Different studies show that transient or persistent immunosuppression is a risk factor for morbidity and mortality in critically ill patients [7]. Especially on subjects suffering from trauma, recent major surgery or sepsis, several authors shown that different parameters obtained from the blood count [i.e., absolute lymphocyte count (ALC) and lymphocyte subsets, such as CD4/CD8 and regulatory T cell] are suitable biomarkers for evaluating the immune function in critically ill patients and strongly correlated to prognosis [8, 9]. In clinical practice, ALC is one of the most briefly available biomarkers, reflecting the immune status in critically ill patients as well representing useful tool for screening patients in various immune regulation therapy conditions [10, 11]. It has long been established that lymphopenia increases the risk of infection and related death in hospitalized patients [1], especially in elderly patients or those admitted to Intensive Care Units (ICU) [12]. In particular, age represents an important risk factor, since the elderly are known to have blunted immunity, a condition responsible for specific organ failures, subverting the functions of immune cells [13].

In our series, conducted in an emergency unit, we reported a high prevalence of transient lymphopenia (more than half of patients), with significant correlations with clinical and biohumoral parameters.

According to persistence of lymphopenia, the trend of this parameter during hospital stay is also associated with different types of adverse clinical outcomes [14, 15]. As regard, in an extensive study, Pei Fei et al. have retrospectively evaluated over 10.000 critically ill patients admitted to ICU, highlighting that patients with persistent lymphopenia showed the highest incidence of negative outcomes [in-hospital mortality HR 1.44, 28-days mortality HR 1.66, development of catabolism syndrome HR 1.79, respectively) [6]. In the long-term prospective cohort study conducted in the Copenhagen General Population Study, Warny et al. found that patients with lymphopenia had higher mortality for all causes (HR 1.63), and, in particular, for CVD (HR 1.88), respiratory (HR 1.88) and infectious diseases (HR 1.86) [1].

In this regard, in our study, we highlighted that lymphopenia is more associated with a higher mean age, highly prevalent in patients > 65 years; moreover, lymphopenia has shown an important impact on some clinical aspects of the patient, such as length of hospital stay, identifying subjects with clinical fragility. Thus, ALC can be recognized as a useful marker easily evaluated through routine blood analysis at hospital admission and at discharge, becoming a worthwhile tool useful to personalized clinical management, to better stratify the risk of patients’ fragility, to target treatment up to adjuvant therapies potentially stimulating lymphocytes.

Infectious diseases, up to sepsis, represent a significant phenomenon related to the host–pathogen interaction, in which the immune response has an important role in determining critically ill patients. In particular, it often leads to identifying major defects in immunity during recovery, conferring increased susceptibility to secondary infections and leading to worsened outcomes [16, 17]. The intensity of the inflammatory response is mainly determined by the patient's background, such as comorbidities (e.g., cancer and hematological malignancies, solid organ transplant, autoimmune and systemic diseases, HIV, renal insufficiency, and liver failure, chronic alcoholism, malnourishment), use of immunosuppressive drugs, as well as the acute event that induces hospitalization [18].

In our study, we demonstrated that subjects with transient lymphopenia were more likely to have infectious and respiratory diseases as diagnosis for hospitalization.

Infection diseases can induce multiple defects both in innate and adaptive immunity including apoptosis-induced depletion of immune effector cells (lymphocytes and dendritic cells), monocyte deactivation, T cell exhaustion, increased myeloid-derived suppressor cells, and increased T regulatory cells [7].

In large population, Juan Carlos Andreu-Ballester et al. have found an high prevalence of lymphopenia (41%) during hospital stay, especially in patients with infectious diseases, highlighting that lymphopenia was closely correlated with higher in-hospital and post-discharge mortality; evaluating the relationship of lymphopenia with the four levels of the severity of illness and the risk of mortality, these authors found that lymphopenia was related to worse indexes at the time of hospital admission [19].

Community-acquired pneumonia (CAP) is an important infectious disease causing sepsis, characterized by high in-hospital mortality (4–14%) and significant development of multi-organ failure [20]. In CAP, the host response has been mainly focused on innate immunity and the inflammatory response [21, 22]. Recently, CAP associated with lymphopenia (L-CAP) has been identified as an independent risk factor for 30-day mortality [23]. As regards, in a large population of patients hospitalized for CAP, Mendez et al. found lymphopenia in over 39% of patients, characterized by decreased levels of all lymphocyte subsets, with partial recovery of CD4+ and CD8+ cells at day 4. Moreover, L-CAP patients presented a worse severity of systemic inflammation (higher levels of proinflammatory, granulocyte colony-stimulating factor, and monocyte chemoattractant protein-1) [22].

In our study, we identified the persistence of lymphopenia in a significant percentage (19%) of patients at hospital discharge, especially in subgroups with a significantly increased mean number of comorbidities, such as diabetes mellitus, previous COVID-19 infection, CVD and cognitive deficit.

Physiologically, infection diseases are associated with an immunological response with consequent activation and increase of T lymphocytes (both CD4+ and CD8+), B lymphocytes and natural killer cells, although after viral infections lymphocyte counts can be reduced [24]. As regards, possible causes can be related to consumption of lymphocytes, direct viral damage to lymphocytes, apoptosis of lymphocytes and immunosuppressive effects of the virus [25].

It has been well described that acute COVID-19 disease, in up to 50% of patients, is associated with a reduction in lymphocyte count, in particular the absolute counts of T lymphocytes (CD4+ and CD8+), suggesting that T cell immune function of COVID-19 patients is weakened [26] and associated with poor outcomes [27].

Recent studies have focused attention on the relationship between acute COVID-19 disease and diabetes mellitus (DM); as regard, Wu et al. have evaluated the circulating levels of lymphocytes in patients hospitalized for acute COVID-9 disease, highlighting that the diabetic subgroup showed a reduction in the average levels of circulating lymphocytes (50%), earlier onset of lymphopenia (52%) and greater duration of hospitalization (20%), compared to non-diabetic patients [28]. Several studies showed that DM patients often may present immune impairment, particularly concerning reduced levels of T lymphocyte (both CD4+/CD8+) and Natural Killer lymphocytes, suggesting decreased host defense to infectious diseases [29, 30]. Furthermore, the acute COVID-19 disease uses angiotensin converting enzyme 2 (ACE2), expressed by epithelial cells of the lung, intestine, and kidney for cellular internalization; in DM patients, increased expression of ACE2 enzyme has been shown, suggesting a greater susceptibility [31], as well as a consensual reduced activity of the T lymphocytes [32].

While acute effects of acute COVID-19 on the immune system have been studied, long-term impacts of SarS-CoV-2 on the cellular immune system remain to be analyzed. In an interesting article, Liu et al. have evaluated the immunological characteristics of peripheral blood mononuclear cells in convalescent patients after 2 months from acute COVID-19 disease, highlighting several morphological and functional aspects, including significant decreases in frequencies of invariant NKT and NKT-like cells, increased expression of Ki67 and TIM-3 on both CD4+ and CD8+ T cells, and reduced cytotoxic potential of T cells and NKT-like [33].

In our cohort, among the main comorbidities already present at hospital admission and associated with the persistence of lymphopenia, CVDs showed a significant prevalence.

Muthiah Vaduganathan et al. have performed a post hoc analysis of the EVEREST trial, conducted on hospitalized patients with worsening heart failure (HF) and ejection fraction (EF) ≤ 40%, evaluated during a 1-year follow-up, focusing attention on relationship between lymphocyte count with post-discharge outcomes. These authors found that patients with lymphopenia were older and with higher rates of comorbidities (diabetes mellitus, atrial fibrillation, and kidney insufficiency) and were clinically characterized by wide QRS duration, high natriuretic peptides, and low EF. Although lymphopenia during hospitalization was normalized in the majority of patients in the early post-discharge period, interestingly mild lymphopenia was associated with an increased all-cause mortality (HR 1.31), cardiovascular mortality or HF hospitalization at 3 months from hospital discharge (HR 1.14) [34].

Beyond hospitalized patients, circulating levels of lymphocytes in outpatients with chronic HF predict survival up to 1 year [35]. In last decades, several possible mechanisms have been proposed explaining the relationship between lymphopenia and CVD and HF; among these the main suggested elements were hemodynamic features, such as elevated bi-ventricular filling pressures, splanchnic congestion, with direct enteric losses of lymphocytes or leukocyte redistribution [36]; immunological features, such as strong immune activation, release of cytokines (i.e., tumor-necrosis factor-1), and apoptotic mechanisms, directly inducing reductions in lymphocyte counts (particularly T-helper cell and B-cell) (27–28); hormonal features, such as the activation of the hypothalamic–pituitary–adrenal axis inducing increased endogenous production of cortisol and catecholamines [34].

In summary, lymphopenia should be valued at the time of hospital admission by physicians as a factor influencing the prognosis, the management and the treatment of these patients. It is useful to pay high attention, especially to subjects with persistent lymphopenia during hospitalization, in order to identify subgroups of patients at higher frailty who require a closer monitoring to avoid a bad prognosis.