key: cord-0889106-18l9juk8 authors: Löffler, Christian; Mahrhold, Juliane; Fogarassy, Peter; Beyer, Martin; Hellmich, Bernhard title: Two immunocompromised patients with diffuse alveolar hemorrhage as a complication of severe COVID-19 date: 2020-07-02 journal: Chest DOI: 10.1016/j.chest.2020.06.051 sha: 6bd62f8213614ae45310cb850d6480d867e10806 doc_id: 889106 cord_uid: 18l9juk8 Abstract Diffuse alveolar hemorrhage (DAH) is a severe and potentially life-threatening disease manifestation. Besides autoimmune diseases such as anti-neutrophil cytoplasmatic antibody (ANCA) associated vasculitis and anti-glomerular basement membrane (anti-GBM) syndrome pulmonary viral infections are also known to be culprits of DAH. The coronavirus disease 2019 (COVID-19) pandemic confronts healthcare providers all around the world with an unprecedented number of viral lung infections with a great variance in symptoms and severity. Hemoptysis being the key symptome of DAH has so far been reported to be rare. We present two cases of immunocompromised patients with rapidly developing hypoxemic respiratory failure and evidence of DAH in the context of SARS-CoV-2 infection. Abstract: Diffuse alveolar hemorrhage (DAH) is a severe and potentially life-threatening disease manifestation. Besides autoimmune diseases such as anti-neutrophil cytoplasmatic antibody (ANCA) associated vasculitis and anti-glomerular basement membrane (anti-GBM) syndrome pulmonary viral infections are also known to be culprits of DAH. The coronavirus disease 2019 (COVID-19) pandemic confronts healthcare providers all around the world with an unprecedented number of viral lung infections with a great variance in symptoms and severity. Hemoptysis being the key symptome of DAH has so far been reported to be rare. We present two cases of immunocompromised patients with rapidly developing hypoxemic respiratory failure and evidence of DAH in the context of SARS-CoV-2 infection. Patient no. 1 is a 79-year-old Caucasian male who was admitted to our hospital with general weakness, malaise and non-productive cough. The symptoms had been present for 8 days prior to admission. Eighteen years prior to admission a diagnosis of autoimmune aortitis of the abdominal aorta was established, which nowadays would have been classified as single organ vasculitis according to the 2012 Chapel Hill Consensus definition 1 . The patient had been on serial immunosuppressive treatments with glucocorticoids either alone or in combination with azathioprine or 6-mercaptopurine, as well as six courses of intravenous cyclophosphamide until 14 months before the current presentation. At this point in time the patient was diagnosed with high-grade urothelial carcinoma of the bladder staged as T2N0M0 (with infiltration of the bladder musculature) after having presented with macrohematuria. He underwent transurethral resection of the bladder (TURB) and received intermittent radiotherapy with a maximum dose of 59.4 Gy and a simultaneous chemotherapy with 5-fluorouracil and mitomycine. During the 8 months prior to admission he was without antineoplastic or immunosuppressive treatment. The patient's further past medical history was comprised of chronic inflammatory demyelinating polyneuropathy, chronic obstructive pulmonary disease, coronary artery disease, type 2 diabetes mellitus, chronic kidney disease stage 3a, Parkinson's disease, osteoporosis and intermittent atrial fibrillation. On admission on March 6 2020, the patient's body temperature was 36.8°C, blood pressure 130/80 mmHg, pulse 80 beats per minute. His respiratory rate was 16/min, peripheral oxygen saturation was 94% while breathing ambient air. The white blood count revealed mild leukocytopenia with absolute lymphopenia of 370 lymphocytes/mm 3 Nowadays, in June 2020 -a time when the first wave of the COVID-19 pandemic is waving off -a patient presenting with a chest CT as seen in patient no. 1 would immediately be identified as highly suspicious for COVID-19 and appropriate measures of health care would be applied instantaneously. Patient no. 2, however, would still give way to a broad differential diagnosis. Interestingly, both cases had alveolar hemorrhage. Guan et al. reported hemoptysis to be a rare symptom of COVID-19, ranging from 0.6% in non-severe to 2.3% in severe cases 3 . It might be speculated that DAH is underrecognized in COVID-19 since the use of bronchoscopy is supposed to be restricted in these patients due to the high risk for health care workers involved in the procedure. DAH is not a specific CT pattern but a clinical and pathological syndrome consisting of anemia, hemoptysis, hypoxemic respiratory failure, diffuse radiographic infiltrates and an increase of intraalveolar red blood cells and hemosiderin-laden macrophages 9 . Both of our patients met these criteria and in both instances we were able to prove intraalveolar bleeding by bronchoscopy. Alternative causes, especially autoimmunological ones, were excluded. In the case of patient no. 2 presenting with an inflammatory disease with hypereosinophilia, renal and suspected myocardial involvement, DAH would generally be highly suspicious for vasculitis, especially for eosinophilic granulomatosis with polyangiitis (EGPA) 10 . However, asthma -a decisive diagnostic feature of EGPA according to the 1990 ACR criteria and the 2012 Chapel Hill definition -was missing in this patient 1, 11 . Furthermore, this case's renal involvement was due to tubulointerstitial eosinophilic infiltration without vasculitis or granulomas which is not a typical renal feature of EGPA where one would expect necrotizing pauci-immune glomerulonephritis. In a large epidemiological study of EGPA patients conducted by the French vasculitis group all patients with histologically proven renal involvement had glomerulonephritis 12 . Moreover, renal involvement in EGPA is significantly more common in ANCA positive individuals 13 . Our patient was ANCA negative. The fourth and perhaps strongest argument against DAH being an expression of EGPA in patient no. 2 is the timing of events: DAH occurred on the fourth day of high-dose intravenous glucocorticoids, at a time, where CRP levels had dropped to the lowest point in 8 weeks and eosinophils were completely absent. Simultaneously, at the onset of DAH in patient no. 2, he (unfortunately and unwillingly) had been exposed to patient no. 1 for at least 96 hours which is consistent with the reported incubation time of SARS-CoV-2 14 . Severe pulmonary infections are recognized as possible triggers for DAH, even in immunocompetent hosts. Among these, viral diseases such influenza A play a major role 15 . Furthermore, according to the current understanding of its mechanism of disease, SARS-CoV-2 causes pulmonary endothelialitis leading to thrombotic microangiopathy, thrombosis and hemorrhage as has been shown in a recent autopsy study 16 . This mode of action resembles that of vasculitic diseases and might be the explanation why DAH can be a complication of both viral infection and ANCA vasculitis or anti-GBM disease. Therefore, we argue that in both reported instances DAH was caused by SARS-CoV-2 infection. Patient no. 1 acquired the disease due to his high susceptibility (age, previous immunosuppression and radiochemotherapy, multiple comorbidities) from an unknown source. Due to the atypical and initially non-severe presentation, the negative travel and contact history, and a low prevalence of SARS-CoV-2 in Germany at the time of the onset of symptoms in February 2020, COVID-19 was not suspected at the time of admission giving way to spreading the disease to patient no. 2 whose immunological defenses, especially lymphocytes and eosinophils, were low as a result of the treatment with high-dose prednisolone. According to the presented data, DAH should be taken into consideration as a complicating feature of severe COVID-19. 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