our unit screens for a wide range of alternative diagnoses. In these cases, positive antibody results led to treat with immunosuppression, with dramatic improvements noted shortly thereafter. It is always important to keep unusual diagnoses in mind when recovery from common conditions does not proceed as expected.