Minh-Ly Nguyen
Minh-Hong Nguyen
Kevin J. Farrell
Cornelius J. Clancy
Fungal Infections
Fungal Pathogens
Medically relevant fungi are classically considered as one of three types of organism: yeasts, molds, or dimorphic agents. The yeasts grow as smooth colonies on culture plates. Microscopically, they are oval or spherical, and they reproduce by budding. The two most common human yeast pathogens are Candida spp. and Cryptococcus spp.; the molds appear as fuzzy colonies on agar plates. Microscopically, they have hyphae, which are tubular or filamentous morphologies that grow by branching and longitudinal extension. Hyphae can be septated (i.e., with cross walls perpendicular to hyphal cell wall) or aseptated (no cross walls). The most common human pathogens are Aspergillus spp. and Rhizopus spp. The term, dimorphic fungi, is used to describe the endemic fungi, which are found in distinct geographic locations. These fungi grow as filaments in the environment at ambient temperatures and as yeasts at higher body temperatures. The three most common pathogens are Histoplasma capsulatum, Coccidioides immitis, and Blastomyces dermatitidis. Clinicians should recognize that the term, dimorphic fungi, as commonly used in the medical literature is misleading. Candida albicans, although not grouped with the endemic dimorphic fungi, frequently assumes filamentous morphologies in tissue (pseudohyphae and hyphae).
Most fungal pathogens, except for Candida spp., are widespread in nature and are acquired by inhalation into the lungs. In immunocompetent hosts, inhaled fungi are generally arrested in the lungs by the host immune system. Candida spp., with the exception of Candida parapsilosis, are part of the human gastrointestinal flora, and infections with these organisms are usually endogenous in origin.
Due to the widespread environmental distribution of many fungal pathogens and the presence of Candida as human commensals, the diagnosis of infection (i.e., fungal disease) is often difficult to distinguish from colonization. As such, definitive diagnoses generally require either the presence of the organism at sterile sites or histopathology demonstrating tissue-invasive disease. Since many fungi show morphologies that are indistinguishable by histopathology (e.g., Aspergillus spp. versus Fusarium spp. and other acute-angle branching, septated molds), identification of the organism from culture is the only means to ascertain the etiologic agent.
In intensive care unit (ICU) settings, Candida spp. and, to a much lesser extent, Aspergillus are the major fungal pathogens. This chapter will concentrate on these fungi.
Infections Caused by Candida species (Candidiasis)
Candida spp. cause a wide range of clinical syndromes, from benign cutaneous to fatal deep-seated infections (Table 114.1). Candida spp. can affect otherwise healthy patients, as well as those with defective immune systems. In the ICU setting, the most common and serious form of disease is invasive candidiasis, which will be the focus of the rest of this section. Other types of candidiasis are alluded to in Table 114.1.
Invasive candidiasis typically refers to candidemia and deep-organ infections resulting from bloodborne dissemination. Candidemia is not always detected, and deep-seated organ involvement is, not infrequently, the first evidence of candidiasis.
Epidemiology
In the ICU, Candida spp. are the third most common cause of blood stream infections (1), accounting for approximately 10% of cases (1,2). The crude mortality rates range from 40% to 75%, and candidemia is associated with excess ICU and hospital stays and increased costs of care (3). Postmortem studies suggest that mortality rates due to invasive candidiasis may be higher than generally realized because of undiagnosed infections.
Risk Factors
The leading predisposing factors for invasive candidiasis include prolonged ICU stay, previous surgery (especially solid organ transplant and gastrointestinal surgery), acute renal failure, receipt of antibacterial agents or hyperalimentation, and the presence of a central venous catheter. In these settings, Candida colonization of different body sites and immunosuppression are major risk factors. Solid organ transplant recipients are at highest risk among the surgical patients, particularly small bowel, liver, and pancreas recipients, in whom the prevalence ranges from 9% to 59%. The types of surgical procedure and posttransplant immunosuppression confer additional risk. Although risk factors are well defined, the diversity of factors and underlying diseases associated with invasive candidiasis make it difficult to reliably identify large subgroups of patients within the ICU who might merit particular attention or targeted interventions.
Microbiology
C. albicans is the most common Candida species involved in invasive candidiasis, followed by C. glabrata, C. tropicalis, and C. parapsilosis. Other species are less common and often associated with underlying malignancy or chemotherapy. Whereas C. tropicalis and C. glabrata are found largely in adults, C. parapsilosis is the leading pathogen in the neonatal population. In many tertiary care centers, C glabrata has surpassed C. albicans to become the most common Candida sp. in invasive candidiasis, accounting for up to 35% of all candidemias (4,5). Among non-albicans Candida species, C. krusei and C. glabrata are particularly important because of their resistance and decreased susceptibility to fluconazole, respectively.
Clinical Manifestations
Clinical manifestations are often nonspecific. Fever is frequently the first and only sign of invasive candidiasis. Other signs that should raise concern for candidemia are papulopustular or macronodular skin lesions or ocular involvement such as chorioretinitis or endophthalmitis. Deep-seated infections often present, with findings localized to the particular tissue site.
Invasive candidiasis can be divided into four major clinical entities: catheter-related candidemia, acute disseminated candidiasis, chronic disseminated candidiasis, and deep-organ candidiasis (Table 114.2).
Diagnosis
The diagnosis of invasive candidiasis is a challenge due to nonspecific clinical manifestations and the low sensitivity of microbiologic culture techniques. Blood cultures should be routinely obtained in patients who have suggestive signs and symptoms, as well as those at high risk for invasive candidiasis. Although candidemia is the most common manifestation of invasive candidiasis, and whereas the other forms of invasive candidiasis generally originate from bloodborne dissemination, deep-seated candidiasis can occur without a positive blood culture. Indeed, blood cultures are positive in less than 50% of patients, and autopsy data demonstrate that as few as 15% to 40% of patients with invasive candidiasis have an antemortem diagnosis of the disease (6). Diagnosis, therefore, should also rely on histopathology and/or fungal cultures obtained by biopsy of sterile sites. As mentioned earlier, Candida spp. are common colonizers of humans, which often makes it difficult to differentiate between colonization or true infections when organisms are isolated from the urine and nonsterile sites (see below).
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Table 114.1 Major Clinical Candidal Syndromes |
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Given the potential for antifungal resistance among the non-albicans Candida spp., isolates recovered from blood or sterile sites should be identified to the species level. The availability of special fungal media (such as CHROMagar) and rapid in situ hybridization techniques have significantly shortened the time to speciation.
Efforts have been devoted to develop nonculture-based diagnostic methods for invasive candidiasis. Antibody-based assays have not been useful. Beta D-glucan assay, an antigen test, has recently been approved for the diagnosis of invasive fungal infections. The assay measures the [1, 3]-beta-D-glucan levels released from the cell wall of most fungi. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for this test in diagnosing invasive candidiasis are 81%, 84%, 84%, and 75%, respectively (7). Although this test is able to detect various Candida spp., a potential drawback is its nonspecificity for Candida, as it also detects Aspergillus, Fusarium, and Trichosporon. Other factors that can contribute to false-positive tests results include dialysis filters, gauze, and sponges.
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Table 114.2 Forms of Invasive Candidiasis |
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Studies have demonstrated that azole minimum inhibitory concentrations (MICs) correlate with the likelihood of success in treating patients. Nevertheless, antifungal susceptibility testing of Candida is currently performed in relatively few clinical laboratories, and it is not considered the standard of care, unlike antibacterial susceptibility testing. In fact, antifungal susceptibility patterns are predictable in most cases based on species and prior exposure to antifungal agents (8). For this reason, identification of isolates to the species level is usually more important than MIC data in the management of individual patients. For example, C. krusei is intrinsically resistant to fluconazole and a significant minority of C. glabrata strains develop resistance to the drug. For other species, the vast majority of bloodstream isolates remain susceptible to fluconazole, although resistance is a concern in the setting of prior exposure to the drug. Cross-resistance to other azoles is often seen, which limits the utility of this class against fluconazole-resistant isolates.
Reports of resistance to the new echinocandin class of antifungals are beginning to appear, but experience is too limited to know how widespread the phenomenon will be or the extent to which use of these agents will be influenced (9). Of note, MICs of echinocandins against C. parapsilosis are generally higher than against other species, and breakthrough infections among patients receiving these agents have been described (10). Since the significance of these observations on the use of echinocandins in the treatment of C. parapsilosis infections is unclear, susceptibility testing does not have a role in the management of individual patients as yet. Amphotericin B resistance is difficult to document using current testing methods. Resistance among C. lusitaniae and C. guilliermondii isolates is well described but not seen with all isolates. Clinicians should probably avoid amphotericin B if elevated MICs are documented. At centers where candidiasis is a particular problem and antifungal use is widespread, it is useful to conduct periodic susceptibility testing to generate an institutional antibiogram. Clinicians should be aware if such reports exist at their institution, as susceptibility patterns against different species can be used to guide empiric antifungal therapy.
Management
Invasive Candidiasis
The major antifungal agents and their activity are summarized in Table 114.3. The current guidelines for management of invasive candidiasis are summarized in Table 114.4 (11,12,13). Amphotericin B (conventional or lipid formulations) or caspofungin should be the first-line treatment of critically ill patients with invasive candidiasis. Caspofungin, an echinocandin agent, is better tolerated and has fewer side effects than amphotericin B. Fluconazole can also be considered once resistant species such as C. krusei are ruled out. Recent data show that anidulafungin and micafungin, two newly approved echinocandin agents, are as effective as caspofungin in management.
All patients with candidemia should have an ophthalmologic exam to rule out retinal involvement. In addition, all vascular catheters should be removed if possible. Candida spp. tend to form biofilms on catheters, which can render otherwise susceptible isolates resistant to antifungal agents.
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Table 114.3 Currently Available Systemic Antifungal Agents |
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Table 114.4 Recommended Antifungal Agents against Invasive Candidiasis |
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Candida Recovered from Urine or Sputum/Bronchoalveolar Lavage (BAL)
As mentioned above, Candida spp. are part of endogenous flora and frequent colonizers of mucosal surfaces. In the ICU setting, urine and sputum are the two most common sites of colonization.
Candida in the Urine
Candida spp. are now the most common organisms recovered from the urine of surgical ICU patients. The risk factors include urinary catheters, old age, and receipt of antibacterial agents. Unlike the assessment of bacteriuria, colony counts and urine analysis are not helpful in deciding whether candiduria is of clinical importance (14,15). Many studies have demonstrated that asymptomatic candiduria in the low-risk patient is of little clinical relevance and should not be treated. In a small subset of patients, candiduria is a marker for invasive candidiasis. Treatment is indicated for symptomatic patients and those who are neutropenic, have undergone a urologic manipulation, or received a kidney transplant (9). Treatment entails removal of the urinary catheter and therapy with a systemic antifungal agent (fluconazole or amphotericin B) for 7 to 14 days. In the event that catheter removal is not possible, changing the catheter might be of benefit and should be performed (9).
Candida in the Sputum
Specimens from the airways—sputum, tracheal aspirates, and BAL—are frequently contaminated with oropharyngeal flora, including Candida spp. Despite the frequency with which Candida spp. are isolated from the respiratory tree of ICU patients, primary Candida pneumonia is extremely rare (16,17). Cases are generally encountered among neutropenic hosts. The diagnosis of Candida pneumonia requires evidence of parenchymal invasion by hyphae on a biopsy specimen. Antifungal therapy should not be instituted in response to Candida isolates recovered from respiratory samples. In fact, strategies of not identifying or reporting Candida spp. in respiratory samples decrease length of stay, hospital costs, and unnecessary antifungal therapy, without any negative effects on the accurate diagnosis of Candida pneumonia or patient outcome (18).
Prevention
Given the nonspecific clinical manifestations, low yield of blood cultures, and high mortality rates of invasive candidiasis, investigators have studied three treatment strategies in the absence of a definitive diagnosis:
· Prophylactic strategy: Administration of an antifungal agent at a period of high risk to prevent candidiasis
· Preemptive strategy: Administration of an antifungal agent to treat suspected invasive candidiasis based on particular warning signs
· Empiric therapy: Administration of an antifungal agent in persistently febrile patients without a known source or with no response to appropriate antibacterial agents
Prophylactic Strategy
The role of prophylactic antifungal therapy is controversial, as results from several clinical trials are contradictory. The most popular antifungal agent used for prophylaxis is fluconazole, given its benign side effect profile and good absorption. Trials that showed a positive clinical impact of fluconazole prophylaxis are summarized in Table 114.5 (19,20,21,22). It should be pointed out that only a small subset of patients is at sufficient risk for invasive candidiasis to justify this strategy. Thus, universal prophylaxis to all ICU patients is not warranted. To date, the specific patient populations that would benefit most are not clearly defined.
Preemptive Strategy
Preemptive antifungal therapy based on specific findings on computed tomography (CT) scan or laboratory markers such as galactomannan is a popular approach in patients undergoing bone marrow transplantation or those with neutropenia from a hematologic malignancy. At this time, however, there are no good indicators for preemptive approaches in nonneutropenic ICU patients.
Empiric Strategy
This practice, although widely used, is not validated by clinical trials. Mathematical models suggest that empiric strategies might be proven effective. A theoretical cost-effectiveness analysis was performed on a target population of ICU patients with fever, hypothermia, or unexplained hypotension who had not responded to 3 days of antibacterial therapy (23). Assuming that 10% of the target population would have invasive candidiasis, the authors concluded that empiric fluconazole was the most reasonable strategy (cost: $12,593 per discounted life-year saved; one life saved for 71 patients treated). Empiric fluconazole was estimated to decrease mortality from 44% to 30.4% in patients with invasive candidiasis, and from 22.4% to 21.0% in the overall target cohort. The authors calculated that this strategy would be justifiable if the likelihood of invasive candidiasis were at least 2.5%. Until clinical trials validate empiric strategies within well defined at-risk populations, however, they cannot be broadly recommended.
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Table 114.5 Clinical Trials Demonstrating a Positive Impact of Antifungal Prophylaxis in Nonneutropenic ICU Patients |
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Infections Caused by Aspergillus Species (Aspergillosis)
Aspergillus spp. are less common human pathogens in the ICU than Candida spp. but cause greater morbidity and mortality. These molds are ubiquitous in the environment. In normal hosts, they are generally saprophytes that colonize the bronchopulmonary tree. The four classical clinical syndromes of pulmonary aspergillosis are presented in Table 114.6. This section will focus on the two syndromes most commonly encountered in ICU setting: chronic necrotizing pulmonary aspergillosis (CNPA) and invasive pulmonary aspergillosis (IPA). In both of these diseases, Aspergillus spp. invade tissue and blood vessels, causing necrosis and possibly disseminating to the brain and elsewhere. Of note, entities similar to allergic bronchopulmonary aspergillosis, CNPA, and IPA are also found in the sinuses.
Epidemiology
IPA is estimated to occur in 5% to 13% of patients who have undergone bone marrow transplantation, 5% to 25% of patients who have received heart or lung transplants, and 10% to 20% of patients receiving intensive chemotherapy for leukemia; mortality rates are 50% to 90%. The disease is not as common in patients with less profound immunosuppression and exceedingly uncommon in immunocompetent hosts. In immunocompetent hosts, the rare cases of IPA often follow influenza or other infectious respiratory processes. CNPA is generally a disease of patients with underlying lung disease.
Risk Factors
The major risk factors predisposing to invasive aspergillosis are summarized in Table 114.7. In addition to these, there are increasing reports of disease among debilitated patients in the ICU.
Microbiology
Although there are over 100 species of Aspergillus, only a few cause diseases in humans. A. fumigatus is most common, followed by A. flavus. Less common pathogens include A. terreus, A. niger, and A. clavatus. Antifungal susceptibility testing against molds is not recommended as routine practice. Reproducible testing methodologies have been developed, but interpretive criteria have not been established. Nevertheless, elevated MICs to amphotericin B have been documented against a number of A. terreus isolates and elevated MICs of itraconazole against a small percentage of A. fumigatus isolates.
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Table 114.6 Clinical Spectrum of Aspergillosis |
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Table 114.7 Predisposing Factors to Invasive Aspergillosis |
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Clinical Manifestations
Most infections caused by Aspergillus spp. originate from the inhalation of fungal spores into the lungs. Cases of direct skin inoculation of Aspergillus have been described in association with the insertion of intravenous devices or the taping of arm boards to the extremities. Patients with severe burns can also develop local burn wound infections, especially if they are rolled in the dirt to extinguish flames. Regardless of the portal of entry, any local form of aspergillosis can disseminate to various sites if host immune function is impaired.
Almost any organ may be involved in disseminated aspergillosis, including integument (onychomycosis, cutaneous aspergillosis), ear (otomycosis), respiratory tract (sinusitis, pneumonia, empyema), heart (endocarditis, myocarditis), gastrointestinal (GI, hepatosplenic aspergillosis), central nervous system (cerebral aspergillosis, meningitis), eye (endophthalmitis), bone (osteomyelitis, mediastinitis), and so forth. The lungs and sinuses are the two most common primary sites of aspergillosis. The central nervous system is the most common secondary site.
Diagnosis
The diagnosis of invasive aspergillosis is problematic. Since Aspergillus spores are ubiquitous, they are common colonizers of the bronchopulmonary tree. A definitive diagnosis, therefore, requires histologic evidence of tissue invasion by hyphal elements, as well as culture of the organism. It should be noted, however, that the sensitivity of tissue biopsy in diagnosing invasive aspergillosis is low (e.g., 30% for lung biopsies). Moreover, recovery of Aspergillus from the blood is extremely rare, with a recovery rate approximating 5% in cases of Aspergillus.
In immunocompromised hosts, a positive culture from a respiratory sample (sputum or BAL) is highly associated with invasive pulmonary disease. However, the sensitivity of culture of sputum or BAL is only 50%.
Radiography
In neutropenic patients and bone marrow transplant recipients, high-resolution CT scan of the chest has become an important adjunct to the diagnosis of IPA. One or more nodules surrounded by halo signs (ground glass opacity or haziness) are early findings of angioinvasive mold infections (24); cavitation is a late finding. Although these lesions are highly suggestive of IPA in high-risk patients, it should be emphasized that other infections (other fungi, Nocardia, and so forth) can also present with halo signs. In one study, classic CT scan findings led to the earlier diagnosis of IPA, more timely administration of antifungal therapy, and improved outcome (24).
Serologic Detection
A double-sandwich enzyme-linked immunosorbent assay (ELISA) for the detection of galactomannan (GM) in serum has been used as a marker for aspergillosis. GM is a cell wall polysaccharide of most Aspergillus and Penicillium species that is released in serum during growth in tissue. The sensitivity of the test in different reports has ranged from 30% to 100%, with the wide range explained in part by various definitions of positive tests (e.g., different cutoff values and number of values above a cutoff) and different patient populations. In adult neutropenic patients, a single serum GM level of 0.8 ng/mL or greater is equivalent to two consecutive serum GM levels of 0.5 ng/mL or greater. The sensitivity, specificity, positive and negative predictive values (PPV and NPV) for these cutoffs are 96.5%, 96.5%, 97.3%, and 98.6%, and 93.3%, 98.6%, 98.6%, and 98.4%, respectively. A major limitation of this assay is false-positive results. Drugs such as piperacillin-tazobactam or cyclophosphamide and certain foods can result in falsely high serum GMs.
In a meta-analysis of 27 studies encompassing about 4,000 patients, the overall sensitivity of the serum ELISA was 61% to 71% with specificity of 89% to 93%, PPV of 26% to 53%, and NPV of 95% to 98% (25). The test performed best among bone marrow transplant recipients and patients with hematologic malignancies; serial testing strategies in these populations are widely accepted. Experience among patients undergoing solid organ transplantation is much more limited. In studies of lung and liver transplant recipients, the sensitivities of the assay were 30% and 56%, respectively (26,27), with specificities of 93% to 95% and 87% to 94%, respectively (26,27,28). Given the lack of data, it is not clear at present whether serial GM testing of serum plays a useful role in surveillance for IPA among solid organ transplant recipients (26,27). It has been suggested that the moderate sensitivity and relatively low positive predictive value of the serum GM in diagnosing IPA might be improved by applying the assay to bronchoalveolar lavage (BAL) samples (29). Among bone marrow transplant recipients and patients with hematologic malignancies, detection of GM within BAL samples has been reported to add to the sensitivity of both BAL culture and serum GM detection (30,31,32,33). Although the specificity of BAL GM detection has generally been good (29,31), high rates of false-positive results were reported in at least one study (34). Moreover, BAL testing is likely to be influenced by the collection techniques of individual bronchoscopists.
Management
Voriconazole should be the first-line therapy against invasive aspergillosis, as it has been proven superior to conventional amphotericin B (35). To date, there have not been head-to-head comparisons of voriconazole versus lipid formulations of amphotericin B. Therapy is generally prolonged for at least 6 weeks or until the primary infection is resolved. The role of other systemic antifungal agents is summarized in Table 114.8 (36,37,38,39,40).
Debridement of the involved sinuses or primary cutaneous aspergillosis should be performed in conjunction with systemic antifungal therapy. Recent data show that combined antifungal therapy and surgical resection of single lesions from the lungs or central nervous system (CNS) might clear the infection faster than antifungal therapy alone, improve outcome, and prevent reactivation during consecutive chemotherapy courses (40,41,42,43,44,45). The procedures are generally well tolerated and associated with low rates of complications and mortality.
Patients who recover from an episode of invasive aspergillosis are at risk for recurrence of disease during subsequent chemotherapy or transplantation. These patients should be treated with a systemic antifungal agent for at least 6 weeks or until the primary infection resolves, whichever is longer, before further immunosuppressive therapy is considered. In addition, secondary prophylaxis is advised during any subsequent periods of immunosuppression.
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Table 114.8 Recommended Antifungal Agents against Aspergillosis |
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Viral Infections
Recent years have seen the emergence of unexpected viral diseases with high case fatality rates, including Hantavirus pulmonary syndrome, West Nile virus encephalitis, severe adult respiratory syndrome, and avian influenza. There are several reasons for critical care physicians to be familiar with a range of viral infections and to consider viral causes in their differential diagnosis. First, there is a small window of time to effectively intervene with antiviral agents in many of these diseases. Second, the timely identification of persons with potentially infectious viral diseases has significant public health implications and may reduce the risk of transmission to other persons. Third, in the era of long-distance travel, clinicians must recognize previously unfamiliar diseases. Finally, viruses such as those causing hemorrhagic fevers are possible agents of bioterrorism.
In general, viral infections can be diagnosed by several means (46):
· Serologic tests: The antibody response to viral antigens can be detected in the serum of patients with viral infections. An IgM response usually indicates recent exposure to a virus, whereas the presence of IgG reflects past exposure.
· Culture: Several types of cells are available for growing viruses, and no single cell line is appropriate for all of them. Therefore, it is helpful for the laboratory to know which virus the clinician suspects.
· Pathology: Histologic examination of biopsy and autopsy tissues may demonstrate changes that are typical of certain viruses (e.g., DNA viruses usually produce inclusions in the cytoplasm).
· Detection of viral antigens: Viral antigens can be detected in tissues by direct or indirect immunofluorescence using appropriate antibodies.
· Amplification of viral nucleic acids: Small copy numbers of viral DNA and RNA can be detected by polymerase chain reaction (PCR) and reverse transcription-PCR (RT-PCR), respectively. Real-time amplification methods permit simultaneous detection and quantification of viral nucleic acids.
Table 114.9 lists the leading viruses that might be encountered in the ICU, as of the writing of this chapter. We will review major viral illnesses encountered in critically ill patients, their diagnosis, and treatment. A review of human immunodeficiency virus (HIV) medicine is covered elsewhere (see Chapter 120).
Viral Infections on Admission to the Intensive Care Unit
Viral Pneumonitis
Severe community acquired pneumonia is caused by bacteria in approximately 60% of cases. In a French ICU, bronchoscopy of 41 patients with severe pneumonia revealed that 30% of all BALs and 63% of bacteria-negative BALs were positive for a respiratory virus (47). Influenza A and B are the most common causes of viral pneumonia in immunocompetent adults, whereas CMV and other herpes viruses are more important in immunocompromised patients.
It is frequently difficult to differentiate bacterial from viral pneumonia, but patients who have viral pneumonia often have a less severe illness and may complain of a dry hacking cough. Cultures are often necessary to make a definitive diagnosis. The radiographic findings of viral pneumonia are generally nonspecific, ranging from minimal changes on chest radiograph to hyperinflation or bilateral reticular opacities that are diffuse in distribution. Uncommonly, viral pneumonias can be associated with thickened interlobular septae that result in Kerley B lines. Viral pneumonias are rarely associated with pleural effusions, unless complicated by secondary bacterial pneumonia (48). CT scan of the chest may show poorly defined air space nodules, patchy areas of peribronchial ground glass opacity, and consolidation.
Influenza Virus
In the United States, epidemics of influenza typically occur during the winter. Approximately 66% of patients hospitalized with influenza are older than 64 years of age. Morbidity and mortality are highest among the elderly, children younger than 2 years of age, and persons of any age who have comorbid illnesses such as cardiac, pulmonary, or renal diseases, diabetes mellitus, and/or immunosuppression (49,50).
Microbiology
Human infections are caused by influenza A, B, or C viruses. Wild birds are the natural host for influenza A, and the virus infects humans, birds, pigs, and other animals. Influenza B and C viruses are usually found only in humans. Influenza A and B can cause severe disease and occur in epidemics. Influenza A can also be responsible for pandemics. Influenza C, on the other hand, causes only mild illness in humans and does not result in epidemics or pandemics.
Influenza A viruses are divided into subtypes on the basis of the two main surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). There are 16 known HA and 9 known NA subtypes of influenza A. New influenza virus variants result from frequent antigenic change, termed antigenic drift, resulting from point mutations that occur during viral replication. Influenza B viruses undergo antigenic drift less rapidly than influenza A viruses. In 2006–2007, H5N1 virus (avian influenza) was the circulating virus in Asia and Europe and caused severe respiratory diseases, life-threatening complications, and death (51).
Immunity to the surface antigens, particularly HA, reduces the likelihood of infection and severity of disease. Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype of influenza. Furthermore, antibody to one antigenic variant of influenza virus might not completely protect against a new antigenic variant of the same type or subtype. Antigenic drift is the basis for seasonal epidemics and the reason for the incorporation of one or more new strains in each year's influenza vaccine. More dramatic antigenic changes, or shifts, occur less frequently and can result in the emergence of a novel influenza virus with the potential to cause a pandemic.
Clinical Manifestations
The classic influenza symptoms in healthy adults include abrupt fever, myalgia, headaches, and upper respiratory symptoms. In the elderly or immunocompromised hosts, these classic symptoms might be absent, and patients might present only with fever and altered mental status.
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Table 114.9 Viral Pathogens Most Likely to Be Encountered in the ICU |
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Influenza-associated lower respiratory tract infections can be classified into four general forms (52):
1. Influenza without radiographic evidence of pneumonia: Up to 30% of hospitalized patients with influenza have no evidence of pulmonary infiltrates (53).
2. Viral pneumonia followed by bacterial pneumonia: The true incidence is unknown. The most common bacteria are Staphylococcus aureus and Streptococcus pneumoniae.
3. Rapidly progressive diffuse viral pneumonia: This entity may be decreasing due to the increased rate of influenza vaccination in the elderly.
4. Concomitant viral and bacterial pneumonia: In addition to S. aureus and S. pneumoniae, the most common bacteria is Haemophilus influenzae. These patients are generally more ill than the other groups, with a higher rate of ICU admission and greater morbidity. Poor outcomes result from worsening of underlying heart or lung conditions, secondary bacterial pneumonia, toxic shock syndrome, endotoxemia, myopericarditis, cytokine-induced shock syndrome, encephalitis, and transverse myelitis.
Diagnosis
Several tests can be performed to diagnose influenza. Nasopharyngeal swabs, nasal washes, and aspirates obtained within the first 4 days of illness are preferred respiratory samples.
· Rapid influenza tests (54) can provide results within 30 minutes, and some distinguish between influenza A and B. The overall sensitivity is 70% to 75%, with a specificity of 90% to 95%. These tests are useful in the diagnosis of individual patients and in detecting outbreaks.
· Direct immunofluorescent antibody (DFA) staining requires 2 to 4 hours for results. It distinguishes influenza A and B and is often performed in a panel that also detects parainfluenza and respiratory syncytial viruses.
· RT-PCR detects and distinguishes both influenza A and B in 1 to 2 days.
· Viral culture might take up to 10 days. The culture is essential for determining influenza A subtypes and influenza A or B strains, information that can be incorporated into the following year's vaccine.
· Serology is used mainly for research or public health investigations, as results are not helpful for clinical decision making.
Treatment
Two classes of antiviral drugs are available for the prevention and treatment of influenza (see Table 114.10 and Fig. 114.1):
1. Amantadine and rimantadine target the M2 protein of influenza A and are not effective against other influenza viruses. These agents were not recommended in the 2006–2007 season due to the emergence of a high level of resistance (54). Both amantadine and rimantadine are generally well tolerated, but central nervous system (CNS) side effects are more common in the elderly. Dosing modification is based on renal function.
2. Zanamivir and oseltamivir are neuraminidase inhibitors that are active for prevention and therapy against both influenza A and influenza B. They work best if initiated within 48 hours of clinical symptoms. Although all antiviral medications lessen symptoms and shorten the duration of illness, only oseltamivir has been shown to reduce lower respiratory tract complications requiring antibiotics. Patients with asthma or chronic obstructive pulmonary disease (COPD) are advised to have a fast-acting inhaled bronchodilator available when inhaling zanamivir. Zanamivir should be stopped if patients develop difficulty breathing.
Prevention
Yearly vaccination is the best means to prevent influenza. Vaccination is particularly important in people who are at high-risk of having serious complications, such as those 65 years of age or older, and those with cardiac or pulmonary diseases, diabetes or other metabolic diseases, renal dysfunction, hemoglobinopathies, or immunosuppression, or people (physicians, nurses) caring for those at high risk for serious complications. During influenza outbreaks within an institution or community, public health practice is to combine influenza vaccine and antiviral medications. The vaccine is given to the exposed patients and staff, and the antiviral agent is also given for about 2 weeks until the vaccine takes effect.
Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) causes acute respiratory illness in persons of all ages. The annual frequency of RSV infection in the elderly and high-risk adults is about 5.5% (55). Among patients admitted to a hospital for community-acquired pneumonia, RSV is second to influenza among viral causes. RSV and influenza A result in comparable lengths of stay, admissions to ICUs, and mortality (8% and 7%, respectively).
Transmission
RSV is transmitted person-to-person through close contact or inhalation of large droplets following sneezing or coughing, or by contact with infected fomites. In the United States, RSV outbreaks occur in the winter. In tropical regions, outbreaks occur usually in the rainy season.
Clinical Manifestations
The clinical presentation varies depending on the patient's age and health status. Older children and young adults typically present with upper respiratory symptoms or tracheobronchitis. The elderly and immunocompromised may develop pneumonia. Wheezing occurs in 35% of elderly patients with RSV infection. The presentations can be difficult to differentiate from other causes of viral illnesses, including influenza. In general, however, the upper respiratory infection (URI) symptoms tend to last longer than those caused by other respiratory viruses, and are associated with a bronchitic cough and wheezing (55). Findings on chest radiograph range from focal interstitial or lobar consolidations to diffuse alveolar interstitial infiltrates. Infections are particularly severe in compromised hosts, with a mortality of 30% to 100% in bone marrow transplant recipients (56).
Diagnosis
The diagnosis is made by viral detection (by culture or immunofluorescence) or by detection of viral antigens, RNA, or serology. Cultures are performed on respiratory secretions and require 4 to14 days for results. Rapid assays using antigen capture technology can be performed in less than 30 minutes, and sensitivity and specificity approach 90%. Multiplex PCR ELISA is being developed to allow the simultaneous diagnosis of multiple respiratory pathogens (55). In general, the diagnosis is more difficult to establish in adults than in children due to the low titers of viral shedding.
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Table 114.10 Antiviral Agents (excluding anti-HIV Drugs) |
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Figure 114.1. Sites of action of antiviral agents. |
Treatment
Therapy is mainly supportive. Bronchodilators may help to relieve bronchospasm in some patients. Early use of inhaled ribavirin has been shown to reduce morbidity and mortality in adult bone marrow transplant patients who develop RSV infections (56). More aggressive therapy with combined ribavirin, intravenous immunoglobulin with high titers of neutralizing RSV antibody, and/or steroids can be considered in immunosuppressed patients with severe RSV pneumonia (55,56,57).
Varicella-zoster Virus
Varicella-zoster virus (VZV) causes chickenpox or shingles. Primary infection usually occurs in childhood and is generally a benign self-limited illness in immunocompetent hosts. Although pneumonia is an uncommon complication of varicella in healthy children, it is the most frequent complication in healthy adults. The reported incidence rate is about 2.3 in 400 cases in the United States, and the overall mortality is between 10% and 30% (58,59). In patients with respiratory failure due to varicella pneumonia who require mechanical ventilation, mortality rates approach 50% despite institution of aggressive therapy and supportive measures. Cigarette smoking, pregnancy, immunosuppression, and male sex are risk factors for varicella pneumonia (58,59).
Clinical Manifestations
Varicella pneumonia develops insidiously 1 to 6 days after the onset of the vesicular rash, with symptoms of cough, shortness of breath, fever, and occasionally pleuritic chest pain or hemoptysis. Examination of the chest may reveal rhonchi or wheezes. Chest radiograph typically reveals diffuse or patchy nodular infiltrates with a prominent peribronchial distribution. Reticular markings, pleural effusions, and hilar adenopathy may be seen as well (60).
Treatment
Prompt treatment with intravenous acyclovir at a dose of 10 mg/kg every 8 hours has been associated with clinical improvement and resolution of pneumonia (58,59). The addition of steroids for the treatment of life-threatening varicella pneumonia is controversial and has not been well studied. In one study, patients who received steroids as adjunctive therapy had shorter hospitalizations and ICU stays and no mortality (61,62). Rapid institution of extracorporeal life support has been reported to improve outcome in patients with severe life-threatening varicella pneumonia (63).
Hantavirus Pulmonary Syndrome
Among the agents causing Hantavirus pulmonary syndrome (HPS), the Sin Nombre (Spanish for “nameless” or “without a name”) virus that caused the 1993 Four Corners outbreak in the southwestern United States is the most severe. Many hantaviruses are shed in the urine, feces, or saliva of infected rodents, and transmission to humans occurs via aerosols (64). The deer mouse Peromyscus maniculatus is the predominant reservoir. The Centers for Disease Control and Prevention (CDC) reported an increase in human cases of HPS during January through March of 2006 in Arizona, Texas, North Dakota, New Mexico, and Washington (65).
Clinical Manifestations
The incubation period is 1 to 3 weeks, after which patients experience fever, muscle pain, and fatigue; some patients also experience headache, dizziness, vomiting, or diarrhea. Four to 10 days later, patients develop cough and respiratory distress. In general, there are no defined sets of symptoms and signs that reliably distinguish HPS from other forms of noncardiogenic pulmonary edema or adult respiratory distress syndrome (ARDS) (64). Features associated with HPS are thrombocytopenia, hemoconcentration, leukocytosis with increased band forms on differential, hypoalbuminemia, and lactic acidosis (64). The classic diagnostic triad includes thrombocytopenia, neutrophilia, and an immunoblast count of greater than 10% of the total lymphocytes. Shock and lactic acidosis are associated with poor prognosis; the case fatality ratio is 30% to 40%.
Diagnosis
Clinicians should consider HPS in the differential diagnosis of previously healthy patients from endemic areas who present with fever greater than 101°F and develop bilateral diffuse interstitial edema of the lungs within 72 hours of hospitalization. The edema can resemble ARDS on chest radiograph (64). Serologic tests are the main method of diagnosing HPS, with high levels of IgM antibodies present by the time symptoms are evident. In the United States, states that offer hantavirus diagnostic testing use IgG and mu capture IgM ELISA assays developed and distributed by CDC (64).
Treatment
There is no specific antiviral therapy for HPS, and treatment is mainly supportive, with early initiation of mechanical ventilation to treat respiratory failure. In specialized centers, the use of extracorporeal membrane oxygenation (ECMO) should be considered in patients with a cardiac index of less than 2.5 L/minute/m2 despite inotropes (66). A placebo-controlled double-blind trial of intravenous ribavirin for the treatment of hantavirus cardiopulmonary syndrome in North America was terminated early due to the drug's probable ineffectiveness (67).
Severe Acute Respiratory Syndrome
Severe acute respiratory syndrome (SARS) is a serious pulmonary illness caused by a coronavirus that jumped species from semidomesticated animals to humans and spread from China to Hong Kong in late 2002 (68,69,70). The infection is spread by close person-to-person contact via respiratory droplets; incubation period is 2 to 10 days. The patients first experience a high fever associated with chills, headache, and myalgia. Diarrhea is seen in approximately 10% to 20% of patients. Two to 7 days later, patients develop a dry nonproductive cough and hypoxia that progresses to ARDS and multiple organ dysfunction (68,69,70,71). Ten percent to 20% of patients require mechanical ventilation. RT-PCR, serology, and cultures of blood, stool, and nasal secretions are possible diagnostic tools but have shortcomings that make routine clinical use difficult. There is no specific treatment against the SARS-associated coronavirus, and supportive care remains the principal therapeutic alternative. Rivabirin and corticosteroids have been used, but their efficacy has not been established. Mortality approximates 11% (68,69,70). Infection control practices are extremely important in halting the progression of an outbreak.
Other Viruses
Although uncommon in adults, adenovirus pneumonia outbreaks have been described among military recruits and among adults in chronic care facilities (72). Diagnosis is established by culture of a nasopharyngeal aspirate or swab, throat swab, or sputum. Other viruses associated with acute pneumonias in adults include measles, parainfluenza (73), and rarely, parvovirus (74).
Viral Meningitis and Encephalitis
The terms, viral meningitis and encephalitis, refer to infections of the leptomeninges and brain parenchyma, respectively. The important feature that differentiates viral meningitis and encephalitis is the presence or absence of altered sensorium. Patients with viral meningitis may be lethargic and have severe headache, but their cerebral function remains normal. In encephalitis, cerebral functions are abnormal, including altered mental status, altered behavior and personality changes, speech or movement disorder, and focal neurologic deficits. Viral meningitis and encephalitis are common, with the reported incidence of 11 and 7 per 100,000 person-years, respectively. Some patients may have both a parenchymal and meningeal process that is called meningoencephalitis.
Viral (Aseptic) Meningitis
The common causes of viral meningitis are summarized in Table 114.11 (75,76,77). Other viruses such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and herpes zoster (reactivation of VZV infection) are even rarer causes of aseptic meningitis. Arboviruses such as St. Louis encephalitis and California encephalitis (SLE and CE, respectively) more commonly cause encephalitis or meningoencephalitis but can also cause aseptic meningitis.
The clinical presentations of viral meningitis are nonspecific with fever, headache, photophobia, and nuchal rigidity as common symptoms. Helpful clues to the diagnosis include travel to arbovirus endemic areas, exposure history (rodents, ticks), sexual activity (HSV-2), and contact with other people with similar symptoms (enteroviruses). Clinicians should look for pharyngitis and pleurodynia (enteroviruses), rash (zosteriform rash of VZV, vesicular rash of HSV, maculopapular rash measles or enteroviruses), and adenopathy (primary HIV or EBV). Cerebrospinal fluid (CSF) findings include white blood cells (WBC) less than 500 per µL, of which greater than 50% are lymphocytes; protein less than 80 mg/dL; normal glucose; and negative Gram stain. CSF should be sent for bacterial and viral cultures, HSV PCR, and HIV viral load. Other tests that can be sent if indicated include enterovirus PCR and acute/convalescent serologic testing for specific viruses.
If the patient is neither immunocompromised nor toxic appearing, one can observe without giving antibiotic therapy. Treatment for enteroviral meningitis is mostly supportive (pain management and hydration). Pleconaril, which inhibits viral attachment to host cells and viral uncoating, has shown disappointing results in the treatment of enteroviral meningitis. If the patient is immunosuppressed, elderly, or toxic appearing, or has received antibiotics before presentation, one may consider empiric antibiotics for 48 hours while waiting for culture results.
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Table 114.11 Common Causes of Viral Meningitis and Encephalitis |
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Viral Encephalitis
In the United States, the most common cause of sporadic encephalitis is HSV-1. Arboviruses account for approximately 5% of viral encephalitis, with SLE virus being the most common. Clues to arboviral infection include the season (arboviruses cause disease when mosquitoes are active, whereas HSV-1 can occur at any time), location (woody or marshy areas would suggest viruses such as the cause of Colorado tick fever or nonviral illness such as Lyme disease or Rocky Mountain spotted fever), geographic region (SLE occurs in the midwest and southern United States, whereas West Nile virus [WNV] occurs in multiple continents), or a history of animal exposure (rabies). Clues on physical exam include parotitis (mumps); flaccid paralysis (WNV); tremors of the eyelids, tongue, lips, and extremities (SLE); or findings of hydrophobia, aerophobia, and hyperactivity (rabies).
The CSF findings can be similar to those of viral meningitis. Depending on clinical suspicion, the CSF can also be sent for PCR for enteroviruses, HSV, or CMV. Acute and convalescent sera against specific viral pathogens such as arboviruses, and lymphocytic choriomeningitis virus (LCMV) might also be useful in determining a cause. CT scan with IV contrast or magnetic resonance imaging (MRI) should be obtained to exclude an intracranial process (cerebritis, abscess, subdural empyema, mass occupying lesions) or to detect findings suggestive of a viral cause. Temporal and basal frontal lobe involvement suggests HSV encephalitis, whereas basal ganglia and thalamic involvement suggest Eastern equine encephalitis.
Until HSV encephalitis is ruled out, acyclovir at 10 mg/dL IV every 8 hours should be considered in patients with suspected viral encephalitis.
HSV Encephalitis
HSV encephalitis is a fulminant hemorrhagic and necrotizing meningoencephalitis that involves primarily the temporal and basal frontal cortices and the limbic system (78). Herpes simplex type 1 (HSV-1) accounts for most fatal cases of sporadic encephalitis in adults. HSV-1 encephalitis can arise either from primary infections or reactivation of a latent infection; there is no difference in outcome from patients suffering encephalitis from a primary or reactivation HSV infection. Herpes simplex virus type 2 (HSV-2) accounts for herpes encephalitis in 80% to 90% of neonates and children.
Clinical Manifestations
The most common early symptoms are fever and headache. Additional symptoms include meningeal irritation, nausea, vomiting, altered consciousness, and generalized seizures. Other changes are referable to the involved areas of the brain and include anosmia, memory loss, abnormal behavior, speech defects, olfactory and gustatory hallucinations, and focal seizures. There can be rapid progression of the disease in some patients with the development of focal paralysis, hemiparesis, and coma.
Diagnosis
The diagnosis of HSV encephalitis can be strongly suggested if the typical clinical presentations are associated with specific findings on electroencephalogram (EEG) and MRI. The typical EEG findings are focal temporal abnormalities, which are found in about 80% of patients; periodic lateralized epileptiform discharges also suggest HSV encephalitis, although they are not as specific. In HSV encephalitis, a normal EEG essentially excludes the diagnosis. The typical MRI appearance is medial temporal abnormalities that do not respect hippocampal borders. CSF findings are similar to other cases of viral meningoencephalitis. Isolation of HSV from the CSF is rare, occurring in less than 5% of cases. A definitive diagnosis is made by detection of HSV DNA in CSF by PCR, which is very sensitive and specific. The availability of PCR has largely obviated the need for brain biopsy, which was the previous gold standard diagnostic test.
Treatment
Morbidity and mortality are reduced by early antiviral therapy. Intravenous acyclovir, 10 mg/kg every 8 hours, is continued for 14 to 21 days. There is a 5% relapse rate after the discontinuation of antiviral therapy.
Rabies
Rabies is caused by neurotropic RNA viruses (79). In addition to the classic rabies virus, at least ten other rabies-related viruses can cause clinically indistinguishable fatal encephalitis (79). Rabies has a worldwide distribution and is found throughout the United States except Hawaii. In developing countries, dogs are the major reservoir. Wild animals remain the most important reservoir in the United States; most reported cases occur in carnivores (raccoons in the northeast, skunks in the south and southwest, and foxes in the southwest and Alaska) or insectivorous bats (79). In the United States, there have been an average of three fatal human cases per year since 1980 (79).
Acquisition of rabies usually occurs after a bite from an infected animal or scratching and licking by a rabid animal. Cases have also been reported after solid organ, cornea, or vascular tissue transplantation from unsuspected rabies-infected individuals (80,81).
Clinical Manifestations
Human rabies assumes two forms: furious (encephalitic) and paralytic (dumb). The furious form (observed in 80% of patients) manifests as hyperactivity, hydrophobia, pharyngeal spasms, and aerophobia. The paralytic presentation can mimic Guillain-Barré syndrome with quadriparesis, sphincter involvement, and late cerebral involvement. Some bat-associated rabies may present atypically with neuropathic pain, sensory or motor deficits, choreiform movements of the bitten limb, focal brainstem signs, myoclonus, and seizures (82). Regardless of presentation, the disease is almost always fatal.
Diagnosis
The diagnosis can be confirmed in several ways: (a) detection of viral RNA in saliva by RT-PCR; (b) biopsy of the nape of the neck for detection of RNA or viral antigen within hair follicles by RT-PCR or immunofluorescence staining, respectively; (c) antibodies in serum and cerebrospinal fluid; (d) the presence of pathognomonic Negri bodies (eosinophilic neuronal cytoplasmic inclusions) in brain biopsy (79).
Treatment
There is no proven effective treatment for rabies after the onset of illness. Only six survivors have been reported, five of whom received postexposure vaccination. The sixth patient survived after induction of coma and treatment with ribavirin and amantadine (83). Clinicians who wish to consider this protocol should contact Dr. Rodney Willoughby at Children's Hospital of Wisconsin (414-266-2000). Rabies vaccination after the onset of illness is not recommended and may be detrimental. After definitive diagnosis, the primary focus is comfort care.
Management of patients with rabies poses no greater risk to health care providers than caring for patients with more common infections. Adherence to standard precautions should be maintained, including gloves, gowns, masks, eye protection, and face shield (particularly during intubation or suctioning). Because of the lack of effective treatment, postexposure prophylaxis should be initiated as soon as possible after exposure to rabid or unknown animals. This includes the administration of human rabies immune globulin (HRIG: HyperRab Tm S/D or Imogam Rabies-HT) and rabies vaccination (purified chick embryo cell vaccine (PCECV; 1-800-244-7668; www.rabavert.com).
West Nile Virus
West Nile virus (WNV) is a single-stranded RNA virus that can infect humans, mosquitoes, and animals such as birds and horses. In temperate climates, WNV is transmitted primarily in the summer or early fall, whereas transmission can occur year round in warmer climates. Most human WNV infections result from mosquito bites. Infection can also be transmitted via transfusion of WNV-infected blood products, transplacental fetal infection, and transplantation of infected organs.
Clinical Manifestations
Patients infected with WNV can be asymptomatic (80%), develop West Nile fever (WNF, 20%) or West Nile neuroinvasive disease (WNND, less than 1%) (84). WNND includes meningitis, encephalitis, and acute flaccid paralysis. WNV encephalitis is more common in the elderly or immunocompromised patients. The incubation period ranges from 3 to 14 days, and symptoms generally last 3 to 6 days. Patients with WNF or WNND present with an abrupt onset of fever, headache, fatigue, anorexia, gastrointestinal complaints, myalgia, lymphadenopathy, and generalized nonpruritic maculopapular rash. Patients with WNND also present with altered mental status (46%–74%), tremor (12%–80% of patients), extrapyramidal features such as rigidity or bradykinesia (67%), and cerebellar abnormalities (11%–57%). Myoclonus, which is present in 33% of cases, is a clue to WN infection since it is rare in other causes of viral encephalitis. Seizures are unusual (1%–16%).
Diagnosis
Diagnosis of WNV infection is based on a high index of suspicion and obtaining specific laboratory tests. An IgM antibody capture ELISA (MAC-ELISA) can detect WNV in nearly all CSF and serum specimens from WNV-infected patients. Because IgM antibody does not cross the blood–brain barrier, IgM antibody in the CSF strongly suggests acute CNS infection. WNV testing of patients with encephalitis, meningitis, or other serious CNS infections can be obtained through local or state health departments.
Treatment
Treatment is supportive, with hospitalization, IV fluids, respiratory support, and prevention of secondary infections for patients with severe disease. Although ribavirin and interferon alpha 2b were found to have some activity against WNV in vitro, no controlled studies have been completed. The role of corticosteroids has not been assessed.
Viral Infections Acquired during Intensive Care Unit Stay
Herpes family viruses have been recognized as pathogens in immunosuppressed transplant patients and HIV/AIDS patients. Recently, they have been increasingly reported as pathogens in the nonimmunosuppressed critically ill. A retrospective review demonstrated that at least 14% of chronic critically ill surgical patients had occult CMV or HSV infection/reactivation (85).
CMV Infection
CMV infects about 60% to 70% of people during their lifetimes. Like other members of the herpes family, CMV becomes latent or persistent after primary infection. The infection can reactivate at a later time, especially in the settings of immunodeficiency or significant stress from operations or injuries.
Transmission
CMV can be found in body secretions (such as urine, saliva, sputum, breast milk, semen, and cervical fluid) or in circulating mononuclear and polymorphonuclear cells, vascular endothelium, and renal epithelium. CMV spreads from person to person by contact with body fluids. Transmission is particularly high among toddlers in day care. Day care employees are also at significant risk for CMV exposure and/or infection, as are health care personnel with direct patient contact. Congenital transmission from a mother with acute infection during pregnancy is a significant cause of neurologic abnormalities and deafness in newborns. CMV can also be transmitted by breastfeeding, blood transfusion, or receipt of an organ transplant. The major risk factors for CMV disease in solid organ transplant recipients are CMV mismatch (i.e., transplantation of a CMV-positive organ into a CMV-seronegative recipient) and the degree of immunosuppression.
Clinical Manifestations
Most immunocompetent children and adults who are infected with CMV do not develop symptoms. Some may experience an illness resembling infectious mononucleosis with fever, swollen glands, and mild hepatitis. Rare complications of primary CMV infection include hepatitis, interstitial pneumonia, Guillain-Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia. In patients who are immunocompromised, primary CMV infection can be life threatening; myelosuppression, encephalitis, hepatitis, pneumonitis, retinitis, and GI infection are the most common manifestations. Moreover, reactivation of latent CMV also causes disease in immunocompromised hosts, although typically milder than primary infection. In general, the severity of CMV disease is related to the degree of immunosuppression. CMV appears to target allografts in particular. Hepatitis, for example, is common in liver transplant recipients, pancreatitis in pancreatic transplant, and pneumonitis in lung and heart-lung transplant. CMV pneumonia is highest among bone marrow transplant recipients.
In solid organ transplant recipients, CMV infections predispose to other opportunistic infections, especially fungal or Pneumocystis infections. CMV infection can also affect graft survival, causing early allograft rejection in renal transplant recipients, chronic allograft rejection in cardiac transplant recipients (allograft atherosclerosis), and vanishing bile duct syndrome in liver transplant recipients.
Diagnosis
Since CMV can be shed in biologic fluids from patients with no evidence of CMV disease, the gold standard for diagnosis remains finding intranuclear inclusion bodies in histologically examined tissue. CMV infection may be confirmed by in situ hybridization or direct or indirect staining of intranuclear inclusions using specific antibodies linked to an indicator system. Histopathology is limited by poor sensitivity. Tests that can detect and quantify CMV or its products in blood, leukocytes, or tissues are reviewed in Table 114.12.
CMV excretion in the saliva and urine is common in patients who are immunocompromised and is generally of little consequence. In contrast, viremia in organ transplant patients identifies those at greatest risk for CMV disease. In bone marrow transplant recipients, the sensitivity of viremia as a marker for CMV pneumonia is 60% to 70%; lack of viremia also has a high negative predictive value. In general, detection of CMV or its products in the blood of transplant recipients is a basis for starting antiviral therapy. The value of positive CMV tests in the nontransplant ICU patient is less clear. Studies indicate that asymptomatic CMV infection is common, and low level viremia can be detected in almost a third of patients after 2 weeks in the ICU (85,86). Viremia, therefore, does not necessarily signify CMV disease in ICU patients. Further studies are needed to elucidate the impact of CMV infection/reactivation in critically ill patients and to clarify the effects of CMV treatment on morbidity and mortality.
Management
Ganciclovir, foscarnet, and cidofovir are antiviral agents active against CMV (Table 114.10). To date, the efficacy of anti-CMV therapy has been evaluated primarily in immunocompromised hosts (transplant recipients and AIDS patients). CMV disease in transplant recipients is typically treated with a 3-week course of ganciclovir. Foscarnet is an alternative for patients who cannot tolerate, or fail to respond to, ganciclovir; but experience is more limited, and foscarnet is associated with high rates of nephrotoxicity. CMV retinitis requires a longer course of systemic therapy; intravitreal administration of ganciclovir or fomivirsen, an antisense inhibitor of CMV, is frequently used in addition to systemic therapy. Although long-term maintenance therapy is required for AIDS patients who do not undergo immune reconstitution, this strategy is generally not required for transplant recipients. Recurrence of CMV disease, which can occur in up to 25% of transplant recipients, appears to respond to ganciclovir as well as the initial episode.
HSV Infection
HSV-1 and HSV-2 are closely related, but the epidemiology of infections by the viruses is distinct. HSV-1 is transmitted mainly by contact with infected saliva, and HSV-2 by contact with the genital tract. HSV-1 is acquired more commonly and at an earlier age than HSV-2. By the age of 50 years, over 90% of people have antibodies against HSV-1. Consistent with this, HSV-1 is also more common among ICU patients.
Clinical Manifestations
HSV encephalitis and meningitis are discussed above. HSV-1 can infect virtually any mucocutaneous or visceral site. Typically, primary infections are associated with systemic signs and symptoms, mucosal and extramucosal involvement, longer duration of symptoms and viral shedding, and higher complication rates. Gingivostomatitis and pharyngitis are the most common clinical syndromes of HSV-1 infection. Lesions are ulcerative with or without exudates, and can be difficult to differentiate from bacterial pharyngitis. HSV-1 also has a predilection for regenerating epithelium. Therefore, healing partial-thickness skin burns, skin donor sites, skin diseases (e.g., eczema, pemphigus, Darier disease), and areas of cutaneous trauma are common sites of infection. HSV-1 keratitis is the most frequent cause of corneal blindness. HSV-1 can also cause chorioretinitis—a sign of disseminated infection—and acute necrotizing retinitis, affecting both immunocompetent and immunocompromised hosts.
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Table 114.12 Diagnostic Tests for CMV Infection |
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In immunocompromised hosts and patients with atopic eczema or burns, severe orofacial HSV lesions can rapidly spread and disseminate infection. Bone marrow and solid organ transplant recipients are at highest risk for HSV reactivation during the pre-engraftment period or within the first month posttransplant. Complications include pneumonitis, tracheobronchitis, esophagitis, hepatitis, and disseminated viral infection.
HSV-1 shedding is observed in immunocompetent but critically ill patients. In one study, HSV-1 was recovered from the mouth swabs or respiratory secretions of 27% of patients requiring mechanical ventilation (87). Although the presence of HSV was associated with a higher APACHE II score and increased mortality (88), it is not clear whether HSV was the cause of the excess deaths or simply a marker for impaired immune function. HSV-1 may predispose to subsequent bacterial or fungal infection (87).
Diagnosis
The diagnosis of HSV-1 infection can be made using a direct immunofluorescence test or by culture of tissue or aspirated fluid. Serology is helpful in diagnosing primary HSV infection. Improved testing methods have led to increased detection of HSV-1 in ICU patients. As with CMV, however, it is often unclear whether HIV-1 is an active pathogen or merely a marker of immune dysfunction. Large randomized trials are needed to determine the impact of CMV and HSV isolation from respiratory specimens of patients in the ICU and the effect of treatment on morbidity and mortality of critically ill patients.
Management
For mucocutaneous and visceral infections, acyclovir or related agents (famciclovir and valacyclovir) are the standard therapy. For disseminated disease or encephalitis due to HSV-1, intravenous acyclovir is recommended. For HSV keratitis, debridement along with topical therapy with idoxuridine or vidarabine is the treatment of choice. Other ophthalmologic disease such as chorioretinitis or retinal necrosis requires systemic antiviral therapy.
Summary
Although the field of antiviral therapy has developed extensively over the last 30 years, many issues remain. Most agents have a similar target of action, which frequently results in cross-resistance among agents. Furthermore, the range of viral infections for which treatment options exist is still limited. A lack of culture systems for many viruses hinders drug development. Moreover, the intracellular parasitism of viruses increases the potential for host toxicity. One needs to keep clinical suspicion for viral illness high since the window of opportunity for treatment is often very narrow. Clearly, there is a critical need for new therapies that expand the rather limited present armamentarium. Until that time, vaccination and other preventive strategies are the best hope for the control of viral infections.
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