**3. Discussion**

We observed a SARS-CoV-2 infection presenting with fever, respiratory and gastrointestinal symptoms in a severely immunosuppressed LTX recipient with good evolution during hospitalization on intravenous empiric antibiotics. We did not administer the drug regimen for COVID-19 recommended at that time, which included lopinavir/ritonavir and hydroxychloroquine due to potential drug–drug interactions and absence of deterioration during hospitalization and also because of emerging evidence of the antiviral combination lacking therapeutic benefits [4]. The special features of this SARS-CoV-2 infection in this LTX recipient were: (1) predominant gastrointestinal symptoms at presentation with a diagnosis of norovirus co-infection and fairly mild respiratory symptoms, despite some new and atypical findings on chest imaging that showed regression in the follow-up chest CT 6 weeks later, (2) a moderately elevated pro-inflammatory response (no "cytokine storm" or hyperinflammation) during early infection, probably blunted by immunosuppression, and (3) a delayed increase in sIL-2R, which normalized after admission.

We assume the positive outcome in this case was due to profound immunosuppression, probably because this averted most inflammatory responses, with an initially reduced cytokine storm and a lack of progression of pulmonary infiltrates, both of which are typically observed in SARS-CoV infection of immunocompetent patients [5,6]. The inflammatory immune reaction was limited to a mildly increased IL-6 at presentation and a sIL-2R peak after 1 week, which returned to reference values one week later. The observed inflammation markers were only slightly raised when compared to the reported cytokine data in immunocompetent COVID-19 patients. This modified inflammatory response correlates with the mild clinical course, since cytokines like IL-6 and sIL-2R are described as useful markers to estimate the severity of COVID-19 [7]. The pathogenetical role of IL-6 in COVID-19 manifestations is still not fully understood and there is currently a lack of evidence of the beneficial therapeutic impact of IL-6 inhibitors. The current multicenter randomized controlled trial of tocilizumab (IL-6 receptor blockade, licensed for cytokine release syndrome) in patients with severe pneumonia due to SARS-CoV-2 and elevated IL-6 may shed more light on this topic. The N-protein of SARS-CoV seems responsible for the cytokine dysbalance and for the inflammatory-mediated acute lung injury [8]. The lower inflammatory response relies on glucocorticoids mitigating the N-protein of SARS-CoV-2-induced pulmonary inflammation and modulating the involved cytokines. In the future, the harm and benefit of corticosteroid treatment needs to be carefully considered in patients after SOT with SARS-CoV-2 infection. In immunocompetent patients, the routine administration of high doses of corticosteroids are currently discussed controversially due to concerns that steroids might even exacerbate lung injury by facilitating viral replication in patients with SARS-CoV-2-associated lung injury [9], as previously shown in influenza pneumonia [10]. Another therapeutic approach supports immunosuppressive therapy by aiming to reduce hyperinflammation in particular by using the mechanisms of action observed for tacrolimus in similar settings. It targets the inhibition of viral replication and, accordingly, leads to a reduction of virus titer [11,12]. Anti-inflammatory and anti-cytokine drugs seem to be a promising therapeutic approach in controlling viral damage, assuming that SARS-CoV-2 invades endothelial cells and induces endothelial inflammation, resulting in microvascular dysfunction with a subsequent pro-coagulant state and ischemia in essential organs like the heart, lung, kidney, liver and intestine, which also explains the worse clinical outcome of patients with pre-existing cardiovascular disease [13]. In LTX recipients, respiratory viral infections have been shown to play a major role in acute and chronic allograft dysfunction. Higher sIL-2R levels released from activated B-cells and monocytes have been found in patients suffering from neoplastic, infectious and autoimmune diseases, but also in SOT recipients affected by allograft rejection [14]. Although these results are suggestive of imminent allograft dysfunction in our patient, the most recent results from the follow-up visit 6 weeks after hospital discharge demonstrated a continuously increasing lung function and the chest CT scan showed no evidence of chronic allograft dysfunction, as judged by the lack of detection of air trapping in expiration images. Of course, a longer follow-up of the patient is needed to allow for a final assessment of this aspect, since the onset of complications may be delayed by months. This case of COVID-19 has an atypical pulmonary presentation in the initial chest CT, showing three small nodular consolidations without predominant ground-glass opacities, which is in contrast to the already published cases in the literature (Figure 1a–c). We attribute this to the suppressed immune system and the thereby modified or reduced cytokine storm, which might explain the mild clinical course of the disease, as mentioned

above. The follow-up chest CT showed diminished or completely dissolved consolidations as a sign of recovery from the modified pulmonary involvement of COVID-19 (Figure 1d–f).

In order to understand the disease evolution and to choose the optimal time point in the disease course for initializing therapy, COVID-19 illness was classified recently into Stages I–III, representing increasing grades of severity [15]. Our patient would be placed between early infection (Stage I: mild symptoms, lymphocytopenia, dry cough and diarrhea) and the beginning of the pulmonary phase (Stage II A: abnormal chest imaging).

Viral diseases can have atypical presentations, as has been observed for the different clinical manifestations of SARS-CoV-2 infection and COVID-19 [2,16,17]. SOT recipients should therefore remain cautious avoiding infection [6,18]. Due to atypical presentations, an infection with SARS-CoV-2 may also lead to delay in diagnosis if there is not a high index of suspicion initially for SARS-CoV-2. A kidney transplant recipient, initially suffering from gastrointestinal symptoms, but then developing respiratory symptoms within 48 h, has recently been described [18].

An important feature was the clinical presentation with vomiting, diarrhea and fever up to 38.9 ◦C. Fever and diarrhea seem to be common initial symptoms in SOT, which has also been reported in SOT recipients under immunosuppressive therapy [19–21]. Until today, SARS-CoV-2-infected patients after SOT are scarce compared to the worldwide incidence of COVID-19 [22–25]. We suspect an underestimated number of SARS-CoV-2 infections in SOT due to atypical clinical presentations thus often not qualifying the patient for SARS-CoV-2 testing in many centers. Moreover, the prudent behavior of LTX recipients and other SOT recipients due to the fear of infectious disease may also explain the low number of COVID-19 cases among these patients.

The stool specimen of our patient was positive for norovirus. Norovirus might increase gastrointestinal wall permeability, resulting in diarrhea and leading to a secondary SARS-CoV-2 infection by fecal–oral transmission [26]. However, this hypothesis cannot be proven, especially since diarrhea is a common manifestation of COVID-19 in immunocompetent and solid organ transplant recipients. Based on the current knowledge we cannot determine the route of infection of this patient since no index patient could be found, and because the patient presented with both gastrointestinal and respiratory symptoms.
