CASE 79-8, QUESTION 2: Should E.O. receive a corticosteroid to treat or prevent the pain associated with

herpes zoster?

The decision to use corticosteroids, such as prednisone or prednisolone, remains

controversial.

93 A number of studies have examined the effect of steroids on pain

during acute neuralgia and on the development of PHN. Early studies revealed that

steroids are effective for both acute pain and PHN, but these studies were small and

uncontrolled, and used various corticosteroid regimens. Most studies suggest relief

of the acute pain but no decrease in PHN.

94–97 Because of recent studies

demonstrating a lack of benefit in preventing PHN, the theoretical concerns of herpes

zoster dissemination, the development of secondary bacterial infections, and the

beneficial effects of antiviral agents such as acyclovir, famciclovir, and valacyclovir

for acute pain, corticosteroids should not be used in E.O.

CASE 79-8, QUESTION 3: Two months after the onset of the rash, E.O. continues to complain of pain. A

diagnosis of PHN is made. What FDA-approved treatments for PHN should be prescribed for E.O.?

Although many different agents have been studied, the only FDA-approved

treatments for PHN are topical capsaicin cream or gel, capsaicin patch 8%

(Qutenza), topical lidocaine 5% patches (Lidoderm), and oral gabapentin

(Neurontin) and pregabalin (Lyrica). Capsaicin depletes substance P, a mediator that

transmits pain from the periphery to the CNS. The largest double-blind, placebocontrolled trial of capsaicin evaluated 143 patients with PHN for at least 6 months.

98

After 6 weeks of treatment with capsaicin 0.075% cream, pain scores were reduced

in 21% and 6% of the capsaicin and placebo groups, respectively. After the doubleblind phase of the study ended, a subset of patients continued to use capsaicin cream

for up to 2 years, and most patients experienced prolonged pain relief.

98 Capsaicin

should be applied 3 or 4 times per day. Qutenza is a capsaicin patch, which is

applied by a health care professional. The patch is applied for 1 hour and cannot be

repeated more frequently than every 3 months. Lidocaine 5% patches have only been

compared with placebo and have been shown to relieve pain for 4 to 12 hours after

administration. Either capsaicin cream or gel or lidocaine patches can be considered

as a first-line option for E.O. A common adverse effect is a burning sensation after

application of capsaicin, which is intolerable in up to one-third of patients. The

burning sensation usually lessens with continued use.

If lidocaine patches are prescribed, E.O. should be instructed to apply up to three

patches to the painful area. Patients should be instructed to wear the patches for a

maximum of 12 hours a day, and proper disposal of used patches should be

emphasized. Even a used patch contains a large amount of lidocaine, and small

children or pets could suffer serious consequences from chewing or swallowing a

used patch.

99

Pregabalin is approved for the treatment of PHN, but it is associated with a greater

risk of adverse effects. Pregabalin binds to a subunit of calcium channels, thereby

decreasing calcium influx at nerve terminals and reducing the release of several

neurotransmitters, including glutamate, norepinephrine, and substance P.

100

In clinical

trials, dizziness was experienced by 29% of patients treated with pregabalin

compared with 9% of placebo-treated patients; somnolence was noted in 22% of

patients who received pregabalin compared with 8% of placebo-treated patients.

Dizziness and somnolence usually occur soon after the pregabalin is started and is

dose dependent.

100

Other agents that have been used in the treatment of PHN include tricyclic

antidepressants (e.g., amitriptyline, desipramine) and opioids.

101

ANTIVIRAL THERAPY IN IMMUNOCOMPROMISED PATIENTS

CASE 79-9

QUESTION 1: R.F. is a 68-year-old woman with a chief complaint of vesicles on her face associated with

severe pain. She has a history of polymyalgia rheumatica and possible temporal arteritis with headaches that are

responsive to steroids. She had been having increasing headaches on the right side of her forehead 5 days

before admission. Two days before admission, her family physician increased the dosage of prednisone from 30

to 60 mg/day. Vesicles developed on her face 1 day before admission. She was admitted for pain control and

diagnosed with herpes zoster infection. Six hours after admission, R.F. began having visual hallucinations,

hearing noises, and talking to herself. A lumbar puncture was performed with the following results:

WBCs, 3 (2 lymphocytes and 1 monocyte)

RBCs, 3

Protein, 84 mg/dL

Glucose, 86 mg/dL

VZV was isolated from the CSF and IV acyclovir was started at a dosage of 10 mg/kg every 8 hours. Why

is antiviral therapy indicated in R.F.? Should her prednisone be continued or discontinued?

Antiviral therapy is indicated for R.F. Acyclovir may halt the progression of acute

herpes zoster infection in immunocompromised hosts such as R.F., who has been

taking large doses of corticosteroids.

102

IV acyclovir 10 mg/kg every 8 hours is effective in severely immunocompromised

patients. Alternatively, in less severely immunocompromised patients, oral therapy

with acyclovir 800 mg 5 times a day, valacyclovir 1,000 mg TID, or famciclovir 500

mg TID, along with close monitoring, can be used.

103 Antiviral therapy is associated

with more rapid clearance of the herpes zoster virus from vesicles. Acyclovir has

little to no benefit in resolution of pain or prevention of PHN.

102

Initial data indicate

that famciclovir or valacyclovir are effective in severe herpes zoster infection in an

immunocompromised host.

104,105

Systemic corticosteroids are of unproven usefulness and may slow the healing of

lesions. Therefore, if possible, R.F.’s prednisone should be slowly tapered.

Acyclovir Toxicity

CASE 79-9, QUESTION 2: On the fourth day of acyclovir therapy, R.F. developed severe nausea and

vomited 3 times. The laboratory data showed a BUN of 45 mg/dL and SCr of 3.2 mg/dL (baseline BUN, 10

mg/dL and SCr, 1.0 mg/dL). Why must R.F.’s acyclovir dosage be altered?

Nausea and vomiting have been reported with acyclovir therapy in patients with

herpes zoster infections.

9 Similarly, elevations of SCr and BUN can occur in

association with acyclovir therapy. This may be secondary to acyclovir

crystallization in the renal tubules, particularly when fluid intake is inadequate

(Table 79-1). Because R.F.’s creatinine clearance is between 10 and 25 mL/minute

per 1.73 m2

, the acyclovir dosage interval should be extended to 24 hours. Every

effort should be made to maintain adequate hydration for the duration of acyclovir

therapy. (See Table 79-3 and Chapter 2, Interpretation of Clinical Laboratory Tests,

for creatinine clearance calculation.)

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INFLUENZA

Influenza is an acute infection caused by the virus of the Orthomyxoviridae family.

Epidemics of influenza are usually caused by the type A virus; type B virus is

generally associated with more sporadic infection. Infection is transmitted by the

inhalation of virus-containing droplets ejected from the respiratory tract of a person

with influenza. Influenza can be spread by direct contact, large droplets, or items

recently contaminated by nasopharyngeal secretions. The incubation period is

typically 2 days (range, 1–4 days).

Influenza A viruses are classified into subtypes of hemagglutinin (H) and

neuraminidase (N) surface antigens. Three subtypes of hemagglutinin (H1, H2, H3)

and two subtypes of neuraminidase (N1, N2) have caused influenza in humans.

Infection with a virus of one subtype may confer little or no protection against viruses

of other subtypes. In addition, significant antigenic variation (antigenic drift) within a

subtype may occur with time. Thus, infection or vaccination with one strain may not

protect against a distantly related strain of the same subtype. This is why major

epidemics of influenza continue to occur, and influenza vaccines must be

reformulated each year with the most likely viral strains to maximize vaccine

benefit.

106

The influenza vaccine is indicated for all individuals 6 months of age or older.

However, there are a number of populations for which vaccination is vital. Persons

at highest risk for influenza infection (Table 79-4) should receive the influenza

vaccine each year. Two influenza virus vaccines are currently available, a trivalent

vaccine which contains two type A strains and one type B strain, and a quadrivalent

vaccine which contains two strains of type A and type B.

107 At this time, no

recommendations exist regarding which vaccine is preferred in specific populations.

Additionally, a high-dose influenza virus vaccine is available which is indicated for

patients 65 years or older. The high-dose vaccine formulation contains 4 times the

amount of antigen contained in other influenza vaccine products. The higher strength

vaccine is intended to illicit a stronger immune response in the elderly, a population

known to have a suboptimal response to the standard-dose influenza vaccine. Early

trials with the higher strength vaccine found the high-dose vaccine was 24.2% more

effective in preventing influenza in adults 65 years of age and older relative to a

standard-dose vaccine.

108 Lastly, an intradermal influenza vaccine is injected

subcutaneously rather than intramuscularly. The intradermal vaccine requires a

smaller gauge needle for administration and less antigen to be as effective as the

regular flu vaccine. It is indicated in adults 18 to 64 years of age.

109

Table 79-4

Persons Who Should Receive the Influenza Vaccine

97

All persons 6 months of age or older

Nursing home or chronic care facility residents

Children and adults with chronic pulmonary or cardiovascular disease

Children and adults who have required medical follow-up because of chronic metabolic diseases (e.g., diabetes

mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (as a result of medications or

diseases such as HIV)

Children and adults who are at risk for aspiration (e.g., cognitive dysfunction, spinal cord injuries, seizures)

Children (6 months–18 years) receiving long-term aspirin therapy

Women who will be pregnant during influenza season

Health care workers

Household members of persons in high-risk groups (including contacts of infants and children 0–59 months)

The efficacy of the influenza vaccine depends on the similarity of the components

of the vaccine to the circulating viruses that year and the immunocompetence of the

host. If there is a good match with the circulating viruses, the vaccine can prevent

illness in approximately 70% to 90% of healthy adults and children. The vaccine is

effective in preventing hospitalization and pneumonia in approximately 30% of

elderly persons living in the community and in 40% of elderly persons residing in

nursing homes.

110 Despite the lower efficacy, vaccination is still associated with less

severe illness and fewer complications in vaccinated individuals.

Individuals at high risk for transmission to patients include physicians, nurses, and

other personnel in both hospital and ambulatory settings; employees of nursing homes

and chronic care facilities; providers of home care services; and household

members, including children. It is vital that all the above individuals should be

vaccinated annually. However, considering the morbidity and mortality associated

with influenza, all individuals should receive an annual influenza vaccination.

The optimal time for vaccine administration is between mid-October and midNovember because influenza activity peaks between late December and early March

in the United States. Vaccinating an individual too early in the season could result in

waning antibody concentrations before the influenza season is over. However,

influenza vaccine should be offered throughout the influenza season, even if outbreaks

of influenza have already been documented in the community.

107

Because the parenteral influenza vaccine is an inactivated vaccine and contains no

infectious viruses, it cannot cause influenza. The most common adverse effect is

soreness at the administration site lasting for up to 2 days.

111 Fever, malaise, myalgia,

and other systemic reactions occur infrequently; these may develop within 6 to 12

hours after the vaccine is given and persist for 1 to 3 days.

110,111

Immediate

hypersensitivity to egg protein (hives, angioedema, allergic asthma, or systemic

anaphylaxis) rarely occurs. Persons with anaphylactic hypersensitivity and those with

acute febrile illness should not be given the vaccine. However, minor illnesses with

or without fever are not contraindications for the influenza vaccine, particularly in

children with a mild upper respiratory tract infection or allergic rhinitis. When the

vaccine is contraindicated, a neuraminidase inhibitor (oseltamivir or zanamivir)

should be used for prophylaxis.

107 Amantadine and rimantadine are no longer

recommended for prophylaxis of influenza because of widespread resistance in the

United States.

107

Clinically, it is impossible to differentiate between influenza A and B. Definitive

diagnosis can be made by isolating the virus from throat washings or sputum and by a

significant increase in antibody titers during the convalescent period.

Clinical Presentation

CASE 79-10

QUESTION 1: K.B., a 40-year-old woman, comes into the pharmacy claiming she has “the flu.” She recently

started a new job and is afraid she will lose her job if she misses too many days from work. What questions

would you ask her to differentiate the common cold from an influenza infection?

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p. 1656

Although it can be difficult to differentiate the common cold from influenza, there

are some clues that may suggest one viral infection from the other. Influenza

infections typically occur from December through March in the United States.

Patients with influenza generally experience more systemic symptoms, such as fever

higher than 102°F, headache, myalgia, and cough. Rhinorrhea, nasal congestion, and

sneezing are more pronounced in patients with the common cold. Sore throat can

occur with both a cold and the flu. Bacterial sore throat (e.g., strep throat) is

somewhat differentiated from a viral sore throat in that a viral sore throat usually has

a slower onset and the throat pain is less severe. Lymph nodes are only slightly

enlarged and not tender in a viral sore throat, whereas with a bacterial sore throat,

lymph nodes are large and tender.

112

K.B. should be questioned about her symptoms and exposure to ill contacts, and

investigation into whether influenza has been documented in the community should be

performed to help differentiate an influenza infection from the common cold.

Treatment

CASE 79-10, QUESTION 2: K.B. describes symptoms consistent with an influenza infection for the past 24

hours. What treatment options exist for the treatment of influenza? Why is she a candidate for a neuraminidase

inhibitor agent such as zanamivir or oseltamivir?

Persons with suspected or confirmed influenza virus infection who are at high risk

of developing complications (e.g., those with preexisting cardiac or pulmonary

disease, unvaccinated infants and children, elderly, immunocompromised) may

benefit from antiviral therapy if started within 48 hours after the onset of symptoms.

Treatment is recommended regardless of influenza vaccination status and severity of

illness in all patients who develop symptoms of influenza and who require

hospitalization. Treatment should be considered in outpatients at high risk of

complications with illness that is not improving or in patients who request antiviral

therapy within 48 hours of onset of symptoms. Therapy will shorten the duration of

illness and decrease the risk for transmission to others in close contact with persons

at high risk of complications secondary to influenza infection. The benefits are less

clear in patients who have had symptoms longer than 48 hours.

113

The neuraminidase inhibitors, zanamivir (Relenza), oseltamivir (Tamiflu), and

peramivir (Rapivab) are active against influenza A and B. These agents work by

selectively inhibiting the enzyme neuraminidase, an enzyme necessary for viral

replication and spread. Oral Oseltamivir is currently indicated for the prevention and

treatment of influenza in patients 1 year of age and older; oral zanamivir is indicated

for the prevention of influenza in patients 7 years of age and older and for the

treatment of influenza in patients 5 years of age and older.

18,24 Peramivir, a parenteral

formulation, is indicated in adults, greater than 18 years of age, and in patients who

cannot tolerate or absorb orally administered oseltamivir or inhaled zanamivir.

114

Zanamivir is available as an oral powder for inhalation. For the treatment of

influenza infection in adults, 10 mg (two inhalations) BID for 5 days should be used.

Patients should inhale two doses, separated by at least 2 hours, on the first day and

then two doses, separated by 12 hours, on days 2 through 5.

24 Bronchospasm after use

can occur, and if bronchodilators are also prescribed, the bronchodilator should be

used before zanamivir.

24 Proper use of the delivery system (Rotadisk/Diskhaler) is

important, and thus patients should be instructed by the pharmacist on proper delivery

technique, with a demonstration device.

Oseltamivir is pharmacologically related to zanamivir but has significantly better

oral bioavailability, allowing oral dosing. It is approved for children over 1 year of

age and for adults. The dosage of oseltamivir for the treatment of influenza in adults

is 75 mg BID for 5 days.

18 Oseltamivir is available as a suspension with pediatric

dosing recommendations. As with zanamivir, treatment with oseltamivir must be

started within 48 hours of the onset of symptoms. Common side effects include

nausea, vomiting, and headache.

18 Of concern is that oseltamivir-resistant influenza

has been reported.

115

In addition, there are reports, predominantly in children, of selfinjury and delirium after the administration of oseltamivir.

116

Peramivir is dosed at 600 mg once and is administered intramuscularly or

intravenously as an infusion over 15 to 30 minutes. As the agent was primarily

studied in patients with influenza A and moderate disease, efficacy is unknown for

patients infected with influenza B or patients with severe infection requiring

hospitalization. The most common side effect is diarrhea; however, severe

dermatologic reactions and abnormal behaviors have been reported with its use.

114

Resistance to amantadine and rimantadine has increased dramatically in recent

years; consequently, these agents are no longer recommended for the routine

prevention or treatment of influenza infections.

117

When administered within 48 hours of onset of illness, zanamivir and oseltamivir

reduce influenza symptoms by approximately 1 day.

118–120

Information regarding the

effectiveness of the neuraminidase inhibitors in preventing serious complications of

influenza, such as pneumonia or worsening of chronic diseases, is limited.

107

Considering the causative agent is unknown and symptoms have been present for only

24 hours, K.B. may benefit from a neuraminidase inhibitor. Oral oseltamivir is easier

to administer than inhaled zanamivir, and the patient has no reason to not tolerate this

drug. Although oseltamivir will not cure influenza, it may reduce the severity and

duration of symptoms by about 1 day. She should be treated with a 5-day course of

oseltamivir.

CASE 79-11

QUESTION 1: J.T., a 74-year-old man, is brought to the ED from a nursing home with chief complaints of

fever (103°F), shaking chills, cough, headache, malaise, anorexia, and photophobia. He has been ill for the past

48 hours but is much worse this evening. On physical examination, he appeared flushed, his skin was hot and

moist, and he was having difficulty breathing. Vital signs included blood pressure, 150/90 mm Hg; pulse, 108

beats/minute; respiratory rate, 22 breaths/minute; and temperature, 103°F. Rales were audible on auscultation

of both lungs. A chest roentgenogram showed bilateral infiltrates but no consolidation. Blood gas studies

showed significant hypoxia, with a Pao2

of 50 mm Hg and a Paco2

of 50 mm Hg. J.T.’s medical history was

significant for chronic bronchitis and a stroke 16 months ago. Blood, sputum, and urine cultures were obtained,

and J.T. was started on antibiotics (ceftriaxone 1 g IV every 24 hours and azithromycin 500 mg IV every 24

hours). Gram stain of the sputum sample showed many WBCs but no bacteria. He was started on oxygen

therapy at 4 L/minute via nasal cannula. Twenty-four hours later, his respiratory symptoms worsened, and his

arterial blood gases deteriorated slightly (Pao2

, 40 mm Hg; Paco2

, 55 mm Hg). J.T. was intubated, and a

sputum sample was obtained and sent to the virology laboratory. Three days later, influenza A virus was

isolated from the sputum. Blood, urine, and sputum cultures were all negative for bacterial pathogens. Why is

this presentation consistent with influenza infection? Is antiviral treatment appropriate in J.T.?

Although symptoms of influenza may vary depending on age, most patients with

influenza A have an abrupt onset of fever, chills, cough, and headache. In elderly

patients such as J.T. and those

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with underlying diseases, the course of influenza can worsen quickly, and patients

are more likely to require hospitalization.

Antiviral therapy in J.T. is inappropriate. None of the antiviral agents has been

studied in patients presenting with symptoms after 48 hours of onset. In addition, the

antiviral agents have shown efficacy only in uncomplicated influenza.

107

Prevention

INFLUENZA VACCINES

CASE 79-11, QUESTION 2: During the next 3 weeks, two other nursing home patients develop influenza A

infections. What measures should be taken to prevent a further outbreak of influenza among other residents?

The nursing home residents and staff should receive influenza vaccine plus

chemoprophylaxis with oseltamivir or zanamivir. The Centers for Disease Control

and Prevention (CDC) recommends immunization of all individuals 6 months of age

or older, and especially those in high-risk groups, primarily all individuals who are

at high risk for influenza-related complications and their household contacts (Table

79-4).

107 Second in priority are otherwise healthy adults 50 years of age or older and

children with chronic metabolic diseases severe enough to warrant regular follow-up

during the preceding year. Any child younger than 9 years in whom the vaccine is

indicated requires two doses of the vaccine for optimal effectiveness. The first dose

should be administered as soon as the vaccine becomes available, if possible by

October, and the second dose is given before influenza infection is present in the

community. Vaccination should continue throughout the season, and can be given as

late as February or March, depending on the duration of the influenza season.

However, the efficacy of influenza vaccine is incomplete (70%).

120 Therefore,

oseltamivir or zanamivir should be used in high-risk individuals who may not

develop an adequate antibody response (e.g., patients with advanced HIV infection,

residents of nursing homes) to supplement the protection by vaccine.

108,113

A live, attenuated influenza vaccine (FluMist) is an option for healthy, nonpregnant

individuals between the ages of 2 and 49 years. In clinical studies with matched

influenza strains, live, attenuated influenza vaccine was approximately 87% effective

in preventing influenza in children and provided 85% efficacy in adults.

121,122

Advantages of the intranasal route of administration include ease of administration

and patient acceptability of an intranasal preparation compared with an intramuscular

(IM) injection. However, because the vaccine is live, viral shedding can occur for 2

or more days after vaccination. Consequently, patients who are immunosuppressed

and close contacts of patients who are severely immunocompromised (including

health care workers who care for them) should not receive the live vaccine. Others

who should not receive the live vaccine include patients with asthma or other chronic

disorders of the pulmonary or cardiovascular systems, those with chronic metabolic

diseases such as diabetes, renal dysfunction, or hemoglobinopathies, and children or

adolescents who are receiving aspirin or other salicylates.

107

OSELTAMIVIR AND ZANAMIVIR

Analysis of clinical trials of oseltamivir in the prevention of influenza showed a

decreased incidence of laboratory-confirmed influenza: 4.8% in the placebo group

and 1.2% in the treatment group.

123 The incidence of influenza in a skilled nursing

facility was 4.4% in the placebo group and 0.4% in the oseltamivir group. In

addition, oseltamivir lowered the rate of infection in patients exposed to influenza at

home from 12% to 1%. Zanamivir has also been found to be effective in preventing

infection.

124,125

Comparative studies between neuraminidase inhibitors have not been published.

Considering that oseltamivir is available in an oral formulation, it is easier to

administer in nursing home patients compared with zanamivir, which requires proper

use of the delivery device and a coordinated inspiratory effort.

RESPIRATORY SYNCYTIAL VIRUS INFECTIONS

Respiratory syncytial virus (RSV) causes bronchiolitis and bronchopneumonia in

infants younger than 2 years. More than one-half of affected infants are infected in the

first 2 years of life. Of these infants, approximately 1% to 2% will require

hospitalization.

126 Children who are severely premature, immunocompromised, or

with underlying congenital heart disease or lung disease may be at increased risk of

mortality because of RSV.

127 Patients with RSV infection before 3 years of age are at

increased risk of wheezing and asthma during childhood.

128

RSV infections usually occur in the winter. The chest radiograph and blood gases

are often abnormal, and the virus can be isolated in the nasopharyngeal secretions.

Clinical Presentation and Ribavirin Therapy

CASE 79-12

QUESTION 1: J.R., a male 6-month-old infant who is lethargic, tachypneic, and cyanotic, is brought to the

ED. J.R.’s medical history is significant for congenital HIV. He has a fever (102°F), his breathing is labored,

and wheezing is audible on expiration. The chest roentgenograms reveal a flattened diaphragm and

hyperinflated lung parenchyma. Because of hypoxemia and hypercarbia, J.R. is placed on ambient oxygen to

maintain the alveolar oxygen pressure at greater than 60 mm Hg. RSV is present in the respiratory secretions.

What therapy is indicated for J.R.?

The goal of RSV therapy is to increase oxygen saturation and decrease airway

resistance in patients such as J.R.

129 Treatment of RSV is highly individualized,

depending on the presenting signs and symptoms and associated comorbidities.

Oxygen is first-line therapy. Although decreases in airway resistance are often

achieved with the use of bronchodilators or corticosteroids in other conditions, such

as asthma, they have not proven to be effective in the treatment of bronchiolitis.

130,131

Hypertonic saline, administered as a nebulized solution, is beneficial in increasing

mucociliary clearance.

130

Infants and children admitted for bronchiolitis with an

expected length of stay (LOS) of at least 3 days (moderate-to-severe presentation)

may experience a shortened LOS by 1 day when prescribed 3% nebulized saline.

131

Adverse reactions include wheezing and excessive secretions.

Ribavirin (Virazole) is active against many DNA and RNA viruses, including

RSV. However, its clinical benefit remains controversial. Early studies with

ribavirin showed significant clinical improvement compared with placebo in both

healthy children and those with underlying disease.

132 These studies reported benefit

in terms of clinical recovery and improvement in arterial oxygenation. Subsequent

studies found ribavirin to be ineffective in patients with a variety of risk factors.

133,134

Consequently, the routine use in previously healthy infants and children has not been

clearly established. Whether ribavirin decreases the long-term sequelae and severity

of illness in high-risk groups (including premature infants, patients with

bronchopulmonary dysplasia, congenital heart disease, cystic fibrosis, and

immunodeficiency) has not been

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determined.

135 Current recommendations include consideration for use of ribavirin

in infants at risk for severe life-threatening infection.

135 Because J.R. has an

underlying immunodeficiency, ribavirin may be considered if J.R.’s condition

worsens.

ADMINISTRATION OF RIBAVIRIN

CASE 79-12, QUESTION 2: How is ribavirin administered, and what precautions should be taken during

drug administration in J.R.?

Ribavirin is administered as an aerosol through a collision generator that generates

particles small enough (1–2 μm wide) to reach the lower respiratory tract. The

concentration of the ribavirin solution in the reservoir is 20 mg/mL (6 g in 300 mL of

sterile water). The dose is administered over the course of 12 to 18 hours, although

in nonventilated patients, 2 g during 2 hours TID (using a 60-mg/mL solution) has

been successfully used.

132 Ribavirin therapy is continued for 3 to 7 days.

19

Ribavirin is approved for use in patients requiring mechanical ventilation.

However, ribavirin is hygroscopic, and aerosol particles can deposit in the tubing

and around the expiratory valve of a ventilator. The precipitated drug can obstruct the

expiratory valve and alter the peak end-expiratory pressure.

19 Ribavirin has been

safely used in such patients,

136,137 but close monitoring of respiratory therapy is

advised to prevent this problem. In addition to the inspection of tubing, modifications

of standard ventilatory circuits have been suggested.

19

ADVERSE EFFECTS

CASE 79-12, QUESTION 3: What are the important adverse effects of ribavirin?

The most common adverse effects of ribavirin are rash, initial mild bronchospasm,

and reversible skin irritation.

138 Although long-term follow-up data are limited, a

study evaluating the effects of ribavirin in patients 1 year after administration showed

a reduction in the incidence and severity of reactive airway disease, as well as in

hospitalizations related to respiratory illness.

139 Further long-term evaluation is still

necessary.

Ribavirin is contraindicated in women who are or may become pregnant during

exposure to the drug. Although there are no human data, ribavirin has been found to

be teratogenic or lethal to embryos in nearly all animal species in which it has been

tested. Teratogenesis was evident after a single oral dose of 2.5 mg/kg in hamsters

and after daily oral doses of 10 mg/kg in rats. Malformation of the skull, palate, eye,

jaw, skeleton, and GI tract have been documented in animals. Ribavirin has reduced

the survival of fetuses and offspring of animals tested. It is lethal to rabbit embryos in

daily oral doses as small as 1 mg/kg. There are no studies that address teratogenicity

in humans, but hospital personnel who are pregnant or may become pregnant should

avoid exposure to this drug.

19

It is important to consider the environmental effects of ribavirin on the personnel

involved with its administration. One study found no detectable plasma or urine

concentrations of ribavirin in 19 nurses, whereas another reported its presence in the

RBCs of a nurse caring for a patient who received ribavirin via oxygen tent.

140 The

ribavirin concentration in the air was highest when it was administered via oxygen

tent, followed by mist mask, and was lowest after administration via endotracheal

tubes of mechanically ventilated patients. This has led to several recommendations:

(a) ribavirin aerosol should be administered solely via endotracheal tube of

mechanically ventilated patients in a closed filtered system126

; (b) children receiving

ribavirin should be placed in a containment chamber equipped with a high-efficiency

particulate air filter exhaust in an isolation room with negative air pressure

19

; (c)

disposable full-body coverings and either a powered air-purifying respirator or

disposable particulate respirator should be made available to all health care

personne

140

; and (d) men and women planning to have children should not care for

patients receiving ribavirin via oxygen tents.

140 Valeant Pharmaceuticals markets an

aerosol delivery system for oxygen and ribavirin that decreases the liberation of

ribavirin into the environment.

19

Prevention

CASE 79-13

QUESTION 1: S.N. is a 7-month-old boy born prematurely at 27 weeks’ gestation. He has chronic lung

disease of prematurity (CLD) and uses oxygen at home. RSV season will begin next month. What treatments

to prevent RSV infection are available? Why is S.N. a candidate for such treatment?

Palivizumab (Synagis), a humanized monoclonal antibody made from recombinant

DNA, is active against RSV and is indicated for children at risk of severe RSV

respiratory tract infections (e.g., infants with CLD or a history of premature birth

before 29 weeks’ gestation). The efficacy of palivizumab has been demonstrated in

children with a history of prematurity or CLD.

141 Children receiving monthly IM

injections of palivizumab for 5 months during RSV season had a reduction in

hospitalizations and intensive care admissions for RSV disease. Palivizumab has

replaced the use of RSV-immunoglobulins in infants because it is easier to administer

(IM vs. IV), does not interfere with the response of live vaccines such as measles–

mumps–rubella or varicella vaccine, and is not likely to transmit blood-borne

diseases because it is a synthetic product rather than one derived from human

blood.

142

Based on S.N.’s age and his CLD, he is a candidate for palivizumab therapy.

130

PALIVIZUMAB DOSAGE AND ADMINISTRATION

CASE 79-13, QUESTION 2: How are the doses of palivizumab calculated, and how should it be

administered?

The dose of palivizumab is 15 mg/kg given IM. The first dose is given before the

start of the RSV season, and then monthly doses are given for a total of 5 months. In

the Northern Hemisphere, the RSV season is typically November through April.

HANTAVIRUS

Infections

Rodents are the primary reservoir hosts of Hantavirus, and in the United States the

deer mouse (Peromyscus maniculatus) is the main reservoir. These viruses

apparently do not cause illness in the reservoir hosts, but infection in humans occurs

when infected saliva, urine, and feces produced by the rodent are inhaled as

aerosols. Most patients recall exposure to rodents or rodent feces within 6 weeks of

the onset of illness.

143 Person-to-person transmission has not been documented.

The case definition includes clinical evidence of (a) febrile illness characterized

by unexplained adult respiratory distress syndrome (ARDS) or acute bilateral

pulmonary interstitial infiltrates, or (b) an autopsy finding of noncardiogenic

pulmonary edema, resulting from an unexplained respiratory illness. In addition,

laboratory evidence consists of (a) a positive serology (i.e., presence of hantavirusspecific immunoglobulin [Ig] M

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or rising titers of IgG), (b) positive immunohistochemistry for hantavirus antigen in

a tissue specimen, or (c) positive PCR for hantavirus RNA in a tissue specimen.

144

Hantavirus infection can cause three different clinical diseases: hemorrhagic fever

with renal syndrome, nephropathia epidemica, and hantavirus pulmonary syndrome

(HPS). Hemorrhagic fever with renal syndrome and nephropathia epidemica occur in

Asian and European countries. HPS occurs only in the Western Hemisphere,

including North America.

145 From 1993 to 2013, 606 cases of HPS were reported in

the United States, with 36% of the cases resulting in death.

146 Most have occurred in

the southwestern United States during spring and summer.

Clinical Presentation

The clinical features of patients with HPS include fever, myalgia, headache, and

cough. Abdominal pain, nausea, or vomiting may also be present. The physical

examination has been unreliable. Laboratory abnormalities may include leukocytosis,

thrombocytopenia, and hypoalbuminemia. The chest radiograph may initially be

normal, but rapid disease progress may show bilateral infiltrates and ARDS. Other

viral pneumonias do not typically progress to ARDS as rapidly as hantavirus

infections. Because of the nonspecific signs and symptoms, some patients may be

misdiagnosed as having influenza.

147

Treatment

Supportive treatment is important. Oxygen therapy and mechanical ventilation may be

necessary. Hypotension can be treated with vasopressor agents and judicious use of

IV crystalloids (i.e., 0.9% NaCl) to prevent worsening of pulmonary edema.

Universal precautions and respiratory isolation should be instituted.

145

There is no FDA-approved drug to treat hantavirus infections. Based on one study

in 242 patients, IV ribavirin was more effective than placebo in reducing morbidity

(oliguria and hemorrhage) and mortality. IV ribavirin was given as a loading dose of

33 mg/kg, followed by 16 mg/kg every 6 hours for 4 days, and 8 mg/kg every 8 hours

for the next 3 days.

148

Two other clinical trials, however, did not show similar clinical efficacy in the

treatment of HPS. One open-label trial conducted by the CDC showed a mortality

rate of 47% in patients who received ribavirin compared with 50% to those who did

not.

147

In addition, a small trial conducted at the National Institutes of Health could

not demonstrate any benefit from ribavirin.

149

WEST NILE VIRUS

West Nile virus (WNV) was first identified in the United States in 1999 in New York

City. Since then, the virus has had rapid geographic expansion and has infected

individuals in all states in the continental United States.

150 Although WNV normally

occurs in tropical climates, the increase in international travel and changes in

weather patterns have led to its spread.

WNV is a member of the Flaviviridae family. Culicine mosquitoes (including

Culex pipiens, Culex restuans, and Culex quinquefasciatus) are the vectors, and they

infect both birds and humans.

151

Infection with the virus involves direct inoculation

by the infecting mosquito. Birds are reservoir hosts. WNV can infect a number of

vertebrates, including horses. Transmission usually occurs from a mosquito bite;

however, reports indicate that transmission of the infection has occurred through

transfusions, organ transplantation, placental transfer, and via breast milk.

152 Because

of the seasonal variations in the life cycle of the mosquito, cases are most commonly

seen during the summer and early fall.

Diagnosis is usually made by high clinical suspicion and laboratory tests. WNV

can cause a wide range of illness, from an asymptomatic disease to West Nile fever

to encephalitis or meningitis. Mortality is low except in the neuroinvasive forms of

the infection. Mortality rates in the elderly, particularly those older than 70 years, can

be 9 times higher than in the general population.

153 The CDC laboratory criteria for

diagnosis of WNV include (a) isolation of the WNV antigen or genomic sequence

from a tissue, blood, CSF, or other body fluids; (b) WNV IgM antibody in a CSF

sample; (c) a fourfold rise in the antibody titer to WNV; and (d) demonstration of an

IgM or rising titers of IgG to WNV in a single serum sample.

154

Clinical Presentation

CASE 79-14

QUESTION 1: A.G. is an 84-year-old woman. She is very active and runs the yearly flower festival in the

community. She was brought to the ED by her granddaughter, who found her at home, confused and

complaining of a headache, fatigue, and increasing muscle weakness. She has a temperature of 103°F, and her

Mini-Mental Status Examination score is 21 of 30. She has decreasing muscle strength and an erythematous,

macular, papular rash on her arms and legs. The complete blood count and electrolytes are normal, with the

exception of slightly decreased sodium. The CSF reveals increased WBCs, increased protein, normal glucose,

and positive IgM antibody to WNV. A CT scan shows no abnormalities. What signs and symptoms are

indicative of WNV encephalitis?

Acute signs and symptoms of WNV include sudden onset of fever, anorexia,

weakness, nausea, vomiting, eye pain, headache, altered mental status, and stiff neck.

A rash may be present on the arms, legs, neck, and trunk. The rash is typically

erythematous, macular, and papular with or without morbilliform eruption.

155

Laboratory parameters may show normal or elevated WBC counts. Low serum

sodium concentrations may be seen in patients with encephalitis. CSF usually shows

pleocytosis, mostly with an elevation of lymphocytes, elevated protein levels, and

normal glucose levels.

155 Magnetic resonance imaging (MRI) shows some

enhancement of the leptomeninges or the periventricular areas in approximately onethird of patients, but no other abnormalities or evidence of acute disease are present

on either CT or MRI examination.

155

With disease progression, further muscle weakness and hyporeflexia may be

observed. Patients may progress to a diffuse, flaccid paralysis similar to Guillain–

Barré syndrome. Ataxia, extrapyramidal symptoms, cranial nerve abnormalities,

myelitis, optic neuritis, and seizures may be seen.

Treatment

CASE 79-14, QUESTION 2: What treatment options are available to A.G.?

Currently, treatment of WNV infection is supportive. Patients with febrile infection

usually have a self-limiting course. In severe cases, patients with muscle weakness

and signs of encephalitis will require admission to an intensive care unit, and many

will need mechanical ventilation. The available antiviral medications do not have

any activity against WNV in vivo, although ribavirin inhibits replication in vitro.

155

Combination therapy of high-dose ribavirin and interferon-α-2b has been used in

patients with severe disease with limited success. Although optimal doses have not

been established, the doses needed to inhibit the virus were 2 to

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3 million units of interferon and 2,400 mg of ribavirin daily.

156–158 Current clinical

trials investigate the efficacy and safety of intravenous immunoglobulin and

humanized monoclonal antibodies for treatment and vaccines for the prevention of

WNV.

SEVERE ACUTE RESPIRATORY DISTRESS

SYNDROME

Severe acute respiratory distress syndrome (SARS), a highly infectious disease, was

first identified in China in early 2003. Since then, the viral syndrome has been

reported in several countries in East Asia, North America (particularly Canada),

South America, and Europe. During the 2003 outbreak, approximately 8,000 cases

were reported, with a case fatality rate of about 10%.

159,160 No cases of SARS have

been reported worldwide since 2004. Many of the pre-2004 cases reported in Asia

and Canada have been traced to a single index case, with outbreaks clustered in

apartments, hotels, health care facilities, or biomedical facilities. There is some

evidence to suggest that increased age (older than 60 years) may be associated with

an increased mortality risk.

161