Epidemiology

VZV is the organism that causes varicella (chickenpox) and herpes zoster (shingles). Before the initiation of the varicella vaccination program, chickenpox was a very common illness, and 90% of cases occurred in children less than 10 years of age. Although most cases were uncomplicated, chickenpox led to 11,000 hospitalizations and 100 deaths every year before the introduction of the varicella vaccine. Adolescents and adults who contracted the illness tended to have a more prolonged and severe course. Since the introduction of widespread vaccination, the incidence of chickenpox has declined by 81%, thus leading to an 88% decline in varicella-related hospitalizations.⁵

Herpes zoster (shingles) occurs when the latent varicella virus is reactivated in the sensory ganglia. The lifetime incidence of herpes zoster is approximately 10% to 20% of the population, and most symptomatic infections occur in older or immunocompromised patients. In 2005, a safe, effective live attenuated vaccine was approved by the U.S. Food and Drug Administration and was recommended by the Advisory Committee on Immunization Practices after clinical trials demonstrated a significant reduction in morbidity secondary to herpes zoster and postherpetic neuralgia.⁶ An observational study reported a significant reduction in incidence of herpes zoster in patients 60 years old or older who received the vaccine regardless of age, race, or the presence of chronic diseases.⁷

Presenting Signs and Symptoms

A primary infection (chickenpox) is characterized by a diffuse, pruritic, vesicular rash 10 to 21 days after exposure. Patients with the illness typically experience a prodrome of 1 to 2 days of fever and malaise, followed by the eruption of macular lesions that progress to papules and then to vesicles that rupture and crust. Most often, the first lesions appear on the face or trunk and then spread to the extremities. Lesions may also involve the mucous membranes of the oropharynx, respiratory tract, vagina, cornea, and conjunctiva. The distinguishing feature of this rash is the presence of lesions in various stages in a single affected area. Patients less than 1 year old or more than 15 years old have the highest risk of complications, including skin infections, central nervous system involvement, and pneumonia. Chickenpox in pregnant women or neonates can lead to life-threatening pneumonitis, and primary infection during pregnancy may result in the congenital varicella syndrome.

As the patient recovers from a primary infection, the virus establishes a latent infection in the sensory dorsal root ganglia. Reactivation of this latent infection leads to the clinical symptoms of shingles. Patients frequently report a prodrome of fever, malaise, headache, and skin sensitivity before the eruption of the characteristic rash of grouped vesicles. The lesions typically crust by 7 to 10 days and resolve in 3 to 4 weeks. Pain is the most common symptom of shingles and is typically described as a burning sensation. The infection typically covers one dermatome, but it can occasionally affect neighboring dermatomes. Postherpetic neuralgia occurs in 10% to 15% of cases and is the most frequent complication of VZV. People who are more than 60 years old account for half of these cases. Postherpetic neuralgia is defined as the persistence of sensory symptoms more than 30 days after the onset of zoster. Herpes zoster ophthalmicus is a vision-threatening condition that requires ophthalmologic consultation. It is caused by involvement of the ophthalmic branch of cranial nerve V. The Hutchinson sign (a lesion on the tip of the nose) suggests the diagnosis, but it is not always present. Other complications include herpes zoster oticus (Ramsay Hunt syndrome) and disseminated herpes zoster, which can be identified by the rash crossing the midline or involving several dermatomes.

Chickenpox

Most cases of chickenpox follow a benign, uncomplicated course, and full recovery without chronic sequelae is expected. Treatment of varicella is aimed primarily at symptomatic relief. Acetaminophen is recommended for discomfort and fever. A small study from 1999 suggested a link between ibuprofen and necrotizing fasciitis in children with varicella.⁸ Although subsequent investigations have not been able to provide causal evidence, antiinflammatory medications continue to be associated with higher risk of invasive group A streptococcal infections, and these agents are not recommended in children with chickenpox.⁹ Another prominent symptom is severe pruritus, leading to excoriations and scarring. Oral antihistamines, calamine lotion, and oatmeal baths may be helpful.

Several antiviral medications are active against VZV. Clinical studies have shown that these drugs may shorten the duration of illness and severity of cutaneous symptoms, but they have not been shown to reduce transmission or complications. To maximize clinical benefit, these agents should be given within 24 hours of rash onset. The decision to start antiviral therapy is based on the characteristics of the host and the extent of infection. Antiviral therapy is not recommended for cases of chickenpox in healthy children with uncomplicated infections or for use as postexposure prophylaxis. The physician should offer oral antiviral therapy to patients who are more than 13 years of age, who have chronic cutaneous or pulmonary disorders, and who are receiving long-term salicylate or steroid therapy. The most common treatment for children is oral acyclovir, at 20 mg/kg (maximum, 800 mg/dose) four times daily for 5 days. Adults should receive 800 mg four times daily for 5 days. An obstetrician should be consulted before therapy is initiated in pregnant or peripartum women because treatment recommendations range from no treatment to admission for intravenous acyclovir. All immunocompromised patients and those who develop complications should be given intravenous acyclovir and admitted (Table 174.2).

Table 174.2 Varicella Complications

Shingles

Pharmacologic treatment of shingles is controversial. Most patients recover within 1 to 2 weeks without therapy. Up to 15% will develop postherpetic neuralgia, a potentially chronic, debilitating pain syndrome. Therapeutic trials support the use of antiviral medications to shorten the course of the acute illness and accelerate resolution of the painful neuritis,¹⁰ but conflict exists regarding the ability of these drugs to prevent postherpetic neuralgia. No clear difference in efficacy among the currently available antiviral medications (acyclovir, famciclovir, and valacyclovir) has been reported. Acyclovir has been studied more extensively, but the dosing regimen of five times daily limits compliance. Valacyclovir is rapidly metabolized to acyclovir, and its dosing schedule makes compliance much more likely. Steroid therapy may heal the rash more quickly, but it has not been shown to prevent postherpetic neuralgia and is not routinely recommended.¹¹ Pain control is difficult in patients with acute shingles and postherpetic neuralgia. Opioids, lidocaine patches, and topical capsaicin have all been shown to provide pain relief, yet no single therapy has emerged as superior to the others. Gabapentin and amitriptyline are considered second-line agents and should be initiated in the primary care setting because patients taking these medications require close follow-up. A summary of treatment recommendations is provided in the “Priority Actions” box. Most patients with herpes zoster may be discharged to home. The exceptions include patients who are immunosuppressed or who have disseminated disease.

Epidemiology

Influenza viruses cause epidemic respiratory illnesses that can range from mild to severe to deadly. The virulence of influenza has tremendous year-to-year variability. In the 30-year period between 1976 and 2006, annual flu deaths ranged from a low of 3000 to a high of 49,000.¹² Influenza causes disease in all age groups. During peak influenza season, the percentage of primary care office visits for influenza-like illness ranges from 3.3% to 7.1%.¹³ Each year, approximately 20% of children and 5% of adults develop symptomatic influenza infection.¹⁴ Although children have the highest infection rates, the rates of serious infection and death are highest in patients more than 65 years old or less than 2 years old and in patients with coexisting comorbidities.

The virus is classified as type A, B, or C, based on differences in the composition of its matrix and nucleus protein. Human disease is caused only by influenza A and B. Influenza A is further subtyped based on the antigenicity of the hemagglutinin and neuraminidase surface glycoproteins. Currently, 16 hemagglutinin and 9 neuraminidase subtypes have been identified.¹⁵ Influenza B viruses are not further subtyped. Hemagglutinin facilitates the entry of the virus into host cells, and neuraminidase assists in the release of the progeny virions from the infected cells. These antigenic determinants are the primary basis for human immunity, thus reducing the likelihood and severity of infection in persons with prior exposure to a particular subtype. Immunity to one subtype, however, confers little to no immunity to another subtype. Antigenic variation in the surface glycoproteins causes the influenza virus to change constantly and enables it to evade immune recognition and produce repeated outbreaks of disease.

Influenza is spread through respiratory droplets that may lodge on fomites. The typical incubation period is 1 to 4 days. Adults can be infectious the day before and 5 days after symptom onset, but children can have a longer period of asymptomatic infectivity both before and after symptoms. The average number of secondary cases caused by an index case ranges from 5 to 25. In comparison, the average number of secondary cases of severe acute respiratory syndrome (SARS) caused by a single case ranges from 2.2 to 3.7.¹⁶

Signs and Symptoms

Uncomplicated cases of influenza are characterized by the abrupt onset of constitutional and respiratory symptoms such as fever, myalgias, headache, malaise, sore throat, and rhinitis. Accompanying gastrointestinal symptoms such as vomiting and diarrhea are more common in children than in adults. A meta-analysis attempting to identify specific symptoms or combinations that could predict influenza infection found that the combination of fever and cough during influenza season was the only clinical criterion that reliably increased the likelihood of influenza.¹³ Fortunately, weekly influenza surveillance data are readily available in the United States at the Centers for Disease Control and Prevention website (www.cdc.org). Surveillance data can be used not only to determine the incidence of influenza in the community, but also to ascertain the predominant circulating type of influenza.

Testing, Treatment, and Disposition

Influenza testing can be performed by culture, immunofluorescence, reverse transcriptase polymerase chain reaction, or rapid tests. Because testing time is typically less than 30 minutes for the rapid diagnostic tests, these are commonly available in emergency departments. Whereas the specificity of these tests is high, the sensitivity is low. One must take care when interpreting test results because a negative result does not rule out influenza infection.¹⁷ Current guidelines encourage testing only when results will change the clinical care of the patient or influence the clinical care of other patients. Given the poor sensitivity of these tests and the recommendation that treatment not be delayed pending results, most patients do not benefit from testing.

Options for controlling influenza include immunoprophylaxis with vaccines, treatment with antiviral agents, and chemoprophylaxis. Available vaccines include inactivated influenza vaccine injection and intranasal live attenuated influenza vaccine.

Although antiviral agents are not a substitute for influenza vaccination, they can offer marginal benefit in controlling symptoms. Two classes of available agents are as follows: the adamantines (amantadine and rimantadine), which display activity against influenza A; and the neuraminidase inhibitors (zanamivir and oseltamivir), which have activity against both influenza A and B. To be effective, all these agents must be started within 48 hours of symptom onset, a feature that limits the use of these agents to patients seeking care promptly.

Pandemic Influenza

Influenza pandemics occur when a new virus emerges that is spread easily from person to person and to which humans have little to no immunity.¹⁸ Three major pandemics occurred in the twentieth century. Pandemic influenza differs from seasonal influenza in that young, healthy individuals are at increased risk of serious complications.

Aquatic birds likely serve as the largest reservoir for influenza viruses. Nearly all strains of influenza A circulate among wild birds, which can infect domestic fowl. Although these avian influenza viruses are not readily transmissible among humans, individuals in close contact with infected fowl may become infected. Concern exists that an avian influenza virus may mutate and trigger a pandemic. The virus that caused the catastrophic pandemic from 1918 to 1919 originated from an avian source and appears to have subsequently infected humans and adapted to allow spread among persons.¹⁹ The viruses causing the pandemics of 1957 and 1968, conversely, seem to have infected an animal (either human or pig) and reassorted with another influenza virus, resulting in the emergence of a new virus that was readily capable of human transmission.

In 2009, a novel influenza A virus (H1N1) caused a worldwide pandemic and resulted in an estimated 59 million illnesses and 12,000 deaths in the United States.²⁰ Although the overall case fatality rate was less than 0.5%, most serious illnesses occurred in children and young adults, with a relative sparing of adults more than 60 years old. In addition to the usual array of chronic medical conditions associated with increased morbidity, pregnancy and obesity were associated with a 4 to 15 times higher risk of hospitalization or death.

Although the overall case fatality rate for the 2009 pandemic was lower than that of seasonal influenza, several lessons were learned. Physical interventions such as hand hygiene, masks, gowns, and gloves were all found to reduce transmission.²¹ Similarly, resources were effectively mobilized to develop and distribute a novel vaccine that was effective at limiting disease spread. Despite effective methods to limit spread, several challenges were identified as well. Shortages of supplies during the pandemic were a significant problem. Surgical masks, N95 respirators, disinfectant wipes, and antiviral medications were all in short supply, particularly in the early stages of the pandemic.

Epidemiology

In the United States, the annual incidence of infectious mononucleosis ranges between 345 and 671 cases per 100,000.²² EBV is the principal cause, and by adulthood nearly all persons have been infected. Other viruses such as cytomegalovirus and human immunodeficiency virus can cause syndromes that resemble acute mononucleosis.

Presenting Signs and Symptoms

In developing nations, EBV is generally a disease of the very young and is often asymptomatic or minimally symptomatic. In industrialized nations, people contract primary EBV infections at slightly later ages. In the United States, approximately one third of cases manifest during adolescence and early adulthood.²³ Nearly half these patients develop clinically evident mononucleosis that can manifest classically or with typical or atypical variations of the classic presentation.

Diagnostic Testing

If performed, laboratory studies may point toward mononucleosis as the cause of the patient’s viral syndrome (Table 174.3). Ultrasonography may reveal hepatosplenomegaly.

Table 174.3 Laboratory Findings in Acute Mononucleosis

↑, increased; ↓, decreased; EBV, Epstein-Barr virus.

Treatment and Disposition

No specific therapies for EBV mononucleosis exist. Patients are supported through the illness by management of their symptoms. Many patients with mononucleosis can be managed as outpatients. Severely ill patients, those with refractory symptoms (pain, dehydration), and those at risk for severe complications should be admitted.²⁶

Epidemiology

In February of 2003, reports of an outbreak of unexplained pneumonia that killed 5 of 305 afflicted individuals emerged in southern China.²⁷ The disease was characterized by flulike symptoms with high fever, myalgias, nonproductive cough with dyspnea, lymphopenia, and infiltrates on chest radiography. The disease often progressed to cause respiratory failure and carried a mortality rate of 11%. The SARS epidemic serves to remind us how global travel contributes to the epidemic spread of disease. A Chinese physician who was treating patients in the afflicted region then traveled to Hong Kong, where 10 guests at his hotel were secondarily infected. These guests then traveled to Singapore, Vietnam, Canada, and the United States, thus creating the first global epidemic spread by air travel. Over the next 100 days, more than 8422 individuals were infected and 916 died in 30 countries.²⁸ Over the next several months, SARS spread to more than 20 countries on 4 continents. The World Health Organization launched a global initiative to characterize and contain this new infection and demonstrated how concerted efforts can successfully contain epidemics. By March of 2003, the offending virus was identified as a coronavirus, termed SARS coronavirus (SARS-CoV), and the genome was mapped by April of that year. Through a remarkable globally concerted effort involving international surveillance and quarantines, SARS was effectively contained by the summer of 2003.²⁹ The last new case was reported in April of 2004, in a scientist studying the virus in a laboratory in China (Table 174.4).

Table 174.4 Features of Severe Acute Respiratory Syndrome That May Help with the Clinical Diagnosis

SARS, severe acute respiratory syndrome.

Adapted from World Health Organization: WHO guidelines for the global surveillance of SARS: Updated recommendations, October 2004. www.who.int/csr/resources/publications/WHO_CDS_CSR_ARO_2004_1.pdf.

Relative to other pandemic infectious agents, the infectivity of SARS-CoV is generally low, but in some cases, a single person can infect a large number of people.²⁷ The greatest population at risk during an epidemic seems to be health care workers because they are often in close contact with infected patients. During the 2003 epidemic, 20% of those infected were health care workers.²⁸

Epidemiology

West Nile virus had not been reported in the Western Hemisphere until the first case was discovered in New York City in 1999.³⁰ Since then, more than 12,000 cases of neuroinvasive disease and more than 1200 deaths have been reported in the United States.³¹ West Nile virus is a member of the Japanese encephalitis complex that includes Japanese encephalitis and St. Louis encephalitis. Birds serve as the primary reservoir for the virus. Mosquitoes become infected when they feed on afflicted birds. No known animal-to-human or human-to-human cases of transmission have occurred other than those in recipients of blood or organ transplants.³²

Presenting Signs and Symptoms

Approximately 80% of persons infected with West Nile virus are asymptomatic.³³ Of those in whom symptoms develop, most will have West Nile fever, but less than 1% will have neuroinvasive disease. Characteristics of each of these illnesses are presented in Table 174.5. The incubation period for West Nile Virus infection ranges from 2 to 14 days.

Table 174.5 Manifestations of West Nile Virus Infection