Sepsis is a frequent condition in critically ill patients and is associated with a substantial increase in health-care resources consumption. The number of cases of sepsis rose by an average of 9% per year. The increase in the incidence of sepsis has been also accompanied by an increase in sepsis-related mortality despite actual decreases in mortality rates among hospitalized patients. On the other hand, the rapidly increased life expectancy in developed countries makes to understand the different characteristics of severe sepsis in older patients a clinical priority and a challenge for clinicians.

For years, there has been a steady increase in the percentage of people older than 60 years as compared to the total population. In the 1950s, they accounted for only 8% of the population, increasing to 10% in 2000, and estimated to reach 21% by 2050 (1). Over the next few decades, the population aged over 80 years will double. In 2050, octogenarians will account for 9.6% of the total population in Europe and 9% in North America (2). One of the problems arising from population aging is an increased incidence and severity of diseases, such as sepsis both in the forms of community-acquired and hospital-acquired, as compared to the younger counterparts (3).

Older persons are more prone to infections due to the effects of aging, comorbidities, use of invasive devices, and factors associated with institutionalization. It has been shown that around 40–50% of all cases of bacteremia occur in older patients (4, 5). In addition, the incidence and mortality of severe sepsis in older patients has increased progressively to achieve a rate of 26.2 cases per 1,000 persons, with a 38.4% mortality rate in patients older than 85 years (3).

This increment in the incidence of severe sepsis in aging people has been reflected in the demographic changes of bed allocation in intensive care units (ICUs), where, at present, older patients represent around two-thirds of occupations (6). This situation will further increase over the forthcoming years as well as the amount of health-care resources required by these patients.

According to the World Health Organization definition, the segment of elderly people can be divided into young patients (less than 65 years), young elderly (aged 65–85 years), and old elderly (over 85 years) (7). It is well known that old elderly patients (over or 85 years) is a high-risk population due to their frailty and associated morbidity (8).

Moreover, there is a concern about the fate of very old patients admitted to the ICU, taking into account that the outcome of young elderly and old elderly ICU patients is usually worse than that of younger patients independently of the underlying diagnosis. Thus, important questions regarding suitability of ICU admission, treatment, and quality of life in this group of patients still remain unanswered.

In this review, we focus on risk factors, age-related pathophysiologic mechanisms, and immunologic events that impair host antimicrobial defenses in elderly patients with septic shock. We also discuss recent findings regarding the clinical impact, therapeutic strategies, and prognosis in older patients with sepsis.

There are several risk factors predisposing elderly patients to an increased incidence of sepsis.

Aging is unavoidable in humans; it is a polygenic process determined genetically on the one hand and intimately related to exogenous factors influencing each of the individuals throughout their life (13, 14). The steady accumulation of somatic mutations during an individual’s life results in a decreased capacity of cell regeneration, cell repair, and an altered function of the immune system.

The immune cells are constantly renewed from the hematopoietic stem cells, and in elderly subjects, both the proliferative capacity and the number of these immune cells are decreased due to progressive telomere shortening, resulting in an immune dysfunction over the years, which is known as immunosenescence (15).

This state of immunosenescence predisposes to the risk for the development of sepsis and also causes alterations in the body’s response leading to a more severe presentation of infection.

The diagnosis of sepsis is challenging and likely to be missed if not anticipated. Early signs and symptom may go unnoticed, while later clinical presentation can be very severe with very rapid progression to septic shock. In fact, the classical manifestations of systemic inflammatory response syndrome may be minimally present.

In elderly septic patients, febrile response could be blunted in up to 47% of cases, but other unusual or non-specific signs, such as weakness, malaise, delirium, confusion, loss of appetite, falls, or urinary incontinence may be present (41).

In many cases, establishing a prompt and correct diagnosis is further complicated by a lack of cooperation in the frail, dehydrated, debilitated, and cognitively impaired patient, which is a common situation in aging population. It is well known that speed in establishing an accurate diagnosis and implementation of rapid and effective resuscitation treatment are essential factors for optimizing survival rates. However, diagnosing sepsis is not always straightforward, particularly in the elderly patient who often have complex ongoing disease processes.

The optimal diagnosis of infection and sepsis in all patients is based on clinical signs and symptoms. Biologic laboratory markers (biomarkers), such as white blood cell count, C-reactive protein, procalcitonin, cytokine levels, and (to some extent) coagulation markers can potentially be used to assess prognosis and development of organ dysfunction, as well as to guide antimicrobial treatment and evaluation of response.

Recently, new definitions of sepsis aimed to facilitate and accelerate the recognition of patients at risk of developing sepsis have been proposed. Original concepts of sepsis were focused on inflammation response, but new definitions underline the pathobiology mechanisms of the disease. This approach helps stratifying patients at risk of sepsis not only for intensivists but also for other clinicians who may be less familiarized with this type of patients (47).

In this new perspective, sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. We need to identify infected patients most likely to develop sepsis as soon as possible, and sequential organ failure assessment (SOFA) is the score most commonly used in the ICU setting. An elevated SOFA score is associated with an increased risk of mortality. Although this score is not useful for the management of patients, it is a valuable indicator to characterize septic patients. The quick SOFA score based on high respiratory rate (≥22 beats/min), low systolic blood pressure (≤100 mm Hg), or altered mentation (Glasgow coma scale <15) is useful to suspect infection in patients who are at greater risk for a poor outcome (47).

In elderly patients, the most common source of sepsis is the respiratory tract followed by genitourinary infections, but, in general, the sites of infection are similar to patients of other age groups, involving the respiratory, urinary, and gastrointestinal systems as well as the skin and soft tissues (9, 48, 49).

Also, elderly patients are at increased risk of infections caused by multidrug-resistant organisms not only due to immunosenescence but also because of a greater exposure to institutionalization and an increased early use of broad-spectrum antibiotics, which may select more virulent and resistant strains (48, 49).

Some studies found an increased rate of methicillin-resistant S. aureus and vancomycin-resistant Enterococci as causative organism of sepsis in older patients. Also, the incidence of extended-spectrum β-lactamase producing Klebsiella spp. has been found to be higher among patients older than 65 years and younger than 14 years (9, 48, 49).

The “Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock” should be followed for the general care of elderly patients with severe sepsis and septic shock with the same aim of rapid initial management, including the 3- and 6-h reanimation bundles, and all measures proposed regarding hemodynamic monitoring, mechanical ventilation strategies, infection source control, fluid therapy, and nutrition (6, 48). On the other hand, a few specific considerations for the elderly septic patient should be taken into account.

In the elderly septic patient, it is mandatory to maintain an adequate preload in order to increase the cardiac output. However, aging patients usually have diastolic dysfunction, so that overzealous fluid administration can be problematic. Dobutamine, which can be used to improve tissue perfusion could produce different effects because of a relative resistance observed in the elderly patient and the arrhythmogenic response, in particular, in patients with cardiac ischemic disease (9, 48).

In relation to blood transfusion, a hemoglobin target of 7–9 g/dL, the same than in young adults should be attained. However, we should be alert in patients with low central venous oxygen saturation and ischemic myocardiopathy, which may be frequent in advanced age, because the protocol contradicts the early goal-directed resuscitation that targets a hematocrit of 30%.

The differences in pharmacokinetic and pharmacodynamic parameters such as reduced renal function make us to adjust the dosage of antibiotics as well as to consider an increased frequency of antimicrobial-related adverse effects in the elderly. In addition, older patients may be more susceptible to adverse drug events than younger patients (29, 50, 51).

Levosimendan is a calcium-sensitizing drug with inotropic and vasodilator properties to treat decompensated heart failure (52). Comparing with dobutamine, levosimendan use in patients with septic shock has shown improvements in hemodynamic variables (microcirculatory flow (53), renal, and hepatic function) (54). Results of a meta-analysis support the use of levosimendan in patients with sepsis but only 125 patients in total had been treated (55). However, data regarding the use of levosimendan in the elderly group are scarce. In a recent randomized controlled trial, levosimendan as standard therapy in a septic shock has not shown any improvement in survival or organ dysfunction (56).

The influence of age on the effect of the vasopressor agents has been recently examined in the study of Biston et al. (51) showing that the doses of vasopressor and adrenergic agents were similar independently of age and, therefore, interaction between age and vasopressor agents has no significant effect on outcome.

There is controversy with the use of steroids for septic shock, despite the fact that adrenal insufficiency is common in patients with advanced age.

In the Surviving Sepsis Campaign, due to scarce evidence of the lack of effectiveness and serious adverse effects of steroids, including hyperglycemia, immunosuppression, and exacerbation of myoneuropathy, low dose of intravenous hydrocortisone is only recommended in patients in which arterial blood pressure cannot be totally restored with fluid resuscitation and vasopressor therapy (29, 30, 51).

Furthermore, adequate management of sepsis and septic shock in the elderly requires supportive therapy including adequate nutrition, ulcer and deep venous thrombosis prophylaxis, and ventilatory support when necessary. Recent studies have documented that older patients are treated less aggressively than their younger counterparts, particularly those >85 years old (51).

It has generally been argued that aged patients have a significantly shorter life span and that survivors become more dependent and require more social and economical support than other age groups (57). However, in the study of Biston et al. (51) of a cohort of patients with mixed circulatory shock, old patients who survived had a good quality of life a few years after the event.

In the last decades, therapeutic modulation trying to attenuate aberrant immune response during sepsis has been attempted without success (58). Based on evidence that pro- and anti-inflammatory response are mounted simultaneously in septic patients (59), new therapeutic strategies have focused to restore homeostasis of the immune system and boosting immunity to control infection rather than inhibition of the inflammatory response (58–60).

It is important to underline the greater emphasis made on the dysregulated immune response in the last definition of sepsis. Two therapeutic approaches are recently proposed for the modulation of the aberrant immune response to sepsis (Table 2). The extracorporeal blood purification therapies, including convection-based strategies such as high-volume hemofiltration, high cutoff membrane, hemoperfusion with different adsorbents like polymyxin-B or Cytosorb™, and coupled plasma filtration adsorption could potentially have a positive impact in the immune response, despite the effects on removing inflammatory and anti-inflammatory cytokines through a modification of the phenotype and function of immune cells (61). Nevertheless, the efficacy regarding improvement of survival has not yet been elucidated and more clinical studies are needed (61, 62).

The second approach is based on reboosting the immune system (63). Recent studies have shown that HLA-DR expression could be useful in predicting infections and death by identification whether or not a patient with sepsis is in the immunosuppressive phase of the disease. Investigations in this line take relevance when establishing the use of immunomodulatory therapies, and it is possible that some patients may benefit from inhibition immune system response but, on the other hand, other patients could benefit from stimulation of the immune system (58). In this context, monocyte HLA-DR expression could be an optimal marker to determine the most adequate treatment option (59). In this respect, novel therapeutic strategies for severe sepsis and septic shock are currently considered to try to moderate the damage caused by innate immune response in endothelial tissues, and, therefore, to prevent secondary infections o reactivation latent viruses. The use of thymosin alpha 1 has shown very promising results inducing T-cells and dendritic cells maturation and was associated with lower mortality in septic patients (64).

Recombinant human IL-7 demonstrated the ability to restore normal lymphocyte functions, CD4 and CD8 T-lymphocyte proliferation, IFN-γ production, or induction of B-cells after stimulation (65). It has been reported that the administration of IFN-γ to septic patients can restore monocyte HLA-DR expression with the result in clearance of sepsis (66). Additionally, it has been also demonstrated that IFN-γ partially reversed immunoparalysis by attenuating the reduction of TNF-α (67). The use of drugs to increase the number of neutrophils has been also investigated but with limited results. Clinical trials found no evidence supporting the use of granulocyte colony-stimulating factor or granulocity macrophage colony-stimulating factor therapy in reducing mortality rate of septic patients (68). Treatment with the IL-1 blocking agent anakinra has recently showed good results improving survival of patients with organ dysfunction (69).

Therapies with intravenous immunoglobulins have not proven effective in sepsis. The differences in the composition, timing of administration of immunoglobulin in addition to a lack of knowledge of the mechanisms of action could be responsible for the different results obtained in the clinical trials (63, 70).

Elderly patients with severe sepsis and septic shock have high mortality rates of around 50–60%. The mortality rate due to severe sepsis in elderly patients is 1.3–1.5 times higher than in younger cohorts. A number of factors independently associated with death have been identified in critically ill patients, including preinfectious immune or genetic status, nosocomial events, comorbidities, severity of illness, age ≥75 years, and impaired level of consciousness (51, 71). Hospital mortality rates are also higher in frail than in non-frail patients.

Data regarding subsequent survival and quality of life after severe sepsis are limited, especially in the elderly who usually have a poorer functional outcome. The long-term prognosis is mainly dependent on previous functional status rather than on severity of illness at ICU admission (72–75).

It has been suggested that baseline physical function and frailty status could aid in prognosis and informed decision-making for very old critically ill patients (76). The severity of acute disease on admission can also influence in-hospital mortality and mortality after discharge in patients aged 80 or over altering greatly physical function of long-term hospital survivors (77–80).

It has been shown that elderly ICU survivors has a poorer quality of life prior to ICU admission than younger people, and although it could improve after hospital discharge, the quality of life remains lower than that of the general population (78, 79).

In a Canadian cohort study of 610 patients aged 80 years or older who where admitted in the ICU, only 26% of them survived and returned to baseline levels of physical function at 1 year (73). In this study, as lower were age, APACHE II score, Charlson comorbidity index, and frailty index, the physical recovery was greater. Also, the baseline physical function score and the specific diagnoses on admission were associated with recovery (73).

Some recent studies observed that advanced age alone is not a predictive negative factor for the success of surgical and ICU interventions, although associated comorbidities could decrease the likelihood of survival at discharge in all age groups (73, 75–77). It is also known that unplanned admissions to the ICU in elderly patients are associated with poorer outcomes as compared to planned admissions (71, 78).

It has been estimated that up to 29.6% of very patients were refused for ICU treatment, showing a significantly higher survival in ICU-admitted octogenarians than for patients who were considered too ill or old for ICU admission (71–77).

Management of sepsis is a frequent ICU challenge, with substantial mortality and a significant consumption of health-care resources. It is estimated that the number of cases of severe sepsis will grow at a rate of 1.5% per year, with a proportional increase in the group of patients with advanced age. The increased incidence of sepsis in elderly people is associated with a number of predisposing factors, including comorbid diseases, preadmission status, malnutrition, frailty, and an impaired function of the immune system (the so-called immunosenescence). The immunosenescence status increases both the risk for sepsis and a more severe presentation of infection and is probably related with a poor outcome.

Different studies have shown that older people have a higher mortality in association with severe sepsis, but it is important for clinicians to consider separately the general prognosis of a population of older patients and the prognosis of the individual patient. Age as a single factor predicts the length of stay in the ICU, but should not be used either to estimate the outcome or to determine treatment options for individual patients, given that the increased mortality observed in older patients with severe sepsis is thought to be due to the increased comorbidities among this group.

Differences in treatment decisions regarding the use of more aggressive treatment based only on age without considering other prognostic factors could lead an important number of older patients to prevent from the benefit from such treatment. On the other hand, although survival is the most important outcome, the quality of life of survivors is also relevant. New therapeutic approaches trying to handle aberrant immune responses like immunomodulatory therapies are emerging and may be the future in the management of infection, particularly in older patients. A better immunologic characterization of the patient is a cornerstone to get a better modulatory therapy of the immune response.

Elderly population will increase in the forthcoming years, so it is a priority for clinicians, especially intensivists, to understand the extent of the problem, socially and economically, and to assess therapeutic challenges and outcomes from a more efficient and effective way.

All authors contributed equally to the conception and design of the study and to the drafting of the article.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.