High rate of HSV-1 reactivation in invasively ventilated COVID-19 patients: Immunological findings

Abstract

SARS-CoV-2 infection can lead to severe acute respiratory distress syndrome with the need of invasive ventilation. Pulmonary herpes simplex-1 (HSV-1) reactivation in invasively ventilated patients is a known phenomenon. To date very little is known about the frequency and the predisposing factors of HSV-1 reactivation in COVID-19. Therefore, we evaluated our cohort of invasively ventilated COVID-19 patients with severe pneumonia for HSV-1 in respiratory specimens and combined these results with functional immunomonitoring of the peripheral blood. Tracheal secretions and bronchial lavages were screened by PCR for HSV-1 positivity. Comprehensive immunophenotyping and quantitative gene expression analysis of Interferon-stimulated genes (IFI44L, MX1, RSAD2, ISIG15 and IFIT1) and IL-1 beta were performed in whole blood. Time course of infection beginning at symptom onset was grouped into three phases (“early” phase 1: day 1–10, “middle” phase 2: day 11–30 and “late” phase 3: day 31–40). Pulmonary HSV-1 reactivation was exclusively observed in the later phases 2 and 3 in 15 of 18 analyzed patients. By FACS analysis a significant increase in activated CD8 T cells (CD38+HLADR+) in phase 2 was found when compared with phase 1 (p<0.05). Expression of Interferon-stimulated genes (IFI44L, RSAD2 ISIG15, MX1, IFIT1) was significantly lower after HSV-1 detection than before. Taken together, reactivation of HSV-1 in the later phase of SARS-CoV-2- infection occurs in parallel with a drop of antiviral innate responsiveness as shown by decreased expression of Interferon-stimulated genes and a concurrent increase of highly activated CD38+HLADR+ CD8 T cells.

CMV seropositivity is a potential novel risk factor for severe COVID-19 in non-geriatric patients

“…HSV reactivation has been more often described in critically-ill COVID-19 patients, despite its impact on hospital mortality is still controversial [ 22 , 23 , 42 ]. Moreover, HSV reactivation was associated to the length of stay on ICU and mechanical ventilation [ 42 ].…”

“…Recently, a few cases of CMV reactivation in the setting of severe COVID-19 have been reported [ 16 – 19 ]. Intriguingly, also reactivation of EBV and Herpes simplex virus (HSV) have been described [ 20 – 23 ], indicating that these latent herpesvirus infections may further contribute to the development of severe COVID-19. However, it remains to elucidate whether herpesvirus reactivations are a direct consequence of SARS-CoV-2 infections or of the treatments related to COVID-19 (for example steroids), and whether they affect the same category of patients.…”

Reactivation of Herpes Simplex Virus Type 1 (HSV-1) Detected on Bronchoalveolar Lavage Fluid (BALF) Samples in Critically Ill COVID-19 Patients Undergoing Invasive Mechanical Ventilation: Preliminary Results from Two Italian Centers

“…A possible speculative hypothesis to be further explored may be the lung inhalation after oropharyngeal reactivation, without significant pulmonary damage [15]. Regarding mortality, it should be considered that the available literature on the prognostic impact of HSV-1 reactivation in non-COVID-19 critically ill populations (which also remains controversial) may be not extrapolated directly to COVID-19 patients, owing to the possibly different immunological background [6,[15][16][17][18][19][20].…”

“…Critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia requiring invasive mechanical ventilation are at risk of developing bacterial, fungal, and viral superinfections [1][2][3][4]. Reactivation of herpes simplex virus type 1 (HSV-1) has been described in intubated critically ill patients with coronavirus disease 2019 (COVID- 19) pneumonia [2,3,[5][6][7][8].…”

COVID-19-associated opportunistic infections: a snapshot on the current reports

“…Reactivation of latent HSV and CMV infections has been reported among COVID-19 patients [ 138 ]. Seeßle et al [ 139 ] found a high rate of HSV-1 reactivation (83.3%, 15 out of 18 patients) in invasively ventilated COVID-19 patients. Encephalitis due to HSV-1 was reported in a 73-year-old woman who suspected to prior COVID-19 infection [ 140 ].…”