key: cord-321064-pe8466n1 authors: Saraceni, Francesco; Scortechini, Ilaria; Mancini, Giorgia; Mariani, Marianna; Federici, Irene; Gaetani, Mariana; Barbatelli, Paolo; Minnucci, Maria Luisa; Bagnarelli, Patrizia; Olivieri, Attilio title: Severe COVID‐19 in a patient with chronic graft‐versus‐host disease after hematopoietic stem cell transplant successfully treated with ruxolitinib date: 2020-07-14 journal: Transpl Infect Dis DOI: 10.1111/tid.13401 sha: doc_id: 321064 cord_uid: pe8466n1 Graft‐versus‐host disease (GVHD) is a common complication of hematopoietic stem cell transplant, which is known to be mediated by cytotoxic T‐cell effectors and dysregulated inflammatory cytokines. Similarly, the lung injury observed in severe COVID‐19 cases appears to be related to a massive production of pro‐inflammatory cytokines. The selective JAK1/2 inhibitor ruxolitinib has shown promising results in the context of GVHD, and different trials are currently underway in patients with severe COVID‐19; nevertheless, no clinical observation of safety or efficacy of treatment with ruxolitinib in this context has been published yet. We describe a first case of severe COVID‐19 developed after hematopoietic stem cell transplantation in a patient with a concomitant chronic GVHD (cGVHD), in which a treatment with ruxolitinib was administered with good tolerance and positive outcome. The institutional review board of the Ancona University Hospital approved the off-label treatment, and an informed consent for data collection and off-label treatment was obtained. A 59-year-old man who had undergone an allogeneic hematopoietic stem cell transplantation from a matched sibling brother for high-risk, triple-negative (JAK2, MPL, CALR) myelofibrosis, presented at our outpatient clinic for a scheduled appointment at 1 year after transplant, on March 3, 2020. He had no complaints, and physical examination was normal. His medical history was remarkable for an insulin-dependent type 2 diabetes and a latent tuberculosis infection. Blood count was normal; bone marrow biopsy showed a complete remission, with no evidence of fibrosis. Chimerism was 100% donor, and CD3+/CD4+ lymphocyte count was 278 per mm3. He has been receiving ruxolitinib 5 mg bid (offlabel use) for a steroid-refractory, moderate cGVHD with involvement of skin and mouth, achieving a complete response at the time of office visit. 6 He was then discharged with a follow-up appointment scheduled 3 months later, confirming ruxolitinib treatment up to the next visit. Two weeks later, he presented at the emergency room complaining of fatigue, dry cough, and mild dyspnea. Oxygen saturation was 97% while breathing in room air; body temperature was 36.8°C. Arterial blood gas analysis was normal. Blood count showed 5.15 × 10 9 /L white blood cells, with slight lymphopenia (0.9 × 10 9 /L); platelet count was 135 × 10 9 /L; and hemoglobin was within normal range. C-reactive protein was elevated (119 mg/L), while procalcitonin was normal. Coagulation parameters showed (Figure 1 ). On day 8, treatment with lopinavir-ritonavir was discontinued, as results of a negative trial had been published meanwhile. 9 On day 10, since the patient condition was not improving (PaO2/FiO2 ratio of 141), ruxolitinib was resumed (off-label use) at the dose of 5 mg bid. In fact, on that day, accumulating evidence suggested that mitigation of the exaggerated inflammatory response associated with COVID-19 might be beneficial in patients with severe symptoms. 10 In order to promptly detect common adverse reactions related to the drug, complete laboratory test was repeated twice weekly. Since no event was recorded, and platelet count remained stable, To our knowledge, this represents the first case of severe COVID-19 successfully treated in a recipient of hematopoietic stem cell transplantation with concomitant cGVHD. A major pathogenetic mechanism of the lung injury observed in severe COVID-19 cases appears to be related to a massive production of pro-inflammatory cytokines, and different approaches targeting this aspect are currently under investigation. 11, 12 In fact, the immunologic F I G U R E 1 Computed tomography scan of the chest performed the day before initiation of treatment with ruxolitinib and inflammatory cascade which follows SARS-CoV-2 infection is complex and not completely understood. Dysregulation of both innate and adaptive immunity leads to an exaggerated macrophage activation and T-cell proliferation, with a consequent abnormal production of pro-inflammatory mediators (ie, IFN-g, IL-2, IL-6, IL-12, TNF-a). Interestingly, a macrophage activation syndrome (MAS) resembling the one causing secondary hemophagocytic lymphohistiocytosis (sHLH) has been described in some patients with COVID-19. 13 Further, T-cell response plays a key role in viral clearance as well as in hyperinflammation. Of note, strikingly high proportion of T helper 17 cells (Th17) have been found in peripheral blood of patients with severe COVID-19, further supporting a TH17 type cytokine production in this disease. 14 Our report suggests that in this patient with severe COVID-19 developed after a hematopoietic stem cell transplant, treatment with ruxolitinib was feasible and well tolerated. Moreover, we observed a dramatic clinical improvement after ruxolitinib administration, albeit we cannot exclude that other factors could have contributed. The present report requires further confirmation, and results from prospective trials testing ruxolitinib in COVID-19 patients are eagerly awaited. 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