Viruses

Clinical Features

Parotitis, either unilateral or bilateral, is the hallmark of this infection, occurring in over 95% of symptomatic patients ( Fig. 119.1 ). Other salivary glands are not commonly affected. Symptoms usually begin with fever, malaise, and headache, but about one-third of mumps infections are asymptomatic. Up to 30% of mumps infections cause orchitis, which usually occurs 1 week after the onset of parotitis and is more commonly seen in older patients. Orchitis is usually unilateral but can occur in both testes in up to one-third of the cases. There is a high incidence of cerebrospinal fluid (CSF) pleocytosis in patients with mumps, but less than 10% have symptomatic meningitis, and less than 1% have encephalitis. The mortality from mumps is very low, and the majority of morbidity and mortality associated with mumps occurs in cases complicated by encephalitis.

Differential Diagnosis

During an outbreak, mumps can be easy to diagnose. Other viral infections that can cause parotitis (Epstein-Barr virus [EBV], parainfluenza, influenza A virus, coxsackievirus, adenovirus, parvovirus B19, lymphocytic choriomeningitis virus, and human immunodeficiency virus [HIV]), bacterial infections, facial cellulitis, and tumor are all other diagnoses that should be considered.

Diagnostic Testing

Mumps can be confirmed by detection of viral RNA, via reverse transcription polymerase chain reaction (RT-PCR), detection of the virus itself from clinical specimens, or detection of antibodies (immunoglobulin M [IgM] or a fourfold rise in immunoglobulin G [IgG] between acute and convalescent serum specimen). This entails collecting a buccal or oral swab specimen for virus isolation and blood sample for serologic testing. Collecting samples early improves yield as virus isolation greatly diminishes after the first week of symptoms.

Management and Disposition

The mainstay of treatment is supportive care with antipyretics and analgesics. There is no specific antiviral treatment. Most cases have a benign, self-resolving course and do not require admission to the hospital. In the hospital setting, these patients should have droplet precautions observed. Patients should be isolated for 5 days after the onset of parotid swelling. Individuals with close contact with the infected patient should receive vaccinations if not immunized.

Clinical Features

The incubation period for measles is 7 to 21 days. The first symptoms manifest during the prodromal phase, which lasts approximately 3 days. During this phase patients have fever, malaise, and the classically taught three Cs (cough, coryza, and conjunctivitis). Koplik spots, small raised bluish white spots on the buccal mucosa, often opposite the lower first and second molars, or the roof of mouth ( Fig. 119.2 ), are pathognomonic for the diagnosis and can be seen during the prodromal phase. The patient will then develop the typical rash; a nonpruritic maculopapular rash beginning on the head and face and spreading down the entire body over the next 2 to 3 days ( Fig. 119.3 ). Patients are contagious 4 days before and 4 days after the onset of the rash.

Complications of measles include otitis media, laryngitis, tracheobronchitis, bronchiolitis, pneumonitis, severe diarrhea, and acute encephalitis. The virus itself can also cause pneumonia. Bacterial superinfection can also occur. The populations that are at high risk for severe disease or complications include children younger than 5 years old, adults older than 20 years old, pregnant women, and the immunocompromised.

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal complication of measles. SSPE is a slow progressive infection of the central nervous systems (CNS) that results from a prior measles infection. It is thought to be due to continual measles infection of the CNS. The mean time of onset of SSPE is 7 years after measles infection. Symptoms include behavior change, decreased intellect, ataxia, and myoclonic seizures followed by progressive neurologic deterioration and death. Since the development of measles vaccine, this disease has almost disappeared in the United States.

Differential Diagnosis

Measles can be mistaken for other acute respiratory viral illnesses with rash or even noninfectious illnesses that present with fever and rash. Other diagnoses to consider include rubella, roseola, dengue, Kawasaki disease, and drug rash. Measles should be considered in patients that have traveled to endemic regions and return with fever and rash.

Diagnostic Testing

The diagnosis was usually made clinically by visualizing both Koplik spots and the characteristic rash along with cough, coryza, and conjunctivitis. However, the disease is not common in the developed world, and it may be mistaken for other illnesses. Clinicians suspecting a diagnosis of measles should contact local health departments. They can help instruct practitioners to obtain the necessary samples for diagnosis and surveillance. The most common methods of confirmation are serologic testing for measles-specific IgM antibody and detection of measles RNA from a nasopharyngeal specimen, blood, or urine by RT-PCR.

Management

The mainstay of treatment is supportive care. Bacterial superinfection should be treated appropriately. Postexposure prophylaxis is important in individuals who do not have evidence of measles immunity and have a measles exposure, because it can provide protection or lessen the severity of disease. Postexposure prophylaxis consists of either the measles, mumps, and rubella (MMR) vaccine within 72 hours, or immunoglobulin within 6 days. Healthy infants should receive 0.25 mL/kg of immunoglobulin intramuscularly, and immunocompromised children should be given 0.5 mL/kg intramuscularly, up to 15 mL. Children and malnourished patients who are hospitalized with severe measles may benefit from vitamin A.

Disposition

Patients with measles require admission to the hospital based on the severity of illness. Uncomplicated measles patients should be treated at home to prevent spread of the disease. It is important, however, to observe appropriate isolation precautions in the hospital setting. All suspected cases of measles should be evaluated with airborne isolation precautions in place. Infected individuals should have airborne isolation for 4 days after they develop the rash, and those who are immunocompromised should remain on airborne precautions until complete recovery.

Clinical Features

Acquired rubella is a mild febrile illness associated with a diffuse maculopapular rash, malaise, headache, and arthritis. Encephalitis and thrombocytopenia are rare complications. Rubella is generally a mild disease, but consequences in pregnant patients can be devastating. It can cause miscarriage, intrauterine death, premature delivery, or congenital rubella syndrome. Congenital rubella syndrome is characterized by severe birth defects, including hearing impairment, cataracts, retinopathy, developmental delay, microcephaly, and a variety of congenital heart defects.

Differential Diagnosis

The diagnosis of rubella on a clinical basis can be difficult because of the overlap with many other illnesses. Diseases that share common features include measles, roseola, erythema infectiosum (fifth disease), toxoplasmosis, and scarlet fever.

Diagnostic Testing

The diagnosis of rubella can be made by virus detection or serologic testing. The most common method is detection of IgM antibodies or fourfold increase in IgG antibody titer between acute and convalescent specimen. Virus culture and RT-PCR can also be isolated from blood or the nasopharynx.

Management and Disposition

There is no specific antiviral treatment for rubella. The management centers on symptom control with antipyretics and analgesics. The course of this disease is short and benign. These patients can generally be treated at home but should be educated about the risks to pregnant women.

Clinical Features

Oral Infection

The first episode of HSV-1 infections usually occurs early in life and manifests as a gingivostomatitis and pharyngitis. Symptoms include fever, malaise, and vesicular lesions anywhere in the mouth or oropharynx. Infections typically last between 10 to 14 days. Reactivation is usually much less severe and occurs as herpes labialis, small vesicles at the vermilion border of the lip ( Fig. 119.4 ). These vesicles usually crust over within 48 hours.

Differential Diagnosis

When suspecting orofacial HSV infection, considerations include other diseases with vesicles and ulcers, such as aphthous ulcers, coxsackievirus infections (herpangina and hand-foot-and-mouth disease), infectious mononucleosis, Stevens-Johnson syndrome, or Behçet disease. The differential diagnosis for genital herpes infection should include other sexually transmitted infections with ulcers and vesicles, such as syphilis or chancroid or noninfectious diseases like Behçet disease. HSV encephalitis can be difficult to distinguish from other acute CNS emergencies like bacterial meningitis, brain abscess, other viral encephalitides, brain tumor, or stroke.

Diagnostic Testing

Frequently, clinicians diagnose oral or genital HSV infections clinically, given the classic appearance of the vesicles and ulcers. However, because of the risk of transmission and the impact of this diagnosis on a patient, testing should be performed if possible. Definitive diagnosis can be made by viral culture, direct fluorescent antibody (DFA), or polymerase chain reaction (PCR) from vesicles, ulcers, or mucocutaneous sites. PCR is more sensitive than viral culture. Tzanck smear has a low sensitivity and specificity and is mainly of historical interest. Serology can differentiate between acute infection and reactivation.

The diagnosis of HSV encephalitis is made by PCR from the CSF. The routine laboratory tests sent after a lumbar puncture (LP) to assess for bacterial meningitis do not adequately assess for HSV encephalitis. Classically, CSF analysis shows an elevated white blood cell (WBC) count, with lymphocyte predominance. Depending on the degree of brain necrosis, an elevated red blood cell (RBC) count can also be seen. Although it is rare, CSF results can be normal in HSV encephalitis, particularly in immunocompromised individuals. This underscores the importance of waiting for PCR results before considering discontinuation of treatment in suspected cases of HSV encephalitis. In cases of negative CSF PCR with a high suspicion of HSV encephalitis, especially those with who present early in their illness, we recommend continuing empirical treatment and resending CSF PCR in 72 hours. Neuroimaging with computed tomography (CT) or magnetic resonance imaging (MRI) can be highly suggestive of HSV encephalitis, but imaging can be negative early in the course of illness ( Fig. 119.5 ).

Management

Antiviral agents are the mainstay of treatment. The treatment dose and duration for herpes simplex depends on the clinical syndrome that is present. Acyclovir, valacyclovir, and famciclovir are the commonly used antiviral drugs with activity against HSV. These drugs are nucleoside analogues that work by inhibiting viral DNA synthesis. Acyclovir is the only agent that is available in an intravenous (IV) formulation.

• Herpes gingivostomatitis or labialis: First episodes are treated with oral acyclovir 200 mg five times a day (alternative regimen: 400 mg three times a day), valacyclovir 1 g twice daily, or famciclovir 250 mg three times a day for 7 days. Recurrent infections are treated with acyclovir 400 mg five times a day for 5 days, valacyclovir 2 g twice daily for 1 day, or famciclovir 1500 mg as a single dose.

• Genital herpes: First episodes are treated with oral acyclovir 200 mg five times a day (alternative regimen: 400 mg three times a day), valacyclovir 1 g twice daily, or famciclovir 250 mg three times a day for 7 to 10 days. A shorter course is usually adequate for treatment of recurrence. For suppression of recurrent episodes, acyclovir 400 to 800 mg twice daily or valacyclovir 500 mg daily can be used.

• Herpetic whitlow and other mucocutaneous manifestations: Administer acyclovir 200 mg five times a day or 400 mg three times a day for 5 days.

• Herpes keratitis: Administer acyclovir 400 mg five times a day or valacyclovir 500 mg three times a day. Topical antiviral therapy with trifluridine, acyclovir, or ganciclovir are all equally effective.

• HSV encephalitis: Administer IV acyclovir 10 mg/kg every 8 hours for 14 to 21 days. Given the high mortality associated with this condition, antiviral therapy should be started as soon as the diagnosis is suspected.

Disposition

The majority of herpes infections can be treated with oral antiviral therapy on an outpatient basis. Patients who are immunocompromised and have severe mucocutaneous disease or disseminated disease benefit from inpatient admission with IV acyclovir treatment. All patients with suspected encephalitis should be admitted for empirical treatment and diagnostic testing. Intensive care unit (ICU) admission may be necessary depending on the severity of neurologic symptoms. For HSV encephalitis patients, we recommend early involvement of infectious disease consultants to help guide treatment and neurology for management of cerebral edema and severe neurologic symptoms.

Clinical Features

Varicella

Chicken pox is a febrile illness characterized by malaise and rash. The rash begins first on the scalp and face and then spreads to the trunk and extremities. The lesions start as maculopapular, and progress to fluid-filled vesicles that eventually crust over and form scabs ( Fig. 119.6 ). The lesions occur as crops at various stages of development. Patients are contagious until all lesions are scabbed over, which can typically take 1 to 2 weeks.

This disease typically has a benign course, although adults have a more severe course than children. The most common complication is a secondary bacterial infection of the skin lesions. VZV has been associated with invasive group A streptococcal infections and necrotizing fasciitis. Immunocompromised patients are at risk for disseminated disease and visceral organ involvement. Pregnant patients are also at risk for severe disease. Varicella pneumonia accounts for most of the morbidity related to this disease. Neurologic complications are rare but can include encephalitis, aseptic meningitis, transverse myelitis, and Reye syndrome. Although exceedingly rare, it is important to recognize the association of aspirin use with Reye syndrome, a progressive encephalopathy with acute liver injury. Thus aspirin and other salicylates should be avoided in varicella treatment, especially in children.

Zoster

Herpes zoster typically causes a vesicular rash with an erythematous base that occurs unilaterally in a single dermatome ( Fig. 119.7 ). The rash is often painful and preceded by paresthesias or hypesthesia. In immunocompetent individuals, the rash crusts in 7 to 10 days, and at that time patients are no longer contagious. Post-herpetic neuralgia, defined as pain that persists for more than 90 days, is the feared complication. Risk factors for post-herpetic neuralgia include older age and severity of pain at onset.

Herpes zoster ophthalmicus is viral reactivation within the trigeminal nerve ganglion. Ocular involvement occurs in over 50% of these cases. The Hutchinson sign, a vesicle on the tip of the nose, is associated with ocular involvement. Herpes zoster oticus (Ramsay Hunt syndrome) is characterized by facial nerve palsy, pain, and vesicular rash on the ear and in the auditory canal. Disseminated zoster involving multiple dermatomes can occur in immunocompromised patients.

Differential Diagnosis

Classic varicella is distinctive, but the other major diagnoses to consider are other febrile illnesses with rashes like disseminated HSV infection, coxsackievirus infection, measles, or rickettsialpox. Prior to eradication, smallpox was a consideration, presenting with lesions in the same stage of development. The rash of zoster is also usually very characteristic. Other diagnoses to consider include herpes simplex infection or contact dermatitis.

Diagnostic Testing

The majority of chickenpox and shingles diagnosis is made clinically. Confirmatory diagnosis can be made through viral culture, DFA, or PCR testing of the vesicle fluid.

Management

Disposition

Most patients with varicella and zoster can be treated at home. Patients with varicella are highly contagious and should be instructed to avoid people who have not been fully vaccinated or never had the disease, immunocompromised persons, or pregnant individuals until all of their lesions have crusted over. Immunocompromised patients, patients with disseminated zoster, or patients with complications require admission to the hospital.

In general, patients with varicella should be under contact and airborne precautions until all of the lesions have crusted over. An immunocompetent localized zoster patient only requires standard precautions, whereas an immunocompromised or disseminated zoster patient is treated like a patient with varicella, requiring contact and airborne precautions.

Clinical Features

EBV infection in young children is usually asymptomatic or presents as mild pharyngitis. Adolescents and young adults tend to have the classic infectious mononucleosis (fever, exudative pharyngitis, lymphadenopathy, myalgias, and fatigue). Splenomegaly is common, seen in up to 50% of cases. Hepatomegaly and jaundice occur less than 10% of the time. The symptom duration is typically 1 to 3 weeks, with some cases having malaise and fatigue for several months. Splenic rupture is rare, occurring in less than 0.5% of patients. It should be suspected in patients with left upper quadrant pain and is more common during the first 3 weeks of illness. Airway obstruction occurs in less than 5% of children with mononucleosis and is one of the common causes of hospital admission. Rare neurologic complications include encephalitis, aseptic meningitis, transverse myelitis, Guillain-Barré syndrome, retrobulbar neuritis, and peripheral neuropathies. Patients treated with amoxicillin or ampicillin for presumed streptococcal pharyngitis may develop a nonallergic maculopapular rash.

Differential Diagnosis

EBV causes 90% of infectious mononucleosis; the remaining 10% is caused by cytomegalovirus (CMV). Acute HIV infection, streptococcal pharyngitis, toxoplasmosis, and other viral pharyngitis causes should be considered in potential mononucleosis patients.

Diagnostic Testing

It is difficult to diagnose mononucleosis based on history and physical examination alone. Laboratory data can help confirm the diagnosis. Historically, the heterophile antibody test (monospot) has been the test of confirmation for primary EBV infection. The test has a sensitivity ranging from 63% to 84% and specificity ranging from 84% to 100%. The test is often not positive in younger children. The WBC count typically demonstrates lymphocyte predominance with many atypical lymphocytes. A lymphocyte count less than 4 × 10 ⁹ /L in adults is highly predictive of a negative monospot test. Health care providers can test for antibodies to EBV viral capsid and nuclear antigen if other testing is equivocal.

Management

Infectious mononucleosis typically has a self-limiting course. The treatment is supportive care with rest, antipyretics, and analgesia. Glucocorticoids have been used to decrease severity of symptoms, but there is insufficient evidence to support this practice. Antiviral treatment with acyclovir does not reduce the clinical symptoms of the disease. It is important to advise patients to avoid contact sports for at least 3 weeks to avoid the feared complication of splenic rupture. Abdominal ultrasound for assessment of spleen size may have a role in determining when it is safe to return to sports.

Disposition

The majority of patients can be treated at home. Admission is necessary for airway obstruction and in patients with significant complications, such as splenic rupture.

Clinical Features

The primary CMV infection is subclinical in most individuals. Some immunocompetent adults develop a mononucleosis-like syndrome. The illness can last from 2 to 6 weeks and is characterized by fever, fatigue, malaise, myalgia, and headache. Unlike EBV mononucleosis, exudative pharyngitis and lymphadenopathy are less common. Although it is rare, CMV can cause severe disease in the immunocompetent individual. CMV colitis and CNS infection (meningitis, encephalitis, transverse myelitis) are the most frequent forms of severe CMV infection in the immunocompetent host. Up to one-third of critically ill immunocompetent patients have evidence of CMV reactivation.

The majority of newborns who are infected with congenital CMV appear healthy or normal at birth. Common problems caused by congenital CMV infection include premature birth, intrauterine growth retardation, microcephaly, seizures, thrombocytopenia, hepatosplenomegaly, or pneumonitis. Sequelae of congenital CMV infection can present up to 2 years after birth. Frequent complications that occur are hearing loss, neurologic impairment, and ocular disturbances.

CMV can cause life-threatening disease in immunocompromised patients. CMV infection occurs in over 40% of solid organ transplant patients during the first 3 months when immunosuppressive therapy is the strongest. Transplant patients that are CMV seronegative and receive a CMV seropositive donor are at highest risk. HIV patients with CD4 count less than 100/μL are at high risk of CMV infection as well. In the immunocompromised host, CMV manifests initially as fever, malaise, and myalgias. The infection can then progress to cause leukopenia, pneumonia, esophagitis/gastritis, hepatitis, colitis, encephalitis, polyradiculopathy, and retinitis. CMV retinitis is the most common cause of blindness in patients with AIDS.

Differential Diagnosis

It is difficult to make the diagnosis of CMV infection solely on a clinical basis. Infectious mononucleosis caused by EBV presents very similarly. In the perinatal phase, infants with apparent infections should be evaluated for the other common congenital infections: toxoplasmosis, rubella, herpes simplex, syphilis, VZV, and parvovirus B19. Because the CMV infection can cause a wide array of disease in the immunocompromised host, the differential diagnosis should be broad and include other viral pathogens, bacterial infections, Pneumocystis infection, and fungal infections.

Diagnostic Testing

Making the diagnosis of CMV is unlikely in the ED. Confirmation of this diagnosis centers on either virus isolation, serologic testing, or histopathology. Common methods involve PCR, viral culture, or antibody testing. The WBC count may show lymphocyte predominance with more than 10% atypical lymphocytes, much like EBV infections.

Management

For the most part, CMV infection in the immunocompetent host only requires symptomatic care for the mononucleosis-like syndrome. The treatment recommendations for critically ill immunocompetent patients with CMV infection are less clear. Immunocompromised patients with CMV infection are treated more aggressively. Antiviral treatment is necessary in sight and life-threatening infections.

Ganciclovir is an IV agent that is used to treat CMV infections. The treatment for CMV retinitis is induction therapy: 5 mg/kg/dose every 12 hours for 14 to 21 days followed by 5 mg/kg/dose once daily maintenance therapy for a prolonged course. Fever, diarrhea, and thrombocytopenia are common adverse reactions. Valganciclovir is an oral prodrug that is metabolized to ganciclovir. The treatment regimen is induction: 900 mg twice daily for 21 days followed by maintenance of 900 mg once daily. Foscarnet and cidofovir are IV agents used to treat CMV resistant to ganciclovir, and both can also be used to treat HSV resistant to acyclovir. The primary limiting toxicity of these drugs is renal toxicity.

Disposition

Most immunocompetent patients with CMV infection can be managed at home. In contrast, immunocompromised patients with CMV infection will usually require admission to the hospital, and depending on the extent of end-organ damage, may require ICU admission.

Differential Diagnosis

Clinicians should consider other diagnoses depending on the specific symptoms and syndrome caused by enterovirus infection. For the diseases with skin and oropharyngeal lesions, herpes simplex, aphthous stomatitis, mononucleosis, and bacterial pharyngitis should be considered. The diseases with primary neurologic manifestation present similarly to bacterial meningitis and other causes of viral meningitis or encephalitis, including herpes simplex encephalitis. Myopericarditis can present similar to pulmonary embolism, myocardial infarction, or pneumonia (see Chapter 68 ).