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KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and website for this

chapter, with the corresponding reference number in this chapter found in parentheses

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Key References

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Pappas PG et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious

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Diagn Microbiol Infect Dis. 2005;52:26. (70)

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p. 1644

Herpes simplex virus (HSV) encephalitis is associated with significant

morbidity and mortality. Intravenous acyclovir for a 21-day period is the

therapy of choice.

Case 79-1 (Questions 2, 4)

Neonatal herpes can present with mucocutaneous, ocular infection, as

well as encephalitis and disseminated HSV infection. Transmission can

be acquired during the first trimester of pregnancy or during vaginal

delivery in an infected mother.

Case 79-2 (Questions 1, 2)

Herpes labialis is the most common oral-facial HSV infection and is

usually self-limiting in an immunocompetent host. Patients who are

immunocompromised must be treated with antiviral therapy, primarily

oral or intravenous acyclovir or oral valacyclovir.

Case 79-3 (Question 1),

Case 79-4 (Question 1)

Individuals with progressive varicella, those with extracutaneous

complications, or those at high risk for developing complications to

varicella infection benefit from antiviral therapy.

Case 79-7 (Question 1),

Case 79-8 (Question 1)

The goal of pharmacotherapy of herpes zoster is to reduce pain and

duration of rash and to prevent the development of postherpetic

neuralgia (PHN). These outcomes can be accomplished with the use of

oral acyclovir, famciclovir, or valacyclovir. For the treatment of PHN,

topical capsaicin gels, creams and patches, topical lidocaine patches,

and oral gabapentin and pregabalin are efficacious.

Case 79-9 (Question 1)

Neuraminidase inhibitors, such as zanamivir, oseltamivir, and peramivir,

are indicated for the treatment of influenza if used within 48 hours after

the onset of symptoms. Zanamivir is administered by oral inhalation with

bronchospasm the most common adverse drug reaction. Oseltamivir is

administered orally, with nausea, vomiting, and headache as common

side effects. Peramivir is administered intravenously and has been

associated with hypersensitivity reactions, such as Steven–Johnson

syndrome.

Case 79-11 (Question 2)

Influenza vaccination is the most effective mechanism to prevent the flu.

However, certain high-risk populations may require additional

prophylaxis with oseltamivir or zanamivir.

Case 79-10 (Question 2)

Infants at high risk for severe disease caused by respiratory syncytial Case 79-13 (Questions 1, 2)

virus (RSV) should receive monthly intramuscular injections of

palivizumab for a total of five doses during RSV season.

West Nile virus can cause disease ranging from a febrile infection to

encephalitis. Treatment is supportive; however, ribavirin and

interferon-α-2b have been tried in this patient population. Clinical trials

evaluating the use of immunoglobulin, monoclonal antibodies, and

vaccines are ongoing.

Case 79-14 (Questions 1, 2)

The common cold is the most prevalent viral infection. Numerous

pathogens can cause this respiratory infection, including rhinovirus,

coronavirus, parainfluenza, RSV, adenovirus, and enterovirus. There are

currently no products that have been conclusively shown to prevent or

treat the common cold.

Case 79-15 (Question 1)

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p. 1646

Viral infections are common causes of human disease. An estimated 60% of illnesses

in developed countries result from viruses, compared with only 15% from bacteria.

These include the common cold, chickenpox, measles, mumps, influenza, bronchitis,

gastroenteritis, hepatitis, poliomyelitis, rabies, and numerous diseases caused by the

herpesvirus. Upper respiratory tract infections, such as the common cold or influenza,

are among the most common reasons for visits to a health care professional.

1 Most of

these patients have a self-limiting illness; however, certain viral infections, such as

influenza, can cause significant mortality, particularly in the elderly. During the

worldwide Spanish influenza epidemic of 1918 to 1920, 20 to 100 million people

died.

2 Although influenza vaccines reduce the morbidity and mortality associated

with this disease, for many other potentially severe viral infections, including herpes

encephalitis and neonatal herpes, no vaccine is available.

Substantial progress has been made in antiviral chemotherapy as a result of

advances in molecular virology and genetic engineering. Antiviral agents can be

designed to inhibit functions specific to viruses, which maximizes their therapeutic

benefits and minimizes adverse effects.

Current technology also permits rapid diagnosis of viral diseases. It is now

possible to make a specific diagnosis of several viral illnesses within hours to a few

days; previously, a specific diagnosis often took days to months. These improved

diagnostics have facilitated rapid selection of an appropriate antiviral drug.

This chapter describes the etiology, pathogenesis, and treatment of common viral

infections. Specific case presentations illustrate the optimal use of antiviral drugs in

patients with viral infections.

HERPES SIMPLEX VIRUS INFECTIONS

Herpes viruses are responsible for a broad spectrum of diseases including acute lifethreatening illness (herpes encephalitis and neonatal herpes), as well as more

chronic, recurrent infection (genital herpes). Antivirals significantly decrease the

morbidity and mortality in most of these infections.

3

Herpes Encephalitis

Herpes simplex virus (HSV) encephalitis is the most common sporadic viral

infection of the central nervous system (CNS). HSV encephalitis occurs in up to

500,000 people yearly, although this may be an underestimate owing to difficulties in

diagnosis. It typically occurs in two populations, those 6 months to 20 years of age

and those older than 50 years. It is characterized by the acute onset of fever,

headache, decreased consciousness, and seizures. Any child with fever and altered

behavior should be evaluated for HSV encephalitis. Without treatment, mortality

approaches 70% and some morbidity is evident in 97% of survivors. Only 2.5% of

patients recover sufficiently to lead normal lives.

3

Herpes simplex virus type 1 (HSV-1) is the etiologic agent in most patients with

herpes encephalitis, but herpes simplex virus type 2 (HSV-2) is more common in

newborns. The infection may be localized to the brain or involve cutaneous and

mucous membranes. Although any area of the brain can be involved, the orbital

region of the frontal lobes and the temporal lobes are most often affected.

4

Herpes encephalitis is often difficult to diagnose. A computed tomography (CT)

scan is usually indicated to rule out other conditions, such as brain abscess or other

space-occupying lesions. The CT or radionuclide scans may be unremarkable early

in the course of the disease.

Cerebrospinal fluid (CSF) examination usually reveals pleocytosis (predominately

lymphocytes) with 50 to 2,000 white blood cells (WBCs)/mcL. Polymorphonuclear

leukocytosis and red blood cells (RBCs) may also be seen. Many patients have an

elevated protein level in the CSF (median, 80 mg/dL; normal values differ per age,

e.g., if ≥6 months, 15–45 mg/dL).

The electroencephalogram (EEG) is the most sensitive but least specific test.

There are usually CT or brain scan abnormalities, but these may take a day or two

longer to appear. The EEG, CT, and brain scan findings compatible with HSV

encephalitis can be mimicked by other conditions, and a brain biopsy is required to

clearly establish the diagnosis. Rapid diagnosis of herpes encephalitis by a

polymerase chain reaction (PCR) assay of HSV DNA in the CSF is available at most

medical centers. This is a highly sensitive, specific, and rapid method for diagnosing

herpes encephalitis.

5

CLINICAL PRESENTATION

CASE 79-1

QUESTION 1: R.F., a 7-year-old boy weighing 20 kg, was seen in the emergency department (ED) after a

seizure. For the previous 3 days, R.F. had decreased appetite, headache, and fever (101°F–102°F), and was

lethargic and disoriented. His leukocyte count was 13,000/mcL with a shift to the left. Ceftriaxone (50 mg/kg

intravenously [IV] every 12 hours) and dexamethasone (0.15 mg/kg IV every 6 hours) were initiated for

presumed bacterial meningitis. Phenobarbital (5 mg/kg IV every 24 hours) was given for seizure control. The

CSF was normal, and no bacteria could be cultured. Acyclovir 20 mg/kg IV every 8 hours was started

immediately. A PCR analysis of HSV-1 was positive. What findings in R.F. are consistent with the diagnosis of

herpes encephalitis?

Fever, headache, lethargy, and disorientation are common features of herpes

encephalitis. As illustrated by R.F., the CSF examination can be normal in some

patients. A negative CSF culture suggests the absence of a bacterial infection.

6

However, the positive HSV-1 DNA by PCR analysis confirms the diagnosis of

herpes encephalitis.

TREATMENT: ACYCLOVIR

CASE 79-1, QUESTION 2: What is the treatment of choice for R.F.’s herpes encephalitis?

Two studies comparing acyclovir and vidarabine (no longer marketed in the

United States) have demonstrated that IV acyclovir (10 mg/kg every 8 hours for 10

days) is the treatment of choice in patients with herpes encephalitis.

7,8 The 12-month

all-cause mortality was 25% in the acyclovir-treated group and 59% in the

vidarabine-treated group. Notably, nearly one-third of the acyclovir-treated patients

returned to normal life, compared with only 12% of those treated with vidarabine.

9

Acyclovir is the treatment of choice for R.F. because it has been shown to

decrease morbidity in patients with herpes encephalitis. Acyclovir should be started

as soon as HSV encephalitis is suspected because early initiation of therapy is

associated with improved outcome. Therapy should be continued for at least 21

days.

10 The role of corticosteroids in the treatment of herpes encephalitis is not well

defined. One small, nonrandomized trial found that corticosteroid therapy, in

combination with IV acyclovir, was associated with an improved outcome.

11

However, prospective, randomized trials are needed before routine use of

corticosteroids can be recommended.

12 Acyclovir-resistant herpes

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p. 1647

is not an important consideration in the management of herpes encephalitis in most

patients.

Adverse Effects

CASE 79-1, QUESTION 3: What adverse effects can occur with IV acyclovir therapy in R.F.? How should

these be monitored, and how can they be minimized?

Acyclovir is a relatively safe drug, but renal toxicity associated with IV acyclovir

is well described (Table 79-1). Blood urea nitrogen (BUN) and serum creatinine

(SCr) levels can increase in 5% to 10% of patients; however, these changes are

generally reversible. Acyclovir is relatively insoluble: maximal urine solubility at

37°C is 1.3 mg/mL. Consequently, the mechanism of acyclovir-associated renal

disease is a transient crystal nephropathy, which may occur at high acyclovir

concentrations.

9

Other common adverse effects include gastrointestinal (GI) complaints, such as

nausea and vomiting and, less commonly, neurologic disturbances, including lethargy,

tremors, confusion, hallucinations, and seizures.

9,25 Neurotoxicity appears to be more

common in patients with impaired renal function and is reversible. Finally, IV

acyclovir can cause phlebitis and pain at the injection site.

9 This complication can be

minimized by administering acyclovir at a concentration of 5 mg/mL (maximum, 7

mg/mL).

25