(BQ) Part 2 book “Infectious diseases in critical care” has contents: Bloodstream infection in the intensive care unit, infection of pulmonary arterial and peripheral arterial catheters, adjunctive and supportive measures for community-acquired pneumonia, assessment of resolution of ventilator associated pneumonia,… and other contents.
Chapter 27 27 Influenza P.R Brookmeyer, K.F Woeltje 27.1 Introduction 27.2 History Influenza infections account for significant morbidity and mortality both in the United States and worldwide Approximately – 15 % of the world’s population develops the disease annually In the United States, 114,000 hospitalizations and 36,000 deaths are thought to occur annually [1], with an estimated annual economic impact of – billion dollars [2] Complications of influenza include primary and secondary pneumonias, respiratory failure and rarely myositis and neurologic failures These complications often lead to ICU admission, especially in the elderly or immunocompromised population Superimposed on these annual epidemics are periodic pandemics, the most famous being the “Spanish Influenza” of 1918 – 1919, in which at least 20 million and perhaps as many as 100 million persons succumbed worldwide [3] Based on conservative attack and mortality rates, it is estimated that in the United States alone the next influenza pandemic may result in 314,000 – 734,000 hospitalizations, and claim between 89,000 and 207,000 lives, with an economic impact of 70 – 170 billion dollars [4] In the new pandemic, it is projected that the ICU capacity in the United States will be overwhelmed, requiring the painful decision to withhold care from patients unlikely to survive, focusing on patients most likely to respond to ventilatory and other therapy The influenza virus has likely been causing annual epidemics and periodic pandemics since antiquity One of the first references to influenza in the “modern literature” appears to be Sydenham’s account in 1679 [5] In a classic review of historical pathology by Hirsch, 299 outbreaks of influenza occurring at an average interval of 2.4 years were calculated between 1173 and 1875 [6] Industrialization and the increased pace of transportation resulted in increasingly rapid spread of severe pandemic influenza This culminated in the 1918 – 1919 “Spanish Influenza.” This famous pandemic was notable for its surprisingly heavy toll on young adults, with mortality rates in some areas reaching – 10 % In the United States, draconian infection control measures included closing public schools, creating quarantines, and travel passes At least three additional somewhat milder pandemics occurred throughout the remainder of the 20th century (Fig 27.1) 1917 H1N1 1957 27.3 Virology The influenza virus is a member of the Orthomyxoviridae family, a family which includes influenza A, B, C, Thogoto virus, and the infectious salmon anemia virus This family is characterized by a host derived envelope, a negative sense single stranded, segmented RNA genome, and envelope glycoproteins important in viral entry and exit from cells The morphology of the three 1977 H1N1 1957 H2N2 1968 1968 H3N2 Fig 27.1 Influenza A antigenic shifts 27.3 Virology subtypes of influenza is similar, with an 80 – 120 nm viron size, – 12 structural proteins, and – gene segments On the surface of the influenza virus are spikelike projections of glycoproteins that possess either hemagglutinin or neuraminidase activity, both of which are critical to viral replication The hemagglutinin facilitates entry of the virus into host cells by attachment to sialic-acid receptors A major function of the neuraminidase is to catalyze the cleavage of glycosidic linkages to sialic acid, which allows the completed virion to be released from infected cells [7] There are at least 16 antigenetically diverse hemagglutinins and distinct neuraminidases in influenza A, the majority of which exist in non-human hosts [8] Influenza A viruses are typically designated HxNy where the x and y represent which hemagglutinin and neuraminidase, respectively, the virus carries Thus influenza A H3N2 possesses a type hemagglutinin and a type neuraminidase The numbering scheme is arbitrary and carries no intrinsic meaning; the numbers only represent a way to distinguish between types of the molecules In contrast, influenza B has only one known hemagglutinin and only one neuraminidase Other viral proteins include the Matrix (M) protein, which controls nuclear transport, the Nucleoprotein (NP), a regulator of transcription, and Matrix (M2) protein, an ion channel required for uncoating Influenza is classified into types A, B and C based on differences in viral proteins Influenza C is somewhat morphologically distinct, and is classified in a different genus from influenza A and B It infects both humans and swine, but tends to cause only mild disease without season variation [9] In contrast, both influenza A and B are major causes of disease Influenza B infects only humans, typically causing severe disease in the elderly or high risk patients It rarely causes epidemics, and does not cause pandemics Influenza A infects many hosts, including humans, birds, swine, horses, and marine mammals It is a common cause of both annual epidemics and periodic pandemics 27.3.1 Antigenic Variation While infection with influenza results in the development of both humoral and cell mediated protective immunity, individuals may be re-infected periodically This is secondary to changes in influenza antigens resulting in virus subtypes to which humans have little or no resistance Through these changes, influenza has remained a significant pathogen over the ages despite the advent of vaccines The changes occur via changes in the surface glycoproteins of the virus, neuraminidase and hemagglutinin Two types of antigenic change are described, known as antigenic drift and antigenic shift 27.3.1.1 Antigenic Drift Antigenic drift refers to the minor antigenic changes which occur in the hemagglutinin and neuraminidase proteins The mechanism of antigenic drift is the gradual accumulation of amino acid substitutions due to point mutations in the hemagglutinin and neuraminidase genes [10, 11] As mutations accumulate, antibodies generated by exposure to previous strains not neutralize current strains to the same extent, resulting in only limited or partial immunity to the new strains It is felt that decreased recognition of the new strains acts as a type of natural selection; new strains with less immune recognition become the predominant strain in annual epidemics Antigenic drift is present in both the influenza A and B subtypes 27.3.1.2 Antigenic Shift Antigenic shift occurs only in influenza A Compared with previous strains, the predominant circulating virus possesses a different hemagglutinin, neuraminidase, or both There is little or no antibody recognition of these new stains, thereby creating strains that may become a source of epidemic and pandemic influenza There is a strong association between antigenic shifts with the occurrence of pandemics The severe pandemics of 1918 – 1919 (shift to H1N1) and 1957 (shift to H2N2) were associated with shifts of both the hemagglutinin and neuraminidase [12, 13] The less extensive pandemic of 1968 was associated with only a shift to a new hemagglutinin (shift to H3N2) [14] Interestingly, the “pseudo-pandemic” of 1977, which involved an influenza A virus which had shifted back to H1N1, affected primarily younger individuals, born after the H1N1 virus had last circulated [15] Antigenic shift can occur through a variety of mechanisms Non-human influenza is selective in its tropism, and cannot easily replicate in humans [16] However, avian influenza viruses may replicate in non-avian, non-human reservoirs (like swine) A pig that was co-infected with both avian and human strains of influenza might result in a genetic reassortment that produces a novel virus capable of replication in and transmission between humans [17] This reassortment process may happen frequently, but may result in viruses with decreased pathogenicity or limited tropism in humans, and therefore severe pandemics not begin Alternatively, mutations may occur directly in a non-human virus, such as an avian virus, that allow the virus to readily spread from person to person [18] This process may occur partially, so that spread from animals to humans is possible, but human-to-human spread does not occur An example is H5N1 avian influ- 285 286 27 Influenza enza Beginning in late 2003 an epizootic developed in Southeast Asia, which by the spring of 2006 had become a panzootic in wild birds and domestic poultry involving parts of Europe and Africa as well Between December 2003 and March 2006, a total of 186 persons had cases of H5N1 influenza confirmed by the World Health Organization, of whom 105 (56 %) died Almost all patients who developed the infection appear to have acquired it directly from sick birds, presumably because the virus had restricted tropism and was not able to spread readily from person to person [19] At the time this chapter was written the H5N1 avian influenza panzootic was still spreading 27.4 Epidemiology In temperate regions influenza spread occurs annually with the peak epidemic during winter months Conversely, in tropical regions outbreaks of influenza may occur year round In annual influenza epidemics between % and 15 % of the population may develop disease While attack rates are greatest in the young, influenza-associated mortality is highest in the elderly and immunocompromised Risk factors for influenza-associated complications include chronic lung, heart and renal disease [20, 21] The entire epidemic appears to take approximately – weeks to circulate through the community How influenza persists between the annual epidemics is poorly understood Epidemic influenza occurs annually However, an influenza pandemic occurs every several decades and involves the entire world Influenza strains causing pandemic influenza are usually the result of antigenic shift, with little immunity in the populace While past pandemics such as the 1918 pandemic took many months to spread throughout the world, the rapid pace of modern travel would likely allow a new pandemic to spread much more rapidly, allowing little time for initially unaffected regions to prepare 27.5 Transmission and Pathophysiology Influenza spreads rapidly in communities The mechanism of spread from person to person is primarily droplet via small particle sized aerosols [22] Once the virus is deposited on the respiratory epithelium, the influenza virus attaches to ciliated columnar epithelial cells via the hemagglutinin molecule The cells are then invaded and viral replication occurs Released viruses then infect large numbers of adjacent epithelial cells, and therefore within a few replication cycles large numbers of cells may be infected The incubation period from exposure to the onset of illness appears to range from to days, with the average period days Adults can be infectious from the day before symptoms begin through approximately days after illness onset Children can be infectious for 10 days or more, and young children can shed virus for several days before their illness onset Severely immunocompromised persons can shed virus for weeks or months [23] Immune responses to influenza infection include both nonspecific and specific immunity Nonspecific defenses include nonspecific mucoproteins which bind virus and the mechanical apparatus of the muco-ciliary apparatus Patients with defective muco-ciliary apparatuses, such as smokers, tend to have higher attack rates and more severe complications of influenza infection Specific defenses include both humeral and cell mediated responses Infection with influenza results in long-lived resistance to re-infection with the same virus subtype However, because of antigenic shift and drift, there is only limited protection against new subtypes A good illustration of the long lived immunity to specific viruses is the 1977 reemergence of the H1N1 subtype, where people alive during the 1918 pandemic were largely immune and not affected Antibody responses to the influenza virus are typically directed against the hemagglutinin, neuraminidase, structural proteins M and NP, and to some degree to the M2 protein Antibodies responses have variable cross protection within viral subtypes depending on the amount of change of the antigen resulting from antigenic shift or drift Antibodies to hemagglutinin appear most important in protecting against disease and future infection with the same subtype Antibodies to neuraminidase reduce efficient release of virus and decreases plaque size in in-vitro assays Peak antibodies are formed approximately – weeks after infection, then slowly decline There appears to be a significant mucosal response to the hemagglutinin antigen, with nasal secretions containing IgG and IgA 27.6 Clinical Disease The clinical features of an uncomplicated influenza are nondescript, and virtually indistinguishable from other respiratory viral infections Influenza is characterized by an abrupt onset of headache, fevers, often high grade, dry cough, myalgia, malaise and anorexia The cough is variable, often initially nonproductive, then productive of small amounts of mucous, usually nonpurulent Duration of fevers average days, with a range of – days Cough and weakness (“post-influenza asthenia”) may persist for weeks after fever and upper respiratory tract symptoms have resolved Physical exam usually reveals flushing, tachycardia, and oc- 27.6 Clinical Disease casionally tachypnea The pulmonary exam is generally unremarkable in uncomplicated cases Early in the illness even otherwise healthy people may appear quite ill, and during times of epidemic both physician practices and emergency rooms are often swamped with influenza patients, which potentiates the spread to noninfected patients 27.6.1 Complications The most common complication of influenza is pneumonia Pneumonia can either be primary influenza pneumonia or a secondary bacterial pneumonia Primary influenza pneumonia was first well documented in the influenza pandemic of 1957 – 1958 [24] It is thought to be a major cause of death during the earlier pandemic of 1918 – 1919 Symptoms include high fever, dyspnea, hypoxemia, and respiratory distress Chest radiographs are similar to other viral pneumonias, revealing scant bilateral interstitial infiltrates Primary influenza pneumonia has become increasingly rare in the current interpandemic era Secondary bacteria pneumonias are similar to noninfluenza associated pneumonias Up to 25 % of all mortality from influenza and a large proportion of ICU admission secondary to influenza are due to secondary bacterial pneumonias [25] S pneumonia is the most common pathogen associated with post-influenza pneumonia, accounting for up to 48 % in some series S aureus, an otherwise uncommon cause of community-acquired pneumonia, is the second most common organism isolated in this setting (19 %) Other more typical pneumonia pathogens, such as Haemophilus influenza, are common as well [26] Secondary pneumonias often develop as the patient is improving from the primary influenza infection, with the patient improving briefly, then becoming again febrile, now with worsening respiratory status and purulent secretion Some patients may have features of both viral and bacterial pneumonia While influenza usually does not require ICU care, high risk patients with severe pneumonia may require intubation and ICU level care Non-pneumonia complications of influenza have also been reported An important complication of influenza is myositis with elevated muscle enzymes This must be differentiated from the myalgias, which are very common with the influenza syndrome Other complications include pericarditis, myocarditis, and CNS complications, the most common of which appears to be a Guillain-Barre type syndrome [27] Finally, Reye’s syndrome has been reported in children infected with influenza B and receiving aspirin [28] 27.6.2 Diagnosis In times of a confirmed epidemic, when influenza is widespread in the community, a clinical definition based on fever greater than 37.8 °C, and two of four symptoms: cough, myalgia, sore throat and headache, was found to have a sensitivity of 77.6 % and specificity of 55 %, for the diagnosis of influenza [29, 30] However, at the beginning of epidemics, with sporadic cases, and with atypical presentation, the clinical laboratory must be utilized to differentiate influenza from other respiratory viruses Available tests include viral culture, a rapid diagnosis using viral antigens, and the investigational PCR tests Viral culture is the gold standard for laboratory diagnosis Virus can be easily isolated by nasal swabs, throat cultures, and sputum or bronchoalveolar lavage samples One study concluded that sputum and nasal aspirates had the highest positive predictive value, and throat swabs the worst; however, this study did not include bronchoalveolar lavage specimens [31] After collection and transport in viral transport medium, the specimens are inoculated into specific cell cultures, where virus is detected by cytopathic effect [32] Less commonly, embryonated eggs can be used for virus propagation, followed by characterization of the virus by hemagglutination inhibition Unfortunately, viral culture takes up to 72 h to see a cytopathic effect, but has the benefit of allowing for sub-typing of viral strains, which is critical in the assessment of the current year’s vaccine and development of the next As rapid diagnosis of influenza is very important for treatment and infection control, a number of commercial rapid diagnostic tests have recently been developed These tests can yield results in as little as 30 They differ in the types of influenza viruses they can detect and whether they can distinguish between influenza types Different tests can detect: (1) only influenza A viruses; (2) both influenza A and B viruses, but not distinguish between the two types; or (3) both influenza A and B and differentiation between the two [33] These tests are based on the immunologic detection of viral antigens via immunofluorescence or enzyme immunoassays The reported sensitivities of these rapid diagnostic methods range from 40 % to 80 % [34] PCR has also been used for diagnosis, though usually in a research setting Some authors have suggested that PCR may be more sensitive than viral culture, as it can detect virons which have lost replicative viability [35] Unfortunately, PCR is expensive, and labor intensive, and currently tends to be confined to research institutions Serological diagnosis of influenza is possible, but can be difficult to interpret as most people have been previously infected Acute and convalescent specimens, which reveal a fourfold rise in titers, are considered diagnostic 287 288 27 Influenza 27.6.3 Treatment While prevention of influenza is by the far the best measure to combat influenza, four antiviral drugs in two mechanistic classes are currently available and FDA approved for the treatment of influenza These drugs, when used in the first 24 – 48 h of illness, appear to shorten duration of symptoms for between and days [36, 37] The M2 inhibitors amantidine and rimantidine have been used since the 1960s, but are only active against influenza A The M2 inhibitors target the M2 ion channel, which is important in replication of the viron The major side effects of amantidine are central nervous system symptoms such insomnia, impaired thinking, dizziness and lightheadedness, resulting in discontinuation rates of up to 13 % Ramantidine appears to have far fewer symptoms, and discontinuation rates of about % have been reported [38] In recent years an increasing M2 channel inhibitor resistance has surfaced During the 2005 – 2006 influenza year, CDC testing of 120 influenza A (H3N2) viruses isolated from patients in 23 states revealed resistance rates of 91 % Therefore, during this season, the CDC has recommended against the use of M2 inhibitors in the treatment or prevention of influenza A [39] Continuation of this resistance trend appears likely in the future Neuraminidase inhibitors, including inhaled zanamivir and oral oseltamivir, are newer potent agents, active and approved against both influenza A and B The neuraminidase inhibitors inhibit the functioning of the viral neuraminidase, which cleaves sialic acid containing receptors, allowing release of completed viron from the infected cell Oseltamivir is generally well tolerated, and major side effects are limited to nausea and vomiting, which typically not require drug cessation Zanamivir is supplied as a dry powder for inhalation, and has been linked to bronchospasm and decrease in peak flows in asthmatics [40], as well as gastrointestinal upset The manufacturer has released a warning advising patients with COPD or asthma to have a fast acting inhaler available prior to administration 27.7 Prevention 27.7.1 Vaccination Vaccination is by far the best method for prevention of influenza Influenza is unique among vaccine preventable illnesses because its high rate of mutation requires development and implementation of a new vaccine annually Worldwide surveillance and a degree of luck are required to select the proper antigenic variants of influenza to include in the vaccine months before the start of the annual flu season [41] In the United States there are currently two licensed vaccines, a trivalent inactivated vaccine (TIV), and a trivalent live-attenuated influenza vaccine (LAIV) The inactivated vaccine was first licensed in 1943, and now usually contains three influenza antigenic strains – two type A, and one type B After the likely predominant strains are identified, the viruses are grown in embryonated chicken eggs They are then inactivated, purified, split into viral fragments, and finally combined into vaccine Nearly months after identification of target strains is required for vaccine production Therefore if the educated guesses regarding the dominant strains are incorrect there is no time to develop alternative vaccines When there is a good match between vaccine and epidemic virus, levels of protection from influenza infection range from 70 % to 90 % [42], although it is typically less in elderly and chronically ill patients Patients who get infected with influenza despite having been vaccinated tend to have less severe disease, and have lower mortality rates The inactivated vaccine is well tolerated; contraindications are limited to allergies to eggs and a history of a severe adverse reaction Individuals with a febrile infection should not be vaccinated until its resolution, since they may have a decreased immune response to the vaccine The live attenuated influenza vaccine was licensed in 2003 Although it is a live viral vaccine, the virus is cold adapted, so that it only replicates at the lower temperatures found in the anterior nares [43] While both the inactivated and live vaccines induce systemic antibody responses, the cold adapted vaccine additionally confers a significant specific mucosal antibody response (IgA) The cold adapted vaccine is currently only FDA approved for those between and 49 years of age Contraindications include immunosuppression, HIV infection, malignancy, leukemia, or lymphoma, and those between age and 17 receiving aspirin products, because of the association of Reye syndrome with aspirin and wild-type influenza infection [44] The live attenuated vaccine can be given to healthcare workers Work restrictions are not necessary after this vaccine except for those caring for immunocompromised patients who require a protective environment (e.g., bone-marrow transplant patients) [45] Influenza vaccine is recommended for patients at increased risk for complications, including those older than 50, and those with chronic pulmonary or cardiac disease, diabetes, renal disfunction, or immunosuppression (see Table 27.1) Vaccination is also strongly recommended for all healthcare workers During the 2004 – 2005 influenza season, manufacture problems resulted in large shortages of the killed vaccine, resulting in rationing of vaccine The CDC has recommended a triage system to identify those at highest risk who should receive vaccination priority in 27.8 Infection Control Table 27.1 Priority groups for the inactivated influenza vaccine in case of shortages (adapted from [54]) Tier Priority group 1A 1B 1C Persons aged & 65 years with comorbid conditions Residents of long-term-care facilities Persons aged – 64 years with comorbid conditions Persons aged > 65 years without comorbid conditions Children aged – 23 months Pregnant women Healthcare personnel Household contacts and out-of-home caregivers of children aged < months Household contacts of children and adults at increased risk for influenza-related complications Healthy persons aged 50 – 64 years Persons aged – 49 years without high-risk conditions Table 27.2 CDC recommendations for influenza vaccination (adapted from [54]) Persons at increased risk for complications Persons aged & 65 years Residents of nursing homes and other chronic care Adults and children who have chronic pulmonary or cardiovascular system diseases, including asthma (hypertension is excluded) Adults and children with chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression Adults and children who have any condition (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders) that can compromise respiratory function or the handling of respiratory secretion Children and adolescents (aged months–18 years) who are receiving long-term aspirin Women who will be pregnant during the influenza season Children aged – 23 months Persons aged 50 – 64 years Vaccination is recommended for all persons aged 50 – 64 years Persons who can transmit influenza to those at high risk Healthcare workers including physicians, nurses, and other personnel Employees of assisted living and other residences for persons in groups at high risk Persons who provide home care to persons in groups at high risk; and household contacts (including children) of persons in groups at high risk Household contacts of children aged – 23 months times of shortages (see Table 27.2) New vaccine development and production techniques, such as acellular vaccines, that allow for rapid production and deployment need to be developed in order to avoid future shortages These methods would also allow rapid vaccine development during the influenza seasons when antigen matches are poor In the setting of a vaccine shortage, consideration could also be given to using the LAIV in an expanded patient population (although this would be an off-label use) [46] 27.7.2 Antiviral Prophylaxis All of the antiviral medicines used for therapy have also been used as post-exposure prophylaxis during times when influenza is circulating in the community However, because of the rapid development of resistance in the H3N2 influenza virus noted during the 2005 – 2006 influenza season, the M2 inhibitors amantadine and rimantadine are no longer recommended for prophylaxis Among neuraminidase inhibitors, zanamivir has not been FDA approved for prophylaxis As antiviral prophylaxis is expensive, and not without side effects, prophylaxis must not be used in place of vaccination Additionally, all individuals who are initiated on antiviral prophylaxis should also receive the influenza vaccine The Advisory Committee on Immunization Practices recommends consideration of antiviral prophylaxis for patients at high risk of complications who have not received vaccination, those who are unlikely to respond to vaccination and healthcare workers who have not received vaccination, during times when influenza is active in the community [47] Duration of prophylaxis is controversial and depends of the aim As a bridge to vaccination, antiviral drugs should be continued for weeks after vaccination In “seasonal prophylaxis,” where the individual cannot receive or is not expected to amount an immune response to the vaccination, prophylaxis should be initiated upon widespread reports of influenza in the community and should continue for – weeks [48] Antiviral drugs can also be used as post-exposure prophylaxis, where drugs are given for – 10 days after contact with an infected person [49] This will not protect against influenza contracted from outside the contact after the prophylactic period, and may be best suited to times of sporadic cases Many anecdotal reports also support the use of antiviral drugs in aborting epidemics in nursing homes, and could be extrapolated to outbreaks in intensive care units [50] 27.8 Infection Control Patients with influenza should be placed in isolation to prevent nosocomial spread of the disease There have also been several well documented cases of intra-ICU spread of influenza [51] The Centers for Disease Control and Prevention (CDC) recommend that patients with known or suspected influenza be placed in “Droplet Precautions.” [52] Patients should be placed 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Hayden FG, Atmar RL, Schilling M, et al (1999) Use of the selective oral neuraminidase inhibitor oseltamivir to prevent influenza N Engl J Med 341(18):1336 – 1343 49 Welliver R, Monto AS, Carewicz O, et al (2001) Effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial JAMA 285(6): 748 – 754 50 Schilling M, Povinelli L, Krause P, et al (1998) Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks Vaccine 16(18):1771 – 1774 51 Oliveira EC, Lee B, Colice GL (2003) Influenza in the intensive care unit J Intensive Care Med 18(2):80 – 91 52 Garner JS, Hospital Infection Control Practices Advisory Committee (1996) Guideline for isolation precautions in hospitals Infect Control Hosp Epidemiol 17:53 – 80 53 Centers for Disease Control and Prevention Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR 53(RR-6):1 – 40 54 Centers for Disease Control and Prevention (CDC) Tiered use of inactivated influenza vaccine in the event of a vaccine shortage MMWR Morb Mortal Wkly Rep 54(30): 749 – 750 291 Chapter 28 28 Bloodstream Infection in the Intensive Care Unit J Valles 28.1 Introduction Nosocomial infections occur in – 10 % of patients admitted to hospitals in the United States [1] The endemic rates of nosocomial infections vary markedly between hospitals and between areas of the same hospital Patients in intensive care units (ICUs), representing – 15 % of hospital admissions, suffer a disproportionately high percentage of nosocomial infections compared with patients in non-critical care areas [2 – 7] Wenzel et al [3] reported that patients admitted to ICUs account for 45 % of all nosocomial pneumonias and bloodstream infections, although critical care units comprise only – 10 % of all hospital beds Severity of underlying disease, invasive diagnostic and therapeutic procedures, contaminated life-support equipment, and the prevalence of resistant microorganisms are critical factors in the high rate of infection in ICUs [8] Donowitz et al [5] reported a threefold increase in the risk of nosocomial infection for ICU patients when compared with ward patients (18 % vs %; p < 0.001); and bloodstream infections were 7.4 times as likely to occur in ICU patients as in ward patients, with an infection rate in the ICU of 5.2 episodes per 100 admissions compared with 0.7 episodes per 100 admissions in a general ward (p < 0.001) Trilla et al [9], in a study of the risk factors for nosocomial bloodstream infection in a large Spanish university hospital, found that among other variables, the admission to an ICU was linked with a marked increase in the risk of nosocomial bloodstream infection (OR = 2.37; CI 95 %: 1.67 – 3.38; p = 0.02) On the other hand, 40 % of patients admitted to the ICU present infections acquired in the community, and 17 % of them present bacteremia [10] The incidence rate of patients with community-acquired bacteremia admitted in a general ICU is about – 10 episodes per 1,000 admissions [11, 12], representing 30 – 40 % of all episodes of bacteremia in the ICU (Fig 28.1) The aim of this chapter is to discuss the clinical importance of bloodstream infection in the ICU, including nosocomial and community-acquired episodes (%) 70 60 50 40 30 20 10 94 95 ICU-BI 96 97 99 N-BI 2000 2001 2002 2003 2004 C-BI years Fig 28.1 Distribution of bacteremias in the medical-surgical ICU of Hospital Sabadell (period 1994 – 2004) ICU-BI intensive care unit-acquired bloodstream infection, N-BI nosocomial (outside ICU)-acquired bloodstream infection, C-BI community-acquired bloodstream infection 28.2 Pathophysiology of Bloodstream Infection Invasion of the blood by microorganisms usually occurs via one of two mechanisms: drainage from the primary focus of infection via the lymphatic system to the vascular system, or direct entry from needles (e.g., in intravenous drug users) or other contaminated intravascular devices such as catheters or graft material The presence of bloodstream infection represents either the failure of an individual’s host defenses to localize an infection at its primary site or the failure of a physician to remove, drain, or otherwise sterilize that focus Ordinarily, host defenses respond promptly to a sudden influx of microorganisms, particularly by efficient phagocytosis by macrophages or the mononuclear phagocytic system that helps clear the blood within minutes to hours Clearance may be less efficient when microorganisms are encapsulated, or it may be enhanced if the host has antibodies specific for the infecting organism Clearance of the bloodstream is not always successful Examples of this problem are bloodstream infections associated with intravascular foci and endovascular infections and episodes that occur in individuals whose host defense mechanisms either are too impaired to respond efficiently or are simply overwhelmed [13] 28.3 Definitions For that reason, the presence of living microorganisms in blood is of substantial clinical importance; it is an indicator of disseminated infection and, as such, generally indicates a poorer prognosis than that associated with localized disease 28.3 Definitions Nosocomial bloodstream infection in the ICU is defined in a patient with a clinically significant blood culture positive for a bacterium or fungus that is obtained more than 72 h after admission to the ICU or previously, if it is directly related to a invasive manipulation on admission to the ICU (e.g., urinary catheterization or insertion of intravenous line) By contrast, a community-acquired bacteremia is defined when the infection develops in a patient prior to hospital and ICU admission, or if this episode of bacteremia develops within the first 48 h of hospital and ICU admission, and it is not associated with any procedure performed after hospital or ICU admission These definitions from the Centers for Disease Control and Prevention (CDC) consider that infections that are not nosocomial infections are community-acquired by default [14] However, there are patients residing in the community, who are receiving care at home, living in nursing homes and rehabilitation centers, receiving chronic dialysis, and receiving chemotherapy in physicians’ offices who may present bloodstream infections These infections have traditionally been categorized as community-acquired infections For this reason, recently a new classification scheme for bloodstream infection has been proposed that distinguishes among patients with community-acquired, healthcare-associated, and nosocomial infections Healthcare-associated bloodstream infection has been defined when a positive blood culture is obtained from a patient at the time of hospital admission or within 48 h of admission if the patient fulfilled any of the following criteria: (1) received intravenous therapy at home, received wound care or specialized nursing care or had self-administered intravenous medical therapy; (2) attended a hospital hemodialysis clinic or received intravenous chemotherapy; (3) was hospitalized in an acute care hospital for or more days in the 90 days before the bloodstream infection; or (4) resided in a nursing home or long-term care facility [15] Bloodstream infections may be classified as primary or secondary according to the source of the infection [14] Primary bloodstream infection occurs without any recognizable focus of infection with the same organism at another site at the time of positive blood culture, and secondary bloodstream infections are infections that developed subsequent to a documented infection with the same microorganism at another site Episodes secondary to intravenous or arterial lines have traditionally been classified as primary bacteremias; however, if local infection (defined as redness, tenderness, and pus) is present at the site of an intravascular line, and if the semiquantitative (yielding > 15 colonies) or quantitative culture of a segment catheter is positive to the same strain as in the blood cultures, they may be classified as secondary bacteremias According to this definition, in the absence of an identified source, primary bacteremias should be designated bacteremias of unknown origin [16 – 19] According to clinical patterns of bacteremia, it may also be useful to categorize bloodstream infection as transient, intermittent, or continuous [13] Transient bacteremia, lasting minutes to hours, is the most common and occurs after manipulation of infected tissues (e.g., abscesses); during certain surgical procedures; when procedures are undertaken that involve contaminated or colonized mucosal surfaces (e.g., gastrointestinal endoscopy); and, predictably, at the onset of acute bacterial infections such as pneumonia, meningitis, and complicated urinary infections Intermittent bacteremia is that which occurs, clears, and then recurs in the same patient due to the same microorganism Classically, this type of bacteremia is associated with undrained closed space infections, such as intra-abdominal abscesses Continuous bacteremia is characteristic of infective endocarditis as well as other endovascular infections such as arterial graft infections, and suppurative thrombophlebitis associated with intravenous line infections commonly seen in critically ill patients Bloodstream infections may also be categorized as unimicrobial or polymicrobial depending on the number of microorganisms isolated during a single bacteremic episode Blood cultures which are found to be positive in the laboratory but which not truly reflect bloodstream infection in the patient have been termed contaminant bloodstream infections or, more recently, pseudobloodstream infections [16] Several techniques are available to assist the clinician and microbiologist in interpreting the clinical importance of a positive blood culture The categorical decision to consider the bloodstream infection as true infection or a contaminant should take into account, at least: the patient’s clinical history, physical findings, body temperature at the time of the blood culture, leukocyte count and differential cell counts, the identity of microorganism isolated and the result of cultures of specimens from other sites Indeed, the type of microorganism isolated may have some predictive value: common blood isolates that always or nearly always (> 90 %) represent true infection include S aureus, E coli and other members of the Enterobacteriaceae, Pseudomonas aeruginosa, Streptococcus pneumoniae, and Candida albicans Other microorganisms such as Corynebacterium spp., Bacillus spp., and Propionibacterium 293 602 55 Biliary Tract Infections tered mental status that accompanies critical illness may obscure any useful information that might be obtained from the history and physical examination Laboratory values are non-specific but usually include leukocytosis and elevated liver enzymes, particularly of bilirubin, transaminases, and alkaline phosphatase Hyperbilirubinemia, perhaps representative of the cholestasis of sepsis, is typical and occurs more often than in calculous cholecystitis Ultrasound is perhaps the ideal radiologic study to investigate the diagnosis of acalculous cholecystitis [53] Ultrasound may reveal hydrops of the gallbladder, pericholecystic fluid, or gallbladder wall thickening When a cut-off of 3.5 mm is used for wall thickness, US has a sensitivity of 98.5 % and a specificity of 80 % [54] Ultrasound is also convenient in that it can be done at the bedside of patients too ill to be transported to the radiology suite and followed immediately by percutaneous drainage Computed tomography is equally accurate in the diagnosis of acalculous cholecystitis [55] (Fig 55.3), but requires that the patient be stable enough to be transported The primary advantage of CT scan over US is the ability to evaluate other potential sources of intra-abdominal infection Whereas a radionucleotide biliary scan is an excellent diagnostic modality for patients with community-onset acute cholecystitis, interpretation in critically ill patients can be confounded by false-positive scans due to fasting, liver disease, or parenteral nutrition, which are sufficiently common to diminish the utility of radionucleotide imaging in this population Upon making the diagnosis of acalculous cholecystitis, a decision about the method of source control must be made and empiric antibiotic therapy must be started Even though up to one-half of cases of acute acalculous cholecystitis are associated with culturenegative bile (at least initially, considering that ischemia-reperfusion is paramount and superinfection is a secondary phenomenon), empiric antibiotics are needed because distinguishing sterile from infected cases can be clinically impossible owing to the massive inflammatory response The organisms most frequently cultured from the bile in acalculous cholecystitis are E coli, Klebsiella spp., and E faecalis [51] In the setting of critical illness, consideration for patterns of antimicrobial resistance amongst local bacterial flora must be considered when instituting empiric intravenous antibiotic therapy The treatment of cholecystitis, whether calculous or acalculous, has traditionally been by cholecystectomy However, patients with acalculous cholecystitis are often critically ill at the time of diagnosis and may be poor surgical candidates In the past decade, other methods of source control have been investigated Percutaneous cholecystostomy tube placement is a minimally invasive alternative to surgical removal of the gallbladder that is increasingly favored over cholecystectomy [56, 57] It can be performed with