Chapter 153: Serious Viral Infections

Viral infections are among the most common illnesses encountered in the ED. Although many are self-limited, some are life-threatening, have specific treatments, or have public health implications. We review serious viral infections that cause disseminated illness or have a predilection for the CNS.

Human influenza is caused by a large, single-stranded RNA virus from the orthomyxovirus family. Influenza A and Influenza B cause the majority of human infections, with influenza A typically being more serious. Other viruses can cause similar febrile respiratory syndromes, including the coronaviruses linked to severe acute respiratory syndrome and Middle Eastern respiratory syndrome, both emanating from limited geographic areas and associated with high mortality.

EPIDEMIOLOGY

Influenza is highly infectious and is transmitted via aerosolized respiratory secretions, large droplets, or fomites. Seasonal influenza has varying severity, typically striking in the winter months of temperate climates. Seasonal disease causes 250,000 to 500,000 annual deaths worldwide and between 5000 and 50,000 deaths in the United States. Outbreaks spread quickly throughout a community, largely among school-age children. Mortality occurs mostly among the elderly and young infants.

New strains occasionally emerge that can lead to pandemics. The 1918 influenza pandemic killed between 50 and 100 million people worldwide, and the potential for devastation by a novel influenza virus drives anxiety among clinicians and public health personnel. Unlike seasonal influenza, mortality during pandemics occurs mostly among healthy adults. In 2009, a pandemic H1N1 strain emerged in Mexico and followed this pattern, reminding us about the potential danger. A highly pathogenic avian strain of influenza emerged in 1997 in China, which was transmitted from infected chickens to humans. A variety of other animal strains of influenza have since been detected. These remain primarily bird viruses that have not developed the ability for efficient human-to-human transmission.

PATHOPHYSIOLOGY

Influenza is transmitted by respiratory secretions, usually by sneezing or coughing, and via touching hands. The incubation period is typically 1 to 4 days. Influenza viruses undergo minor variations (antigenic drift) in their surface antigens that allow the virus to reinfect individuals and reemerge each winter. Occasionally, there are major antigenic changes (antigenic shift) that increase population susceptibility and lead to a pandemic.

CLINICAL FEATURES

Patients with influenza typically present with an abrupt onset of fevers and respiratory symptoms. Most cases are self-limited; however, some patients, particularly the elderly, the very young, and those with comorbid conditions, require hospitalization or die from complications of influenza. Additionally, influenza can lead to exacerbations of chronic medical conditions, such as congestive heart failure or chronic obstructive lung disease. Delirium is common in the elderly.

Pneumonia complicates some influenza infections. Primary influenza pneumonia develops quickly and progresses to acute respiratory distress syndrome, often within 24 hours. Bacterial super-infections also occur. Classically, influenza is associated with secondary Staphylococcus aureus pneumonia and, more recently, with community-acquired methicillin-resistant S. aureus.

DIAGNOSIS

Most cases of influenza are diagnosed clinically when a patient presents with fever, aches, and cough with influenza virus circulating in the community. However, clinical features of influenza overlap with other respiratory infections; laboratory confirmation can occasionally be helpful in patient care and infection control, especially before influenza has been documented in the community.

Rapid antigen assays identify the surface proteins in influenza A and B. These tests are simple to perform and give results within 15 minutes. However, they can have a low sensitivity, with ranges between 10% and 80% reported in clinical use. Specificity of these tests is between 90% and 95%, so a positive test indicates high likelihood of influenza, especially during an outbreak.

Molecular diagnostic tests, such as polymerase chain reaction for nucleic acids, are available and are more sensitive and specific than antigen tests. They are recommended for patients hospitalized with influenza.¹ Several rapid polymerase chain reaction–based tests return results within the time frame of an ED visit, although they are more costly than rapid antigen tests.

TREATMENT

The majority of patients will have a self-limited, uncomplicated illness requiring only symptomatic care. Patients with more severe influenza may benefit from IV fluids, respiratory support, and occasionally vasopressors. Those with pneumonia should be treated with antibiotics, targeting methicillin-resistant S. aureus if severe pneumonia exists.

The benefits of neuraminidase inhibitors for otherwise healthy adults and children are debated;² the Centers for Disease Control and Prevention recommend treating higher risk populations. Studies of neuraminidase inhibitors for influenza in uncomplicated cases note benefits limited to patients treated within 48 hours of symptom onset. Antiviral treatment can also benefit patients hospitalized with influenza or bacterial complications of influenza, even if started after 48 hours of illness. Consider empiric antiviral treatment for patients with severe or progressive illness and those with higher risk of complications (Table 153–1). Oseltamivir is the most widely used neuraminidase inhibitor (75 milligrams twice daily for 5 days), with longer treatment for critically ill patients. Extracorporeal membrane oxygenation aids those with severe cardiorespiratory dysfunction, especially in pandemic settings where younger patients are afflicted.

Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are related double-stranded DNA viruses that cause oral and genital infections; rarely, these create devastating CNS disease. Herpes simplex infections are treatable with antiviral drugs, making early recognition of serious infection important.

EPIDEMIOLOGY

HSV is common throughout the world. Transmission occurs when a susceptible individual is exposed to the virus. HSV-1 is usually acquired during childhood through nonsexual contact; HSV-2 is almost always sexually transmitted (see chapter 149, "Sexually Transmitted Infections"). HSV-1 seroprevalence varies by socioeconomic status, age, and geographic location. More than 50% of the U.S. population is seropositive for HSV-1, and 15.7% is seropositive for HSV-2.⁴ Rates are higher in developing countries. HSV-1 is one of the most common viral causes of encephalitis in the United States. It occurs most commonly in patients <20 years and >50 years of age.⁵ The mortality rate for untreated disease is >70%.

Neonates with HSV infection have a high frequency of both visceral involvement and CNS disease. Encephalitis in neonates is most often caused by HSV-2, which is acquired from the maternal genital tract at the time of delivery. The risk is highest when the mother acquires the infection in the third trimester.

PATHOPHYSIOLOGY

HSVs are transmitted through contact with persons with ulcerative lesions or by those who are shedding the virus by the exchange of saliva, vesicle fluid, semen, and cervical fluid. The virus must come in contact with a mucosal surface or abraded skin, where it replicates and causes localized symptoms before becoming latent in the sensory ganglia. HSV-1 typically resides in the trigeminal ganglia, and HSV-2 is found in the sacral ganglia. Reactivated virus travels to the cutaneous surface and results in localized vesicular eruptions (Figure 153–1).

In herpes simplex encephalitis, the virus is thought to gain access to the brain by the olfactory or the trigeminal nerve, with a predilection for the medial and inferior temporal lobes of the brain.

Most healthy hosts are able to control the virus and limit its replication to mucosal surfaces. Rarely during primary infection, the virus can spread beyond the local dorsal root ganglia and cause more widespread involvement. Multiorgan disease is much more common in the immunosuppressed and in neonates.

CLINICAL FEATURES

HSV infections occur year round. Symptoms of HSV depend on multiple factors, including the anatomic site involved, the immune status of the host, virus type, and whether the infection is primary or recurrent. Most HSV infections are subclinical. Symptomatic HSV-1 infection most commonly results in recurrent orolabial lesions, whereas HSV-2 is most often implicated in genital herpes. Primary infections typically produce more extensive lesions involving mucosal and extramucosal sites, often accompanied by systemic signs and symptoms. Gingivostomatitis and pharyngitis are typical manifestations of primary HSV-1 infection (Figure 153–2), and recurrence presents as herpes labialis (Figure 153–3). Less common skin manifestations include herpetic whitlow and herpes gladiatorum (skin). Eczema herpeticum (see Figure 251–14) can occur in patients with atopic dermatitis. Bell's palsy may result from latent HSV-1 in the geniculate ganglia (see chapter 172, "Acute Peripheral Neurologic Disorders"). Herpetic keratitis presents as a painful, red eye, and can be identified by characteristic dendritic lesions on fluorescein slit lamp exam. HSV-1 and HSV-2 can cause identical genital lesions. Genital HSV-2 is more common and has a higher relapse rate, but the proportion of genital disease caused by HSV-1 is increasing.⁴ Primary genital infections can present with aseptic meningitis, which is a complication more common in women.

The hallmark of HSV encephalitis is acute onset of fever and neurologic symptoms. Patients can present with hemiparesis, cranial nerve abnormalities, ataxia, focal seizures, and altered mental status or behavioral abnormalities. It can be difficult clinically to distinguish HSV encephalitis from other types of meningoencephalitis. Meningitis occurs in up to 25% of females with primary HSV-2 infections. HSV-2 meningitis, unlike encephalitis, has a benign course, and patients recover uneventfully. Some patients develop recurrent lymphocytic meningitis (Mollaret's syndrome).

HSV infections in immunocompromised hosts can lead to widespread dissemination with multiorgan involvement (Figure 153–4). Organ transplant patients may develop esophagitis, hepatitis, colitis, and pneumonia (see chapter 297, "The Transplant Patient"). Severely burned patients are also prone to potentially fatal disease. HSV infections can also cause immune-mediated manifestations such as erythema multiforme, hemolytic anemia, and thrombocytopenia.

DIAGNOSIS

The preferred diagnostic test for confirmation of suspected HSV infection depends on the presentation. Because mucocutaneous infection is lifelong, we recommend laboratory confirmation of the clinical diagnosis. A specimen for viral culture can be obtained from the fluid of an unroofed vesicle. The sensitivity of culture is highest in the early stages and in primary disease. Polymerase chain reaction testing or a direct fluorescent antibody test can be performed on swabbed tissue. A Tzanck test is generally not useful.

Identification of temporal lobe lesions on CT scan or MRI is strongly suggestive of HSV encephalitis (Figure 153–5). An electroencephalogram shows typical intermittent, high-amplitude slow waves localized to the temporal lobes.

Cerebrospinal fluid analysis typically shows a lymphocytic pleocytosis with the presence of red blood cells. However, some patients can have normal cerebrospinal fluid parameters. Polymerase chain reaction testing of the cerebrospinal fluid is the testing modality of choice for HSV meningoencephalitis, with high sensitivity and specificity.⁵ Viral DNA can be detected within the first 24 hours, and results remain positive for a week or longer. To perform this test, most laboratories need an additional 0.5 to 1.0 mL of fluid beyond that required for standard analysis. Brain biopsy is reserved for difficult cases and for investigation of alternative diagnoses.

TREATMENT

Treatment depends on the severity of the disease and the immune status of the patient (see chapter 149, "Sexually Transmitted Infections"). IV acyclovir is the drug of choice in patients with HSV encephalitis or disseminated disease and in immunocompromised patients with severe mucocutaneous disease (Table 153–2). Valacyclovir is a prodrug of acyclovir with higher bioavailability. Famciclovir and valacyclovir require fewer doses per day.

Even with early treatment, patients with HSV encephalitis have a high mortality. Without treatment, mortality is >70%. Survivors are often left with long-term neurologic sequelae. Independent predictors of a poor outcome for patients with HSV encephalitis include a Glasgow Coma Scale score of ≤6, focal CNS lesions on CT scan, increased patient age, and start of antiviral therapy >4 days after onset of symptoms.⁵ Because altered mental status and focal neurologic abnormalities are key features of encephalitis and because it can be clinically difficult to distinguish meningitis from encephalitis, consider adding acyclovir to empiric antibiotic therapy in patients with neurologic findings when the diagnosis of acute bacterial meningitis is also being considered.^6,7

Healthy patients with primary HSV-1 or HSV-2 infections can be treated with oral acyclovir, valacyclovir, or famciclovir for 7 to 10 days. Recurrent herpes labialis usually does not require treatment. Those with severe or frequent recurrences may benefit from daily suppressive therapy.

Varicella-zoster virus is the causative organism of both varicella (chickenpox) and herpes zoster (shingles). It is extremely contagious; prior to routine vaccination, it was usually acquired in childhood.

Varicella occurs year round, but there is a higher incidence during winter and spring months. The infection rate ranges from 60% to 100% in exposed individuals. The introduction of the varicella vaccine to routine childhood immunizations in 1995 has dramatically reduced the clinical burden of the virus.⁸

Herpes zoster can occur once immune response against the virus wanes, usually with advancing age. Over 90% of adults have serologic evidence of varicella-zoster virus infection, and unvaccinated persons who live to 85 years of age have a 50% risk of herpes zoster.⁹ Iatrogenic immune suppression, certain diseases such as lymphoproliferative disorders, human immunodeficiency virus infection, and organ transplantation increase the risk of herpes zoster.

Vaccines are available to prevent both chickenpox and herpes zoster, although neither is 100% effective. Encourage parents to vaccinate their children, and remind those age 60 or older about the availability of a vaccine to prevent herpes zoster. Varicella-zoster immune globulin is available, but its use is generally limited to postexposure prophylaxis for nonimmune pregnant women and the severely immunosuppressed. Healthy individuals who are not immune can be vaccinated after exposure. Exposed individuals should be watched closely, and antivirals should be given to high-risk patients if they develop symptoms.¹⁰

PATHOPHYSIOLOGY

Varicella-zoster virus spreads to the respiratory mucosa of a susceptible host via aerosolized droplets of respiratory secretions of patients with chickenpox. It can also spread from direct contact with vesicle fluid in herpes zoster but is not as highly contagious in this situation. The virus multiplies in regional lymph nodes and then disseminates to the nasopharyngeal surfaces and the skin, causing the characteristic rash. It is contagious until all the lesions have crusted over. Varicella-zoster virus remains latent in the dorsal root ganglion and can later reactivate along dermatomes, resulting in shingles (Figure 153–6).

VARICELLA CLINICAL FEATURES

Varicella (chickenpox) is a febrile illness with a vesicular rash. Often it is associated with nonspecific symptoms of headache, malaise, and loss of appetite. The rash is superficial and appears in crops, so patients typically have lesions at varying stages, including papules, vesicles, and crusted lesions (Figure 153–7). Lesions are concentrated more on the torso and face and typically crust and slough off after 1 to 2 weeks. Most infections are minor and self-limited. Immunized patients can occasionally develop mild chickenpox.

A range of complications can occur, more often in those at extremes of age or the immunocompromised. Bacterial superinfections of skin lesions, most often with group A streptococci, can cause serious illness including necrotizing fasciitis. Children with lymphoma and leukemia may develop progressive varicella in which vesicles continue to erupt into the second week of illness, sometimes with visceral involvement of the lung, liver, and brain. CNS complications such as cerebellar ataxia, meningitis, meningoencephalitis, and vasculopathy are well described. Pneumonitis can be severe and is more common in pregnant women.⁸

HERPES ZOSTER CLINICAL FEATURES

Herpes zoster (shingles) often begins with a prodrome of malaise, headache, and photophobia. The patient notes pain, itching, and paresthesias in one or more dermatomes. These symptoms are followed by the development of a maculopapular rash that becomes vesicular. The eruption does not cross the midline (Figure 153–8). Most commonly, herpes zoster affects the chest or face, but it can affect any dermatomal level. Herpes zoster ophthalmicus can cause blindness and is the result of reactivation along the ophthalmic distribution of the trigeminal nerve (see chapter 241, "Eye Emergencies"). The seventh cranial nerve can be involved, causing facial nerve paralysis and lesions along the auditory canal (herpes zoster oticus). Postherpetic neuralgia, pain that persists for >30 days, is a feared complication. The incidence increases with advancing age, and pain may last months or years.

Dissemination of varicella-zoster virus can occur in immunocompromised patients. Herpes zoster involving more than three dermatomes is often a clue to an immunodeficient condition. The presence of herpes zoster in a young, healthy person may be a sign of human immunodeficiency virus infection. In many cases of disseminated disease, the skin is the only involved structure. However, the virus may spread to the visceral organs and cause pneumonitis, hepatitis, and encephalitis.

DIAGNOSIS

Varicella-zoster virus infections have a characteristic appearance, so a clinical diagnosis is sufficient in most cases. Clinicians should look for the characteristic rash of chickenpox, which involves vesicles that appear in crops in different stages of development. Herpes zoster is diagnosed when clusters of vesicles and papules appear in a dermatomal pattern.

Laboratory diagnosis is needed in patients with atypical illness or severe disease. This is accomplished through viral culture, antigen testing, or polymerase chain reaction testing of vesicle fluid. Although smallpox has been eradicated, it remains a potential threat as a biologic weapon, and the lesions could be confused with those of varicella. The lesions of smallpox are larger and distributed more on the extremities, and all lesions are at the same stage of development.

Obtain a chest radiograph if pneumonitis is suspected. An MRI of the brain, lumbar puncture, and polymerase chain reaction testing for varicella-zoster virus are appropriate for suspected brain involvement.

VARICELLA TREATMENT

Most healthy patients need only supportive care for chickenpox. Acyclovir and similar antiviral agents decrease the number of lesions and shorten the course if therapy is started within 24 hours of rash onset. However, the impact of treatment is modest, so it is not routinely recommended for those who are otherwise healthy. Secondary skin infections are typically caused by group A streptococci and can be treated with a first-generation cephalosporin.

Consider acyclovir for those at higher risk for complications, including adults and children >12 years of age, patients with chronic skin or pulmonary disorders, those receiving long-term salicylate therapy, and immunocompromised patients. Varicella-zoster virus is less sensitive to acyclovir than herpesvirus and requires higher and more frequent dosing. Although chosen by some for dosing simplicity, famciclovir and valacyclovir are not licensed for the treatment of varicella (chickenpox) in the United States.

HERPES ZOSTER TREATMENT

Antiviral agents hasten lesion resolution, reduce new lesions, reduce viral shedding, and decrease acute pain, but do not reduce the severity of postherpetic neuralgia.⁹ Using antiviral therapy in immunocompromised patients may reduce the risk of severe disseminated disease. Start antiviral medication within 72 hours of the onset of rash, and consider treatment at >72 hours if new vesicles are still present or developing. Treat immunocompromised patients regardless of the time since rash onset. Benefits are more pronounced in patients >50 years of age. Therapy is well tolerated, and the risk of adverse events is minimal.

Treat those with disseminated herpes zoster, those with CNS involvement, and severely immunosuppressed patients with herpes zoster with IV acyclovir. Use valacyclovir in those with herpes zoster ophthalmicus, along with ophthalmologist consultation (see chapter 241, "Eye Emergencies").

Herpes zoster can be extremely painful and require opioid analgesia. Corticosteroids in combination with antivirals may provide a modest decrease in acute pain but do not decrease the development of postherpetic neuralgia.⁹ Adjunctive corticosteroids can be considered in older individuals with severe pain who do not have contraindications to their use.

Epstein-Barr virus (EBV) is implicated in a variety of human illnesses. It is the causative agent of heterophile-positive infectious mononucleosis. EBV infection is also associated with cancers such as B-cell lymphoma, Hodgkin's disease, Burkitt's lymphoma, and nasopharyngeal carcinoma.

There are two age-related peaks of infection: early childhood and young adulthood. In developing countries, EBV infection is widespread in early childhood and is often asymptomatic. College students and military recruits experience the highest morbidity. EBV requires close contact for transmission. The infection is usually contracted from an asymptomatic individual who sheds the virus.

PATHOPHYSIOLOGY

EBV is transmitted via salivary secretions. After infecting the oropharyngeal epithelium, it disseminates through the bloodstream. The virus infects B lymphocytes and causes an increase in T lymphocytes, which results in enlargement of lymphoid tissue. In immunocompromised patients with decreased T-cell function, the B cells continue to proliferate, and proliferation may lead to neoplastic transformation.

CLINICAL FEATURES

The manifestations of EBV infection depend on age and immune status. Infections in infants and young children are often asymptomatic or have mild pharyngitis. Teenagers and young adults can develop infectious mononucleosis, which presents as fever, lymphadenopathy, and pharyngitis. Tonsillar exudates are frequent and often extensive and may be necrotic appearing (Figure 153–9). Splenomegaly occurs in more than half of patients. Symptoms generally resolve over 2 to 3 weeks, and most patients recover uneventfully. Severe fatigue is a prominent feature and can persist for months. Patients treated with ampicillin or amoxicillin for suspected streptococcal pharyngitis often develop a nonallergic morbilliform rash if they have infection with EBV.

EBV can affect nearly all organ systems. Neurologic complications such as encephalitis, meningitis, and Guillain-Barré syndrome have been described. Hepatitis, myocarditis, and hematologic disorders are also known complications. Rarely death results from splenic rupture, CNS complications, and airway obstruction. A rare form of chronic EBV infection characterized by a high titer of viral DNA has been reported. Patients are ill for ≥6 months and have histologic evidence of major organ involvement. The prognosis is poor, and treatment is not well defined.

DIAGNOSIS

If infectious mononucleosis is suspected based on the history and physical examination, a CBC and a monospot test can provide confirmation. Typically, there is lymphocytosis with >50% lymphocytes, and atypical lymphocytes are found on examination of the smear. These are reactive cytotoxic T cells that can also be found in other illnesses, including cytomegalovirus infection, human immunodeficiency virus infection, and viral hepatitis. The monospot test identifies heterophile antibodies that agglutinate animal erythrocytes, and a positive result is considered diagnostic of EBV infection in the right clinical setting. The monospot test result may be negative early in the course of disease, requiring a second test later if unclear. The sensitivity of the test is also decreased in infants and the elderly. Testing is particularly important in pregnant patients, because some other causes of heterophile-negative mononucleosis can be teratogenic. Tests for specific antibodies to the EBV viral capsid and nuclear antigen are available but are usually not needed because of the high sensitivity and specificity of the monospot test.

TREATMENT

Rest and analgesia are the mainstays of therapy, with most cases self-limited and not requiring specific therapy. Use of corticosteroids is associated with increased complications and is recommended only for patients with severe disease, such as upper airway obstruction, neurologic disease, or hemolytic anemia. Acyclovir is active against EBV but is thought to be effective only for oral hairy leukoplakia associated with human immunodeficiency virus infection. Advise patients to avoid all contact sports for a minimum of 3 weeks after illness onset to avoid splenic injury.¹¹

Cytomegalovirus (CMV) is an important human pathogen that causes a wide variety of diseases, ranging from asymptomatic infections in most to life-threatening pneumonia in transplant patients. Like other herpesviruses, it causes a primary infection and then recedes into lifelong latency.

CMV is not highly contagious, and transmission requires repeated or prolonged exposure. The virus is spread by sexual contact, saliva, breastfeeding, and transplantation, as well as transplacentally and through blood transfusion. Seroprevalence rates approach 100% in Africa and in some Asian countries. In the developed world, it is not unusual for older individuals to acquire a primary infection. This is of particular concern in women of childbearing age because of teratogenic effects. The risk of fetal CMV infection is highest in the first trimester of pregnancy in a previously seronegative mother who acquires a primary infection.

Organ transplant patients can acquire infection, most often between 1 and 4 months after transplant. The risk is highest when a seronegative patient receives a CMV-positive organ.

PATHOPHYSIOLOGY

CMV is usually inoculated on the mucosal surface of the upper respiratory or genital tract, where the virus multiplies and then disseminates. Most infections are only mildly symptomatic. Primary disease in late adolescence and adulthood results in an infectious mononucleosis syndrome. The virus remains latent in most individuals unless immunity is severely suppressed.

CLINICAL FEATURES

Primary infection in healthy individuals is usually asymptomatic. CMV can cause a heterophile-negative infectious mononucleosis syndrome, characterized by prolonged fever, myalgias, and lymphocytosis, but no exudative pharyngitis. Severe disease in the otherwise healthy host includes hepatitis, colitis, Guillain-Barré syndrome, encephalitis, and hemolytic anemia.¹²

Congenital and neonatal infections are associated with some of the most important complications of primary CMV infection. Symptoms in infants can be devastating and include hepatosplenomegaly, jaundice, microcephaly, petechiae, and growth retardation. Severe infections carry a high mortality, and those who survive often have neurologic sequelae.

Infections in immunocompromised patients can be severe and involve any organ. Infection can be primary or the result of reactivation of latent virus. Severe disease can develop in previously healthy CMV-seropositive individuals with an abnormal T-cell response during critical illness. Infections after solid-organ and hematopoietic stem cell transplantation are a leading cause of morbidity (see chapter 297, "The Transplant Patient"). The infection typically begins in the transplanted organ and subsequently may disseminate, causing pneumonia, hepatitis, and CNS involvement. CMV infections can also cause late-onset chronic graft-versus-host disease in stem cell transplant patients. Symptoms often begin with prolonged fever, night sweats, and fatigue.

In human immunodeficiency virus–infected patients with CD4 counts of <50 cells/mm³, retinitis is the most common manifestation of infection, causing painless loss of vision. Other manifestations associated with human immunodeficiency virus infection include encephalopathy, colitis, and peripheral polyradiculopathy.

DIAGNOSIS

A specific diagnosis is not made in the ED. Body fluids such as urine, saliva, blood, tears, semen, and vaginal fluid can be subjected to antigen testing, polymerase chain reaction testing, antibody testing, histologic analysis, and viral culture. The hallmark of CMV infection on histologic examination is a large cell containing a large basophilic intranuclear "owl's eye" and intracytoplasmic inclusion bodies.

TREATMENT

Several systemic antiviral agents are active against CMV infection, including ganciclovir, valganciclovir, foscarnet, and cidofovir (Table 153–3). Illness in the otherwise healthy host is usually self-limited and does not require antiviral therapy. CMV-induced infectious mononucleosis is treated symptomatically.

Transplant recipients with CMV disease are treated more aggressively (see chapter 297). Treatment may include the use of CMV hyperimmune globulin along with ganciclovir or valganciclovir.¹³ Ganciclovir implants are available for human immunodeficiency virus patients with CMV retinitis.

Measles was a common childhood illness before vaccination became routine in the 1960s. Most measles deaths occur among children in developing countries, but developed countries are now seeing occasional outbreaks related to parents choosing not to vaccinate their children, largely due to unfounded fears about vaccine safety. Measles is caused by an RNA virus that is the most infectious virus known to humans and is communicable before symptoms begin. Illness starts with fever, malaise, cough, and runny nose, often with conjunctivitis. Small, white Koplik's spots (Figure 153–10) appear on the buccal mucosa early in the illness, followed by a red maculopapular rash that typically starts on the head and spreads throughout the body. Diagnosis is usually clinical, with pathognomonic Koplik's spots and the characteristic rash. Measles can be confirmed by detection of immunoglobulin M antibodies, which are present at rash onset. Treatment is supportive, with particular attention to insuring adequate nutrition, especially vitamin A. Mortality in developed countries is less than 1/1000, but can be up to 20% to 30% among infants in developing countries, often from pneumonia.

Arboviral infections are infections spread by biting mosquitoes, ticks, and flies. Japanese encephalitis is one of the most common and important causes of encephalitis in the world. The emergence of West Nile virus infection has caused renewed interest in North America regarding epidemic viral encephalitis. This section reviews some of the more important and severe arboviral infections, concentrating on those that occur in North America¹⁴ (Table 153–4). Other significant arboviral diseases are discussed in chapter 161, "Global Travelers."

EPIDEMIOLOGY

Arboviral infections tend to be seasonal, with increased incidence in warmer months due to the breeding patterns of the arthropod vectors. The major hosts are mammals and birds. When migratory birds are involved, the virus can spread quickly over large distances. Humans are usually an incidental host and acquire the diseases when they venture into areas occupied by the reservoir host.

The age group affected often depends on local prevalence. Japanese encephalitis, which is highly endemic in certain parts of Asia, usually affects children. Most adults have been exposed and are immune. Elderly adults are at risk for St. Louis encephalitis.

Dengue, yellow fever, Rift Valley fever, and chikungunya viruses are among the viruses causing hemorrhagic fever syndromes (see chapter 161). Dengue virus is a common cause of fever and rash (Figure 153–11) in tropical areas with large mosquito populations, and transmission has been found in the southern United States. Severe dengue hemorrhagic fever can develop in locals who are exposed to a second infection with a different serotype. Chikungunya fever causes rash, myalgias, arthralgias, and fever. Although fatalities are rare, arthralgias can be debilitating and last for months. The disease is reported in Asia, Africa, and more recently in the Caribbean and southeastern United States. Yellow fever is found in the tropics of Africa and South America. The Aedes aegypti mosquito vector for the yellow fever virus was once eradicated in the United States, but it is now starting to reappear. This mosquito can also spread dengue and chikungunya viruses.

Japanese encephalitis virus causes >15,000 deaths yearly, primarily in Asia, and is now spreading to Australia. West Nile virus and the viruses causing La Crosse encephalitis, St. Louis encephalitis, eastern equine encephalitis, and western equine encephalitis are found in North America.^13,14

PATHOPHYSIOLOGY

A mosquito or other appropriate vector becomes infected after it feeds on the blood of a viremic host. Humans are infected when the arthropod takes a blood meal. The virus replicates near the site of inoculation before it enters the reticuloendothelial system and then disseminates to various target organs.^14,15 There is often a low-grade viremia until the host can produce immunoglobulin M neutralizing antibodies. If the immune system is unable to clear the virus, then the more serious manifestations of hemorrhagic fever or encephalitis may become evident.

CLINICAL FEATURES

Most arbovirus infections are either asymptomatic or cause a nonspecific mild illness. Only a few individuals develop hemorrhagic fever or encephalitis. Severe human arboviral diseases most commonly manifest as four syndromes: fever and myalgia, arthritis and rash, encephalitis, and hemorrhagic fever. These syndromes can overlap; viruses that cause encephalitis and hemorrhagic fever may also cause fever and myalgia. Headache is a common symptom of most arboviral infections and may be quite severe. Hemorrhagic fever presents with bleeding from the gums, petechiae, and GI tract. The classic presentation of viral encephalitis is fever, headache, and altered level of consciousness. Patients can be lethargic and confused and occasionally present with seizures.¹⁴ In general, individuals at extremes of age are more likely to have severe disease.

DIAGNOSIS

Obtaining a detailed travel and exposure history and knowing local epidemiologic patterns help in diagnosing arboviral infections. Patients with encephalitis should undergo CT or MRI of the brain. MRI is more sensitive and may show foci of increased signal intensity in the parenchyma.

Cerebrospinal fluid typically shows a lymphocytic pleocytosis and a slightly elevated protein level, although these findings are nonspecific. When encephalitis is in the differential diagnosis, save an extra vial of cerebrospinal fluid for further testing, because less common infections are often diagnosed only with stepwise testing after more common causes have been ruled out.

Serologic testing is the main method for diagnosis of arboviral infections. Viral cultures are labor intensive and technically demanding. Furthermore, patients are viremic for only a few days after the onset of illness. Generally, immunoglobulin M appears within a few days. Patients who are tested very early in the course of illness may have a false-negative result. A presumptive diagnosis of the suspected arboviral infection can be made based on an elevated immunoglobulin M level, and this can be confirmed with an increase in antibody titers between acute and convalescent samples. Many arboviruses are antigenically similar and cross-react on testing. Arboviral infections are reportable to public health authorities in many areas.¹⁶

TREATMENT

Symptomatic management is the mainstay of treatment after excluding other serious, treatable causes of meningitis and encephalitis. Antiviral drugs, interferon, and steroids are not useful. Empiric treatment with acyclovir and antibiotics is appropriate until HSV encephalitis and bacterial meningitis are ruled out. Anticonvulsant therapy may be required if seizures occur.

Hemorrhagic fever is also treated with supportive care. Patients with hemorrhagic fever require diligent fluid management to avoid overload.^14,15

Viral hemorrhagic fevers are caused by several groups of RNA viruses with varying geographic distributions. These rare diseases elicit tremendous fear among the public and healthcare providers, now exacerbated by the large outbreak in Western Africa. Examples include Hantavirus pulmonary syndromes, Lassa fever, and perhaps the most notorious, Ebola virus disease. Geographic exposure and contact with an infected traveler are the most important clues to suspecting viral hemorrhagic fevers in an individual patient. Clinical presentation varies between viruses, with some causing relatively minor illness and some with high mortality. Symptoms typically begin with fever, myalgia, and malaise, which then progress to GI and other system involvement. Increased vascular permeability results in hypotension, pulmonary edema, and renal failure. Coagulation defects lead to diffuse hemorrhage, which can be worse in patients with thrombocytopenia or platelet dysfunction, sometimes with extensive bleeding, organ damage, and shock. Ebola and most other viral hemorrhagic fevers can be confirmed with acute serology to identify antibodies or, more commonly, reverse transcriptase polymerase chain reaction identification of the virus that is performed at specialized labs such as the Centers for Disease Control and Prevention.

Periodic Ebola virus outbreaks in western Africa have occurred with high mortality. The virus is spread through contact with infected body fluids such as bloody vomit and diarrhea, and the lack of personal protective equipment in developing countries contributes to spread within healthcare facilities.¹⁷ Important aspects of preparing for Ebola and other severe viral hemorrhagic fevers in EDs include screening at triage for illness in travelers returning from areas of current outbreak, and rapid initiation of appropriate isolation. Ebola and many other viral hemorrhagic fevers require contact and droplet precautions including full gown, gloves, and face mask with eye protection. Staff should be instructed on proper donning and removal of protective equipment to avoid contamination with body fluids. It is important to notify the hospital laboratory to take proper precautions and to plan for sending specimens to specialized labs. Treatment of Ebola and most other VHFs is supportive, with fluids, renal replacement, and respiratory support. Experimental serologic treatments and vaccines are in development.

Rebecca L. Liggin, MD

Zika is a viral illness spread through the bite of the Aedes aegypti mosquito or spread human to human through sexual contact or blood products. The first outbreaks were identified in Polynesia, and by 2015 Zika transmission had expanded to South and Central America, the Caribbean, Mexico, and the United States. Zika virus has an incubation period of 2-14 days and presents with headache, fever, maculopapular rash, malaise, arthralgias, and conjunctivitis. Infection tends to be mild. The major concerns with Zika virus infection are its potential complications and teratogenicity.¹⁸ Guillain-Barré syndrome, meningoencephalitis, and myelitis can result in a small percentage of patients. Infants born to mothers infected with Zika have an increased risk of developing CNS abnormalities, including microcephaly, seizures, clubfoot, and arthrogyryposis. Transmission from mother to fetus can occur during pregnancy or delivery, but so far transmission through breast milk has not been reported. Zika can persist in the system for 6 weeks or longer after patient exposure.

Prevention against Zika infection is important. Avoid mosquito bites by applying mosquito repellent, and use mosquito netting during sleep. There is no current vaccine. The management of Zika infection is supportive care, with hydration, pain and fever control, and antihistamines for itching.

Avoid NSAIDs and ASA due to potential for increased bleeding. Pregnant women should not travel to Zika infested areas and should avoid unprotected sexual intercourse with individuals who have traveled to Zika areas. Testing to confirm Zika infection is recommended in exposed pregnant women. Obtain serum and urine samples within the first 2 weeks of infection. For complete information on how to obtain the specimens, who should be tested, and where to send specimens, please refer to www.cdc.gov/zika/hc-providers. Given the concern for transmission of the virus by blood products, health care personnel should follow universal precautions when caring for infected, or potentially infected, patients.