Age: 52.0
Sex: M
Vaccine: FLU3, HEPAB, HIBV, IPV, MEN, PNC13, TDAP, DTAP, FLUX, HEPAB, HIBV, IPV, MEN, PNC13
Symptoms: Cough, Dyspnoea, Endotracheal intubation, Hypoxia, Intensive care
Clinical narrative: This Literature - Spontaneous case, initially received on 14-Feb-2017, was reported by a health professional and concerns a 52-year-old male patient. Weight: not provided; Height: not provided. Past medical history includes stage IV angioimmunoblastic T-cell lymphoma (with bone marrow involvement, diagnosed: 2011), refractory lymphoma, matched unrelated donor hematopoietic cell transplant (HCT), mild classic chronic GvHD (graft versus host disease). Drug history includes cyclosporine (reaction: seizures), ifosphamide, carboplatin, etoposide, romidepsin, rabbit anti-thymocyte globulin, tacrolimus, mycophenolate, CHOP, hydrocortisone, refresh eye drops. Concomitant medication: not reported. Following diagnosis with stage IV angioimmunoblastic T-cell lymphoma, the patient was originally treated with CHOP (chemotherapeutic agents) x6. Owing to refractory lymphoma, he received salvage ifosphamide, carboplatin, etoposide x2, a clinical trial with high-dose cyclosporine discontinued due to seizures, and reached a partial response with seven cycles of romidepsin before matched unrelated donor hematopoietic cell transplant (HCT). His conditioning regimen was reduced intensity with rabbit anti-thymocyte globulin, 2.5 mg/kg from day - 9 to - 7 followed by TBI to a total dose of 4.5 Gy, delivered in three 1.5 Gy fractions on day -1 to 0. For GvHD prophylaxis, he received tacrolimus and mycophenolate. His post-transplant course was uncomplicated by day +180. His days +60 and +100 bone marrow, blood and T cells were 100% donor and no evidence of disease recurrence was found on radiographic imaging. Pulmonary function testing day +100 revealed a FEV1 (forced expiratory volume in 1 sec) of 93% and DLCO (diffusing capacity of the lung for carbon monoxide) of 78%; pre-transplant FEV1 and DLCO were 93 and 80%, respectively. The patient had mild classic chronic GvHD of skin and eyes treated with topical hydrocortisone and Refresh eye drops. He was off immunosuppression by day +168. Administration of company suspect drug(s): On day +240 following HCT, the patient received Influenza Virus Vaccine (INN) for indication not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. Non-company suspect drugs: DTAP, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. HAEMOPHILUS INFLUENZA TYPE B VACCINE, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. HEPATITIS A VACCINE, HEPATITIS B VACCINE, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. MENINGOCOCCAL VACCINE, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. PNEUMOCOCCAL 13 VALENT VACCINE, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. POLIO VACCINE, Indication: not reported. Dose regimen: Not reported, Route of administration: Not Reported. Batch number: Not reported. Adverse reactions/events and outcomes: On an unknown date, the patient experienced erythematous rash (outcome: not reported), hypoxemic respiratory failure (medically significant, hospitalised, outcome: recovering / resolving), pneumomediastinum (medically significant, hospitalised, outcome: recovering / resolving) and pneumothorax (medically significant, hospitalised, outcome: recovering / resolving). On an unknown date, the patient experienced acute organising fibrinous pneumonia (AFOP) (medically significant, hospitalised, outcome: recovering / resolving). Associated symptoms included: dyspnea, hypoxemia, oxygen saturations of 68%, subacute cough. On day +325 after transplant the patient presented to the outpatient bone marrow transplant clinic with subacute cough, dyspnea, hypoxemia and no other clinical symptoms of GvHD. Pulse oximetry showed oxygen saturations of 68% on room air. Computed tomography (CT) of the chest showed rapidly progressive pulmonary infiltrates. He was admitted to the inpatient bone marrow transplant floor, started on broadspectrum antimicrobials, and subsequently underwent bronchoscopy that was non-diagnostic. Over the next 2 days he developed worsening hypoxemia requiring transfer to the medical intensive care unit for hypoxemic respiratory failure. High-dose methylprednisolone 125 mg every 6 h was initiated. On day +328 he underwent video-assisted thoracoscopic surgery (VATS) and left upper lobe/left lower lobe wedge resection. He was extubated on day +329, but remained hypoxic, requiring non-invasive ventilation. On day +331 the pathology from the wedge resections showed Acute organizing fibrinous pneumonia (AFOP). Given the lack of clinical improvement, methylprednisolone was increased from 125 to 250 mg every 6 h, tacrolimus was continued (goal trough level 10) and etanercept 25 mg SC twice weekly was started for a total of eight doses. After the initiation of etanercept, the patient had significant improvement in respiratory status. His hypoxemia improved, he was off non-invasive ventilation after two days and supplemental oxygen was rapidly weaned. He completed 8 doses of etanercept; continued tacrolimus and steroids were tapered off over 2 weeks. His VATS was complicated by pneumothorax and pneumomediastinum, which required small bore thoracostomy placement and eventually mechanical pleurodesis due to persistent air leak. On day +364 he was discharged home off supplemental oxygen with significant clinical and radiographic improvement. His post hospitalization FEV1 was 72% and DLCO was 58%. Currently, the patient is 2.5 years from HCT and remains in remission from his lymphoma; he is on tacrolimus and twice weekly every other week extracorporeal photopheresis for GVHD as a steroid sparing agent that was started after day +364 upon discharge from the hospital. Prednisone was discontinued at day +393. He has had no other symptoms of GVHD except for an erythematous rash on day +519. He was started on 20 mg of prednisone, which was tapered off by day +756. He is off supplemental oxygen and recent CT scans reveal mild air trapping, however, a significant improvement from prior CT scans and his spirometry is normal, FEV1 (96%) and DLCO 89%. Lung biopsy was positive for both HO-1 (heme oxygenase-1) and TNF (tumour necrosis factor)-alpha. Reporter's Comments: Reporter's assessment: The pathogenesis of AFOP is unknown but the patient's response to etanercept suggests a role of TNF-alpha as part of a cytokine-modulated immune response causing inflammation and fibrosis. To the reporter's knowledge, this is the first case AFOP after HCT successfully treated with etanercept. Although, there is a lack of clinical evidence to support the use of entanercept in patients with AFOP, the rational for the use of etanercept in this critically ill patient with a non-infectious lung injury was that AFOP may be driven by oxidative stress, which may be modulated by TNF-alpha (the patient's lung biopsy was positive for both HO-1 and TNF-alpha). This supports the reporter's hypothesis that AFOP may be driven by oxidative stress induced by TNF-alpha. The reporter proposes that etanercept may be responsible for the marked clinical improvement in the patient because with high-dose steroids and tacrolimus, the patient was requiring non-invasive ventilation and high-flow oxygen 15 L nasal canula until the addition of etanercept. The reporter speculates that AFOP is a manifestation of GvHD, and that TNF-alpha is implicated in its pathogenesis. The reporter stated that erythematous rash was a symptom of GvHD. Sender's Comments: Listedness: Brand of Influenza vaccine not specified. Assessment according to CCSI for CSL's Inactivated Influenza Virus Vaccine, Acute organizing fibrinous pneumonia (AFOP), pneumothorax, pneumomediastinum, respiratory failure, are unlisted. Erythematous rash is listed. Causality: Not Related. Time to onset is 12 weeks following vaccination. Patient had refractory T-cell lymphoma and donor hematopoietic cell transplant. According to the authors of literature, pathogenesis of AFOP is unknown; due to clinical response to etanercept treatment, AFOP is proposed as due to oxidative stress induced by TNF-alpha as part of a cytokine-modulated immune response causing pulmonary inflammation and fibrosis. The prolonged delay in event onset and presence of significant alternate etiology makes causality not related to vaccination for all events.