Lower respiratory tract infections (LRTIs) are among the leading causes of ICU resource utilization (4). Before the advent of the SARS-CoV-2 pandemic, the incidence of viral-associated LRTIs requiring ICU admission varied greatly among different studies, and ranged between 16 and 49%, with the most frequently isolated viruses being influenza, human rhinoviruses (HRhV), human coronaviruses (HCoV), respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIV), and adenoviruses (HAdV) (4–7). Common viruses are detected in respiratory samples of patients with nosocomial pneumonia with an incidence ranging from 13.8 to 32% in adults, and as high as 69.2% in pediatric population (8–13).

Current seasonal influenza epidemics are caused by influenza A strains (A/H3N2 and the 2009 pandemic strain H1N1—A/H1N1pdm09) and influenza B lineages (B/Yamagata and B/Victoria), resulting in 3–5 million cases of severe infections annually around the world (14). The annual casualties from influenza epidemics are estimated up to 650,000 people globally, while the respiratory excess mortality rate is estimated between 0.1 and 6.4/100,000 for patients younger than 65 years, 2.9 and 44/100,000 for people 65 and 74 years old, and as high as 17.9–223.5/100,000 for those older than 75 years old (15). The Centers for Disease Control and Prevention (CDC) reported that annual estimates of flu cases, hospitalizations and deaths in the United States (U.S.) ranged among 9–45 million, 140,000–810,000 and 12,000–61,000, respectively during 2010–2020, with the 2017–2018 flu season bearing the highest disease burden (16). A U.S. study estimated that among 114,000–633,000 influenza-hospitalizations during three flu seasons (2010–2013), 18,000–96,000 patents required ICU admission (17). The same study demonstrated that the risk of death during influenza admissions increased with age (0.2–0.9% in children<18 years old, 1.8–2.8% of adults 18–64 years old, and 3.4–4.7% of those ≥65 years old), and the majority of hospitalizations (54–70%) and deaths (71–85%) occurred in patients aged ≥65 years old (17).

HCoVs are ubiquitous viruses with worldwide distribution and yearlong transmissibility [Figure 1; (18, 19)]. Among them, three betacoronoviruses have caused epidemics of severe pneumonia within the last 20 years. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) caused outbreaks and epidemics of severe acute respiratory infections mainly in China and the Arabian peninsula (19–22). SARS-CoV-2 emerged in China in December 2019 and has led to an unprecedented pandemic with more than 90 million confirmed cases of the so-called Coronavirus Disease 2019 (COVID-19) and nearly 2 million deaths across the globe (23). Since the onset of the pandemic, cumulative data from the U.S. demonstrate that the majority of SARS-CoV-2 infections (54%) are diagnosed among people aged 18–49 years old; while only 10% of the total diagnoses are made in older adults (≥65 years old), this age group represents the majority of symptomatic cases and COVID-19-associated hospitalizations (90 and 46%, respectively) (24). Both symptomatic illness and hospitalization rates are very low among children aged 0–4 years old (3 and 1%, respectively) (24). The current global case fatality rate ranges between 1.1 and 4.4% among different countries, although during the first wave of the pandemic this rate was much higher in Italy and Spain, reaching up to 14.5 and 11.4%, respectively (25). Finally, the number of COVID-19 patients requiring ICU admission varies greatly among countries and among the different phases of the pandemic, but it ranges between 0.2 and 108 cases per million population (26). MERS-CoV causes outbreaks in Middle East mainly within hospital settings (27). Since the first confirmed case in 2012, the World Health Organization (WHO) has reported 2,494 cases of MERS-CoV in 27 countries and 858 deaths among them, leading to a case fatality rate of 36% (28, 29).

HPIVs are common causes of RTIs, targeting primarily young children and causing nearly 40% of all acute RTIs in this age group (30). Adults can also be infected; up to 11.5% of adult hospitalizations for RTIs attributed to HPIVs (31–33). An epidemiological study in Kuwait demonstrated that HPIVs were isolated from 2.6% of immunocompetent patients with viral infections requiring admission in pediatric and adult ICUs (34). Concerning HRhV, a recent epidemiological study in mechanically ventilated adult patients in five ICUs demonstrated that HRhV were the second most prevalent virus (5%) after HPIV (6%), independently of the cause of ICU admission (35). Moreover, the prevalence of HRhVs was significantly higher in patients with severe RTIs (9.6%) compared to those admitted for other reasons (2.6%), thus signifying their contribution in severe LRTIs (35). Another retrospective study reported a prevalence of HRhV of 7.5% and a mortality rate of 18.2% among adult critically ill patients, although not all these deaths were directly connected to HRhV detection; however, among all HRhV-positive patients, 59.1% fulfilled the definition of pneumonia (36). The incidence of RSV infections in adults is surprisingly higher than what it was previously believed. Notably, RSV is detected in 12% of all medically attended adults aged ≥50 years old with RTIs (37–39). In 2015, about 1.5 million older adults in industrialized countries suffered from RSV-associated acute RTIs, and 214,000 (14.5%) were admitted to hospital; the same year, RSV was associated with 14,000 in-hospital deaths in older adults globally (40). According to data from the U.S., the annual incidence of RSV infection in elderly adults has been reported about 3–7% and 4–10% of healthy and high-risk patients, respectively (41). Moreover, this study found similar clinical outcomes for both RSV and influenza A infections in terms of length of hospital stay, need for ICU and mortality rates (41). Specific adult groups are at high risk for severe infections and intubation form HMPV infections, but younger patients may also develop severe LRTI and ARDS requiring intubation and mechanical ventilation (35, 42–44). A recent multicenter study in France found an incidence of HMPV-positive patients of 3% among 3,148 hospitalized adults with acute RTIs (45). In this study, 21% required admission in ICU and 4% died during hospitalization among HMPV-positive patients (45). Other studies have reported HMPV-related mortality rates in adults comparable with or slightly lower than those of influenza and RSV (43, 44).

The most commonly identified viral pathogens among critically ill patients with neurological infections (mainly encephalitis and meningoencephalitis) include herpes simplex virus (HSV), varicella zoster virus (VZV), and arboviruses like West Nile Virus (WNV). The epidemiology of the viruses that are implicated in central and/or peripheral nervous system infections is outlined in Table 1.

Ebola virus is among the deadliest pathogens of viral hemorrhagic fever (VHF) syndrome, with a case fatality rate varying from 25 to 90% and an average mortality rate of 50% (59). Between 2014 and 2016, an Ebola epidemic resulted in more than 28,000 cases with more than 11,300 casualties in Sierra Leone, Liberia and Guinea, while an outbreak is currently ongoing in West Africa [Figure 1; (59)]. Marburg virus has a case fatality rate ranging from 24% to as high as 88% (average 50%) (60). The virus was initially discovered during a European outbreak caused by imported African monkeys in 1967, and since then is responsible for sporadic cases and outbreaks mainly in Central and South Africa (60). Dengue virus is currently endemic in more than 100 countries across 5 WHO regions, and is accountable for approximately 390 million infections annually; although Asia has about 70% of the global dengue burden, a steep worrisome rise in cases and associated deaths was observed in 2019 across several countries (61). The disease has also caused outbreaks in the European continent, representing the second most common cause of fever (after malaria) in returning travelers from low- and middle-income countries, although these data were drawn before the onset of SARS-CoV-2 pandemic (61). Severe dengue requiring hospitalization is estimated to affect 500 000 people annually, with a case fatality rate of 2.5% (62). Lassa virus is currently endemic in Western Africa (63). In contrast to other VHF pathogens, 80% of infected people remain asymptomatic with an overall mortality rate being as low as 1%; however, case fatality rate among those who develop VHF is 15% (63). Of note, pregnant women at the third trimester are at increased risk for severe infection with Lassa virus with high mortality rates (maternal death and/or fetal loss occurring in more than 80% of the cases) (63). Hantaviruses are divided into the “New World” strains, that cause sporadic cases and outbreaks of “hantavirus cardiopulmonary syndrome” (HCPS) mainly in the Americas, and the “Old World” strains that cause the “hemorrhagic fever with renal syndrome” (HFRS) in Europe and Asia (64, 65). HCPS is a potentially fatal disease with a case fatality rate of 40% (66). One third of the HFRS-deaths are associated with fulminant unresponsive shock. However, case fatality rate in HFRS is not as high as the HCPS, which ranges from <1% to 5–15% (67). Finally, the Crimean-Congo hemorrhagic fever (CCHF) virus is distributed in countries of the Africa, the Balkans, the Middle East and the Asia, and causes outbreaks with mortality rates up to 40% (68).

Adequate innate and adaptive immune responses play a pivotal role in controlling viral infections. Innate immune response begins with the recognition of pathogen-associated molecular patterns (PAMPs) by the pathogen recognition receptors (PRRs) of the host cells (69). The activation of these receptors via signaling pathways induces the production of pro-inflammatory cytokines and anti-viral molecules, notably type I and III interferons (IFNs), as well as the migration of innate immune cells at the site of infection (69). Dendritic cells bridge innate and adaptive immunity by mediating antigen presentation in lymphoid tissues (70). Viral peptides are presented to CD8+ T cells by major histocompatibility complex (MHC) class I molecules, leading to their transformation into effector cells. CD4+ helper T cells are activated by the recognition of antigen-MHC class II complexes on antigen-presenting cells and induce both CD8+ T cell and B cell responses, the latter leading to specific antibody formation (71).

After primary infection, multiple viruses fall into latency within the host cells; characteristic examples are the members of Herpesviridae family, which become dormant inside neurons (VZV, HSV-1, HSV-2), B cells (EBV), or myeloid cells (CMV). The capacity of latency allows these viruses to reactivate in response to triggering factors, like stress-induced immune paresis leading to clinical manifestations that vary from minor infections to serious complications (Table 2). A prospective cohort study demonstrated that non-immunocompromised patients with sustained sepsis exhibited considerably high frequencies of detectable viral DNA from a variety of viruses like CMV (24.2%), EBV (53.2%), HSV (14.1%), human herpesvirus 6 (HHV-6) (10.4%), and Transfusion transmitted virus (TTV) (77.5%), with two or more viruses being detected in 42.7% of these patients (95).

CMV infection is defined by the isolation of CMV antigens or nucleic acid in body fluids or tissue specimens, as opposed to CMV disease that necessitates the presence of concurrent symptoms and/or signs (96). According to multiple meta-analyses, the incidence of CMV infection in non-immunocompromised critically ill patients has been reported as high as 35%, occurring usually between the 14th and 21st day of ICU admission (97, 98). The highest incidence is observed among patients with prior seropositivity, indicating that reactivation rather than primary infection is the main mode of CMV infection in this population (98). The flawed balance between exaggerated inflammation and transient immunosuppression in the subset of patients with sepsis sets the grounds for CMV reactivation. Tumor necrosis factor alpha (TNF-α) promotes directly CMV gene expression (99). As T cell immunity plays a major role in suppressing the CMV replication, both CMV-induced immunodeficiency and sepsis-induced immune dysfunction may contribute in CMV reactivation (100–102). A meta-analysis by Lachance et al. reported that CMV reactivation in immunocompetent critically ill patients is associated with adverse outcomes, including higher ICU and overall mortality, prolonged duration of mechanical ventilation and ICU stay, more nosocomial infections and increased need for renal replacement therapy (103).

HSV reactivation has been frequently reported in non-immunocompromised critically ill patients (104). Isolation of HSV from bronchoalveolar lavage fluid specimens has been associated with adverse outcomes, like longer duration of mechanical ventilation, prolonged ICU stay and increased mortality (105). HSV detection has been associated with several risk factors in critically ill patients, such as intubation, prolonged mechanical ventilation, ARDS, extensive burns, advanced age, HSV-IgG seropositivity, use of corticosteroids and herpetic mucocutaneous lesions (97). However, it remains unclear whether HSV isolation in mechanically ventilated patients equals to actual HSV infection (either as reactivation or as a de novo infection) or it is just a surrogate marker of underlying disease severity (106). Hence, it is still controversial whether, how or when treatment should be applied in these cases (107, 108).

VZV reactivation has been associated with prolonged duration of fever in immunocompetent children in the ICU (109). EBV DNA, detected in blood samples of ICU patients, has been correlated with increased morbidity and mortality (110). Nonetheless, the clinical significance and the need of pre-emptive treatment of these reactivations remain obscure and will only be answered by large, well-designed, randomized controlled trials in the diverse population of immunocompetent critically ill patients.

The advent of potent immunosuppressive drugs has increased the survival rate of previously bleak diagnoses, especially in hematological patients and solid organ transplant recipients (SOTRs), but at the same time has increased the incidence of opportunistic viral infections and viral reactivations leading to an upsurge in the need for higher level of care.

Diagnosis of viral infections cannot be solely based on symptoms and signs, especially among critically ill patients who may have atypical clinical presentations. Laboratory-based techniques like viral cultures, electron microscopy and serology have been largely substituted by nucleic acid amplification tests (NAATs), sequencing (including next generation sequencing) and antigen detection methods, due to their increased accuracy and faster turnaround times (148, 149). Many commercially available rapid tests using nucleic acid amplification or antigen-based techniques are currently available for respiratory viruses (148, 150, 151). NAATs have advanced the sensitivity and specificity of influenza detection, as well as the identification of mutant variants that may be associated with increased disease severity, like the NA V263I and NS1 K196E for the influenza A H3N2 strain and the D222G for the influenza H1N1 pandemic strain 2009 (1, 152–154). Similarly, the diagnosis of SARS-CoV-2 infection is based on real time reverse transcription polymerase chain reaction (rRT-PCR) in respiratory tract specimens, although sensitivity of rRT-PCR is not 100% (155). Many factors may jeopardize the accuracy of the currently utilized SARS-CoV-2 NAATs, like inappropriate specimen collection techniques, handling of specimens, presence of interfering substances or antiviral treatment, manual errors, sample contamination, and testing outside the diagnostic window; all these factors should be considered when interpreting a negative result, especially during an ongoing pandemic (156). Although novel techniques have advanced our capacity to detect viruses, one should keep in mind that detection does not always correlate with pathogenicity (157). Results of such tests should guide clinical decisions in the context of a compatible clinical syndrome. Although antigen-based diagnostics for SARS-CoV-2 are generally less sensitive than molecular techniques, their utilization is rising globally, as they are usually less expensive than NAATs and provide results within minutes of sample acquisition (158).

Diagnosis of central nervous system (CNS) infections is typically made by detecting the viral genome in cerebrospinal fluid (CSF) by PCR, which yields high sensitivity and specificity rates (159). False negative results may occur early in the course of the infection (<72 h), in which case it is prudent to repeat PCR a few days later (159). Intrathecal serology may complement nucleic acid detection in some viruses like in VZV and arboviral CNS infection (159, 160).

Imaging studies in viral pneumonias have low specificity compared to molecular tests, but can complement and guide both diagnosis and management of critically ill patients. Distinct patterns of chest computed tomography (CT) scan, may distinguish between some viral families that tend to induce specific radiological patterns (161). For SARS-CoV-2-induced pneumonia specifically, chest CT was found sensitive and moderately specific for the diagnosis of COVID-19 in patients with suspected infection, thus offering limited capacity of distinguishing between SARS-CoV-2 infection and other causes of acute lung injury (162).

Brain imaging may be highly characteristic in certain viral CNS infections. High signal on T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences in temporal lobes, especially when asymmetrical, are highly characteristic magnetic resonance imaging (MRI) findings of HSV encephalitis (163). MRI findings in arboviruses are not specific, but may show a predilection for deep gray matter (basal ganglia) and the brainstem (160).

Clinical manifestations of viruses causing severe respiratory infections may range from asymptomatic or mild upper RTI to severe pneumonia with respiratory failure, septic shock-like syndrome, multi-organ dysfunction, and numerous other complications (Table 3), depending on both viral and host factors. The WHO has designated the terms of influenza-like illness (ILI) and severe acute respiratory infection (SARI) to embrace the typical presentation of viral pneumonias (188). Since there are no major differences in the initial management of most viral pneumonias (especially those who not have a specific treatment) these umbrella-terms allow healthcare professionals to quickly identify and manage these patients accordingly.

A wide array of viral pathogens causes encephalitis (Table 4). In affected patients, a detailed travel, exposure and sexual history should be obtained, along with meticulous clinical examination for rashes and/or focal neurologic deficits that could suggest a certain viral pathogen (e.g., HSV). Geographic and epidemiologic clues are frequently the only suggestive features of a specific viral pathogen (Figure 1 and Table 1). Examples include current mosquito activity for arboviral encephalitis, regions with high tick population for tick-borne encephalitides and animal bite wounds for rabies. HSV-1 is the most common cause of sporadic viral encephalitis (189). Prompt and accurate diagnosis of HSV CNS infection is crucial as the timely initiation of targeted treatment has a significant impact on the outcome.

Fever, headache, lethargy and clinical signs of meningismus are features of aseptic meningitis. Abnormal sensorium is the hallmark of encephalitis, and although not often, signs of both entities can be found concurrently leading to the diagnosis of meningoencephalitis. Viral encephalitis and meningoencephalitis frequently lead to altered mental status and decreased level of consciousness that warrants intubation and management in ICU. Acute disseminated encephalomyelitis (ADEM) is a post-infectious sequela of viral encephalitis, precipitated by numerous possible viruses that may necessitate the need of critical care due to coma, seizures, or tetraplegia (190). The absence of viral detection along with histological findings of perivascular inflammation and demyelination suggest an immune-mediated disease (191). Other viral illnesses, not necessarily confined in the brain, can produce post-viral neurologic syndromes with prominent clinical manifestation from the CNS leading to severe morbidity and mortality (Table 5).

Infection control measures are of paramount importance for prevention of viral infection transmission, especially within hospital settings. Modes of viral transmission can be either direct or indirect depending on the viral strain: direct transmission occurs through contact with infectious materials such as skin, secretions, blood, body fluids, contaminated surfaces and materials, etc. as well as via large droplets (diameter >5 μm), while indirect modes involve transmission through suspended air particles (airborne transmission of droplet nuclei, <5 μm) (201). Typically, droplet and contact precaution measures (for example in influenza and SARS-CoV-2 cases) involve patient isolation, source control (e.g., placement of face mask in non-intubated patients) and donning of level two personal protective equipment (PPE) (202, 203). Patients with airborne viruses such as measles and VZV require isolation in a specialized airborne infection isolation room and source control (as above); furthermore, donning of a level 3 PPE is prerequisite for contacting patients infected with airborne viruses, as well as when aerosol producing procedures are performed in patients with other respiratory viruses like influenza, SARS-CoV-2, and MERS-CoV (202). Ebola and other VHF pathogens are contracted via direct contact with patient's body fluids, contaminated medical supplies and equipment, or contaminated environmental surfaces (204). Therefore, although most blood-borne and contact-transmitted viruses do not require high level self-protective measures, donning of level 3 or higher PPE is essential when caring for patients with Ebola or other human-to-human transmitted VHF viruses (205). Imperatively, proper donning and doffing of PPE as well as meticulous hand hygiene are of paramount importance for infection control and reduction of in-hospital/in-ICU viral transmissions.

Although severe de novo viral infections necessitating ICU admission or viral reactivations in immunocompromised patients generally require treatment, provided that an effective therapy or management plan actually exists (Table 7), data on when and how to treat immunocompetent critically ill patients with viral reactivation are still inconclusive. To date, there is no evidence-based guidance for CMV or HSV reactivation treatment in critically ill immunocompetent patients. Regarding HSV reactivation (especially when it is clinically evident, e.g., in the oropharynx), treatment with aciclovir has been proposed in immunocompromised patients, not only because of cytotoxic therapies but also due to conditions such as extensive burns; moreover, treatment should probably be administered in patients with positive HSV test in respiratory samples who have evidence of pulmonary invasion or clinical deterioration that cannot be attributed to other etiology (206, 207). Besides clinical features and organ involvement-directed decision making, it has been proposed that patients with high viral loads (≥10⁵ copies/mL) may also be entitled to treatment for HSV reactivation (208).

The effects of CMV reactivation on adverse clinical outcomes in immunocompetent critically patients have been associated with higher blood viral loads (208). Although no studies have robustly responded to whether and when CMV reactivation should be treated in this patient population (209), it has been suggested that therapy should be administered if CMV reactivation is associated with organ-involvement and/or if high viral loads are detected (≥10³ copies/mL) (208).

Two randomized controlled trials assessing the use of prophylactic or preemptive treatment with aciclovir for HSV reactivation in mechanically ventilated patients, found that aciclovir administration did not improve clinical outcomes (207). As for HSV, two randomized controlled studies (the GRAIL-trial and the CCCC-trial) evaluating the efficacy of preemptive treatment for CMV reactivation in seropositive patients, failed to show benefit in IL-6 levels changes and in clinical outcomes, respectively (209–211). The GRAIL-trial, however, demonstrated that ganciclovir group had significantly more ventilator-free days in the sepsis subgroup analysis (209, 211). Based on expert-opinion, it has been suggested that preemptive treatment may be given in patients either at high-risk for HSV or CMV reactivation or in those who already have reactivation but at an early stage, before the advent of clinically evident infection (208). On the other hand, both aciclovir and ganciclovir have potentially serious adverse effects, thus the need for their administration in critically ill patients should be weighed against patient safety and cost-effectiveness (212).