Dear Editor,

Coronavirus disease 2019 (COVID-19) is a global public health emergency and new knowledge about it and its etiological agent, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is deemed necessary in order to reduce the death burden around the world [1]. In this regard, a 67-year-old Italian male patient, dyslipidemic, hypertensive, active smoker, and a 49-year-old Italian male patient, affected by hypertrophic cardiomyopathy, were admitted to the intensive care unit (ICU) in feverish state (> 38.1 °C) for SARS-CoV-2 pneumonia complicated with acute respiratory distress syndrome, characterized by diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH) (Fig. 1a). Upon ICU admission, IgG and IgM serum immunoassay against herpes simplex virus 1 (HSV1) turned out negative (IgG: 3 U/mL and 1 U/mL; IgM: 5 U/mL and 2 U/mL; negativity ranges: IgG < 7.5 U/mL and IgM < 16 U/mL). During the hospitalization period, both the patients received ab initio oxygen and antipyretic and steroid therapy (methylprednisolone: 80 mg/day for 1 day; then 40 mg/day for 3 days; and, at last, 20 mg/day for 1 day), in addition to hydroxychloroquine and low-molecular-weight heparin; on the second day and on the thirteenth day of hospitalization, respectively, an interleukin-6 (IL-6) immunoassay revealed high values (587.86 ρg/mL and 813.34 ρg/mL) and tocilizumab was started in both cases. Persistently positive at molecular diagnostics for SARS-CoV-2 on nasopharyngeal swab or bronchoalveolar lavage, the patients died after 17 days and 39 days from the admission and minimally invasive autopsies in a negative pressure room with 6 air changes per hour were performed, in accordance with the guidelines from the Centers for Disease Control and Prevention of Atlanta (GA, USA) [2]. The quantitative polymerase chain reactions applied to plasma samples had detected in both patients more than 14,000,000 copies/mL of HSV1, respectively, 3 and 7 days before death, occurred despite acyclovir administration. Serum tests performed on the death days had revealed very high value of alanine transaminase (2.888 U/L and 3.102 U/L), aspartate transaminase (4.482 U/L and 2.889 U/L), lactate dehydrogenase (22.102 U/L and 12.427 U/L), total bilirubin (5.57 mg/dL and 7.35 mg/dL), and international normalized ratio (3.55 and 2.10), all laboratory data consistent with fulminant hepatitides. Moreover, 76 h prior to death, the oldest patient had undergone a computed tomography (CT) showing signs of acute hepatitis (Fig. S1). Therefore, the ultimate cause of death is presumably to be traced back to acute liver failure in both patients. Since caused by a novel pathogen, the ongoing pandemic surely requires innovative pharmacological approaches in the attempt to save critically ill patients [3]. Among these, corticosteroids and tocilizumab (atlizumab), a humanized monoclonal antibody against IL-6 receptor, have gain consensus for their ability to mitigate at some extent the cytokine storm in COVID-19 [4, 5]. In 2017, the USA Food and Drug Administration has approved tocilizumab use for the treatment of cytokine release syndrome, whose IL-6 is the key mediator, in course of chimeric antigen receptor T cell therapy [6]. However, superimposed infections are the most common adverse effects in oncohematological or rheumatic patients treated with tocilizumab due to induced immunosuppression [7]. In COVID-19 critical patients, lymphocytopenia worsens this clinical scenario [8, 9], as ascertained also in our two patients during the disease course, with absolute lymphocyte counts of 0.36 × 103/μL and 0.23 × 103/μL (normal range 1.00–4.50 × 103/μL), favoring opportunistic infections, such as invasive pulmonary aspergillosis (Fig. 1b, c) or fulminant herpetic hepatitis (Fig. 1d, e). They are burden by a high mortality rate and their incidence is rising because of an increased number of immunocompromised patients (e.g., bone marrow transplant, chemotherapy, AIDS) [10, 11]. Opportunistic sequelae should be also considered in serious COVID-19 patients submitted to anti-cytokine storm drug regimens.

Fig. 1
figure 1

Invasive pulmonary aspergillosis arisen on DAD and DAH from SARS-CoV-2 infection (a H&E, × 10 objective); at higher magnification (b H&E, × 20 objective), fungal angioinvasion is noticeable. Spores and septate hyphae at acute angles of around 45° are well highlighted in black by Grocott’s methenamine silver stain (c × 20 objective). The liver is massively involved by an acute necrotizing inflammation due to herpetic infection (d H&E, × 20 objective): almost all the hepatocytes are in fact positive for HSV1, as shown in brownish staining by specific immunohistochemical assay (e 10A3 clone, DAB chromogen kit, × 20 objective)

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