key: cord-1044832-366js2km authors: Collange, Olivier; Tacquard, Charles; Delabranche, Xavier; Leonard-Lorant, Ian; Ohana, Mickaël; Onea, Mihaela; Anheim, Mathieu; Solis, Morgane; Sauer, Arnaud; Baloglu, Seyyid; Pessaux, Patrick; Ohlmann, Patrick; Kaeuffer, Charlotte; Oulehri, Walid; Kremer, Stephane; Mertes, Paul Michel title: COVID-19-associated multiple organ damage date: 2020-06-21 journal: Open Forum Infect Dis DOI: 10.1093/ofid/ofaa249 sha: dc869c482413b671b21e0e66223758e0ec8fc164 doc_id: 1044832 cord_uid: 366js2km A 56 years old man presented a particularly severe and multisystemic case of COVID-19. In addition to the common lung and quite common pulmonary embolism and kidney injuries, he presented ocular and intestinal injuries that, to our knowledge, have not been described in COVID-19 patients. Although it is difficult to make pathophysiological hypotheses about a single case, the multiplicity of injured organs argues for a systemic response to pulmonary infection. A better understanding of physiopathology should feed the discussion about therapeutic options in this type of multifocal damage related to SARS-CoV-2. A c c e p t e d M a n u s c r i p t Due to the emergence of an epidemic cluster in Mulhouse, a city located 100 km south of Strasbourg, Alsace was one of the first French regions to be affected by the coronavirus (SARS-CoV-2). As a result, all hospitals in the region, including the Strasbourg University Hospitals, had to deal with the epidemic wave earlier and more intensely than the rest of (Figure 1c ). Curative anticoagulation with unfractionated heparin (UFH) was started 6h after surgery. SARS-CoV-2 RT-PCR on fecal samples was negative. Major endothelial activation was evidenced (FVIII >600%, vWF:Ag 766%). Lupus anticoagulant was present but antiphospholipid antibodies were negative against cardiolipid, β2-GPI, phosphatidylserine, phosphatidylethanolamine, annexin and prothrombinase. Antithrombin was 108%, protein C 86%, and complement was normal (HC50, C3 and C4). Non-significant anti-nucleosomes were detected in HEp2 cells. We did not find more than 1% of schizocyte on peripheral blood smear.At day 16, pulmonary and hemodynamic functions were dramatically improved but the patient presented consciousness disorders, 3 days after sedation withdrawal. The Glasgow coma score (GCS) was 4. The patient displayed diffuse areflexia, tetraparesis and a left extensor plantar reflex. Direct and consensual pupillary reflexes were normal. The patient had a slow horizontal pendular movement of the eyes. Electroencephalography showed a A c c e p t e d M a n u s c r i p t bifrontal and reactive slowing, possibly related to residual sedation. Brain magnetic resonance imaging (MRI) revealed bilateral deep cerebral nuclei (dentate nucleus, pallidum, and thalamus), bilateral internal capsules, corpus callosum and adjacent white matter lesions corresponding to the association of cytotoxic and vasogenic edema with intralesional hemorrhage and contrast enhancement secondary to blood-brain barrier leakage. These abnormalities were suggestive of necrotizing-hemorrhagic encephalitis (Figure 2a and 2b) . At day 30, kidney function had also improved but the patient still needed dialysis. Consciousness level progressed very slightly but the patient remained comatose (GCS 5). The slow pendular movements of the eyes were no longer present. A second brain MRI showed no change. A c c e p t e d M a n u s c r i p t Our patient had a particularly severe, multisystemic case of COVID-19. In addition to the common lung and quite common kidney injuries, he presented bilateral pulmonary embolism, mesenteric ischemia, encephalitis and eye damage. commonly have neurologic manifestations [1] . After the first phase of resuscitation, he developed severe consciousness disorders. MRI images were compatible with necrotizinghemorrhagic encephalitis especially located in deep cerebral nuclei and internal capsules, which was in accordance with the observed parkinsonism and behavioral disorders as well as the tetraparesis and extensor plantar reflex, respectively [2] . Concerning the eye injury, to our knowledge, this is the first description of posterior uveitis or scleritis during COVID-19 [3] . Pulmonary embolism has recently been identified as a frequent complication in ICU COVID-19 patient populations [4] . We observed in our cohort of COVID-19 patients 30% of acute pulmonary embolus [5] . The digestive complication is rare. In our university hospital and among the 315 COVID-19 ICU patients, this was the only case of bowel resection. The patient had no rhythm disorder and the abdominal angioscan showed no mesenteric vascular involvement. The pathological examination showed no classic sign of mesenteric venous ischemia [6] , but the presence of submucosal small thrombi rather indicated thrombotic microangiopathy. This kind of microthrombi has already been described in the lungs in a recent series of 10 minimally invasive autopsies [7] . To our knowledge, we report here the first pathological description of intestinal injury possibly linked with COVID-19. Although it is difficult to make pathophysiological hypotheses about a single case, the multiplicity of involved organs and the absence of virus in the various fluids collected outside the lungs argue for systemic response to infection [8, 9] . We previously described that ICU A c c e p t e d M a n u s c r i p t patients with severe COVID-19 developed life-threatening thrombotic complications [10] . Perturbations of hemostasis, bilateral pulmonary embolism and the presence of microthrombi on the intestinal resection piece would be in favor of multifocal thrombotic microangiopathy (TMA) without a diagnosis of disseminated intravascular coagulation. Antiphospholipid syndrome (APLS) is another possible diagnosis but this can only be confirmed after a second positive test at three months. A rate of less 1% of schizocyte does not allow us to strictly affirm the diagnosis of TMA [11] . Nevertheless, the multiplicity of organ injuries and especially the histology of intestinal injury allow us to hypothesize that the pathophysiological process accompanying the COVID-19 in our patient is linked to a form of TMA. TMA syndromes are very diverse and the pathological features are vascular damage that is manifested by arteriolar and capillary thrombosis with characteristic abnormalities in the endothelium and vessel wall [12] . In this way, we provide a complementary and interesting element to the other work linking COVID-19 to an atypical form of TMA [13] . For instance, Ciceri et al. proposed a new term to define the atypical form of TMA accompanying the COVID-19 (microvascular COVID-19 lung vessels obstructive thrombo-inflammatory syndrome, micro-CLOTS) [14] . We treated this patient presenting a bilateral pulmonary embolism with curative anticoagulation. If the physiopathological process involved in the multifocal injuries we observed was related to TMA or APLS, a plasma exchange could have been considered. Nevertheless, plasma exchanges are probably not conceivable in this epidemic context, where health care resources are limited. We think it is useful to share our experience to feed the discussion about therapeutic options in this type of multifocal damage related to SARS-CoV-2. A c c e p t e d M a n u s c r i p t M a n u s c r i p t Cerebral MRI (a,b) : Bipallidal (arrow), right thalamic (arrow head), both internal capsules (star) lesions, hyperintense on FLAIR (a), with areas of contrast enhancement on T1 after contrast (b) corresponding to blood-brain barrier leakage. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Can the Coronavirus Disease 2019 (COVID-19) Affect the Eyes? A Review of Coronaviruses and Ocular Implications in Humans and Animals Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Acute Pulmonary Embolism in COVID-19 Patients on CT Angiography and Relationship to D-Dimer Levels Mesenteric Thrombosis Complicating Influenza B Infection Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19 At the heart of COVID-19 COVID-19 and Multiorgan Response High risk of thrombosis in patients in severe SARS-CoV-2 infection: a multicenter prospective cohort study ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes Syndromes of thrombotic microangiopathy The case of Complement activation in COVID-19 multiorgan impact Microvascular COVID-19 lung vessels obstructive thromboinflammatory syndrome (MicroCLOTS): an atypical acute respiratory distress syndrome working hypothesis Written consent was obtained from the next to kin of the patient. The work has been approved by local ethic committee and it conforms to the correct standards. A c c e p t e d M a n u s c r i p t