Key points

Introduction

The world is aging. The number of individuals aged 60 years and older is expected to increase globally from 841 million in 2013 to more than 2 billion by 2050. In the United States, persons aged 65 years and older are anticipated to double in number from 43.1 million in 2012 to 83.7 million by 2050. Fueled by a generation of baby boomers born between 1946 and 1964, more than a fifth of the US population will surpass 65 years of age by 2030. From 2009 to 2010, elders accounted for more than 19 million visits made to US emergency department (ED) visits, representing 15% of all ED visits nationally. More than a third of these visits warranted hospital admission for further care. As new advances in medicine and improved access to health care continue to extend the envelope of life expectancy worldwide, emergency physicians must be well versed in the timely, comprehensive, and compassionate care of our elders.

Infectious diseases account for widespread morbidity and mortality among the elderly. In 2012 alone, infectious diseases accounted for 13.5% (3.1 million) of all visits made by elders to US EDs. Hospitalization rates for infectious diseases in this segment of our population have steadily risen over the past 2 decades. Although respiratory tract infections, primarily pneumonia, account for most of these admissions, hospitalization rates for sepsis and urinary tract infections (UTIs) have dramatically increased since 2000, particularly in those aged 85 years and older. From 1998 to 2004, infectious diseases accounted for almost 14% of all hospitalizations of older adults in the United States, with total charges in excess of $261 billion. Not surprisingly, pneumonia and sepsis accounted for almost 60% of those charges. In a large retrospective study of 323 acute-care hospitals in California from 2009 to 2011, infection-related readmissions comprised more than a quarter of 30-day all-cause readmissions. Although mortality from heart disease, malignancy, chronic pulmonary disease, and cerebrovascular disease far outpaces mortality from infectious diseases in persons aged 65 years and older, pneumonia, influenza, and sepsis remain significant causes of death among elders in the United States.

The spectrum of infectious diseases in the elderly is wide ranging. This review examines the unique risk factors that render the elderly vulnerable to infection and focuses on the diagnosis and emergent management of severe sepsis and septic shock, pneumonia, urinary tract infections, central nervous system infections, and skin and soft tissue infections.

Introduction

The world is aging. The number of individuals aged 60 years and older is expected to increase globally from 841 million in 2013 to more than 2 billion by 2050. In the United States, persons aged 65 years and older are anticipated to double in number from 43.1 million in 2012 to 83.7 million by 2050. Fueled by a generation of baby boomers born between 1946 and 1964, more than a fifth of the US population will surpass 65 years of age by 2030. From 2009 to 2010, elders accounted for more than 19 million visits made to US emergency department (ED) visits, representing 15% of all ED visits nationally. More than a third of these visits warranted hospital admission for further care. As new advances in medicine and improved access to health care continue to extend the envelope of life expectancy worldwide, emergency physicians must be well versed in the timely, comprehensive, and compassionate care of our elders.

Infectious diseases account for widespread morbidity and mortality among the elderly. In 2012 alone, infectious diseases accounted for 13.5% (3.1 million) of all visits made by elders to US EDs. Hospitalization rates for infectious diseases in this segment of our population have steadily risen over the past 2 decades. Although respiratory tract infections, primarily pneumonia, account for most of these admissions, hospitalization rates for sepsis and urinary tract infections (UTIs) have dramatically increased since 2000, particularly in those aged 85 years and older. From 1998 to 2004, infectious diseases accounted for almost 14% of all hospitalizations of older adults in the United States, with total charges in excess of $261 billion. Not surprisingly, pneumonia and sepsis accounted for almost 60% of those charges. In a large retrospective study of 323 acute-care hospitals in California from 2009 to 2011, infection-related readmissions comprised more than a quarter of 30-day all-cause readmissions. Although mortality from heart disease, malignancy, chronic pulmonary disease, and cerebrovascular disease far outpaces mortality from infectious diseases in persons aged 65 years and older, pneumonia, influenza, and sepsis remain significant causes of death among elders in the United States.

The spectrum of infectious diseases in the elderly is wide ranging. This review examines the unique risk factors that render the elderly vulnerable to infection and focuses on the diagnosis and emergent management of severe sepsis and septic shock, pneumonia, urinary tract infections, central nervous system infections, and skin and soft tissue infections.

Aging and infection

The aging immune system creates a natural state of immunosuppression in the elderly, predisposing to infection. Immunosenescence is characterized prominently by a decline in adaptive immunity. Although circulating memory T cells increase over time in response to continued antigenic stimulation, the pool of naïve T cells is depleted through age-related thymic involution, compromising the primary T-cell response to new antigens. Loss of T-cell receptor repertoire diversity and intrinsic age-related naïve T-cell defects further impair the effectiveness of this cell-mediated immune response. As the pool of antigen-experienced memory B cells expands with age displacing naïve B cells necessary for new antibody formation, humoral immunity is likewise blunted. Reduced B-cell repertoire diversity, devolution of critical T-cell interactions needed for B-cell activation and differentiation, and decreased antibody affinity dampen the humoral response to infection and vaccines alike. Immunosenescence is also marked by the dysregulation of innate immunity. Polymorphonuclear neutrophils exhibit reduced chemotaxis, phagocytosis, and intracellular killing of pathogens, due in part to reduced toll-like receptor expression and activation. Similarly, age-associated decreases in macrophage, natural killer, and dendritic cell function are apparent. Impaired immune responses to new pathogens may also arise from basal activation of the innate immune system with increasing age, evidenced by increased levels of proinflammatory cytokines (eg, interleukin 6, tumor necrosis factor-α), clotting factors, and acute phase reactants (eg, C-reactive protein). Attributed to chronic viral infections (eg, cytomegalovirus) and cellular damage as well as age-related hormonal and metabolic changes, such dysregulated inflammatory responses may likewise contribute to the development of noninfectious diseases, such as atherosclerosis and Alzheimer disease. The aging immune system is a complex phenomenon that we have yet to fully comprehend.

Physical barriers to infection, such as the skin, wane with age, hastened in the setting of immobility. Weakening of the gag and cough reflexes, incomplete urinary bladder emptying, and other age-related changes allow pathogens to access and establish infection in previously protected compartments. Surgical wounds and medical devices (eg, central venous catheters, urinary catheters, endotracheal tubes) commonly used in health care circumvent these natural defenses altogether. Prosthetic joints, heart valves, cardiac pacemaker-defibrillators, and other implanted hardware can serve as a nidus for infection. Dementia, impaired coordination, and frequent falls and injuries further predispose the elder to infection. Malnutrition and peripheral vascular disease can impede wound healing. Other comorbid conditions, including diabetes mellitus, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and malignancy, may also increase an elder’s overall risk of infection. Those receiving immunosuppression for solid organ or bone marrow transplants, malignancy, or a host of inflammatory conditions are at even greater risk of infection involving a broad range of pathogens.

Atypical presentations are a hallmark of most diseases in the elder, often rendering the diagnosis of infection challenging. Nonspecific symptoms associated with acute functional decline are common including confusion, frequent falls, difficulty ambulating, reduced food intake, dysphagia, incontinence, weight loss, and failure to thrive, all of which can also be seen in a wide range of noninfectious processes in the elderly. Age-related dementia and polypharmacy can further limit the clinician’s ability to obtain a reliable history of symptoms from patients. Underreporting or downplaying of symptoms by patients can delay presentation to care for significant infections.

Fever, traditionally defined as a body temperature greater than 38°C (100.4°F), is absent or blunted in up to a third of elderly patients with an acute infection. Diminished thermoregulatory capacity and abnormal production and response to endogenous pyrogens with aging may be partly to blame. In patients hospitalized with moderate to severe pneumonia, the average temperature during the first 3 days of illness decreases by 0.15°C (0.3°F) with each decade increase in age, equating to a 1°C (1.8°F) difference in temperature between a 20-year-old and an 80-year-old patient with pneumonia. Healthy elders are also likely to have lower baseline body temperatures than younger adults. Febrile response may be delayed in many instances. In view of this, fever in older long-term care residents has been defined as (1) a single oral temperature greater than 37.8°C (>100.0°F), (2) repeated oral temperatures greater than 37.2°C (>99.0°F) or rectal temperatures greater than 37.5°C (>99.5°F), or (3) more than a 1.1°C (>2.0°F) increase in temperature greater than baseline; it may be reasonable to apply this definition to the elderly population as a whole. Tympanic thermometry is comparable in diagnostic accuracy with rectal thermometry for identifying infection when a lower fever cutoff of 37.3°C (99.1°F) is used; temporal artery thermometry is significantly less accurate. However, body temperatures greater than 38°C (100.4°F) generally equate with serious illness in elders presenting to the ED. Likewise, hypothermia relative to baseline body temperatures may also signal life-threatening infection, particularly in sepsis.

Severe sepsis and septic shock

Sepsis is a clinical syndrome that is characterized by a dysregulated inflammatory response to severe infection ( Table 1 ). Severe sepsis is defined as sepsis-induced organ hypoperfusion and dysfunction, outwardly manifesting as acute kidney injury, coagulopathy, encephalopathy, acute respiratory distress syndrome, and hypotension due to vasodilation, increased endothelial permeability, and functional adrenal insufficiency. Septic shock is distinguished by sepsis-induced hypotension that is refractory to adequate fluid resuscitation. More than half of all cases of sepsis in the United States occur in adults older than 65 years. The relative risk (RR) for developing sepsis is 13.1 times greater in elders (95% confidence interval [CI], 12.6–13.6) compared with those less than 65 years of age, and elders are 1.56 times more likely to die of sepsis (95% CI, 1.52–1.61). The incidence, disease severity, and mortality associated with sepsis are disproportionately high among the elderly in part because of immunosenescence, prolonged host inflammatory responses, a tendency toward coagulation activation and impaired fibrinolysis, and an increased susceptibility to microbial mediators, including endotoxin leading to profound and persistent hypotension. This hyperinflammatory state is followed by profound immunosuppression as a result of T-cell exhaustion in elderly patients, further increasing mortality and morbidity through secondary infections. Although significant advances have been made in emergency and critical care, mortality can range anywhere from 12.1% to 25.6% in severe sepsis to 30% to 50% in septic shock. Increasing age is an independent risk factor for severe sepsis and related mortality. Nursing home residence, a likely marker of frailty and multiple comorbidities, has also been associated with an increased risk of severe sepsis and death in elders.

Respiratory infections, bloodstream infections, and genitourinary infections are the most common underlying causes of sepsis in the elderly. Elders are more likely to develop sepsis due to gram-negative infections, particularly in the setting of pneumonia, and fungal infections compared with those less than 65 years of age. Those residing in long-term care facilities or with frequent health care contact may be at risk for infection with multidrug-resistant organisms. Clinical presentations of sepsis in the elderly can be muted until overwhelming infection devolves into septic shock. Severe infections, including those involving the bloodstream, are heralded predominantly by atypical symptoms, such as confusion, falls, malaise, incontinence, immobility, and syncope, rather than classic presentations of subjective fever, chills, cough, dysuria, or other symptoms of localized infection. Elders with severe bloodstream infections are often febrile, but this may be less common with advanced age (>85 years). Compared with younger adults, elders are less likely to be tachycardic and more prone to tachypnea and acute respiratory distress with severe infection. Most elders mount a significant leukocytosis in the setting of sepsis and bloodstream infection.

The initial management of severe sepsis and septic shock in elderly patients should focus on timely empirical antimicrobial therapy and aggressive volume resuscitation in accordance with current established international guidelines. Although several paradigms have been proposed to explain the role of infection in triggering and sustaining the immunologic cascade leading to cellular injury, irreversible organ damage, and death in severe sepsis and septic shock, appropriate antimicrobial therapy is critical to rapidly reducing pathogen load and improving mortality. Empirical antimicrobial therapy is considered appropriate if it has in vitro activity against a causative pathogen before it has been identified in the laboratory workup (eg, microbiologic culture, rapid molecular diagnostics). In a retrospective study of 5715 patients with septic shock, inappropriate initial antimicrobial therapy occurred in almost 20% of patients and was associated with a 5-fold reduction in survival. For this reason, empirical antimicrobial therapy should cover both gram-positive and gram-negative bacteria. When available, hospital antibiograms can help inform empirical therapy by highlighting regional and patient population–specific differences in antimicrobial susceptibilities for common bacteria. The most likely anatomic source of infection should also guide antimicrobial selection so that therapeutic drug levels are achievable in infected tissue and fluid (eg, lung, urine, cerebrospinal fluid [CSF]). Recent hospitalization, residence in a long-term care facility, antimicrobial exposure, and prior colonization or infection with a resistant organism should prompt expansion of empirical therapy to include organisms such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus , and multidrug-resistant gram-negative bacilli. Antifungal therapy is warranted in the setting of immunosuppression (eg, human immunodeficiency virus infection, hematologic malignancy, solid organ or hematologic stem cell transplant), neutropenia, prior extensive antimicrobial exposure, or extensive colonization with Candida . Empirical antimicrobial therapy should be initiated within the first hour of recognition of severe sepsis or septic shock. In a major retrospective study of septic shock, administration of appropriate antimicrobial therapy within the first hour of hypotension was associated with a 79.9% survival to hospital discharge. Survival declined by 7.6% with each subsequent hour, with a survival rate of 42% at a median delay of 6 hours. Early and appropriate antimicrobial therapy is essential to survival in severe sepsis and septic shock. Microbiologic cultures (eg, blood cultures) should be obtained before administering antimicrobials to help tailor pathogen-specific therapy but should not significantly delay treatment (>45 minutes), particularly in septic shock.

Pharmacokinetic and pharmacodynamic optimization of antimicrobial therapy to rapidly achieve therapeutic serum drug concentrations further enhances the clearance of pathogens in severe sepsis and septic shock. Initial antimicrobial therapy should start at the maximum recommended dose while taking into account baseline renal or hepatic insufficiency that may predispose an elder to drug toxicity. Age-related changes in body composition, total body water, and serum albumin all impact drug concentrations. Interstitial third spacing due to increased capillary permeability in sepsis can lead to subtherapeutic drug concentrations for many antimicrobials. Clinical pharmacists can play an invaluable role in selecting dosing strategies that maximize antimicrobial effect in severe sepsis, septic shock, and other severe infections in the ED. In addition to antimicrobial therapy, adequate source control (eg, abscess drainage, removal of an infected central venous catheter) is also integral to decreasing pathogen burden.

Protocolized, quantitative resuscitation strategies using intravenous fluids, vasopressors, inotropes, and blood transfusions seek to correct the circulatory dysfunction that results from the intense inflammatory response in severe sepsis and septic shock. Early goal-directed therapy using invasive hemodynamic monitoring has been shown to significantly reduce mortality in a landmark study. However, several recent randomized, multicenter studies have failed to recreate the success of this strategy, likely because of improved awareness, timely diagnosis, and early treatment of severe sepsis and septic shock over the past decade. Current guidelines support an initial minimum fluid challenge of 30 mL/kg of crystalloid in patients with sepsis-induced organ hypoperfusion, hypovolemia, or hyperlactatemia (≥4 mmol/L). Additional fluid challenges may be administered based on dynamic or static measures of fluid responsiveness. Elders with congestive heart failure, chronic renal insufficiency, or end-stage renal disease may benefit from guarded resuscitation with smaller fluid boluses to avoid volume overload. Vasopressors are recommended in the setting of hypotension that has not responded to initial volume resuscitation, with norepinephrine being the preferred agent. Although many sepsis intervention trials include elderly patients, those with significant medical comorbidities at risk of death are often excluded. Trials targeting high-risk elderly patients with severe sepsis or septic shock are greatly needed to better inform specific recommendations taking into account the altered physiology of aging. Nevertheless, standardized resuscitation protocols for severe sepsis and septic shock improve mortality in the elderly, likely through earlier recognition, empirical antimicrobial therapy, and aggressive volume resuscitation.

Indicators of poor prognosis in elderly patients with severe sepsis include the presence of shock, elevated serum lactate levels, and organ failure (particularly respiratory or cardiac). When present, hypothermia is an independent predictor of increased mortality in elderly patients with sepsis. Leukemoid reactions (white blood cell count >30.0 × 10 ³ /μL) carry a grave prognosis in elderly patients with sepsis. There is evidence to suggest that Predisposition Insult Response and Organ failure (PIRO), Sequential Organ Failure Assessment (SOFA), and Mortality in Emergency Department Sepsis (MEDS) scores may be useful in predicting mortality in elderly patients with sepsis presenting to the ED. Biomarkers, including cardiac troponin I and N-terminal probrain natriuretic peptide, may also have a role in predicting mortality in elders with severe sepsis or septic shock.

Elderly survivors of sepsis incur significant morbidity, frequently requiring skilled nursing and rehabilitative care after their acute hospitalization. Severe sepsis exacts a considerable toll on elderly survivors in the form of long-term functional disability and moderate to severe cognitive impairment. Controlling for individual presepsis levels and trajectories of geriatric comorbid conditions (eg, cachexia, incontinence, injurious falls), higher rates of low body mass index (<18.5 kg/m ² ) have also been demonstrated in elderly survivors of severe sepsis, suggesting that severe sepsis increases sarcopenia, the age-related loss of skeletal muscle mass. Such changes in brain function and body composition contribute to frailty, increasing elders’ need for assistance with activities of daily living and threatening their independence. Survivors of severe sepsis and other critical illness often require significant additional health care compared with their premorbid state, frequently in inpatient settings. From the vantage point of both the patients and the health care system, the early recognition and treatment of infectious diseases commonly encountered in elderly patients presenting to the ED must, therefore, assume an added urgency in order to prevent progression to severe sepsis and septic shock. Likewise, candid discussions with patients, family, and other care providers in the ED centered on patient preferences, goals of care, and anticipated clinical outcomes in severe sepsis and septic shock are particularly important given the high mortality and morbidity associated with this disease.

Pneumonia and influenza

Sir William Osler penned, “pneumonia may well be called the friend of the aged.” Furthermore, “a knowledge that the onset of pneumonia is insidious and that the symptoms are ill-defined and latent, should put the practitioner on his guard.” A century later, this characterization of pneumonia in the elderly holds true. More than 900,000 cases of community-acquired pneumonia (CAP) occur annually among US seniors, and approximately 1 in 20 adults older than 85 years develop CAP each year. Pneumonia is the most common infectious disease indication for hospitalization among adults more than 65 years of age. In 2013, influenza and pneumonia resulted in more than 48,000 deaths among elders in the United States. Elders are at increased risk for CAP because of impaired mucociliary clearance and diminished protective cough reflexes, which allow inhaled or aspirated pathogens to gain access to the lower respiratory tract. Increased lung compliance and reduced vital capacity contribute to decreased functional reserve in old age, rendering the elder less able to compensate for serious pulmonary infection. These vulnerabilities are further compounded by chronic pulmonary disease (eg, COPD), asthma, and tobacco dependence, all well-established risk factors for CAP. Congestive heart failure, diabetes mellitus, poor functional status, low body weight, and recent weight loss also place elders at risk for developing pneumonia.

A combination of cough, fever, and dyspnea was absent in two-thirds of elders diagnosed with CAP in one study, whereas almost half presented with delirium or acute confusion. Fever was absent in more than a third of elders. Other symptoms, including chills, sweats, pleuritic chest pain, headache, and myalgias, are also less common in the elders with CAP compared with changes in mental status. This characterization holds true as well for elders residing in long-term care facilities, even in those with severe pneumonia. The presence of tachypnea with CAP increases with age.

In the United States, Streptococcus pneumoniae is the most common cause of CAP in community-dwelling elders. Haemophilus influenzae , Legionella pneumophila , Chlamydia pneumoniae , Mycoplasma pneumoniae , and less commonly gram-negative bacilli are also causative pathogens. Elders residing in long-term care facilities are susceptible to pneumonia from the same organisms but also to S aureus , gram-negative bacilli including Klebsiella pneumoniae and Pseudomonas aeruginosa , and anaerobes, the last category of organisms occurring in the context of aspiration. Pneumonia due to multidrug-resistant organisms, such as MRSA and gram-negative bacilli, varies among elderly long-term care facility populations. Elders older than 75 years have a 15-fold higher incidence of pneumonia due to influenza than young adults. Other respiratory viruses commonly associated with pneumonia in the elderly include human metapneumovirus, parainfluenza virus, respiratory syncytial virus, and rhinovirus.

Elders presenting to the ED with fever, tachypnea, or any clinical suspicion for pneumonia should undergo chest radiography. However, the accuracy of radiography may be limited in the face of poor functional status, early pneumonia, or immunocompromised states; computed tomography of the chest may have increased utility. In addition to standard laboratory tests, patients requiring hospitalization, particularly to an intensive care unit, should have 2 blood cultures drawn before the administration of antimicrobials to guide definitive therapy. Pneumococcal and Legionella urinary antigen testing can further aid in determining the cause of pneumonia. Severity-of-illness scores taking into account epidemiologic, clinical, and diagnostic factors can help identify elders at high risk for mortality with CAP and inform admission decisions. The Pneumonia Severity Index (PSI) has been evaluated in elders and in EDs as a strategy for identifying low risk patients with CAP who can be safely treated as outpatients ( Table 2 ). The CURB-65 score ( C onfusion, U remia, blood urea nitrogen >7 mmol/L or 20 mg/dL; R espiratory rate ≥30 breaths per minutes; B lood pressure, systolic <90 mm Hg or diastolic ≤60 mm Hg; Age ≥ 65 years) has also been validated in older adults presenting with CAP ( Table 3 ). No difference in overall test performance has been identified between PSI, CURB-65, or CRB-65 (which excludes laboratory testing to assess for uremia). These scores incorporate age as a primary variable; therefore, increasing age translates to greater predicted mortality risk. In the end, clinical judgment taking into account comorbid illness, new supplemental oxygen requirements, the inability to take oral medications, patient safety, and other social considerations also factor into ED decision-making regarding hospitalization for CAP.

Table 2

Pneumonia severity index

Characteristic	Points
Demographic factors
Age (y)
Men	Age
Women	Age −10
Nursing home residence	+10
Coexisting illness
Malignancy (active)	+30
Liver disease	+20
Congestive heart failure	+10
Cerebrovascular disease	+10
Chronic kidney disease	+10
Physical examination findings
Altered mental status	+20
Respiratory rate ≥30 breaths/min	+20
SBP <90 mm Hg	+20
Temperature <35°C (95°F) or ≥40°C (104°F)	+15
Pulse ≥125 beats/min	+10
Laboratory and radiographic findings
Arterial pH <7.35	+30
BUN ≥11 mmol/L or 30 mg/dL	+20
Sodium <130 mmol/L	+20
Glucose ≥14 mmol/L or 250 mg/dL	+10
Hematocrit <30%	+10
Pa o 2 <60 mm Hg	+10
Pleural effusion on chest radiograph	+10

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