Emergent Pandemic Infections


Emergent Pandemic Infections



An epidemic of communicable infection that becomes very widespread, affects a whole region or continent, or spreads over several countries and affects many people is termed a pandemic. Three key factors set the conditions for a pandemic: the emergence of a new strain of microorganism; the ability of that strain to infect humans and cause serious illness: that is, the capacity of the organism to cause disease in an infected host (pathogenicity) and the severity of the disease produced (virulence); and the ability of the microorganism to spread easily among humans. Within intensive care units (ICUs) in tertiary care hospitals, factors that decrease transmission of communicable infection between individuals (e.g., reducing the likelihood of contact through isolation), adherence to infection control guidelines, immunization, herd immunity, increasing levels of natural immunity following infection, or depression of agent reservoirs and viability by control programs or seasonal climatic change are offset by the ICU environment, where patients generally have relatively high severity of illness scores and in situ medical devices (e.g., intravascular and urinary catheters), and antimicrobial prescribing remains uncurbed. Compounding the problem are fluctuations in staffing levels, varying degrees of immunization or vaccination among patients, and exposure of patients to health care personnel who move freely among other patients and health care personnel within the institution.

The relevance and importance of pandemic preparedness in critical care medicine is underscored by the reality that while there has been a general decrease in the total number of beds in US hospitals during the 1990s, the number of ICU beds has increased during the same period (1). This increase in the numbers of ICU beds suggest larger numbers of critically ill patients are being admitted to the inpatient services with the expected parallel increases in medical device usage and antimicrobial prescribing. The increases in device use and severity of illness scores increase the susceptibility of ICU patients to health care–associated infections—a problem compounded by the crowding that one would expect with the increased patient census in the event of a pandemic. In the wake of a pandemic, tertiary care hospitals with large numbers of beds will, by default, have to provide critical care management for greater numbers of patients in the first instance. The implications of this scenario are serious and complex, and include the increased human and material resources that would be required to manage very sick patients during a pandemic; limited availability of designated areas for cohorting patients who need to be isolated; the logistics of implementing and maintaining adherence to infection control practices and procedures during a pandemic; and the ever present risk of transmission of the pandemic agent among patients and personnel who may be called upon to “float” in other areas of the hospital.

This chapter addresses the following true or potentially emergent pandemic infections:

  • Severe acute respiratory syndrome (SARS)—a true pandemic caused by a previously unrecognized corona virus
  • Avian influenza—not yet a true pandemic but one which infectious diseases experts believe is imminent and long overdue
  • Dengue fever and Dengue hemorrhagic fever—a mosquito-borne infection that has insidiously spread across the globe and considered a pandemic by many experts
  • Tuberculosis—a pandemic caused by Mycobacterium tuberculosis and largely attributable directly to the nearly almost four-decade-long human immunodeficiency virus (HIV) pandemic
  • Infections caused by Staphylococcus aureus resistant to methicillin group penicillins (methicillin-resistant S. aureus [MRSA])—perhaps the only bacterial microorganism that to reach pandemic proportions in health care settings around the world during the space of three decades
  • Cholera

The importance of being able to address illnesses like Dengue has implications for the management of the newly recognized emerging infections caused by the Middle East respiratory syndrome coronavirus (MERS-CoV) and the Zika virus, which will be discussed briefly at the conclusion of the chapter.

The SARS pandemic in 2002 emerged suddenly and unexpectedly, affected health care workers, but was successfully controlled through the application of basic infection control principles and guidelines that had already been established, ratified, and validated. The expected, but not-as-yet seen, emergence of the impending avian influenza pandemic has underscored the importance of preparedness for an event that is so oftentimes decried as “crying wolf” by some and at the same time characterized as “a matter of when rather than if” by others. The fact remains that should an influenza pandemic occur, substantial numbers of persons with the infection will certainly require critical care management, underscoring the need for preparedness from diagnostic, management, control, and preventive perspectives. Although the epidemiology of the respective infections and public health preparedness will be alluded to, this chapter focuses more on the diagnosis and management of the infections, the relevant infection prevention and control interventions for the respective infections, and the obstacles that might be faced by ICU care givers during a pandemic.


In November 2002, the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) reported an investigation of a multicountry outbreak of unexplained pneumonia referred to as SARS—officially, the first pandemic of the 21st century (2–5). SARS began as an outbreak of atypical pneumonia among patients in the Guangdon province, China. A Chinese physician, who had taken care of patients with SARS, subsequently traveled to Hong Kong and transmitted the infection to guests at the Metropole Hotel. These guests, in turn, unwittingly became the index cases for SARS outbreaks in Canada, Hong Kong, Singapore, Vietnam, and Taiwan (6–9). Subsequently, the condition was reported in more than 8,400 people globally and resulted in over 800 deaths (6,8,10). The case-fatality rate was estimated at 13% for patients under 60 years and 43% for those over 60 years (11).

SARS is caused by a novel strain of coronavirus (SARS-CoV) that was first identified in Canada in early March 2003 (12). Because genetic changes occur frequently in these viruses, it is thought that the outbreak might have been facilitated by cross species transmission of the virus; exotic animals from a Guangdong marketplace are likely to have been the immediate origin of the SARS-CoV that infected humans in the winters of 2002–2003 and 2003–2004 (13). Before the SARS pandemic, coronaviruses already were known to be ubiquitous and were recognized as the underlying cause of illness in various animals, including pigs, cattle, dogs, cats, and chickens, and had been found to be associated with upper respiratory infections and sometimes pneumonia in humans (14). Although the natural reservoir of SARS-CoV remains uncharacterized, the virus has been isolated from all of the above animals as well as civet cats, a delicacy in the Far East (15,16).

The primary mode of transmission of SARS-CoV is direct or indirect contact of mucous membranes (eyes, nose, or mouth) with large infectious respiratory droplets (17–19). This mode of transmission suggests that the major risk factor for infection in susceptible persons is intimate direct contact with one or more individuals who are already infected or colonized. However, the unusually rapid transmission of SARS-CoV suggests that airborne transmission through droplet nuclei (i.e., droplets <10 µm in diameter) might by playing a significant role in transmission. Droplet nuclei (the mode of transmission of influenza, measles, and tuberculosis), enable SARS-CoV to reach the lung alveoli in at-risk contacts (20). This would explain why aerosol-producing procedures, such as bronchoscopy or nebulized medication, have been implicated as independent risk factors in SARS-CoV transmission and outbreaks (21–23). The hospital environment provides an efficient site for transmission of SARS-CoV infection and, because the virus survives for many days in feces and when dried on environmental surfaces, fomites can play a role in transmission (24). The problem is compounded by the difficulty in differentiating SARS from other clinical syndromes (25).

The phenomenon of “superspreading events” plays an important role in the transmission of SARS-CoV in health care settings (19,22,26–28). The mechanism of “superspreading events” involves SARS-CoV transmission from one individual to several secondary cases (22,23,25,26,29,30). Risk factors associated with “superspreading events” include high severity of illness scores, higher age, and increased numbers of secondary contacts (25). Superspreading has played major roles in the transmission of SARS-CoV within health care settings in Singapore and Toronto (12,25,26,31,32).

SARS is characterized by rapid onset of high fever, malaise, myalgia, chills, rigors, and sore throat, followed by shortness of breath, cough, and radiographic evidence of pneumonia (10,12,26,29,33). The median incubation period ranged is generally between 4 and 7 days (range 2 to 10) (21). Some patients develop profuse watery diarrhea, though, as stated above, the role of feco-oral transmission remains uncharacterized (33). After 1 week (34,35) of illness, patients with SARS frequently develop respiratory failure, which often requires critical care management for respiratory support and mechanical ventilation (10,33). Chest radiographs frequently show nonspecific patchy opacification, but may be normal during the early stages of the infection (34). Because of the nonspecific clinical manifestations at presentation, all cases of community-acquired pneumonia are suspect during a SARS pandemic, and a history of exposure to a patient with probable SARS or travel to SARS-affected geographic areas should heighten clinical suspicion and increase the likelihood of the diagnosis (36). In patients with suspected SARS or patients who develop respiratory symptoms during a SARS pandemic, the workup for known causes of community-acquired pneumonia should certainly be performed, and appropriate specimens should be sent to the designated State Health Department or CDC for viral identification and serologic analysis.

Laboratory features include lymphopenia, thrombocytopenia, and elevated levels of lactate dehydrogenase, aspartate aminotransferase, and creatinine kinase (12). SARS-CoV can be detected by the polymerase chain reaction (PCR) in respiratory secretions and other body fluids; however, PCR is not sensitive during the early stages of the illness. Specific SARS-CoV antibodies are detectable, but play little or no role in making a diagnosis during the acute stages of the pneumonia, especially during a pandemic. However, detection of antibodies provides a retrospective diagnosis as part of clinical confirmation or surveillance activities. In virologically or serologically documented infections caused by SARS-CoV, viral RNA may persist for some time in patients who seroconvert, and some patients may lack an antibody response to SARS-CoV more than 21 days after illness onset. An upsurge of antibody response is associated with the aggravation of respiratory failure that requires ventilator support (37). The presence of underlying disease, high initial C-reactive protein levels, and positive SARS-CoV in nasopharyngeal aspirate samples are associated with a higher risk of respiratory failure and mortality (36).

Prevention and Control of SARS

In Canada, transmission of the SARS-CoV occurred predominantly among health care workers, presumably through close contact with symptomatic persons (12,38). Health care workers made up a large proportion of cases, accounting for 37% to 63% of suspected SARS cases in highly affected countries (17,39–41). Thus, the basic tenets of prevention and control include institution and implementation of traditional infection control practices and procedures, early detection and prompt isolation of infected patients, contact tracing, and quarantine of contact persons (27,42). Because SARS-CoV is likely not going to be identified before recommended infection control precautions are implemented, the primary strategy to reduce transmission is early recognition and isolation of patients who might have the syndrome. In Vietnam and Canada, the pandemic was brought under control through the institution of a constellation of interventions that included the following: (i) early detection, and prompt isolation of case-patients; (ii) implementation of traditional infection control practices (i.e., scrupulous handwashing, and environmental decontamination; (iii) use of personal protective equipment, where deemed necessary; (iv) initiation of surveillance activities for patients with SARS; and (v) education and training of patients, relatives, and care givers (43,44).

Transmission of SARS-CoV may occur on an aircraft when infected persons fly during the asymptomatic phase of illness (45). Moreover, because asymptomatic persons (i.e., unrecognized cases) remain a significant source of transmission, a detailed travel history for patients during a pandemic is essential—more specifically, travel to or from SARS-endemic regions. In a retrospective cohort study of nurses in Toronto, assisting during intubation, suctioning before intubation, and manipulation of oxygen masks were found to be significant risk factors for acquiring SARS (27). This study also found that consistently wearing a mask, regardless of type (i.e., whether surgical or particulate respirator N-95 type) was protective for nurses and resulted in an 80% reduction in risk of infection (27). Of note, the risk of SARS-CoV transmission and infection among nurses who consistently wore N-95 masks was approximately half that for the surgical mask; however, this difference was not statistically different (27). These data concur with the findings of Seto et al., who established that both surgical and N-95 masks were protective against SARS for health care workers in Hong Kong (19), and with anecdotal reports from Bach Mai hospital in Hanoi, Vietnam, where SARS was controlled and contained largely through adherence to basic infection control principles, use of surgical masks, and quarantine of close contacts (unpublished communication, Bach Mai Hospital, Hanoi, Vietnam). Finally, Loeb et al. established unequivocally that use of personal protective equipment (N-95 masks, gowns, gloves, and goggles) were important preventive measures when caring for SARS patients (27). Ultimately, improvement in the outcomes of patients with SARS is dependent on heightened levels of clinical suspicion, rapid case detection and isolation, strict attention and adherence to infection control policies and guidelines, and development of reliable diagnostic tests and effective antiviral and immunomodulatory agents, and vaccines (36,37).


Influenza is an acute febrile illness that is caused by a group of respiratory viruses that primarily infect the columnar cells of the upper respiratory tract. Humans are the major hosts of these viruses, which are the most important cause of wintertime respiratory morbidity throughout the world. Despite vaccines and antiviral therapies, influenza epidemics still occur every year. The occurrence of three major influenza pandemics during the 20th century was not an aberration but rather a manifestation of the continuing emergence of virulent strains of a virus that has adapted for efficient human transmission and which continues to undergo point mutations and genetic exchange or reassortment (46,47). The magnitude of influenza outbreaks during the winter is dictated by the trilateral interaction between the influenza virus, susceptible persons, and the environment in which this interaction takes place. Intrinsic viral factors that determine the size of an outbreak for a particular year include the degree of molecular change in the virus compared with the previous year, and the pathogenicity and virulence of the new winter strain. Patient factors that determine the size of the outbreak for a particular year include the numbers of susceptible individuals and the proportion of individuals who received that year’s influenza vaccine. Important environmental factors that facilitate transmission include crowding, the ever-present issue with hospital ICUs.

Influenza viruses belong to the orthomyxovirus family; these viruses are enveloped, pleomorphic, and contain negative, single-stranded RNA, which are organized into eight gene segments that code for ten proteins. They are classified into three major serotypes—influenza A, B, and C—based on differences in a stable, internal ribonucleoprotein antigen. Two surface glycoproteins—hemagglutinin and neuraminidase—constitute the major antigens and are therefore the prime targets of the protective host immune response and vaccine prophylaxis.

Influenza A is the most extensively studied of the three types; influenza B is more antigenically stable and usually occurs in more localized outbreaks; influenza C appears to be a relatively minor cause of disease and differs considerably from A and B types, possessing only seven RNA segments and no neuraminidase. Only influenza A and B cause epidemic infections and disease in humans.

Hemagglutinin is so named because of its ability to agglutinate red blood cells from chickens or guinea pigs in vitro, and facilitates viral attachment to the host respiratory epithelial cells via sialic acid-containing receptors. Once bound, hemagglutinin facilitates the entry of the viral genome into the target cells by causing the fusion of host endosomal membrane with the viral membrane; antibody to hemagglutinin is protective. The neuraminidase glycoprotein is involved in viral entry into the host cell by helping release virions from cells, and is important in the process of the viral envelope fusion with the host cell membrane as a prerequisite to viral entry into the human cell. Antibodies to neuraminidase appear to modify disease severity by inhibiting the spread of virus in the infected host and limiting the amount of virus released from host cells.

Among the 18 known hemagglutinins subtypes (H1 through H18) and eleven neuraminidase glycoprotein subtypes (N1 through N11) of influenza A viruses, three major subtypes of hemagglutinins (H1, H2, and H3) and two subtypes of neuraminidases (N1 and N2) are currently in general circulation among people (H1N1, H1N2, H3N2). The three 20th century pandemics were caused by strains of avian influenza A viruses classified as H1N1 for 1918, H2N2 for 1957, and H3N2 for the 1968 pandemic virus. The 1968 H3N2 strain had the same neuraminidase glycoprotein as the 1957 H2N2 strain. Influenza viruses are named on the basis of the following nomenclature: type/geographic source/strain number/year isolated (specific H and N subtypes). Thus, for the 2015/2016 influenza season, the vaccine includes A/California/7/2009 (H1N1) 09-like virus, A/Switzerland/9715293/2013 (H3N2)-like virus, B/Phuket/3073/2013-like virus, and B/Brisbane/60/2008-like antigens (CDC, Atlanta, GA). These viruses were used because they are representative of influenza viruses that are anticipated to circulate in the United States during the 2015–2016 influenza season and have favorable growth properties in eggs (CDC, Atlanta, GA).

A key feature of influenza A viruses is their ability to undergo periodic antigenic change, more commonly and to a much greater degree than other respiratory viruses. These antigenic changes occur through two completely different mechanisms: antigenic “drift” and antigenic “shift.” In antigenic drift, point mutations in the hemagglutinin or neuraminidase genes cause minor antigenic changes to the main surface glycoproteins resulting in strain variants. Antigenic drift within major subtypes can involve either the hemagglutinin or neuraminidase antigen or the genes encoding nonstructural proteins, and can result from a single mutation on the viral RNA. Antigenic drift is a continuous process that leads to emergence of strain variants, most of which form evolutionary dead ends. Eventually, however, a strain becomes predominant worldwide for 1 to 3 years on average. Immunity against one strain might be limited and antibodies formed to older viruses gradually lose their ability to protect against newer strains. As a result, people recurrently become susceptible to influenza and vaccine strains must be updated annually. Only antigenic drifts in the hemagglutinin have been described for influenza B viruses.

Antigenic shift is the emergence of a novel human influenza virus subtype through genetic reassortment between human and animal viruses or through direct animal- or poultry-to-human transmission resulting in a virus bearing new hemagglutinin or neuraminidase antigens. Basically, reassortment occurs when an avian virus and human-adapted virus “swap genes” in a coinfected cell of an animal or human, and a third virus results that can be readily transmitted by and between humans. Antigenic shift is relatively infrequent and, because there is little or no immunity to a novel virus, it remains the initiating event for pandemics, which occur if there is efficient and sustained virus transmission among humans. Compared with regular seasonal epidemics, the emergence of a novel influenza virus through antigenic shift will result in greater numbers of infections and more serious illness among infected persons. Antigenic shifts are associated with epidemics and pandemics of influenza A (c.f., antigenic drifts which are associated with more localized outbreaks).

The incubation period of the influenza A virus is about 2 days. Symptoms characteristically begin with the abrupt onset of fever (>37.8°C), chills, headache, myalgia, and malaise, anorexia, sore throat, coughing, sneezing, and shortness of breath. Fever peaks within 24 hours of onset and lasts 1 to 5 days. Within 6 to 12 hours, the illness reaches maximum severity and a dry nonproductive cough develops. Symptoms may range from afebrile respiratory illnesses, similar to the common cold, to systemic involvement with relatively little involvement of the respiratory system. In uncomplicated influenza, physical findings are generally few or nonspecific and may improve over 2 to 5 days, followed by gradual improvement although the illness may last for 1 week or more. Some patients develop persistent weakness or easy fatigability that may last for several weeks. The clinical outcome is directly dependent on the viral load, which peaks at about 48 hours after exposure. The larger the infecting dose of virus, the more severe the course of illness. Viral shedding begins 24 to 48 hours before the onset of symptoms and continues for about a week after the onset of the illness.

Complications Associated with Influenza A

Influenza can result in significant pulmonary (involving the tracheobronchial tree and lungs) and extrapulmonary complications. Pulmonary complications include acute viral or secondary bacterial pneumonia. Persons at high risk for influenza complications include the following: children under 2 years; adults over 65 years; pregnant and postpartum women (within 2 weeks after delivery); American Indians and Alaska Natives; persons who are morbidly obese (BMI >40); residents of long-term care facilities; persons with immunosuppression; persons under 19 years who are receiving long-term aspirin therapy; persons with chronic medical conditions, such as chronic obstructive pulmonary disease, chronic cardiovascular disease, cirrhosis of the liver, chronic renal failure, diabetes, long-standing rheumatoid arthritis; immunocompromised patients; or neurologic and neurodevelopmental conditions; the elderly are particularly susceptible.

The respiratory epithelium becomes damaged within 24 hours of infection, rendering the patient susceptible to secondary bacterial pneumonia. At-risk patients usually develop secondary bacterial pneumonia 4 to 14 days after the onset of influenza symptoms. Bacterial pathogens that commonly cause superinfection include Streptococcus pneumoniae, S. aureus, Haemophilus influenzae, or group A Streptococcus. Bacterial superinfection can develop at any time in the acute or convalescent phase of the infection and is often characterized by an abrupt worsening of the patient’s condition after initial stabilization. Although acute viral pneumonia is relatively uncommon, patients with significant underlying cardiovascular disease appear to be most susceptible and commonly affected. Mortality rates among patients with bacterial pneumonia and acute viral pneumonia are relatively high in the elderly.

The clinician must be alert because patients with viral pneumonia usually present with the typical features of influenza but then develop an exacerbation of respiratory symptoms, hemoptysis, and respiratory failure. Chest radiographs in patients with viral pneumonia generally have a reticular interstitial pattern rather than radiologic characteristics of consolidation; blood gases reflect severe hypoxemia; and cultures of the blood and respiratory tract are generally negative for bacterial growth.

Extrapulmonary complications include musculoskeletal abnormalities, such as myositis and rhabdomyolysis; neurologic sequelae—encephalopathy, encephalitis, transverse myelitis, or Guillain–Barré syndrome; myocarditis; and rarely, Reye syndrome (48). The latter is almost never seen nowadays with the decreased use of aspirin as an antipyretic and analgesic in children. Mortality rates attributable to influenza in patients with underlying chronic medical conditions are probably underestimated because many of these patients die ostensibly through exacerbation of the underlying chronic respiratory or cardiovascular condition, which in fact rendered them susceptible to the influenza virus in the first place.

Avian Influenza A

Influenza A viruses naturally infect avian and mammalian species; wild aquatic birds are considered the prime reservoir. Through antigenic shift, influenza A viruses that are naturally resident in wild waterfowl (e.g., aquatic ducks, geese, and swans) acquire the potential for transmission to humans. Viruses are shed in respiratory secretions and feces of birds and can survive at low temperatures and low humidity for days to weeks. Avian influenza A viruses are classified in one of the following two categories: low pathogenic or highly pathogenic forms. The criteria for high pathogenicity include one or more of the following: (i) any avian influenza A virus that is lethal for 4-week-old chickens in the laboratory; (ii) any H5 or H7 virus that has a multibasic amino acid sequence at the hemagglutinin cleavage site; or (iii) any non-H5 or non-H7 that kills one to five of eight inoculated chickens and grows in cell culture without trypsin (49); low pathogenic infections are generally much milder in all avian species. With rare exceptions, highly pathogenic avian influenza viruses are usually H5 or H7 subtypes.

Risk factors for H5N1 infection include the presence in the household and the handling of dead or sick poultry in an H5N1-affected area, and lack of access to an indoor water source (50). Human-to-human transmission, though limited, has been documented and is particularly relevant for health care personnel—a retrospective case-control study has presented epidemiologic evidence that H5N1 viruses were transmitted from patients to health care workers (51). Some studies suggest that exposure alone to persons who might be a source of H5N1 infection might not necessarily be the only risk factor for this mode of transmission (50,52,53). These data suggest two possible mechanisms for transmission: inhalation or conjunctival deposition of large infectious droplets that could travel short distances, or presence or consumption of infected poultry in the home (54).

The incubation period for human avian influenza A (H5N1) infection is 2 to 8 days but may be as long as 17 days (48). The clinical course in humans is characterized by rapid deterioration and high mortality rates. Patients tend to develop high viremic levels and intense inflammatory responses—a finding that had been established previously for seasonal influenza A virus strains (55). Early symptoms of influenza A H5N1 include a high fever, diarrhea, vomiting, abdominal pain, chest pain, and bleeding from the nose and gums (48). Pneumonia that did not respond to antimicrobials is a common complication, suggesting that the process is likely a viral pneumonia, usually without bacterial superinfection at the time of hospitalization (48). Data from Vietnam suggest that multifocal consolidation involving at least two zones is the most common radiographic abnormality at the time of admission (48). In severe cases, respiratory failure occurs within 3 to 5 days after the onset of symptoms and may progress to the acute respiratory distress syndrome (ARDS) within a week from the time of onset of illness (56). Other documented complications include the reactive hemophagocytic syndrome, extensive hepatic central lobular necrosis, acute renal tubular necrosis, rhabdomyolysis, pancytopenia, cardiac dilatation, and dysrhythmias, ventilator-associated pneumonia (VAP), pulmonary hemorrhage, pneumothorax, or the systemic inflammatory response syndrome (SIRS) without documented bacteremia (48,56–60).

The mortality rate among patients who acquire influenza A (H5N1) infection is high. Since 2003, over 50% of persons who have been treated for avian H5N1 infection have died, with the highest death rates among persons younger than 15 years in Thailand (48). The most common cause of death is progressive respiratory failure.

Laboratory Diagnostic Tests

Common laboratory findings include leucopenia (especially lymphopenia), thrombocytopenia, raised aminotransferase levels, and elevated creatinine levels (48). Diagnosis of influenza requires collection of appropriate clinical specimens. For example, respiratory viruses grow in the epithelial lining of the nasal mucosa. Thus, a nasal wash is the optimal specimen for recovering respiratory viruses. Because the influenza virus is enveloped, it is less stable and may become nonviable during specimen collection and processing. The specimen, ideally, should be transported immediately to the laboratory in a sterile container; specimens that cannot be delivered immediately to the laboratory should be refrigerated until transported. Dry nasal swabs, throat swabs, or calcium alginate swabs are not appropriate for recovering respiratory viruses and should be discouraged. Unlike human influenza A infection, avian influenza (H5N1) is more commonly detected in, and has higher viral RNA levels in, pharyngeal versus nasal specimens (48).

Rapid enzyme immunoassay (EIA) testing of nasal washes for influenza A and B are available and are useful in the outpatient clinic or the emergency room. In these settings, physicians may use the EIA test results to discharge patients or to initiate prompt therapy and infection control measures. The EIA test is approved for nasopharyngeal swabs, though nasal washes afford the best sensitivity. Rapid antigen tests are less sensitive in detecting influenza A (H5N1) infections compared with real-time PCR assays (56).

Rapid inpatient diagnosis is achievable through use of fluorescent antibody to directly detect the influenza antigen. This immunofluorescence testing of properly taken specimens for influenza A and B is usually performed with a respiratory viral battery that includes adenovirus; influenza A and B; parainfluenza 1, 2, and 3; and respiratory syncytial virus. The fluorescent antibody test has a relatively high sensitivity and specificity and turnaround time is approximately 2 hours. Fluorescent antibody-negative specimens should be cultured for the above respiratory viruses (influenza cell cultures take about 5 to 7 days to grow). As with respiratory syncytial virus, viral culture is the gold standard for laboratory diagnosis of influenza A.

Serologic testing requires testing of paired serum specimens: the first taken during the acute phase; the second taken 2 to 4 weeks later; the diagnosis is made by demonstrating a fourfold or greater increase in complement-fixing or hemagglutination inhibition antibody titers in the paired serum specimens. However, serologic testing for influenza A and B has a low sensitivity. For these reasons, serologic testing is not useful for diagnosis in the acute phase of influenza; it may, however, be used for establishing a retrospective diagnosis and for surveillance activities and epidemiologic studies.

Rapid influenza antigen diagnostic test (RIDT) platforms are now used by the majority of hospitals in the United States and generally yield results within 30 minutes. In areas of low prevalence, false-negatives are frequent and specificity is reduced (61). A negative RIDT does not exclude a diagnosis of influenza. Thus, all hospitalized and all high-risk patients with suspected or confirmed influenza should be treated as soon as possible without waiting for confirmatory testing (62). The CDC has published a comprehensive guidance for clinicians on the use of RIDTs at www.cdc.gov/flu/professionals/diagnosis/clinician_guidance_ridt.htm#figure 1.


Medical management of influenza A infection comprises three essential components: (i) symptomatic, supportive therapy—rest, fluid replacement (oral or intravenous as deemed appropriate), and cautious use of analgesics, keeping in mind the association between salicylate use and Reye syndrome in children; (ii) initiation of antiviral therapy; and (iii) timely anticipation of complications, such as bacterial superinfection. Antimicrobial prophylaxis has not been shown to increase or reduce the risks for developing bacterial superinfection. However, there is always a risk that empirical antimicrobial therapy could increase the emergence of antimicrobial resistance among microorganisms in the respiratory tract.

Antiviral treatment is recommended as soon as possible for all persons with suspected or confirmed influenza requiring hospitalization or who have progressive, severe, or complicated illness regardless of previous health or vaccination status. Treatment should not be delayed while the results of diagnostic testing are pending.

Neuraminidase inhibitors, such as Oseltamivir and Zanamivir are the mainstay antiviral agents currently prescribed. They act by inhibiting the cleavage of the virus from sialic acid, which blocks the release of new virus thereby preventing the propagation of infection. Oseltamivir is FDA approved for patients ages one and older and therapy should be started within 24 to 48 hours of symptoms. Neuraminidase inhibitors are active against both influenza A and B; for hospitalized patients, treatment with oral or enterically administered Oseltamivir is recommended. Limited data suggest that Oseltamivir administered by oro/nasogastric tube is well absorbed in critically ill patients with influenza, including those persons on continuous renal replacement therapy (CRRT), or patients on extracorporeal membrane oxygenation (ECMO). In patients with severe influenza disease, inhaled Zanamivir is not recommended because of lack of data for use in this patient population. Finally, for patients who remain severely ill after 5 days of treatment, longer treatment courses may be considered.

At the present time, there are insufficient data to support routine IV Peramivir in hospitalized patients. However, for critically ill patients who cannot tolerate or absorb oral Oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of intravenous Peramivir or investigational intravenous Zanamivir may be considered. If Peramivir is used in severely ill patients, single dose treatment should not be given. For severely ill patients, adult dose of 600 mg IV once daily for 5 days is recommended (dose for children >6 years: 10 mg/kg once daily [≤600 mg] for 5 days); minimum of 5 days duration (63).

Adamantanes, such as amantadine and rimantadine, are M2 protein blockers that used to be active against influenza A. These M2 protein blockers work by causing a loss in ion channel function, inhibition of ribonucleoprotein release, and of the uncoating process. However, the occurrence of adamantane resistance among circulating influenza A viruses increased rapidly worldwide beginning during 2003–2004. The percentage of influenza A virus isolates submitted from throughout the world to the World Health Organization Collaborating Center for Surveillance, Epidemiology, and Control of Influenza at CDC that were adamantane-resistant increased from 0.4% during 1994–1995 to 12.3% during 2003–2004 (64). High levels of resistance to the adamantanes (amantadine and rimantadine) persist among the influenza A viruses currently circulating (65–68). Moreover, the adamantanes are not effective against influenza B viruses (65). For this reason, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A virus strains at the present time.

Current recommendations for treating influenza A are summarized as follows:

  • Oral oseltamivir (Tamiflu)—recommended for treatment of all ages and chemoprophylaxis for age over 3 months
  • Inhaled zanamivir (Relenza): effective against influenza A and B. Used when predominant circulating strain is resistant to Tamiflu and recommended for treatment in persons aged over 7 years and chemoprophylaxis for age over 5 years
  • Intravenous peramivir (Rapivab): approved on December 19, 2014, for the treatment of acute uncomplicated influenza in persons over 18 years (600-mg dose infused over 15 to 30 minutes).

Patients with suspected influenza A (H5N1) should promptly receive a neuraminidase inhibitor pending the results of diagnostic laboratory testing (48); early treatment provides the greatest clinical benefit (56). Any patient with suspected or confirmed influenza in the following categories should be treated with a neuraminidase inhibitor:

  • All hospitalized patients
  • Has severe, complicated, or progressive illness, including individuals in the outpatient setting, who have severe or prolonged progressive symptoms or who develop complications such as pneumonia
  • Individuals who are at higher risk for influenza complications (hospitalized or outpatient). Patients in this group include the following:

    • Children younger than 2 years (although all children younger than 5 years are considered at higher risk for complications from influenza, the highest risk is for those younger than 2 years)
    • Adults aged 65 years and older
    • Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension alone), renal, hepatic, hematologic (including sickle cell disease), and metabolic disorders (including diabetes mellitus), or neurologic and neurodevelopment conditions (including disorders of the brain, spinal cord, peripheral nerve, and muscle such as cerebral palsy, epilepsy [seizure disorders], stroke, intellectual disability [mental retardation], moderate to severe developmental delay, muscular dystrophy, or spinal cord injury)
    • Persons with immunosuppression, including that caused by medications or by HIV infection
    • Women who are pregnant or postpartum (within 2 weeks after delivery)
    • Persons aged younger than 19 years who are receiving long-term aspirin therapy
    • American Indians/Alaska Natives
    • Persons who are morbidly obese (i.e., body mass index is equal to or >40)
    • Residents of nursing homes and other chronic-care facilities.

Antiviral treatment may be prescribed on the basis of clinical judgment for any previously healthy (non-high risk) patient with suspected or confirmed influenza. When indicated, antiviral treatment should be started as soon as possible after illness onset. Ideally, treatment should be initiated within 48 hours of symptom onset and should not be delayed even for a few hours to wait for the results of testing; a negative RIDT does not rule out a diagnosis of influenza.

Of note, antiviral therapy initiated after 48 hours can still be beneficial in some patients. Some observational studies of hospitalized patients suggest that treatment might still be beneficial when initiated 4 or 5 days after symptom onset. Observational data in pregnant women have shown antiviral treatment to provide benefit when started 3 or 4 days after onset and a randomized placebo-controlled study suggested clinical benefit when Oseltamivir was initiated 72 hours after illness onset among febrile children with uncomplicated influenza (66,69–72).

Resistance to oseltamivir has been recognized and documented; in addition, some influenza viruses may become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents and remain susceptible to zanamivir. For this reason, investigational use of intravenous zanamivir should be considered for treatment of severely ill patients with Oseltamivir-resistant influenza virus infection.

Adverse events associated with neuraminidase inhibitors have been recognized and documented: oral Oseltamivir is associated with a slightly increased risk of nausea and vomiting over placebo. However, these symptoms are mild and transient and improve when taken with food. Inhaled zanamivir can cause bronchospasm and is not recommended for persons with underlying airways disease such as asthma, COPD. Intravenous peramivir is associated with a slightly increased risk of diarrhea and neutropenia over placebo.

The utility of antiviral therapy in noncomplicated influenza infection remains a highly debatable issue. Some studies have shown that oseltamivir therapy is associated with modest reduction in the duration of symptoms and virus shedding in people with uncomplicated influenza infections, even when treatment was started 48 hours or longer after illness onset (69). Overall, though, there is a paucity of data on the utility of antiviral agents in patients who have already developed complications, such as viral pneumonia or bacterial superinfection. Neuraminidase inhibitors are efficacious in preventing febrile illness though systemic infection can still occur; they also provide a degree of protection against the next wave of the pandemic virus (73). The role of corticosteroids and immunomodulators, such as interferon alpha, remains uncharacterized.

Infection Control within the Health Care Setting

Transmission of influenza in health care settings is well documented, and can occur between patients and health care personnel or health care workers can transmit the virus to patients or other health care workers. During a pandemic, control and prevention of influenza A (H5N1) transmission in the inpatient setting requires institution of current guidelines for the prevention of transmission in health care settings (74); scrupulous attention to infection control practices and procedures, including strict attention to handwashing and hygienic practices in conjunction with established guidelines for the prevention of hospital-acquired pneumonia (42,48,74). As recommended for the control of SARS, use of N-95 masks has been shown to be effective in reducing person-to-person transmission. However, surgical masks are acceptable if N-95 masks are not available (19,27,75).

The best prevention for influenza is to avoid the illness, though this is largely unavoidable during a pandemic. Annual influenza vaccination is recommended for all high-risk patients (e.g., those with chronic lung or cardiac disease) and their close contacts, including medical personnel and household members and universal vaccination of all children is recommended (76). However, it is widely appreciated that should an avian influenza A pandemic occur, a vaccine against the pandemic strain will not be immediately available. Moreover, because the major determinant of protection afforded by the influenza vaccine recipient is the generation of hemagglutinin antibodies that provide protection approximately 2 weeks after administration, immediate benefit will not be rendered to vaccine recipients. Chemoprophylaxis with Oseltamivir once daily for 7 to 10 days has been suggested for persons who might have had an unprotected exposure to avian influenza H5N1 (48,77,78). Other data suggest that preexposure prophylaxis might warrant consideration if there is evidence that the influenza A (H5N1) strain is being transmitted person-to-person with increased efficiency or if there is a likelihood of a high-risk exposure (48).


Dengue fever is a mosquito-borne disease caused by a Flavivirus, and is currently the most common arthropod-borne viral disease in the world. Though most cases have been reported in Asia, the number of countries with endemic Dengue activity has increased dramatically in recent decades (79–82). The Dengue fever virus is now endemic in over 100 tropical and subtropical countries in Southeast Asia, Africa, the Western Pacific, Africa, the Americas, the Caribbean, and the Eastern Mediterranean (83). The annual occurrences of Dengue fever and its serious sequelae—Dengue hemorrhagic fever—are estimated at about 100 million and 500,000 cases, respectively, with an estimated mortality rate of 25,000 per year (79,81,83). Because many of the countries where the virus is endemic remain popular tourist areas and international travelers can both acquire and spread Dengue virus infection, the public and clinical implications of this infection remain pertinent to critical care specialists in both developed and economically less-developed countries (79–81,83–85).

The Dengue fever virus is a small mosquito-borne virus from the viral family Flaviviridae, genus Flavivirus, and contains a single strand of nonsegmented, positive sense RNA enclosed in a tight envelope. Disease is caused by four closely related but antigenically distinct serotypes—DENV types 1 to 4. Worldwide, the virus is transmitted person-to-person primarily by the female Aedes aegypti mosquito (79–81,83–86); in the continental United States, two major Dengue vectors, Ae. aegypti and Ae. albopictus mosquitoes, are widely distributed and are likely to play important roles in transmission of the virus in North America during a Dengue fever pandemic (81,87). These are day-biting species well adapted to urban settings and found inside and around houses, particularly in places where clean stagnant water has collected in receptacles, such as tires, domicile house rainwater tanks, empty oil drums, discarded plastic containers and soft drink cans, or plant pots. Humans are the principal reservoir for the Dengue virus and are able to sustain a viremia for up to 10 days after acquiring the infection; there is no known natural animal reservoir of infection. After it takes a blood meal from an infected human, the mosquito vector transmits the virus to new hosts during subsequent blood feeds. Transmission of Dengue virus infection in patient care settings and among laboratory personnel has been described and attributed largely to mucocutaneous contact with infected blood from travelers, needle stick injury, or blood transfusion (88–94).

The incubation period of Dengue fever ranges from 3 to 14 days during which the virus multiplies in lymph nodes. Infection with any of the four serotypes can cause disease ranging from mild infection (Dengue fever) with complete recovery to severe disease (i.e., Dengue hemorrhagic fever and Dengue shock syndrome) that may result in substantial morbidity and mortality. “Typical” Dengue fever has an abrupt onset and is characterized by high fever, headache, retro-orbital pain worsened by moving the eyes, pain in the joints, limbs, and muscles (“breakbone fever”), and a rash that resembles sunburn. Other symptoms include abdominal pain and vomiting, and cough is particularly common in children. On examination, the face is usually flushed, the eyes congested, and cervical lymph nodes enlarged. The fever lasts for about a week, but after 2 to 4 days often falls to normal, returning after another 24 hours, giving rise to the so-called saddle-back fever curve. During the second fever phase, the patient often develops a characteristic maculopapular rash over the entire body except the face, and the pulse tends to be disproportionately slow. Uncomplicated Dengue fever is a mild form of the condition with the characteristic clinical features of fever, joint ache, severe headaches, weakness, and skin rashes. This form of Dengue fever is not fatal, rarely affects children, and usually lasts just 3 to 4 days.

Through a mechanism known as antibody-dependent enhancement (or immune enhancement), previous or sequential infection with the Dengue virus increases the risk for progression to Dengue hemorrhagic fever and Dengue shock syndrome in subsequent infections, which are also more likely on reinfection with a different serotype (95,96). The immunologic response is an anamnestic reaction with IgG antibodies persisting from the previous infection. Dengue hemorrhagic fever is characterized by high fever, alteration in microvascular permeability leading to plasma leakage, hepatomegaly, and circulatory failure—the key feature of Dengue shock syndrome (85,95,97). The patient’s face is pale or mottled and cyanosed, skin clammy and cold, and pulse thready. In addition, the palms and soles become red and edematous, and the patient may develop petechiae and purpuric lesions. Bleeding varies from these skin lesions to epistaxis, bleeding from the gums or gastrointestinal tract, or hematuria. Unless urgently treated, death ensues from profound shock, severe bleeding, or both within a few hours of presentation.

Plasma leakage is a result of damage to endothelial cells during the course of Dengue infection; this damage is attributable to cytokine release rather than a cytopathic effect of the virus itself on the endothelium (87,95). Progression to the Dengue hemorrhagic syndrome is not uniform among persons infected with the Dengue virus. Several factors determine whether or not an infected person will develop the syndrome:

  • HLA gene linkage or ethnicity has been shown to make a person susceptible or resistant to the virus; for example, persons of African ethnicity harbor a gene that proffers resistance, and Dengue hemorrhagic fever appears to occur rarely in European travelers (87,98–100).
  • Vascular permeability is age related with very young children and the elderly most susceptible (81,101,102).
  • Differences in intrinsic virulence of various virus strains explain the ability of some strains, more than others, to cause progression of Dengue fever to Dengue hemorrhagic fever and the Dengue shock syndrome (87,95).

Vascular permeability is the key feature in Dengue hemorrhagic fever; however, as Halstead pointed out, at its onset, vascular permeability exhibits only subtle changes, which can make early diagnosis difficult (87,95,103). The sphygmomanometer cuff tourniquet test has been widely used to screen children for vascular permeability, and though a positive test is an early correlate of Dengue hemorrhagic fever (87), the test itself has a sensitivity of only 42% and a specificity of 94% (104–107). The tourniquet test is carried out by inflating a blood pressure cuff to midway between the systolic and diastolic BP for 15 minutes. The number of petechiae that form within a 2.5-cm diameter circle are counted; greater than 20 petechiae is suggestive of capillary fragility. It should be borne in mind that a negative tourniquet test alone does not exclude an ongoing Dengue infection.

A better screening test for incipient Dengue hemorrhagic fever and early evidence of vascular permeability is detection of protein or heparin sulfate in acute-phase urine (87,107,108). The diagnosis is made principally on epidemiologic and clinical grounds, but may be confirmed by serologic testing. Dengue hemorrhagic fever should be suspected in children with WHO-defined clinical criteria: that is, sudden fever that stays high for 2 to 7 days, hemorrhagic manifestations, and hepatomegaly. Hemorrhagic manifestations include at least a positive tourniquet test and petechiae, purpura, ecchymoses, bleeding gums, hematemesis, or melena.

There are no specific therapies for Dengue fever, Dengue hemorrhagic fever, or Dengue shock syndrome, which must be differentiated from the toxic shock syndrome. Treatment is directed against the shock and hemorrhage rather than against the infection. Clinical outcomes are largely dependent on careful history and physical examination, and a low threshold of suspicion among physicians for the diagnosis, especially among travelers who present with symptoms (83). Dengue fever, Dengue hemorrhagic fever, and Dengue shock syndrome cause substantial morbidity; death rates can be as high as 30% if these complications are not managed properly (84,87,95,102,109–111). Although vaccines for flaviviruses, such as yellow fever and Japanese encephalitis, are available, Dengue vaccine is still under development, made complicated by the need to incorporate all four virus serotypes into a single preparation (81,82,84,110–112). Thus, until a safe and effective tetravalent vaccine becomes available, prevention will be attained only through vector control programs and avoidance of mosquito bites through protective gear and insect repellent.


In summary, Dengue fever and Dengue hemorrhagic fever have reached pandemic proportions in countries across the globe and Dengue has become one of the most important tropical diseases in the first decade of the 21st century (79). The resurgence has been linked to population growth, urbanization, air travel, and changes in the environment that have all favored extension of the ranges of the mosquito vector or its ability to thrive. Unfortunately, lack of or inadequate existing surveillance activities have resulted in reduced ascertainment of the early stages of epidemic transmission, with gross underreporting of cases until the epidemic is recognized as Dengue (79,113). Travelers returning from endemic regions are at particular risk of acquiring Dengue fever. Persons who travel repeatedly to countries with high Dengue endemicity put themselves at risk of becoming reinfected with a different serotype of the Dengue virus thereby predisposing themselves to Dengue hemorrhagic fever. In the characterization of fever in the tropics or among returning travelers, clinicians need to have a high degree of suspicion and maintain Dengue high on their list of differential diagnoses following a thorough history and physical examination.


Before the HIV pandemic, M. tuberculosis infection and disease were already endemic in many economically less-developed countries, though not at pandemic proportions. With the onset of the HIV pandemic, there has been a dramatic, parallel increase in rates of tuberculosis among HIV-infected patients, especially those in sub-Saharan Africa, Southeast Asia, and increasingly, the Indian subcontinent; over 80% of all patients with tuberculosis live in sub-Saharan Africa and Asia (114). Tuberculosis now ranks alongside HIV as a leading cause of death worldwide: the death toll attributed to HIV in 2014 was estimated at 1.2 million, which included almost one-half million deaths attributed to tuberculosis among HIV-positive people (114); worldwide, 9.6 million people are estimated to have fallen ill with M. tuberculosis infection in 2014—12% of the 9.6 million new TB cases in 2014 were HIV-positive (114).

The WHO generally considers M. tuberculosis infections a true pandemic that is linked primarily with immunosuppression resulting from HIV infection, though the problem has certainly been compounded by other factors associated with poverty, such as overcrowding, malnutrition, lack of access to health care, and poor sanitation, made particularly worse in refugee camps resulting from natural and man-made disasters and war (114). The fact remains that at the middle of the second decade of the 21st century, tuberculosis remains a leading cause of death worldwide.

The major issues relevant to the management of tuberculosis within the critical care setting include the following:

  • The ability of clinicians to recognize active or disseminated tuberculosis
  • The need to have a low threshold of suspicion for active tuberculosis when interpreting sputum smear results and abnormal chest radiographs, especially for at-risk patients or individuals who resided in HIV-endemic regions
  • The importance of collecting appropriate sputum specimens for screening smears and cultures, and rational interpretation of results
  • The utility and interpretation of tuberculin skin tests and interferon gamma assays
  • The timely institution of infection control measures for the prevention of transmission of the tubercle bacillus from infected patients or health care personnel to other individuals in the unit through isolation of patients with active disease or positive smears in properly designed rooms maintained at negative pressure differentials
  • Collection of appropriate sputum specimens for follow-up smears and cultures per CDC’s recommendations (115,116)
  • Involvement of infection control and occupational health personnel in the preventive decision making for patients and staff who might have been exposed inadvertently to persons with active tuberculosis (74,115,116)
  • Awareness by all health care personnel of the basic tenets of guidelines published by CDC for the prevention of tuberculosis in health care settings (74,115,116)

Perhaps the most insidious occurrence resulting from the tuberculosis pandemic is the emergence of strains of M. tuberculosis resistant to standard antituberculous agents. During the 1990s, multidrug-resistant (MDR) tuberculosis, defined as resistance to at least both isoniazid and rifampin, emerged as a threat to therapy, control, and prevention of tuberculosis, both in the United States and worldwide (117–120). MDR tuberculosis is associated with the ready availability and overprescribing of antituberculous agents. The treatment of MDR tuberculosis has clinical and public health implications largely related to the fact that therapy requires the use of alternative second-line drugs that are more expensive, toxic, and less effective than first-line isoniazid- and rifampin-based regimens (118,119).

There have now been numerous reports of tuberculosis caused by extensively drug-resistant (XDR) strains of M. tuberculosis (i.e., strains resistant to practically all second-line agents) (114,121–124). To assess the frequency and distribution of XDR tuberculosis, CDC and WHO carried out a survey of an international network of tuberculosis laboratories during 1993 through 2004 (127). Of 17,690 M. tuberculosis isolates characterized, 20% were MDR and 2% were found to be XDR. In addition, the study found that 4% of MDR tuberculosis cases in the United States were in fact caused by XDR M. tuberculosis (122). In October 2006, the WHO Global Task Force on XDR tuberculosis met in Geneva, Switzerland, to review available information on the emergence of XDR tuberculosis and to recommend measures to prevent and control this serious international public health threat (125). The Task Force approved the following revised laboratory case definition for XDR tuberculosis: “XDR tuberculosis is tuberculosis showing resistance to at least rifampin and isoniazid, which is the definition of MDR tuberculosis, in addition to any fluoroquinolone, and to at least one of the three following injectable drugs used in antituberculosis treatment: capreomycin, kanamycin, and amikacin” (125).

CDC and WHO have deemed XDR tuberculosis a serious emerging public health threat, raising the specter of a pandemic of untreatable tuberculosis (120,122). Patients with XDR tuberculosis generally have poor outcomes, prolonged infectious periods and limited treatment options. Thus, rapid detection of drug-resistant strains, enhanced infection control and the development of new therapeutics remain the basis of management in the inpatient setting (126). The current management of patients with MDR/XDR tuberculosis is difficult and complex. There is an increasing, but still as yet limited, body of literature that provides evidence for the use of carbapenems (ertapenem, imipenem, meropenem) in treating MDR and XDR tuberculosis (127,128). The therapeutic difficulty is underscored by the lack of comprehensive four-drug protocols to treat XDR-tuberculosis. Moreover, despite recent scientific advances in MDR/XDR tuberculosis care, decisions for the management of patients with MDR/XDR tuberculosis often rely on expert opinions, rather than on clinical evidence (129,130). Ultimately, strategies for treating cases of difficult MDR-/XDR-tuberculosis will rely on harnessing existing drugs (e.g., newer generation fluoroquinolones, high-dose isoniazid, linezolid, and pyrazinamide) in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases (131).

Compounding the problem is the emergence of totally drug-resistant (TDR) tuberculosis (124,132). The first cases of TDR tuberculosis were reported in Italy in 2007 (133). These strains show in vitro resistance to all first- and second-line antituberculosis drugs (isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, ethionamide, paraaminosalicylic acid, cycloserine, ofloxacin, amikacin, ciprofloxacin, capreomycin, kanamycin). Subsequently, cases were reported in Iran, India, and South Africa. The treatment of TDR tuberculosis includes agents with disputed or minimal effectiveness against M. tuberculosis and the fatality rate is high (132). MDR tuberculosis is difficult to cure and requires 18 to 24 months of treatment after sputum culture conversion with a regimen that consists of four to six medications with toxic side effects. Moreover, the attributable mortality is significantly greater than that associated with susceptible strains of M. tuberculosis. Following clinical trials, FDA has approved use of bedaquiline (an oral diarylquinoline) under the provisions of the accelerated approval regulations for “serious or life-threatening illnesses” (132,134,135).


S. aureus is an important cause of infections of the skin, soft tissue, wounds, respiratory tract, urinary tract, central nervous system, and the bloodstream, and can be rapidly fatal if not treated effectively. Soon after the introduction of antimicrobials, S. aureus resistance to penicillin became widespread, quickly followed by resistance to semisynthetic penicillinase-resistant antimicrobials, such as methicillin, oxacillin, and nafcillin (i.e., MRSA)—first detected in the United Kingdom in 1960 (136). By the 1980s, MRSA had spread throughout health care institutions worldwide and in the United States, thereby compromising the effectiveness of therapy for staphylococcal infections, and dramatically increasing the empiric use of vancomycin, with its own attendant risks.

By 2006, MRSA was recognized as the most commonly identified antimicrobial-resistant pathogen in many parts of the world, including Europe, the Americas, North Africa, the Middle East, and East Asia (137). Grundmann et al. have pointed out that the increases in MRSA rates in these regions should be taken seriously because it is possible that the threshold for losing control might actually be low, albeit not well defined (137).

It is estimated that some 2 billion individuals are carrying S. aureus worldwide and between 2 and 53 million people carry MRSA across the globe (138). Despite more awareness among health care professionals of the adverse implications associated with MRSA colonization and infection, and despite more attention being paid to implementation of infection control guidelines, the prevalence of health care–associated MRSA infections in US acute care hospitals remains significant—the myriad of MRSA publications in the medical literature attests to the fact that MRSA is beating current prevention and control efforts.

In recent years, epidemics of hospital-acquired MRSA infections have highlighted attributable risk factors both intrinsic to the patient (e.g., age, underlying chronic heart or pulmonary disease, connective tissue disorders, high severity of illness scores, diabetes mellitus, immunosuppression, dialysis) and extrinsic (invasive medical devices and foreign bodies, surgical wounds, contact with other patients or health care personnel who are carriers). The clinical and diagnostic issues that must be addressed in ICUs and some of the tenets of infection control and hospital epidemiology that are necessary for the prevention of MRSA infection among unaffected patients, medical personnel, and other ancillary health care personnel have been made more complicated by the relatively recent emergence of community-associated MRSA.

Antimicrobial resistance among MRSA isolates is linked to a large mobile genetic element known as the staphylococcal cassette chromosome mec (SSCmec) gene that has been introduced into methicillin-susceptible S. aureus strains (the origin of this mec element remains unknown). The SCCmec element carries a methicillin-resistance determinant—mecA—that encodes for an additional penicillin-binding protein (PBP2A) with reduced affinity for beta-lactam antimicrobials, in addition to the regulatory genes (mec I and mecRI) of mec A (137,139). Five types of SCCmec (SCCmec I–V) have been described; most health care–associated strains carry either type I, II, or III, whereas community-acquired MRSA tend to be predominantly type IV and less commonly type V.

Individuals colonized with MRSA in their anterior nares can function as reservoirs for the organism over long periods (140). Recognition of colonized individuals is important because such persons may become infected; in the critical care setting, these persons may be a source of infection or colonization to other patients or health care personnel. Various epidemiologic studies have shown that the risk factors for MRSA carriage are similar to those for MRSA infection and include hospitalization (particularly in ICUs, surgery wards, other nursing units with documented high prevalence rates), invasive medical device use, the elderly, open wounds, underlying debilitation, proximity to other patients infected or colonized with MRSA, prior detection of MRSA, diabetes mellitus, treatments by injection, prior antimicrobial therapy, long inpatient stays, prior nursing home stays, visits at home by a nurse, or long periods of antimicrobial therapy (140–143). Health care personnel caring for MRSA-infected or MRSA-colonized patients with risk factors may themselves become colonized with MRSA and subsequently transmit the organism to noncolonized at-risk patients. Work carried out by Huang et al. have established that approximately 29% of newly detected MRSA carriers develop invasive disease within 18 months (144–146). There is now ample evidence that MRSA does not simply replace methicillin-susceptible S. aureus as a cause of health care–associated infection, but rather adds to the burden of infections caused by S. aureus.

In 2006, population-based estimates of nasal carriage of S. aureus, MRSA and identification of risk factors for carriage were carried out by two groups that independently analyzed the 2001–2002 National Health and Nutrition Examination Survey (NHANES) data for the noninstitutionalized US population, including children and adults (138,147,148). The findings of both groups were similar: close to 90 million persons (i.e., 32% of the US population) were colonized with S. aureus; and the prevalence of MRSA among S. aureus isolates was 2.6%, for an estimated population carriage of MRSA of 0.8% or 2.2 million persons adults. One of the studies also found that while S. aureus colonization prevalence was highest in participants 6 to 11 years old, MRSA colonization was associated with age 60 years of age or greater, and not necessarily with recent health care exposure (138).

Standard approaches to preventing MRSA transmission include implementing CDC guidelines that recommend isolation of patients colonized or infected with MRSA in a private or dedicated room, and use of gowns, gloves, and masks when appropriate, by all personnel entering the room (i.e., contact isolation). Many hospitals actively screen all patients when they are admitted to high-risk hospital areas (i.e., ICUs, transplant units, or surgical wards), and implement appropriate contact isolation for those identified as carriers. This approach, referred to as “active screening and isolation,” minimizes the possibility of transmitting MRSA between patients via the hands or clothes of health care workers, and has been effective in some centers (149–152). The major criticism of “active screening and isolation” programs is that it takes about 3 days on average from the time a nasal screening swab is obtained from a patient and is logged in the microbiology laboratory specimen receiving station, to the time the information that a patient is indeed an MRSA carrier gets reported back to those who need to know in the inpatient service. Person-to-person MRSA transmission may occur during those 3 days. Therefore, decreasing the time it takes to identify a patient as an MRSA carrier will eliminate this delay and may provide a rational strategy for reducing the transmission of MRSA in the inpatient setting. There has been an increasing body of literature regarding new methods for rapid identification of MRSA from clinical specimens (150,152–154). Few studies, however, have established the utility of rapid MRSA identification in reducing MRSA transmission and infection in the critical care setting (150,153,155–160).

In 1993, new strains of MRSA were identified among people in Western Australia who had not been in contact with the health care system (161). Since then, there has been a worldwide recognition of the emergence of community-associated MRSA strains. Previously healthy young adults are particularly affected and numerous reports of community-associated MRSA have been reported involving children, prison inmates, Alaskan Natives, Native Americans, Pacific Islanders, intravenous drug abusers, the homeless, children in daycare, athletes who participate in contact sports, and military personnel, though infections are by no means restricted to these populations. A single toxin, Panton-Valentine leukocidin (PVL), has been linked by epidemiologic studies to community-associated MRSA infection. Subsequent studies, however, have established that MRSA strains lacking PVL are just as likely to be virulent and to cause severe infection as PVL-positive strains, suggesting that PVL is not the major virulence determinant of community-associated MRSA.

Approximately 85% of community-associated MRSA infections involve the skin and subcutaneous tissues, with the most common presentations being an abscess or folliculitis in otherwise healthy individuals who do not have MRSA-associated risk factors. A predominant clone of community-associated MRSA, the US 300 clone, appears to be the predominant cause of community-onset S. aureus skin and soft-tissue infection. Also, the presence of unique virulence factors may be responsible for potentially lethal necrotizing pneumonia and other invasive infections in both immunocompetent and immunosuppressed individuals. Community-associated MRSA isolates are generally susceptible to multiple classes of antimicrobials other than beta-lactams, and infections can be treated with trimethoprim—sulfamethoxazole, doxycycline, or clindamycin; for severe infections, vancomycin, daptomycin, quinupristin/dalfopristin, or linezolid can be used, though delay in initiating appropriate antimicrobial therapy for severe infections can cause substantial morbidity or even be life-threatening (162–164).

The diversity of strain types involved in epidemiologically clear outbreaks of MRSA suggests the spread of genetic information among different strains that have strong predispositions for causing infections in hospital patients. Alternatively, the association could be due merely to the fact that resistance provides a dramatic marker that increases the likelihood that an epidemic will be recognized and investigated. If so, as infection control personnel in hospitals initiate surveillance activities and develop more sensitive means for recognizing outbreaks and clusters of infections, and more effectively share surveillance data with their counterparts in other local hospitals (e.g., through area-wide surveillance systems supported by local health departments), interhospital transmission of infection will likely be more readily recognized and controlled. The main obstacle to endeavors that properly and comprehensively address the clinical and public health challenges of MRSA infections both in hospitals and the community remains the changing face of health care in the United States. Adding to the complexity of the issue are the uncharacterized confounding variables of long-term care facilities, free-standing medical clinics and surgery centers, and home care, where substantial amounts of patient care are now provided or delivered. Admission of these varied populations to ICUs adds to the complexity of inter- and intrahospital transmission of MRSA, and continues to render control of MRSA transmission in critical care units a perennial problem notwithstanding prevention and control efforts.

Control and Prevention

That endemic and epidemic health care–associated infections are preventable have periodically been reaffirmed by the myriad of single-center studies published over the past three decades dealing with the unequivocal effect of handwashing with soap and water, proper care of urinary catheters, respirators, intravascular catheters, and surgical wounds, numerous evidence-based infection control guidelines published by CDC, and position papers issued by the Society of Healthcare Epidemiology of America, the Association of Practitioners of Infection Control, and the Infectious Diseases Society of America (82,176–178). However, according to CDC data, although overall rates of health care–associated infections at the main anatomic sites (i.e., bloodstream, respiratory tract, wounds, urine) have been falling, infections caused by MRSA have been increasing in hospitals across the United States.

There is little doubt that we would not be where we are today had more attention been paid to the published evidence-based data regarding which interventions have been effective in controlling the transmission of health care–associated, antimicrobial-resistant pathogens. After decades of discussing control of antimicrobial-resistant health care–associated pathogens in the medical literature, there is actually very little evidence of success either in the control of the infections caused by these pathogens or in halting the increasing incidence of resistance among isolates. The myriad articles published have in effect helped explain this failure because much of the published data on health care–associated infections have been carried out in hospitals that had implemented untried control programs or had substantially ineffective programs. Moreover, despite all the resources put into surveillance activities and “quality programs” for health care–associated infections in facilities across the country, there remains substantial variation in surveillance activities from one medical center to another, inconsistent use of effective control measures—for example, surveillance cultures not being performed as recommended, or failure of hospitals to use effective measures due to lack of commitment by health care companies and administrators alike to initiate and sustain these measures. In addition, there appears to be moderate compliance with goals to optimize antimicrobial use, and to detect, report, and control the spread of antimicrobial-resistant pathogens.

In the Netherlands and Nordic countries, rates of health care–associated MRSA infections have been held to less than 3% through programs that include screening of patients and exposed health care workers in aggressive “search and destroy” MRSA prevention programs (165–175). There are some differences in the choice of measures and target groups in the search and destroy strategy toward MRSA in some countries. For example, in the draft of a new Norwegian MRSA guideline it is suggested to have a search and destroy strategy in hospitals, while the measures outside health care institutions are targeted toward people with the highest risk of transmitting the bacteria to hospitals or nursing homes (165). American guidelines advocate an approach similar to the search and destroy paradigm (176); the value of obtaining screening cultures in areas with high MRSA endemicity, however, remains controversial (137).

Numerous reports presented at various Annual Meetings of the Society for Healthcare Epidemiology of America have repeatedly shown control of endemic or epidemic MRSA infections through implementation of the SHEA guidelines with more emphasis on contact precautions and less on standard precautions. In fact, CDC has never been able to provide any evidence-based data showing that standard precautions and passive surveillance have led to the control of MRSA in health care settings.

The tenets of the SHEA guidelines are based on identification and containment of spread through the following (176):

  • Active surveillance cultures to identify the reservoir for spread
  • Routine hand hygiene
  • Barrier precautions for patients known or suspected to be colonized or infected with MRSA
  • Implementation of an antimicrobial stewardship program
  • Decolonization or suppression of colonized patients

There is increasing evidence that screening of high-risk patients combined with a comprehensive prevention program consisting of contact precautions and scrupulous hand hygiene program can reduce transmission of MRSA (136,142,143,149–152,168,170,175,177–184). Grundmann et al. have pointed out that virtually all published analyses comparing the costs of screening patients on admission and using contact precautions when dealing with colonized patients with the cost savings made by preventing health care–associated MRSA infections have concluded that the combination of surveillance cultures and barrier precautions results in substantial cost savings for health care facilities (137).

In summary, active surveillance cultures for MRSA in the ICU setting with isolation of colonized persons is a highly effective strategy for control of MRSA. Isolation purely on the basis of history of previous detection, at least for MRSA, appears to be of little benefit. Standard precautions and isolation of the occasional patient recognized to be colonized through routine clinical cultures are minimally effective. The onus is now on health care professionals and health care administrators to invest intelligently in prevention programs, to enhance existing surveillance activities in targeted areas, and to avoid regarding death and morbidity attributable to MRSA as inevitable. However, it must be equally understood and appreciated by relatives, the patients themselves, lawyers, administrators, and health care personnel alike that the following types of patients are particularly susceptible to or likely to acquire health care–associated MRSA infections: those born very prematurely; the elderly; those who are debilitated or have severe congenital abnormalities; patients with diabetes mellitus, connective tissue disorders, or end-stage respiratory, liver, renal, or cardiac disease; patients with solid organ or hematologic malignancies; transplant patients; patients on steroids or immunosuppressive agents; and patients with numerous invasive medical devices or who have undergone one or more major surgical procedures or other invasive procedures.

The challenge that faces us now is controlling transmission of strains of community-associated MRSA that become endemic within the inpatient setting, especially in ICUs. New MRSA clones have emerged in the community that combine antimicrobial resistance with easy transmissibility and virulence (137,183). The worry is that these could take hold in hospitals, where patients are particularly vulnerable.


Cholera is a secretory gastroenteritis caused by Vibrio cholerae, a small, comma-shaped gram-negative microorganism. The natural reservoir is aquatic invertebrates in brackish or marine environments. The spread of cholera is primarily through ingestion of fecally contaminated water or food. Cholera is endemic in Asia, Africa, the Middle East and parts of Oceania and there are an estimated 3 to 5 million cases, and over 100,000 deaths each year around the world. In endemic areas, the disease is most common in children. However, nonimmune adults traveling to an endemic region is susceptible and at risk of acquiring the infection. Since 1817, there have been seven recorded cholera pandemics that affected populations across the entire globe, resulting in hundreds of thousands of deaths (184–186); the seventh pandemic began in 1961 and affects 3 to 5 million people each year, killing 120,000. CDC and WHO surveillance data indicate that there has been an ongoing global pandemic in Asia, Africa, and Latin America for the last four decades. Resource-poor areas continue to report the vast majority of cases with the African continent having the worst case fatality rates. There are 139 serotypes of V. cholerae, defined by the O surface antigen; the continuing pandemics are caused by two serogroups: O1 or O139.

V. cholerae is sensitive to gastric acid. Thus, the infectious inoculum in healthy hosts is relative large (about 1010 organisms). In persons who have achlorhydria, are taking antacids, or have had gastrectomy, the infectious inoculum is much lower (≤106). The organism tends to colonize the small intestine and secretes one major (cholera toxin) and two minor enterotoxins. The cholera toxin binds to the ganglioside on the small bowel epithelium and activates adenylate cyclase, which in turn leads to accumulation of cycle adenosine monophosphate (cAMP). The increased levels of cAMP inhibit sodium absorption and increase chloride secretion, leading to the characteristic, profuse, watery diarrhea.

The incubation period is 1 to 5 days. Profuse watery diarrhea containing flecks of mucus (the so-called “rice-water stools”) is the hallmark of cholera. This is followed by vomiting without retching, rapid heart rate, loss of skin elasticity due to dehydration, dry mucous membranes, low blood pressure, thirst, muscle cramps as a result of electrolyte shifts, restlessness or irritability. Patients characteristically do not have fever, abdominal pain, or tenesmus.

Isolation and identification of V. cholerae serogroup O1 or O139 by culture of a stool specimen remains the gold standard for the laboratory diagnosis of cholera. Cary Blair media is ideal for transport, and the selective thiosulfate–citrate–bile salts agar (TCBS) is ideal for isolation and identification. Laboratory test results usually reveal an elevated hematocrit, elevated blood urea nitrogen and creatinine, an elevated anion gap with significantly reduced bicarbonate levels and a metabolic acidosis.

Management of patients with cholera involves prompt aggressive fluid and electrolyte replacement–effective therapy can decrease mortality from greater than 50% to less than 0.2% (184). Replacement fluid and electrolytes should be administered intravenously in patients with severe dehydration, patients with moderate dehydration who are unable to take fluids orally, and patients who are purging copious amounts (>10 mL/kg/hr). The treatment and rehydration of cholera, based on the degree of dehydration, is summarized in a useful document published by the WHO (187). Antimicrobial therapy is merely adjunct to rehydration therapy and should be reserved for patients with severe dehydration only. In patients with severe disease, antibiotics can ameliorate the duration of symptoms and fluid requirements:

  • For adults, doxycycline is given as a single dose 300 mg or tetracycline 12.5 mg/kg, four times a day for 3 days
  • For young children: erythromycin 12.5 mg/kg, four times a day for 3 days
  • For children under 6 months of age: 10 mg daily for 10 days
  • For children 6 months to 5 years of age: 20 mg daily for 10 days

Of note, normal feeding should continue during treatment, if at all possible.

Infection control is of paramount importance. Chemoprophylaxis with antibiotics is not indicated for health care providers. One needs to protect oneself from contamination: the basic tenets of prevention in the inpatient setting are as follows:

  1. Scrupulous hand hygiene with soap and clean water before and after taking care of a patient. If no water and soap are available, use an alcohol-based hand cleaner (with at least 60% alcohol).
  2. Cut fingernails.
  3. Isolate cholera patients:

    1. Stool, vomit, and soiled clothes of patients are highly contagious.
    2. Patients’ utensils need to be washed and disinfected with chlorine.
    3. Cholera patients have to be in a special ward, isolated from other patients.

At present, two oral cholera vaccines are available: Dukoral (manufactured by SBL Vaccines) and ShanChol (manufactured by Shantha Biotec in India), which are WHO prequalified. These are two-dose vaccines; thus, multiple weeks can elapse before people receiving the vaccines are protected. Further, vaccines offer incomplete protection; therefore, vaccination should not replace standard prevention and control measures. In the United States, cholera vaccines are not yet available, and the disease is a reportable infection.


Over the past 5 years, two viruses with the potential for pandemic spread have emerged: the Middle East respiratory syndrome coronavirus (MERS-CoV) and the Zika virus. One bacteria—V. cholera—has been associated with infections of Pandemic proportions over the past 100 years.


Most people infected with MERS-CoV develop severe acute respiratory illness. MERS-CoV infection was first reported in Saudi Arabia in 2012 and has since spread to several other countries. As of September 30, 2015, a total of 1,589 laboratory-confirmed cases of infection with MERS-CoV have been reported to the WHO. Although most cases of MERS-CoV have occurred in Saudi Arabia and the United Arab Emirates, cases have been reported in Europe, the United States, and Asia in people who travelled from the Middle East or their contacts (188). Epidemiologic and genomic studies show zoonotic transmission to humans from camels and possibly bats. In contrast to the SARS-CoV pandemic, very limited global spread of fatal MERS-CoV has occurred outside the Arabian Peninsula (189,190). Both community-acquired and hospital-acquired cases of MERS-CoV infection have been reported with little human-to-human transmission reported in the community. Clinical features of MERS-CoV range from asymptomatic or mild disease to ARDS and multiorgan failure resulting in death, especially in individuals with underlying comorbidities. Zumla has underscored the fact that although MERS-CoV continues to be an endemic, low-level public health threat, there is always a risk that the virus could mutate, leading to increased person-to-person transmissibility, thereby increasing its pandemic potential (188). No specific drug treatment exists for MERS-CoV and there is no vaccination available at the present time. Supportive care is the mainstay of therapy; the use of convalescent plasma has been suggested as a potential therapy based on existing evidence from other viral infections (190). Corticosteroids used empirically have showed no survival benefit. Various trial therapies have included interferon alpha and ribavirin; these were tested in severely ill patients and showed an improvement in survival at 14 days but not at 28 days. Other investigational agents have included cyclophilin inhibitors, inhibitors of MERS-CoV cell receptors (CD26), and MERS neutralizing antibodies. None of these agents have been shown to be effective. CDC and ECDC recommend airborne isolation for patients at health care facilities. The WHO recommends airborne precautions during aerosol-generating procedures. Eye protection should be used when heath care workers care for probable or confirmed patients. Since it is not known how long the virus is present in respiratory secretions, patients should remain on contact and airborne precautions until discharge. Exposed individuals should be monitored for any symptoms, for 14 days, from date of exposure. Health care workers in contact or taking care of MERS patients are a high risk for acquiring the infection. Prolonged shedding occurs since the virus was found to be excreted even after 1 month of illness (96,188).

Zika Virus

The emergence of the Zika virus is more recent phenomenon: it is a flavivirus that emerged in Brazil in 2015 and then rapidly spread throughout the tropical and subtropical Americas, and the Caribbean. It is transmitted largely by the Aedes mosquito (191). Based on clinical criteria alone, Zika virus infection cannot be reliably distinguished from infections caused by two other common arboviruses transmitted by Dengue virus and Chikungunya virus. One or more of the following symptoms can be associated with Dengue or Zika: fever, rash, conjunctivitis, arthralgia, myalgia, or headache; unlike Dengue, hemorrhage and shock are not characteristic of Zika virus infection. Since specific diagnosis would be difficult at the time of presentation, the key factor for prevention of intrahospital transmission is obtaining a detailed travel history and implementation of contact and airborne precautions until a diagnosis is made.

Key Points

  • We have highlighted infections that have caused pandemics or, in the case of avian influenza, Dengue, MERS-CoV, or cholera, has a high potential to do so.
  • Patients with any of these infections may require management in an ICU. Knowledge of these infections is important for ICU personnel if appropriate management, as well as infection control and preventive measures, is to be instituted in a timely manner.
  • The common threads running through all of these pandemic infections include the need for physicians to have high indices of clinical suspicion and, early on, consider these diagnoses and the importance of infection control, surveillance, and education for staff and patients alike.
  • Apart from infections caused by MRSA and tuberculosis, critical care management of SARS, influenza, Dengue, MERS-CoV, and cholera are largely supportive.
  • SARS was controlled largely through early detection and implementation of traditional infection control practices, environmental decontamination, use of personal protective equipment, surveillance activities, and education and training of patients, relatives, and caregivers.
  • Avian influenza, where there have been outbreaks, has largely been controlled through early recognition, scrupulous attention to infection control practices and procedures, appropriate use of surgical masks, institution of established guidelines for the prevention of hospital-acquired pneumonia, and annual influenza vaccination for all high-risk patients and their close contacts—including medical personnel as well as household members.
  • Dengue and Zika virus infection must be considered in the characterization and workup of fever among returning international travelers, especially persons returning from Central and South America, Puerto Rico, and the Eastern Caribbean islands. Clinicians in critical care medicine need to have a high degree of suspicion for the associated clinical syndromes.
  • Preventing the transmission of tuberculosis in the in-patient setting is made all the more imperative because of the limited therapeutic options available once a patient has acquired infection caused by MDR, XDR, and totally resistant strains. Compounding the risk of tuberculosis in the in-patient setting is the looming possibility of transmission of untreatable XDR strains to previously healthy humans, including health care personnel.
  • Control and prevention of MRSA infections, too, have been made especially difficult since the emergence of community-associated strains that have insidiously crept into the in-patient setting, raising the possibility of transmission of MRSA to healthy personnel with no obvious risk factors. Antimicrobial therapeutic options for MRSA infection are also limited largely to vancomycin, daptomycin, and ceftaroline; idiosyncratic reactions or renal dysfunction reduces these choices even further.

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Feb 26, 2020 | Posted by in CRITICAL CARE | Comments Off on Emergent Pandemic Infections
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