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InternalMed_Harrison. If recognized in a timely fashion, rickettsial disease is very responsive to treatment. Doxycycline (100 mg twice daily for 3–14 days) is the treatment of choice for both adults and children. The newer macrolides and chloramphenicol may be suitable alternatives, but mortality rates are higher when a tetracycline-based treatment is not given. Purpura Fulminans (See also Chaps. 180 and 325) Purpura fulminans is the cutaneous manifestation of DIC and presents as large ecchymotic areas and hemorrhagic bullae. Progression of petechiae to purpura, ecchymoses, and gangrene is associated with congestive heart failure, septic shock, acute renal failure, acidosis, hypoxia, hypotension, and death. Purpura fulminans has been associated primarily with N. meningitidis but, in splenectomized patients, may be associated with S. pneumoniae, H. influenzae, and S. aureus.


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InternalMed_Harrison. N. meningitidis but, in splenectomized patients, may be associated with S. pneumoniae, H. influenzae, and S. aureus. Ecthyma Gangrenosum Septic shock caused by P. aeruginosa or Aeromonas hydrophila can be associated with ecthyma gangrenosum (see Figs. 189-1 and 25e-35): hemorrhagic vesicles surrounded by a rim of erythema with central necrosis and ulceration. These gram-negative bacteremias are most common among patients with neutropenia, extensive burns, and hypogammaglobulinemia.


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InternalMed_Harrison. Other Emergent Infections Associated with Rash Vibrio vulnificus and other noncholera Vibrio bacteremic infections (Chap. 193) can cause focal skin lesions and overwhelming sepsis in hosts with chronic liver disease, iron storage disorders, diabetes, renal insufficiency, or other immunocompromising conditions. After ingestion of contaminated raw shellfish, typically oysters from the Gulf Coast, there is a sudden onset of malaise, chills, fever, and hypotension. The patient develops bullous or hemorrhagic skin lesions, usually on the lower extremities, and 75% of patients have leg pain. The mortality rate can be as high as 50–60%, particularly when the patient presents with hypotension. Outcomes are improved when patients are treated with tetracycline-containing regimens. Other infections, caused by agents such as Aeromonas, Klebsiella, and E. coli, can cause hemorrhagic bullae and death due to overwhelming sepsis in cirrhotic patients. Capnocytophaga canimorsus can cause septic shock


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InternalMed_Harrison. caused by agents such as Aeromonas, Klebsiella, and E. coli, can cause hemorrhagic bullae and death due to overwhelming sepsis in cirrhotic patients. Capnocytophaga canimorsus can cause septic shock in asplenic patients. Infection typically follows a dog bite. Patients present with fever, chills, myalgia, vomiting, diarrhea, dyspnea, confusion, and headache. Findings can include an exanthem or erythema multiforme (see Figs. 70-9 and 25e-25), cyanotic mottling or peripheral cyanosis, petechiae, and ecchymosis. About 30% of patients with this fulminant form die of overwhelming sepsis and DIC, and survivors may require amputation because of gangrene.


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InternalMed_Harrison. Erythroderma TSS (Chaps. 172 and 173) is usually associated with erythroderma. The patient presents with fever, malaise, myalgias, nausea, vomiting, diarrhea, and confusion. There is a sunburn-type rash that may be subtle and patchy but is usually diffuse and is found on the face, trunk, and extremities. Erythroderma, which desquamates after 1–2 weeks, is more common in Staphylococcus-associated than in Streptococcus-associated TSS. Hypotension develops rapidly—often within hours—after the onset of symptoms. Multiorgan failure occurs. Early renal failure may precede hypotension and distinguishes this syndrome from other septic shock syndromes. There may be no indication of a primary focal infection, although possible cutaneous or mucosal portals of entry for the organism can be ascertained when a careful history is taken. Colonization rather than overt infection of the vagina or a postoperative wound, for example, is typical with staphylococcal TSS, and the mucosal areas appear


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InternalMed_Harrison. when a careful history is taken. Colonization rather than overt infection of the vagina or a postoperative wound, for example, is typical with staphylococcal TSS, and the mucosal areas appear hyperemic but not infected. Streptococcal TSS is more often associated with skin or soft tissue infection (including necrotizing fasciitis), and patients are more likely to be bacteremic. TSS caused by Clostridium sordellii is associated with childbirth or with skin injection of black-tar heroin. The diagnosis of TSS is defined by the clinical criteria of fever, rash, hypotension, and multiorgan involvement. The mortality rate is 5% for menstruation-associated TSS, 10–15% for nonmenstrual TSS, 30–70% for streptococcal TSS, and up to 90% for obstetric C. sordellii TSS.


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InternalMed_Harrison. Viral Hemorrhagic Fevers Viral hemorrhagic fevers (Chaps. 233 and 234) animal reservoirs or arthropod vectors. These diseases occur worldwide and are restricted to areas where the host species live. They are caused by four major groups of viruses: Arenaviridae (e.g., Lassa fever in Africa), Bunyaviridae (e.g., Rift Valley fever in Africa; hantavirus hemorrhagic fever with renal syndrome in Asia; or Crimean-Congo hemorrhagic fever, which has an extensive geographic distribution), Filoviridae (e.g., Ebola and Marburg virus infections in Africa), and Flaviviridae (e.g., yellow fever in Africa and South America and dengue in Asia, Africa, and the Americas). Lassa fever and Ebola and Marburg virus infections are also transmitted from person to person. The vectors for most viral fevers are found in rural areas; dengue and yellow fever are important exceptions. After a prodrome of fever, myalgias, and malaise, patients develop evidence of vascular damage, petechiae, and local hemorrhage.


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InternalMed_Harrison. in rural areas; dengue and yellow fever are important exceptions. After a prodrome of fever, myalgias, and malaise, patients develop evidence of vascular damage, petechiae, and local hemorrhage. Shock, multifocal hemorrhaging, and neurologic signs (e.g., seizures or coma) predict a poor prognosis. Dengue (Chap. 233) is the most common arboviral disease worldwide. More than half a million cases of dengue hemorrhagic fever occur each year, with at least 12,000 deaths. Patients have a triad of symptoms: hemorrhagic manifestations, evidence of plasma leakage, and platelet counts of <100,000/μL. Mortality rates are 10–20%. If dengue shock syndrome develops, mortality rates can reach 40%. Supportive care to maintain blood pressure and intravascular volume with careful volume-replacement therapy is key to survival. Ribavirin also may be useful against Arenaviridae and Bunyaviridae.


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See also Chap. 156.

InternalMed_Harrison. See also Chap. 156.


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InternalMed_Harrison. Necrotizing Fasciitis This infection is characterized by extensive necrosis of the subcutaneous tissue and fascia. It may arise at a site of minimal trauma or postoperative incision and may also be associated with recent varicella, childbirth, or muscle strain. The most common causes of necrotizing fasciitis are group A streptococci alone (Chap. 173), the incidence of which has been increasing for the past two decades, and a mixed facultative and anaerobic flora (Chap. 156). Diabetes mellitus, IV drug use, chronic liver or renal disease, and malignancy are associated risk factors. Physical findings are initially minimal compared with the severity of pain and the degree of fever. The examination is often unremarkable except for soft tissue edema and erythema. The infected area is red, hot, shiny, swollen, and exquisitely tender. In untreated infection, the overlying skin develops blue-gray patches after 36 h, and cutaneous bullae and necrosis develop after 3–5 days. Necrotizing


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InternalMed_Harrison. hot, shiny, swollen, and exquisitely tender. In untreated infection, the overlying skin develops blue-gray patches after 36 h, and cutaneous bullae and necrosis develop after 3–5 days. Necrotizing fasciitis due to a mixed flora, but not that due to group A streptococci, can be associated with gas production. Without treatment, pain decreases because of thrombosis of the small blood vessels and destruction of the peripheral nerves—an ominous sign. The mortality rate is 15–34% overall, >70% in association with TSS, and nearly 100% without surgical intervention. Necrotizing fasciitis may also be due to Clostridium perfringens (Chap. 179); in this condition, the patient is extremely toxic and the mortality rate is high. Within 48 h, rapid tissue invasion and systemic toxicity associated with hemolysis and death ensue. The distinction between this entity and clostridial myonecrosis is made by muscle biopsy. Necrotizing fasciitis caused by community-acquired MRSA also has been reported.


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InternalMed_Harrison. Clostridial Myonecrosis (See also Chap. 179) Myonecrosis is often associated with trauma or surgery but can develop spontaneously. The incubation period is usually 12–24 h long, and massive necrotizing gangrene develops within hours of onset. Systemic toxicity, shock, and death can occur within 12 h. The patient’s pain and toxic appearance are out of proportion to physical findings. On examination, the patient is febrile, apathetic, tachycardic, and tachypneic and may express a feeling of impending doom. Hypotension and renal failure develop later, and hyperalertness is evident preterminally. The skin over the affected area is bronze-brown, mottled, and edematous. Bullous lesions with serosanguineous drainage and a mousy or sweet odor can develop. Crepitus can occur secondary to gas production in muscle tissue. The mortality rate is >65% for spontaneous myonecrosis, which is often associated with Clostridium septicum or C. tertium and underlying malignancy. The mortality rates


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InternalMed_Harrison. production in muscle tissue. The mortality rate is >65% for spontaneous myonecrosis, which is often associated with Clostridium septicum or C. tertium and underlying malignancy. The mortality rates associated with trunk and limb infection are 63% and 12%, respectively, and any delay in surgical treatment increases the risk of death.


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InternalMed_Harrison. NEUROLOGIC INFECTIONS WITH OR WITHOUT SEPTIC SHOCK Bacterial Meningitis (See also Chap. 164) Bacterial meningitis is one of the most common infectious disease emergencies involving the central nervous system. Although hosts with cell-mediated immune deficiency (including transplant recipients, diabetic patients, elderly patients, and cancer patients receiving certain chemotherapeutic agents) are at particular risk for Listeria monocytogenes meningitis, 783 most cases in adults are due to S. pneumoniae (30–60%) and N. meningitidis (10–35%). The classic presentation of fever, meningismus, and altered mental status is seen in only one-half to two-thirds of patients. The elderly can present without fever or meningeal signs. Cerebral dysfunction is evidenced by confusion, delirium, and lethargy that can progress to coma. In some cases, the presentation is fulminant, with sepsis and brain edema; papilledema at presentation is unusual and suggests another diagnosis (e.g., an intracranial


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InternalMed_Harrison. that can progress to coma. In some cases, the presentation is fulminant, with sepsis and brain edema; papilledema at presentation is unusual and suggests another diagnosis (e.g., an intracranial lesion). Focal signs, including cranial nerve palsies (IV, VI, VII), can be seen in 10–20% of cases; 50–70% of patients have bacteremia. A poor outcome is associated with coma, hypotension, a pneumococcal etiology, respiratory distress, a CSF glucose level of <0.6 mmol/L (<<0 mg/dL), a CSF protein level of >2.5 g/L, a peripheral white blood cell count of <5000/μL, and a serum sodium level of <135 mmol/L. Rapid initiation of treatment is essential; the odds of an unfavorable outcome may increase by 30% for each hour that treatment is delayed. Mortality also increases linearly with age of the patient.


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InternalMed_Harrison. Suppurative Intracranial Infections (See also Chap. 164) In suppurative intracranial infections, rare intracranial lesions present along with sepsis and hemodynamic instability. Rapid recognition of the toxic patient with central neurologic signs is crucial to improvement of the dismal prognosis of these entities. Subdural empyema arises from the paranasal sinus in 60–70% of cases. Microaerophilic streptococci and staphylococci are the predominant etiologic organisms. The patient is toxic, with fever, headache, and nuchal rigidity. Of all patients, 75% have focal signs and 6–20% die. Despite improved survival rates, 15–44% of patients are left with permanent neurologic deficits. Septic cavernous sinus thrombosis follows a facial or sphenoid sinus infection; 70% of cases are due to staphylococci (including MRSA), and the remainder are due primarily to aerobic or anaerobic streptococci. A unilateral or retroorbital headache progresses to a toxic appearance and fever within days.


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InternalMed_Harrison. staphylococci (including MRSA), and the remainder are due primarily to aerobic or anaerobic streptococci. A unilateral or retroorbital headache progresses to a toxic appearance and fever within days. Three-quarters of patients have unilateral periorbital edema that becomes bilateral and then progresses to ptosis, proptosis, ophthalmoplegia, and papilledema. The mortality rate is as high as 30%. Septic thrombosis of the superior sagittal sinus spreads from the ethmoid or maxillary sinuses and is caused by S. pneumoniae, other streptococci, and staphylococci. The fulminant course is characterized by headache, nausea, vomiting, rapid progression to confusion and coma, nuchal rigidity, and brainstem signs. If the sinus is totally thrombosed, the mortality rate exceeds 80%.


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InternalMed_Harrison. Brain Abscess (See also Chap. 164) Brain abscess often occurs without systemic signs. Almost half of patients are afebrile, and presentations are more consistent with a space-occupying lesion in the brain; 70% of patients have headache and/or altered mental status, 50% have focal neurologic signs, and 25% have papilledema. Abscesses can present as single or multiple lesions resulting from contiguous foci or hematogenous infection, such as endocarditis. The infection progresses over several days from cerebritis to an abscess with a mature capsule. More than half of infections are polymicrobial, with an etiology consisting of aerobic bacteria (primarily streptococcal species) and anaerobes. Abscesses arising hematogenously are especially apt to rupture into the ventricular space, causing a sudden and severe deterioration in clinical status and a high mortality rate. Otherwise, mortality is low but morbidity is high (30–55%). Patients presenting with stroke and a parameningeal infectious


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InternalMed_Harrison. and severe deterioration in clinical status and a high mortality rate. Otherwise, mortality is low but morbidity is high (30–55%). Patients presenting with stroke and a parameningeal infectious focus, such as sinusitis or otitis, may have a brain abscess, and physicians must maintain a high level of suspicion. Prognosis worsens in patients with a fulminant course, delayed diagnosis, abscess rupture into the ventricles, multiple abscesses, or abnormal neurologic status at presentation.


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InternalMed_Harrison. Cerebral Malaria (See also Chap. 248) This entity should be urgently considered if patients who have recently traveled to areas endemic for malaria present with a febrile illness and lethargy or other neurologic signs. Fulminant malaria is caused by Plasmodium falciparum and is associated with temperatures of >40°C (>104°F), hypotension, jaundice, adult respiratory distress syndrome, and bleeding. By definition, any patient with a change in mental status or repeated


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InternalMed_Harrison. Approach to the Acutely Ill Infected Febrile Patient 784 seizure in the setting of fulminant malaria has cerebral malaria. In adults, this nonspecific febrile illness progresses to coma over several days; occasionally, coma occurs within hours and death within 24 h. Nuchal rigidity and photophobia are rare. On physical examination, symmetric encephalopathy is typical, and upper motor neuron dysfunction with decorticate and decerebrate posturing can be seen in advanced disease. Unrecognized infection results in a 20–30% mortality rate.


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InternalMed_Harrison. Intracranial and Spinal Epidural Abscesses (See also Chap. 456) Spinal and intracranial epidural abscesses (SEAs and ICEAs) can result in permanent neurologic deficits, sepsis, and death. At-risk patients include those with diabetes mellitus; IV drug use; chronic alcohol abuse; recent spinal trauma, surgery, or epidural anesthesia; and other comorbid conditions, such as HIV infection. Fungal epidural abscess and meningitis can follow epidural or paraspinal glucocorticoid infections. In the United States and Canada, where early treatment of otitis and sinusitis is typical, ICEA is rare but the number of cases of SEA is on the rise. In Africa and areas with limited access to health care, SEAs and ICEAs cause significant morbidity and mortality. ICEAs typically present as fever, mental status changes, and neck pain, while SEAs often present as fever, localized spinal tenderness, and back pain. ICEAs are typically polymicrobial, whereas SEAs are most often due to hematogenous seeding,


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InternalMed_Harrison. changes, and neck pain, while SEAs often present as fever, localized spinal tenderness, and back pain. ICEAs are typically polymicrobial, whereas SEAs are most often due to hematogenous seeding, with staphylococci the most common etiologic agent. Early diagnosis and treatment, which may include surgical drainage, minimize rates of mortality and permanent neurologic sequelae. Outcomes are worse for SEA due to MRSA, infection at a higher vertebral-body level, impaired neurologic status on presentation, and dorsal rather than ventral location of the abscess. Elderly patients and persons with renal failure, malignancy, and other comorbidities also have less favorable outcomes.


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InternalMed_Harrison. Other Focal Syndromes with a Fulminant Course Infection at virtually any primary focus (e.g., osteomyelitis, pneumonia, pyelonephritis, or cholangitis) can result in bacteremia and sepsis. Lemierre’s disease— jugular septic thrombophlebitis caused by Fusobacterium necrophorum—is associated with metastatic infectious emboli (primarily to the lung) and sepsis, with mortality rates of >15%. TSS has been associated with focal infections such as septic arthritis, peritonitis, sinusitis, and wound infection. Rapid clinical deterioration and death can be associated with destruction of the primary site of infection, as is seen in endocarditis and in infections of the oropharynx (e.g., Ludwig’s angina or epiglottitis, in which edema suddenly compromises the airway).


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InternalMed_Harrison. Rhinocerebral Mucormycosis (See also Chap. 242) Individuals with diabetes or immunocompromising conditions are at risk for invasive rhinocerebral mucormycosis. Patients present with low-grade fever, dull sinus pain, diplopia, decreased mental status, decreased ocular motion, chemosis, proptosis, dusky or necrotic nasal turbinates, and necrotic hard-palate lesions that respect the midline. Without rapid recognition and intervention, the process continues on an inexorable invasive course, with high mortality rates.


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InternalMed_Harrison. Acute Bacterial Endocarditis (See also Chap. 155) This entity presents with a much more aggressive course than subacute endocarditis. Bacteria such as S. aureus, S. pneumoniae, L. monocytogenes, Haemophilus species, and streptococci of groups A, B, and G attack native valves. Native-valve endocarditis caused by S. aureus (including MRSA strains) is increasing, particularly in health care settings. Mortality rates range from 10% to 40%. The host may have comorbid conditions such as underlying malignancy, diabetes mellitus, IV drug use, or alcoholism. The patient presents with fever, fatigue, and malaise <2 weeks after onset of infection. On physical examination, a changing murmur and congestive heart failure may be noted. Hemorrhagic macules on palms or soles (Janeway lesions) sometimes develop. Petechiae, Roth’s spots, splinter hemorrhages, and splenomegaly are unusual. Rapid valvular destruction, particularly of the aortic valve, results in pulmonary edema and hypotension. Myocardial


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InternalMed_Harrison. Petechiae, Roth’s spots, splinter hemorrhages, and splenomegaly are unusual. Rapid valvular destruction, particularly of the aortic valve, results in pulmonary edema and hypotension. Myocardial abscesses can form, eroding through the septum or into the conduction system and causing life-threatening arrhythmias or high-degree conduction block. Large friable vegetations can result in major arterial emboli, metastatic infection, or tissue infarction. Older patients with S. aureus endocarditis are especially likely to present with nonspecific symptoms—a circumstance that delays diagnosis and worsens prognosis. Rapid intervention is crucial for a successful outcome.


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InternalMed_Harrison. Inhalational Anthrax (See also Chap. 261e) Inhalational anthrax, the most severe form of disease caused by B. anthracis, had not been reported in the United States for more than 25 years until the use of this organism as an agent of bioterrorism in 2001. Patients presented with malaise, fever, cough, nausea, drenching sweats, shortness of breath, and headache. Rhinorrhea was unusual. All patients had abnormal chest roentgenograms at presentation. Pulmonary infiltrates, mediastinal widening, and pleural effusions were the most common findings. Hemorrhagic meningitis was seen in 38% of these patients. Survival was more likely when antibiotics were given during the prodromal period and when multidrug regimens were used. In the absence of urgent intervention with antimicrobial agents and supportive care, inhalational anthrax progresses rapidly to hypotension, cyanosis, and death.


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InternalMed_Harrison. Avian and Swine Influenza (See also Chap. 224) Human cases of avian influenza have occurred primarily in Southeast Asia, particularly Vietnam (H5N1) and China (H7N9). Avian influenza should be considered in patients with severe respiratory tract illness, particularly if they have been exposed to poultry. Patients present with high fever, an influenza-like illness, and lower respiratory tract symptoms; this illness can progress rapidly to bilateral pneumonia, acute respiratory distress syndrome, multiorgan failure, and death. Early antiviral treatment with neuraminidase inhibitors should be initiated along with aggressive supportive measures. Unlike avian influenza, for which human-to-human transmission has been rare so far and has not been sustained, a novel swine-associated influenza A/H1N1 virus has spread rapidly throughout the world. Patients most at risk of severe disease are children <5 years of age, elderly persons, patients with underlying chronic conditions, and pregnant


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InternalMed_Harrison. A/H1N1 virus has spread rapidly throughout the world. Patients most at risk of severe disease are children <5 years of age, elderly persons, patients with underlying chronic conditions, and pregnant women. Obesity also has been identified as a risk factor for severe illness.


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InternalMed_Harrison. Hantavirus Pulmonary Syndrome (See also Chap. 233) Hantavirus pulmonary syndrome has been documented in the United States (primarily the southwestern states), Canada, and South America. Most cases occur in rural areas and are associated with exposure to rodents. Patients present with a nonspecific viral prodrome of fever, malaise, myalgias, nausea, vomiting, and dizziness that may progress to pulmonary edema and respiratory failure. Hantavirus pulmonary syndrome causes myocardial depression and increased pulmonary vascular permeability; therefore, careful fluid resuscitation and use of pressor agents are crucial. Aggressive cardiopulmonary support during the first few hours of illness can be life-saving. The early onset of thrombocytopenia may help distinguish this syndrome from other febrile illnesses in an appropriate epidemiologic setting.


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InternalMed_Harrison. Acutely ill febrile patients with the syndromes discussed in this chapter require close observation, aggressive supportive measures, and—in most cases—admission to intensive care units. The most important task of the physician is to distinguish these patients from other infected febrile patients whose illness will not progress to fulminant disease. The alert physician must recognize the acute infectious disease emergency and then proceed with appropriate urgency.


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InternalMed_Harrison. Immunization Principles and vaccine use Anne Schuchat, Lisa A. Jackson Few medical interventions of the past century can rival the effect that immunization has had on longevity, economic savings, and quality 148 of life. Seventeen diseases are now preventable through vaccines routinely administered to children and adults in the United States (Table 148-1), and most vaccine-preventable diseases of childhood are at historically low levels (Table 148-2). Health care providers deliver the vast majority of vaccines in the United States in the course of providing routine health services and therefore play an integral role in the nation’s public health system.


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InternalMed_Harrison. VACCINE IMPACT Direct and Indirect Effects Immunizations against specific infectious diseases protect individuals against infection and thereby prevent symptomatic illnesses. Specific vaccines may blunt the severity of clinical illness (e.g., rotavirus vaccines and severe gastroenteritis) or reduce complications (e.g., zoster vaccines and postherpetic neuralgia). Some immunizations also reduce transmission of infectious disease agents from immunized people to others, thereby reducing the impact of infection spread. This indirect impact is known as herd immunity. The level of immunization in a population that is required to achieve indirect protection of unimmunized people varies substantially with the specific vaccine.


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InternalMed_Harrison. Since childhood vaccines have become widely available in the United States, major declines in rates of vaccine-preventable diseases among both children and adults have become evident (Table 148-2). For example, vaccination of children <5 years of age against seven types of Streptococcus pneumoniae led to a >90% overall reduction in invasive disease caused by those types. A series of childhood vaccines targeting 13 vaccine-preventable diseases in a single birth cohort leads to prevention of 42,000 premature deaths and 20 million illnesses and saves nearly $70 billion (U.S.). Control, Elimination, and Eradication of Vaccine-Preventable Diseases Immunization programs are associated with the goals of controlling,


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InternalMed_Harrison. Control, Elimination, and Eradication of Vaccine-Preventable Diseases Immunization programs are associated with the goals of controlling, Pertussis Children, adolescents, adults Diphtheria Children, adolescents, adults Tetanus Children, adolescents, adults Poliomyelitis Children Measles Children Mumps Children Rubella, congenital rubella syndrome Children Hepatitis B Children Haemophilus influenzae type b Children infection Hepatitis A Children Influenza Children, adolescents, adults Varicella Children Invasive pneumococcal disease Children, older adults Meningococcal disease Adolescents Rotavirus infection Infants Human papillomavirus infection, Adolescents and young adults cervical and anogenital cancers Zoster Older adults Smallpox 29,005 0 100 Diphtheria 21,053 1 ≥99 Measles 530,217 55 ≥99 Mumps 162,344 229 ≥99 Pertussis 200,752 48,277 76 Polio (paralytic) 16,316 0 100 Rubella 47,745 9 >99 Haemophilus influenzae 20,000 30b 99 type b infection


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InternalMed_Harrison. Measles 530,217 55 ≥99 Mumps 162,344 229 ≥99 Pertussis 200,752 48,277 76 Polio (paralytic) 16,316 0 100 Rubella 47,745 9 >99 Haemophilus influenzae 20,000 30b 99 type b infection Hepatitis A 117,333 2,890c 98 Hepatitis B (acute) 66,232 18,800c 72 Invasive pneumococcal 63,067 31,600d 50 infection: all ages Invasive pneumococ-16,069 1,800d 89 cal infection: <5 years of age Varicella 4,085,120 216,511 95 aExcept for cases of hepatitis A and hepatitis B, for which 2011 figures are shown. bAn additional 13 type b infections are estimated to have occurred among 210 reports of H. influenzae infection caused by unknown types among children <5 years of age. cData are from the CDC’s Viral Hepatitis Surveillance, 2011. dData are from the CDC’s Active Bacterial Core Surveillance 2012 Provisional Report. Source: Adapted from SW Roush et al: JAMA 298:2155, 2007; and MMWR 62(33); 669, 2013.


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InternalMed_Harrison. Source: Adapted from SW Roush et al: JAMA 298:2155, 2007; and MMWR 62(33); 669, 2013. eliminating, or eradicating a disease. Control of a vaccine-preventable disease reduces poor illness outcomes and often limits the disruptive impacts associated with outbreaks of disease in communities, schools, and institutions. Control programs can also reduce absences from work for ill persons and for parents caring for sick children, decrease absences from school, and limit health care utilization associated with treatment visits.


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InternalMed_Harrison. Elimination of a disease is a more demanding goal than control, usually requiring the reduction to zero of cases in a defined geographic area but sometimes defined as reduction in the indigenous sustained transmission of an infection in a geographic area. As of 2013, the United States had eliminated indigenous transmission of measles, rubella, poliomyelitis, and diphtheria. Importation of pathogens from other parts of the world continues to be important, and public health efforts are intended to react promptly to such cases and to limit forward spread of the infectious agent.


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InternalMed_Harrison. Eradication of a disease is achieved when its elimination can be sustained without ongoing interventions. The only vaccine- preventable disease of humans that has been globally eradicated thus far is smallpox. Although smallpox vaccine is no longer given routinely, the disease has not reemerged naturally because all chains of human transmission were interrupted through earlier vaccination efforts and humans were the only natural reservoir of the virus. Currently, a major health initiative is targeting the global eradication of polio. Sustained transmission of polio has been eliminated from most nations but has never been interrupted in three countries— Afghanistan, Nigeria, and Pakistan—while recent outbreaks in Syria and the Horn of Africa underscore that other countries remain at risk for importation until these reservoirs have been addressed. Detection of a case of disease that has been targeted for eradication or elimination is considered a sentinel event that could permit the


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InternalMed_Harrison. for importation until these reservoirs have been addressed. Detection of a case of disease that has been targeted for eradication or elimination is considered a sentinel event that could permit the infectious agent to become reestablished in the community or region. Therefore, such episodes must be promptly reported to public health authorities.


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InternalMed_Harrison. 786 Outbreak Detection and Control Clusters of cases of a vaccine-preventable disease detected in an institution, a medical practice, or a community may signal important changes in the pathogen, vaccine, or environment. Several factors can give rise to increases in vaccine-preventable disease, including (1) low rates of immunization that result in an accumulation of susceptible people (e.g., measles resurgence among vaccination abstainers); (2) changes in the infectious agent that permit it to escape vaccine-induced protection (e.g., non-vaccine-type pneumococci); (3) waning of vaccine-induced immunity (e.g., pertussis among adolescents and adults vaccinated in early childhood); and (4) point-source introductions of large inocula (e.g., food-borne exposure to hepatitis A virus). Reporting episodes of outbreak-prone diseases to public health authorities can facilitate recognition of clusters that require further interventions.


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InternalMed_Harrison. public HealtH reporting Recognition of suspected cases of diseases targeted for elimination or eradication—along with other diseases that require urgent public health interventions, such as contact tracing, administration of chemoor immunoprophylaxis, or epidemiologic investigation for common-source exposure—is typically associated with special reporting requirements. Many diseases against which vaccines are routinely used, including measles, pertussis, Haemophilus influenzae type b invasive disease, and varicella, are nationally notifiable. Clinicians and laboratory staff have a responsibility to report some vaccine-preventable disease occurrences to local or state public health authorities according to specific case-definition criteria. All providers should be aware of state or city disease-reporting requirements and the best ways to contact public health authorities. A prompt response to vaccine-preventable disease outbreaks can greatly enhance the effectiveness of control


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InternalMed_Harrison. city disease-reporting requirements and the best ways to contact public health authorities. A prompt response to vaccine-preventable disease outbreaks can greatly enhance the effectiveness of control measures.


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InternalMed_Harrison. global considerations Several international health initiatives currently focus on reducing vaccine-preventable diseases in regions throughout the world. These efforts include improving access to new and underutilized vaccines, such as pneumococcal conjugate, rotavirus, human papillomavirus (HPV), and meningococcal A conjugate vaccines. The American Red Cross, the World Health Organization (WHO), the United Nations Foundation, the United Nations Children’s Fund (UNICEF), and the Centers for Disease Control and Prevention (CDC) are partners in the Measles & Rubella Initiative, which targets reduction of worldwide measles deaths by 95% from 2000 to 2015. During 2000–2011, global measles mortality rates declined by 71%—i.e., from an estimated 548,000 deaths in 2000 to 158,000 deaths in 2011. Rotary International, UNICEF, the CDC, and the WHO are leading partners in the global eradication of polio, an endeavor that reduced the annual number of paralytic polio cases from 350,000 in 1988 to


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InternalMed_Harrison. Rotary International, UNICEF, the CDC, and the WHO are leading partners in the global eradication of polio, an endeavor that reduced the annual number of paralytic polio cases from 350,000 in 1988 to <250 in 2012. The GAVI Alliance and the Bill and Melinda Gates Foundation have brought substantial momentum to global efforts to reduce vaccine-preventable diseases, expanding on earlier efforts by the WHO, UNICEF, and governments in developed and developing countries.


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InternalMed_Harrison. Enhancing Immunization in Adults Although immunization has become a centerpiece of routine pediatric medical visits, it has not been as well integrated into routine health care visits for adults. This chapter focuses on immunization principles and vaccine use in adults. Accumulating evidence suggests that immunization coverage can be increased through efforts directed at consumer-, provider-, institution-, and system-level factors. The literature suggests that the application of multiple strategies is more effective at raising coverage rates than is the use of any single strategy.


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InternalMed_Harrison. recommendations for adult immunizations The CDC’s Advisory Committee on Immunization Practices (ACIP) is the main source of recommendations for administration of vaccines approved by the U.S. Food and Drug Administration (FDA) for use in children and adults in the U.S. civilian population. The ACIP is a federal advisory committee that consists of 15 voting members (experts in fields associated with immunization) appointed by the Secretary of the U.S. Department of Health and Human Services; 8 ex officio members representing federal agencies; and 26 nonvoting representatives of various liaison organizations, including major medical societies and managed-care organizations. The ACIP recommendations are available at www.cdc .gov/vaccines/hcp/acip-recs/. These recommendations are harmonized to the greatest extent possible with vaccine recommendations made by other organizations, including the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians,


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InternalMed_Harrison. to the greatest extent possible with vaccine recommendations made by other organizations, including the American College of Obstetricians and Gynecologists, the American Academy of Family Physicians, and the American College of Physicians.


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InternalMed_Harrison. adult immunization scHedules Immunization schedules for adults in the United States are updated annually and can be found online (www .cdc.gov/vaccines/schedules/hcp/adult.html). In January, the schedules are published in American Family Physician, Annals of Internal Medicine, and Morbidity and Mortality Weekly Report (www.cdc.gov/ mmwr). The adult immunization schedules for 2013 are summarized in Fig. 148-1. Additional information and specifications are contained in the footnotes to these schedules. In the time between annual publications, additions and changes to schedules are published as Notices to Readers in Morbidity and Mortality Weekly Report.


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InternalMed_Harrison. Administering immunizations to adults involves a number of processes, such as deciding whom to vaccinate, assessing vaccine contraindications and precautions, providing vaccine information statements (VISs), ensuring appropriate storage and handling of vaccines, administering vaccines, and maintaining vaccine records. In addition, provider reporting of adverse events that follow vaccination is an essential component of the vaccine safety monitoring system.


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InternalMed_Harrison. Deciding Whom to Vaccinate Every effort should be made to ensure that adults receive all indicated vaccines as expeditiously as possible. When adults present for care, their immunization history should be assessed and recorded, and this information should be used to identify needed vaccinations according to the most current version of the adult immunization schedule. Decision-support tools incorporated into electronic health records can provide prompts for needed vaccinations. Standing orders, which are often used for routinely indicated vaccines (e.g., influenza and pneumococcal vaccines), permit a nurse or another approved licensed practitioner to administer vaccines without a specific physician order, thus lowering barriers to adult immunization.


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InternalMed_Harrison. Assessing Contraindications and Precautions Before vaccination, all patients should be screened for contraindications and precautions. A contraindication is a condition that increases the risk of a serious adverse reaction to vaccination. A vaccine should not be administered when a contraindication is documented. For example, a history of an anaphylactic reaction to a dose of vaccine or to a vaccine component is a contraindication for further doses. A precaution is a condition that may increase the risk of an adverse event or that may compromise the ability of the vaccine to evoke immunity (e.g., administering measles vaccine to a person who has recently received a blood transfusion and may consequently have transient passive immunity to measles virus). Normally, a vaccine is not administered when a precaution is noted. However, situations may arise when the benefits of vaccination outweigh the estimated risk of an adverse event, and the provider may decide to vaccinate the patient


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InternalMed_Harrison. when a precaution is noted. However, situations may arise when the benefits of vaccination outweigh the estimated risk of an adverse event, and the provider may decide to vaccinate the patient despite the precaution.


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InternalMed_Harrison. In some cases, contraindications and precautions are temporary and may lead to mere deferral of vaccination until a later time. For example, moderate or severe acute illness with or without fever is generally considered a transient precaution to vaccination and results in postponement of vaccine administration until the acute phase has resolved; thus the superimposition of adverse effects of vaccination on the underlying illness and the mistaken attribution of a manifestation of the underlying illness to the vaccine are avoided. Contraindications and precautions to vaccines licensed in the United States for use in civilian adults are summarized in Table 148-3. It is important to recognize conditions that are not contraindications in order not to miss opportunities for vaccination. For example, in most cases, mild acute illness (with or without fever), a history of a mild to moderate local reaction to a previous dose of the vaccine, and breast-feeding are not contraindications to


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InternalMed_Harrison. example, in most cases, mild acute illness (with or without fever), a history of a mild to moderate local reaction to a previous dose of the vaccine, and breast-feeding are not contraindications to vaccination.


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InternalMed_Harrison. FOOTNOTES: (Influenza vaccine)1 There are several flu vaccines available—talk to your healthcare professional about which flu vaccine is right for you. (Tdap vaccine)2 Pregnant women are recommended to get Tdap vaccine with each pregnancy to increase protection for infants who are too young for vaccination but at highest risk for severe illness and death from pertussis (whooping cough). (HPV vaccine)3 There are two HPV vaccines but only one HPV vaccine (Gardasil®) should be given to men. Gay men or men who have sex with men who are 22 through 26 years old should get HPV vaccine if they haven’t already started or completed the series.


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InternalMed_Harrison. (MMR vaccine)4 If you were born in 1957 or after, and don’t have a record of being vaccinated or having had these infections, talk to your healthcare professional about how many doses you may need. (Pneumococcal vaccine)5 There are two different types of pneumococcal vaccine: PCV13 and PPSV23. Talk with your healthcare professional to find out if one or both pneumococcal vaccines are recommended for you. If you are traveling outside of the United States, you may need additional vaccines. Ask your healthcare professional which vaccines you may need. For more information, call toll free 1-800-CDC-INFO (1-800-232-4636) or visit http://www.cdc.gov/vaccines FIGURE 148-1 Recommended adult immunization schedules, United States, 2013. For complete statements by the Advisory Committee on Immunization Practices (ACIP), visit www.cdc.gov/ vaccines/hcp/acip-recs/.


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InternalMed_Harrison. FOOTNOTES: (Influenza vaccine)1 There are several flu vaccines available—talk to your healthcare professional about which flu vaccine is right for you. (HPV vaccine)2 There are two HPV vaccines but only one HPV vaccine (Gardasil®) should be given to men. Gay men or men who have sex with men who are 22 through 26 years old should get HPV vaccine if they haven’t already started or completed the series. (Zoster)3 You should get zoster vaccine even if you’ve had shingles before. (MMR vaccine)4 If you were born in 1957 or after, and don’t have a record of being vaccinated or having had these infections, talk to your healthcare professional about how many doses you may need. All vaccines Contraindication Severe allergic reaction (e.g., anaphylaxis) after a previous vaccine dose or to a vaccine component Moderate or severe acute illness with or without fever. Defer vaccination until illness resolves.


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InternalMed_Harrison. Moderate or severe acute illness with or without fever. Defer vaccination until illness resolves. Td Precautions GBS within 6 weeks after a previous dose of TT-containing vaccine History of arthus-type hypersensitivity reactions after a previous dose of TDor DT-containing vaccines (including MCV4). Defer vac cination until at least 10 years have elapsed since the last dose. Tdap Contraindication History of encephalopathy (e.g., coma or prolonged seizures) not attributable to another identifiable cause within 7 days of administration of a vaccine with pertussis components, such as DTaP or Tdap GBS within 6 weeks after a previous dose of TT-containing vaccine


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InternalMed_Harrison. GBS within 6 weeks after a previous dose of TT-containing vaccine Progressive or unstable neurologic disorder, uncontrolled seizures, or progressive encephalopathy. Defer vaccination until a treatment regimen has been established and the condition has stabilized. History of arthus-type hypersensitivity reactions after a previous dose of TTor DT-containing vaccines (including MCV4). Defer vaccina tion until at least 10 years have elapsed since the last dose. HPV Contraindication History of immediate hypersensitivity to yeast (for Gardasil) Pregnancy. If a woman is found to be pregnant after initiation of the vaccination series, the remainder of the 3-dose regimen should be delayed until after completion of the pregnancy. If a vaccine dose has been administered during pregnancy, no intervention is needed. Exposure to Gardasil during pregnancy should be reported to Merck (800-986-8999); exposure to Cervarix during pregnancy should be reported to GlaxoSmithKline (888-452-9622).


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InternalMed_Harrison. History of immediate hypersensitivity reaction to gelatina or neomycin Known severe immunodeficiency (e.g., hematologic and solid tumors; chemotherapy; congenital immunodeficiency; long-term immunosuppressive therapy; severe immunocompromise due to HIV infection) Recent receipt (within 11 months) of antibody-containing blood product History of thrombocytopenia or thrombocytopenic purpura Varicella Contraindications Pregnancy Known severe immunodeficiency History of immediate hypersensitivity reaction to gelatina or neomycin Recent receipt (within 11 months) of antibody-containing blood product Influenza, inactivated, Precautions injectable History of severe allergic reaction (e.g., anaphylaxis) to egg proteinb (note: not a precaution for Flublok recombinant influenza vaccine, which is approved for persons 18–49 years of age and is manufactured without the use of eggs) History of GBS within 6 weeks after a previous influenza vaccine dose


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InternalMed_Harrison. History of GBS within 6 weeks after a previous influenza vaccine dose Influenza, live Contraindications attenuated nasal spray History of severe allergic reaction (e.g., anaphylaxis) to egg proteinb Immunosuppression, including that caused by medications or by HIV infection; known severe immunodeficiency (e.g., hematologic and solid tumors; chemotherapy; congenital immunodeficiency; long-term immunosuppressive therapy; severe immunocompromise due to HIV infection) Certain chronic medical conditions, such as diabetes mellitus; chronic pulmonary disease (including asthma); chronic cardiovascular disease (except hypertension); renal, hepatic, neurologic/neuromuscular, hematologic, or metabolic disorders Close contact with severely immunosuppressed persons who require a protected environment, such as isolation in a bone marrow transplantation unit


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InternalMed_Harrison. Close contact with severely immunosuppressed persons who require a protected environment, such as isolation in a bone marrow transplantation unit Close contact with persons with lesser degrees of immunosuppression (e.g., persons receiving chemotherapy or radiation therapy who are not being cared for in a protective environment; persons with HIV infection) is not a contraindication or a precaution. Health care personnel in neonatal intensive care units or oncology clinics may receive live attenuated influenza vaccine. History of GBS within 6 weeks of a previous influenza vaccine dose Receipt of specific antiviral agents (i.e., amantadine, rimantadine, zanamivir, or oseltamivir) with 48 h before vaccination Pneumococcal None, other than those listed for all vaccines Pneumococcal None, other than those listed for all vaccines History of immediate hypersensitivity to yeast Meningococcal Contraindication conjugate


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InternalMed_Harrison. Pneumococcal None, other than those listed for all vaccines History of immediate hypersensitivity to yeast Meningococcal Contraindication conjugate History of severe allergic reaction to dry natural rubber (latex) (certain vaccine formulations; see text) History of severe allergic reaction to dry natural rubber (latex) History of immediate hypersensitivity reaction to gelatina or neomycin


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InternalMed_Harrison. History of severe allergic reaction to dry natural rubber (latex) History of immediate hypersensitivity reaction to gelatina or neomycin Receipt of specific antiviral agents (i.e., acyclovir, famciclovir, or valacyclovir) within 24 h before vaccination aExtreme caution must be exercised in administering MMR, varicella, or zoster vaccine to persons with a history of anaphylactic reaction to gelatin or gelatin-containing products. Before administration, skin testing for sensitivity to gelatin can be considered. However, no specific protocols for this purpose have been published. bRecommendations for safely administering influenza vaccine to persons with egg allergies are reported in the annual ACIP recommendations for influenza vaccination (www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html).


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InternalMed_Harrison. Abbreviations: DT, diphtheria toxoid; DTaP, diphtheria, tetanus, and pertussis; GBS, Guillain-Barré syndrome; HPV, human papillomavirus; MCV4, quadrivalent meningococcal conjugate vaccine; MMR, measles, mumps, and rubella; Td, tetanus and diphtheria toxoids; Tdap, tetanus and diphtheria toxoids and acellular pertussis; TT, tetanus toxoid.


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InternalMed_Harrison. History of immediate Hypersensitivity to a vaccine component A severe allergic reaction (e.g., anaphylaxis) to a previous dose of a vaccine or to one of its components is a contraindication to vaccination. While most vaccines have many components, substances to which individuals are most likely to have had a severe allergic reaction include egg protein, gelatin, and yeast. In addition, although natural rubber (latex) is not a vaccine component, some vaccines are supplied in vials or syringes that contain natural rubber latex. These vaccines can be identified by the product insert and should not be administered to persons who report a severe (anaphylactic) allergy to latex unless the benefit of vaccination clearly outweighs the risk for a potential allergic reaction. The much more common local or contact hypersensitivity to latex, such as to medical gloves (which contain synthetic latex that is not linked to allergic reactions), is not a contraindication to administration of a vaccine


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InternalMed_Harrison. or contact hypersensitivity to latex, such as to medical gloves (which contain synthetic latex that is not linked to allergic reactions), is not a contraindication to administration of a vaccine supplied in a vial or syringe that contains natural rubber latex. Vaccines routinely indicated for adults that, as of December 2012, were sometimes supplied in a vial or syringe containing natural rubber include Havrix hepatitis A vaccine (syringe); Vaqta hepatitis A vaccine (vial and syringe); Engerix-B hepatitis B vaccine (syringe); Recombivax HB hepatitis B vaccine (vial); Cervarix HPV vaccine (syringe); Fluarix, Fluvirin, Agriflu, and Flucelvax influenza vaccines (syringe); Adacel and Boostrix Tdap (tetanus and diphtheria toxoids and acellular pertussis) vaccines (syringe); Td (tetanus and diphtheria toxoids) vaccines (syringe); Twinrix hepatitis A and B vaccine (syringe); and Menomune meningococcal polysaccharide vaccine (vial).


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InternalMed_Harrison. pregnancy Live-virus vaccines are contraindicated during pregnancy because of the theoretical risk that vaccine virus replication will cause congenital infection or have other adverse effects on the fetus. Most live-virus vaccines, including varicella vaccine, are not secreted in breast milk; therefore, breast-feeding is not a contraindication for live-virus or other vaccines. Pregnancy is not a contraindication to administration of inactivated vaccines, but most are avoided during pregnancy because relevant safety data are limited. Two inactivated vaccines, Tdap vaccine and inactivated influenza vaccine, are routinely recommended for pregnant women in the United States. Tdap vaccine is recommended during each pregnancy, regardless of prior vaccination status, in order to prevent pertussis in neonates. Annual influenza vaccination is recommended for all persons 6 months of age and older, regardless of pregnancy status. Some other vaccines, such as meningococcal vaccines, may be given


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InternalMed_Harrison. in neonates. Annual influenza vaccination is recommended for all persons 6 months of age and older, regardless of pregnancy status. Some other vaccines, such as meningococcal vaccines, may be given to pregnant women in certain circumstances.


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InternalMed_Harrison. immunosuppression Live-virus vaccines elicit an immune response due to replication of the attenuated (weakened) vaccine virus that is contained by the recipient’s immune system. In persons with compromised immune function, enhanced replication of vaccine viruses is possible and could lead to disseminated infection with the vaccine virus. For this reason, live-virus vaccines are contraindicated for persons with severe immunosuppression, the definition of which may vary with the vaccine. Severe immunosuppression may be caused by many disease conditions, including HIV infection and hematologic or generalized malignancy. In some of these conditions, all affected persons are severely immunocompromised. In others (e.g., HIV infection), the degree to which the immune system is compromised depends on the severity of the condition, which in turn depends on the stage of disease or treatment. For example, measles-mumps-rubella (MMR) vaccine may be given to HIV-infected persons who are not


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InternalMed_Harrison. depends on the severity of the condition, which in turn depends on the stage of disease or treatment. For example, measles-mumps-rubella (MMR) vaccine may be given to HIV-infected persons who are not severely immunocompromised. Severe immunosuppression may also be due to therapy with immunosuppressive agents, including high-dose glucocorticoids. In this situation, the dose, duration, and route of administration may influence the degree of immunosuppression.


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InternalMed_Harrison. A VIS is a one-page (two-sided) information sheet produced by the CDC that informs vaccine recipients (or their parents or legal representatives) about the benefits and risks of a vaccine. VISs are mandated by the National Childhood Vaccine Injury Act (NCVIA) of 1986 and— whether the vaccine recipient is a child or an adult—must be provided for any vaccine covered by the Vaccine Injury Compensation Program. As of July 2011, vaccines that are covered by the NCVIA and that are licensed for use in adults include Td, Tdap, hepatitis A, hepatitis B, HPV, trivalent inactivated influenza, trivalent live intranasal influenza, MMR, 13-valent pneumococcal conjugate, meningococcal, polio, and varicella vaccines. When combination vaccines for which no separate VIS exists are given (e.g., hepatitis A and B combination vaccine), all relevant VISs should be provided. VISs also exist for some vaccines not covered by the NCVIA, such as pneumococcal polysaccharide, Japanese encephalitis, rabies,


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InternalMed_Harrison. A and B combination vaccine), all relevant VISs should be provided. VISs also exist for some vaccines not covered by the NCVIA, such as pneumococcal polysaccharide, Japanese encephalitis, rabies, zoster, typhoid, and yellow fever vaccines. The use of these VISs is encouraged but is not mandated.


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InternalMed_Harrison. All current VISs are available on the Internet at two websites: the CDC’s Vaccines & Immunizations site (www.cdc.gov/vaccines/hcp/vis/) and the Immunization Action Coalition’s site (www.immunize.org/vis/). (The latter site also includes translations of the VISs.) VISs from these sites can be downloaded and printed.


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InternalMed_Harrison. Injectable vaccines are packaged in multidose vials, single-dose vials, or manufacturer-filled single-dose syringes. The live attenuated nasal-spray influenza vaccine is packaged in single-dose sprayers. Oral typhoid vaccine is packaged in capsules. Some vaccines, such as MMR, varicella, zoster, and meningococcal polysaccharide vaccines, come as lyophilized (freeze-dried) powders that must be reconstituted (i.e., mixed with a liquid diluent) before use. The lyophilized powder and the diluent come in separate vials. Diluents are not interchangeable but rather are specifically formulated for each type of vaccine; only the specific diluent provided by the manufacturer for each type of vaccine should be used. Once lyophilized vaccines have been reconstituted, their shelf-life is limited and they must be stored under appropriate temperature and light conditions. For example, varicella and zoster vaccines must be protected from light and administered within 30 min of reconstitution; MMR


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InternalMed_Harrison. they must be stored under appropriate temperature and light conditions. For example, varicella and zoster vaccines must be protected from light and administered within 30 min of reconstitution; MMR vaccine likewise must be protected from light but can be used up to 8 h after reconstitution. Single-dose vials of meningococcal polysaccharide vaccine must be used within 30 min of reconstitution, while multidose vials must be used within 35 days.


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InternalMed_Harrison. Vaccines are stored either at refrigerator temperature (2–8°C) or at freezer temperature (–15°C or colder). In general, inactivated vaccines (e.g., inactivated influenza, pneumococcal polysaccharide, and meningococcal conjugate vaccines) are stored at refrigerator temperature, while vials of lyophilized-powder live-virus vaccines (e.g., varicella, zoster, and MMR vaccines) are stored at freezer temperature. Diluents for lyophilized vaccines may be stored at refrigerator or room temperature. Live attenuated influenza vaccine—a live-virus liquid formulation administered by nasal spray—is stored at refrigerator temperature.


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InternalMed_Harrison. Vaccine storage and handling errors can result in the loss of vaccines worth millions of dollars, and administration of improperly stored vaccines may elicit inadequate immune responses in patients. To improve the standard of vaccine storage and handling practices, the CDC has published detailed guidance (available at www.cdc.gov/vaccines/recs/ storage/toolkit/storage-handling-toolkit.pdf). For vaccine storage, the CDC recommends stand-alone units—i.e., self-contained units that either refrigerate or freeze but do not do both—as these units maintain the required temperatures better than combination refrigerator/freezer units. Dormitory-style combined refrigerator/freezer units should never be used for vaccine storage.


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InternalMed_Harrison. The temperature of refrigerators and freezers used for vaccine storage must be monitored and the temperature recorded at least twice each workday. Ideally, continuous thermometers that measure and record temperature all day and all night are used, and minimum and maximum temperatures are read and documented each workday. The CDC recommends the use of calibrated digital thermometers with a probe in a glycol-filled bottle; more detailed information on specifications of storage units and temperature-monitoring devices is provided at the link given above.


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InternalMed_Harrison. Most parenteral vaccines recommended for routine administration to adults in the United States are given by either the IM or the SC route; one influenza vaccine formulation approved for use in adults 18–64 years of age is given intradermally. Live-virus vaccines such as varicella, zoster, and MMR are given SC. Most inactivated vaccines are given IM, except for meningococcal polysaccharide vaccine, which is given SC. The 23-valent pneumococcal polysaccharide vaccine may be given either IM or SC, but IM administration is preferred because it is associated with a lower risk of injection-site reactions.


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InternalMed_Harrison. Vaccines given to adults by the SC route are administered with a 5/8-inch needle into the upper outer-triceps area. Vaccines administered to adults by the IM route are injected into the deltoid muscle (Fig. 148-2) with a needle whose length should be selected on the basis of the recipient’s sex and weight to ensure adequate penetration into the muscle. Current guidelines indicate that, for men and women weighing <152 lbs (<70 kg), a 1-inch needle is sufficient; for women weighing 152–200 lbs (70–90 kg) and men weighing 152–260 lbs (70–118 kg), a 1to 1.5-inch needle is needed; and for women weighing >200 lbs (>90 kg) and men weighing >260 lbs (>118 kg), a 1.5-inch needle is required. Additional illustrations of vaccine injection locations and techniques may be found at www.immunize.org/ catg.d/p2020a.pdf.


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InternalMed_Harrison. FIGURE 148-2 Technique for IM administration of vaccine. (Photo credit: James Gathany, Centers for Disease Control and Prevention; acces-sible at Public Health Image Library, www.cdc.gov. PHIL ID#9420.) Aspiration, the process of pulling back on the plunger of the syringe after skin penetration but prior to injection, is not necessary because no large blood vessels are present at the recommended vaccine injection sites.


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InternalMed_Harrison. Multiple vaccines can be administered at the same visit; indeed, administration of all needed vaccines at one visit is encouraged. Studies have shown that vaccines are as effective when administered simultaneously as they are individually, and simultaneous administration of multiple vaccines is not associated with an increased risk of adverse effects. If more than one vaccine must be administered in the same limb, the injection sites should be separated by 1–2 inches so that any local reactions can be differentiated. If a vaccine and an immune globulin preparation are administered simultaneously (e.g., Td vaccine and tetanus immune globulin), a separate anatomic site should be used for each injection.


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InternalMed_Harrison. For certain vaccines (e.g., HPV vaccine and hepatitis B vaccine), multiple doses are required for an adequate and persistent antibody response. The recommended vaccination schedule specifies the interval between doses. Many adults who receive the first dose in a multiple-dose vaccine series do not complete the series or do not receive subsequent doses within the recommended interval. For example, at least one-third of adults who receive the first dose of hepatitis B vaccine in the three-dose series do not complete the series. In these circumstances, vaccine efficacy and/or the duration of protection may be compromised. Providers should implement recall systems that will prompt patients to return for subsequent doses in a vaccination series at the appropriate intervals. With the exception of oral typhoid vaccination, an interruption in the schedule does not require restarting of the entire series or the addition of extra doses.


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InternalMed_Harrison. Syncope may follow vaccination, especially in adolescents and young adults. Serious injuries, including skull fracture and cerebral hemorrhage, have occurred. Adolescents and adults should be seated or lying down during vaccination. The majority of reported syncope episodes after vaccination occur within 15 min. The ACIP recommends that vaccine providers strongly consider observing patients, particularly adolescents, with patients seated or lying down for 15 min after vaccination. If syncope develops, patients should be observed until the symptoms resolve. 792 Anaphylaxis is a rare complication of vaccination. All facilities providing immunizations should have an emergency kit containing aqueous epinephrine for administration in the event of a systemic anaphylactic reaction.


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InternalMed_Harrison. All vaccines administered should be fully documented in the patient’s permanent medical record. Documentation should include the date of administration, the name or common abbreviation of the vaccine, the vaccine lot number and manufacturer, the administration site, the VIS edition, the date the VIS was provided, and the name, address, and title of the person who administered the vaccine. Increasing use of two-dimensional bar codes on vaccine vials and syringes that can be scanned for data entry into compatible electronic medical records and immunization information systems may facilitate more complete and accurate recording of required information.


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InternalMed_Harrison. VACCINE SAFETY MONITORING AND ADVERSE EVENT REPORTING Prelicensure Evaluations of Vaccine Safety Before vaccines are licensed by the FDA, they are evaluated in clinical trials with volunteers. These trials are conducted in three progressive phases. Phase 1 trials are small, usually involving fewer than 100 volunteers. Their purposes are to provide a basic evaluation of safety and to identify common adverse events. Phase 2 trials, which are larger and may involve several hundred participants, collect additional information on safety and are usually designed to evaluate immunogenicity as well. Data gained from phase 2 trials can be used to determine the composition of the vaccine, the number of doses required, and a profile of common adverse events. Vaccines that appear promising are evaluated in phase 3 trials, which typically involve several hundred to several thousand volunteers and are generally designed to demonstrate vaccine efficacy and provide additional information on vaccine


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InternalMed_Harrison. in phase 3 trials, which typically involve several hundred to several thousand volunteers and are generally designed to demonstrate vaccine efficacy and provide additional information on vaccine safety.


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InternalMed_Harrison. Postlicensure Monitoring of Vaccine Safety After licensure, a vaccine’s safety is assessed by several mechanisms. The NCVIA of 1986 requires health care providers to report certain adverse events that follow vaccination. As a mechanism for that reporting, the Vaccine Adverse Event Reporting System (VAERS) was established in 1990 and is jointly managed by the CDC and the FDA. This safety surveillance system collects reports of adverse events associated with vaccines currently licensed in the United States. Adverse events are defined as untoward events that occur after immunization and that might be caused by the vaccine product or vaccination process. While the VAERS was established in response to the NCVIA, any adverse event following vaccination— whether in a child or an adult, and whether or not it is believed to have actually been caused by vaccination—may be reported through the VAERS. The adverse events that health care providers are required to report are listed in the


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InternalMed_Harrison. and whether or not it is believed to have actually been caused by vaccination—may be reported through the VAERS. The adverse events that health care providers are required to report are listed in the reportable-events table on the VAERS website at vaers.hhs.gov/reportable.htm. Approximately 30,000 VAERS reports are filed annually, with ~13% reporting serious events resulting in hospitalization, life-threatening illness, disability, or death.


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InternalMed_Harrison. Anyone can file a VAERS report, including health care providers, manufacturers, and vaccine recipients or their parents or guardians. VAERS reports may be submitted online (vaers.hhs.gov/esub/step1) or by completing a paper form requested by email (info@vaers.org), phone (800-822-7967), or fax (877-721-0366). The VAERS form asks for the following information: the type of vaccine received; the timing of vaccination; the time of onset of the adverse event; and the recipient’s current illnesses or medications, history of adverse events following vaccination, and demographic characteristics (e.g., age and sex). This information is entered into a database. The individual who reported the adverse event then receives a confirmation letter by mail with a VAERS identification number that can be used if additional information is submitted later. In selected cases of serious adverse reaction, the patient’s recovery status may be followed up at 60 days and 1 year after vaccination. The FDA and


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InternalMed_Harrison. used if additional information is submitted later. In selected cases of serious adverse reaction, the patient’s recovery status may be followed up at 60 days and 1 year after vaccination. The FDA and the CDC have access to VAERS data and use this information to monitor vaccine safety and conduct research studies. VAERS data (minus personal information) are also available to the public.


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InternalMed_Harrison. While the VAERS provides useful information on vaccine safety, this passive reporting system has important limitations. One is that events following vaccination are merely reported; the system cannot assess whether a given type of event occurs more often than expected after vaccination. A second is that event reporting is incomplete and is biased toward events that are believed to be more likely to be due to vaccination and that occur relatively soon after vaccination. To obtain more systematic information on adverse events occurring in both vaccinated and unvaccinated persons, the Vaccine Safety Datalink project was initiated in 1991. Directed by the CDC, this project includes nine managed-care organizations in the United States; member databases include information on immunizations, medical conditions, demographics, laboratory results, and medication prescriptions. The Department of Defense oversees a similar system monitoring the safety of immunizations among active-duty military


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InternalMed_Harrison. conditions, demographics, laboratory results, and medication prescriptions. The Department of Defense oversees a similar system monitoring the safety of immunizations among active-duty military personnel. In addition, postlicensure evaluations of vaccine safety may be conducted by the vaccine manufacturer. In fact, such evaluations are often required by the FDA as a condition of vaccine licensure.


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InternalMed_Harrison. By removing barriers to the consumer or patient, providers and health care institutions can improve vaccine use. Financial barriers have traditionally been important constraints, particularly among uninsured adults. Even for insured adults, out-of-pocket costs associated with newer, more expensive adult vaccines (e.g., zoster vaccine) are an obstacle to be overcome. After influenza vaccine was included by Medicare for all beneficiaries in 1993, coverage among persons ≥65 years of age doubled (from ~30% in 1989 to >60% in 1997). Other strategies that enhance patients’ access to vaccination include extended office hours (e.g., evening and weekend hours) and scheduled vaccination-only clinics where waiting times are reduced. Provision of vaccines outside the “medical home” (e.g., through occupational clinics, universities, pharmacies, and retail settings) can expand access for adults who do not make medical visits frequently. Increasing proportions of adults are being vaccinated in these


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InternalMed_Harrison. clinics, universities, pharmacies, and retail settings) can expand access for adults who do not make medical visits frequently. Increasing proportions of adults are being vaccinated in these settings.


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InternalMed_Harrison. Health promotion efforts aimed at increasing the demand for immunization are common. Direct-to-consumer advertising by pharmaceutical companies has been used for some newer adolescent and adult vaccines. Efforts to raise consumer demand for vaccines have not increased immunization rates unless implemented in conjunction with other strategies that target strengthening of provider practices or reduction of consumer barriers. Attitudes and beliefs related to vaccination can be considerable impediments to consumer demand. Many adults view vaccines as important for children but are less familiar with vaccinations targeting disease prevention in adults. Several vaccines are recommended for adults with certain medical risk factors, but self-identification as a high-risk individual is relatively rare. Communication research suggests that many adults with chronic diseases may be more motivated to receive a vaccine by a desire to protect their family members rather than to reduce their own


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InternalMed_Harrison. rare. Communication research suggests that many adults with chronic diseases may be more motivated to receive a vaccine by a desire to protect their family members rather than to reduce their own risk. Some vaccines are explicitly recommended for persons at relatively low risk of serious complications, with the goal of reducing the risk of transmission to higher-risk contacts. For example, for protection of newborns, vaccinations against influenza and pertussis are recommended for pregnant women and for others who will be around the infant.


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InternalMed_Harrison. STRATEGIES FOR PROVIDERS AND HEALTH CARE FACILITIES Recommendation from the Provider Health care providers can have great influence on patients with regard to immunization. A recommendation from a doctor or nurse carries more weight than do recommendations from professional societies or endorsements by celebrities. Providers should be well informed about vaccine risks and benefits so that they can address patients’ common concerns. The CDC, the American College of Physicians, and the American Academy of Family Physicians review and update the schedule for adult immunization on an annual basis and also have developed educational materials to facilitate provider–patient discussions about vaccination (www.cdc .gov/vaccines/hcp.htm).


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InternalMed_Harrison. System Supports Medical offices can incorporate a variety of methods to ensure that providers consistently offer specific immunizations to patients with indications for specific vaccines. Decision-support tools have been incorporated into some electronic health records to alert the provider when specific vaccines are indicated. Manual or automated reminders and standing orders have been discussed (see “Deciding Whom to Vaccinate,” above) and have consistently improved vaccination coverage in both office and hospital settings. Most clinicians’ estimates of their own performance diverge from objective measurements of their patients’ immunization coverage; quantitative assessment and feedback have been shown in pediatric and adolescent practices to increase immunization performance significantly. Some health plans have instituted incentives for providers with high rates of immunization coverage. Specialty providers, including obstetrician–gynecologists, may be the only providers serving


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InternalMed_Harrison. Some health plans have instituted incentives for providers with high rates of immunization coverage. Specialty providers, including obstetrician–gynecologists, may be the only providers serving some high-risk patients with indications for selected vaccines (e.g., Tdap, influenza, or pneumococcal polysaccharide vaccine).


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InternalMed_Harrison. Immunization Requirements Vaccination against selected communicable diseases is required for attendance at many universities and colleges as well as for service in the U.S. military or in some occupational settings (e.g., child care, laboratory, veterinary, and health care). Immunizations are recommended and sometimes required for travel to certain countries (Chap. 149).


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InternalMed_Harrison. Vaccination of Health Care Staff A particular area of focus for medical settings is vaccination of health care workers, including those with and without direct patient-care responsibilities. The Joint Commission (which accredits health care organizations), the CDC’s Healthcare Infection Control Practices Advisory Committee, and the ACIP all recommend influenza vaccination of all health care personnel; recommendations also focus on requiring documentation of declination for providers who do not accept annual influenza vaccination. As part of their participation in the Centers for Medicare and Medicaid Services’ Hospital Inpatient Quality Reporting program, acute-care hospitals are required to report the proportion of their health care personnel who have received seasonal influenza vaccine. Some institutions and jurisdictions have added mandates on influenza vaccination of health care workers and have expanded on earlier requirements related to vaccination or proof of immunity for


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InternalMed_Harrison. Some institutions and jurisdictions have added mandates on influenza vaccination of health care workers and have expanded on earlier requirements related to vaccination or proof of immunity for hepatitis B, measles, mumps, rubella, and varicella.


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InternalMed_Harrison. Receipt of vaccination in medical offices is most frequent among young children and adults ≥65 years of age. People in these age groups make more office visits and are more likely to receive care in a consistent “medical home” than are older children, adolescents, and nonelderly adults. Vaccination outside the medical home can expand access to those whose health care visits are limited and reduce the burden on busy clinical practices. In some locations, financial constraints related to inventory and storage requirements have led providers to stock few or no vaccines. Outside private office and hospital settings, vaccination may also occur at health department venues, workplaces, retail sites (including pharmacies and supermarkets), and schools or colleges.


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InternalMed_Harrison. When vaccines are given in nonmedical settings, it remains important for standards of immunization practice to be followed. Consumers should be provided with information on how to report adverse events (e.g., via provision of a VIS), and procedures should ensure that documentation of vaccine administration is forwarded to the primary care provider and the state or city public health immunization registry. Detailed documentation may be required for employment, school attendance, and travel. Personalized health records can help consumers keep track of their immunizations, and some occupational health clinics have incorporated automated immunization reports that help employees stay up-to-date with recommended vaccinations. Some pharmacy chain establishments are using automated systems to report immunization information to the state or local immunization information system.


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InternalMed_Harrison. Tracking of immunization coverage at national, state, institution, and practice levels can yield feedback to practitioners and programs and facilitate quality improvement. Healthcare Effectiveness Data 793 and Information Set (HEDIS) measures related to adult immunization facilitate comparison of health plans. The CDC’s National Immunization Survey and National Health Interview Survey provide selected information on immunization coverage among adults and track progress toward achievement of Healthy People 2020 targets for immunization coverage. Influenza and pneumococcal vaccine coverage rates have been higher among persons ≥65 years of age (60–70%) than among high-risk 18to 64-year-olds. Figures on state-specific immunization coverage with pneumococcal polysaccharide and influenza vaccines (as measured through the CDC’s Behavioral Risk Factor Surveillance System) reveal substantial geographic variation in coverage. There are persistent disparities in adult immunization coverage rates


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InternalMed_Harrison. (as measured through the CDC’s Behavioral Risk Factor Surveillance System) reveal substantial geographic variation in coverage. There are persistent disparities in adult immunization coverage rates between whites and racial and ethnic minorities. In contrast, racial and economic disparities in immunization of young children have been dramatically reduced during the past 20 years. Much of this progress is attributed to the Vaccines for Children Program, which since 1994 has entitled uninsured children to receive free vaccines.


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InternalMed_Harrison. Although most vaccines developed in the twentieth century targeted common acute infectious diseases of childhood, more recently developed vaccines prevent chronic conditions prevalent among adults. Hepatitis B vaccine prevents hepatitis B–related cirrhosis and hepatocellular carcinoma, zoster vaccine prevents shingles and postherpetic neuralgia, and HPV vaccine prevents some types of cervical cancer, genital warts, and anogenital cancers and may also prevent some oropharyngeal cancers (although this outcome was not studied in prelicensure randomized controlled trials). New targets of vaccine development and research may further broaden the definition of vaccine-preventable disease. Research is ongoing on vaccines to prevent insulin-dependent diabetes mellitus, nicotine addiction, and Alzheimer’s disease. Expanding strategies for vaccine development are incorporating molecular approaches such as DNA, vector, and peptide vaccines. New technologies, such as the use of transdermal and


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InternalMed_Harrison. disease. Expanding strategies for vaccine development are incorporating molecular approaches such as DNA, vector, and peptide vaccines. New technologies, such as the use of transdermal and other needle-less routes of administration, are being applied to vaccine delivery.


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Jay S. Keystone, Phyllis E. Kozarsky

InternalMed_Harrison. Jay S. Keystone, Phyllis E. Kozarsky


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InternalMed_Harrison. According to the World Tourism Organization, international tourist arrivals grew dramatically from 25 million in 1950 to >1 billion in 2012. Not only are more people traveling; travelers are seeking more exotic and remote destinations. Travel from industrialized to developing regions has been increasing, with Asia and the Pacific, Africa, and the Middle East now emerging destinations. Figure 149-1 summarizes the monthly incidence of health problems during travel in developing countries. Studies continue to show that 50–75% of short-term travelers to the tropics or subtropics report some health impairment. Most of these health problems are minor: only 5% require medical attention, and <1% require hospitalization. Although infectious agents contribute substantially to morbidity among travelers, these pathogens account for only ~1% of deaths in this population. Cardiovascular disease and injuries are the most frequent causes of death among travelers from the United States, accounting for


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InternalMed_Harrison. these pathogens account for only ~1% of deaths in this population. Cardiovascular disease and injuries are the most frequent causes of death among travelers from the United States, accounting for 49% and 22% of deaths, respectively. Age-specific rates of death due to cardiovascular disease are similar among travelers and nontravelers. In contrast, rates of death due to injury (the majority from 794 10.001% 0.0001% 0.01% 0.1% Cholera Meningococcal disease Typhoid (other areas) Legionella infection Typhoid (India, northern/ northwestern Africa, Peru) HIV infection Hepatitis B (expatriates) Hepatitis A Gonorrhea Animal bites with rabies risk Dengue infection (Southeast Asia) Acute febrile respiratory tract infection Malaria (no chemoprophylaxis, West Africa) Travelers’ diarrhea ETEC diarrhea 10% 100% 30–80% 100,000 10,000 10 100 1% 1,000 recommended (immunizations that are desirable because of travel-related risks).


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InternalMed_Harrison. Any health problem: used medication or felt ill Felt subjectively ill commonly given to travelers are listed in Table 149-1. Consulted MD abroad or back home Routine Immunizations • dipHtHeria, teta- Stayed in bed nus, and polio Diphtheria (Chap. 175) continues to be a problem worldwide. Large outbreaks have occurred in countries that do not have rigorous vaccination programs or that have reduced their public vaccination programs. Serologic Incapacity to work after return surveys show that tetanus (Chap. 177) antibodies are lacking in many North Americans, especially in women over the age of 50. The risk of polio (Chap. 228) to the international traveler is extremely low, and wild-type poliovirus Died in high-altitude trekking has been eradicated from the Western Hemisphere and Europe. However, studies in the United States suggest that 12% of adult travelers are unprotected against at least one poliovirus serogroup. In addition, challenges continue to be faced


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InternalMed_Harrison. Died abroad (average) by polio eradication programs. Foreign travel offers an ideal opportunity to have these immunizations updated. With the recent increase in pertussis among adults, the diphtheria–tetanus–acellular pertussis (Tdap) combination is now recommended for adults as a once-only replacement for the 10-year tetanus–diphtheria FIGURE 149-1 Monthly incidence rates of health problems during stays in developing countries. (Td) booster.


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InternalMed_Harrison. FIGURE 149-1 Monthly incidence rates of health problems during stays in developing countries. (Td) booster. ETEC, enterotoxigenic Escherichia coli. (From R Steffen et al: Int J Antimicrob Agents 21:89, 2003.) measles Measles (rubeola) continues to be a major cause of morbidity and death motor vehicle, drowning, or aircraft accidents) are several times higher in the developing world (Chap. 229). Several outbreaks of measles among travelers. Motor vehicle accidents account for >40% of travelers’ in the United States and Canada have been linked to imported cases, deaths that are not due to cardiovascular disease or preexisting illness. especially from Europe, where large outbreaks have occurred recently. The group at highest risk consists of persons born after 1956 and vac-GENERAL ADVICE cinated before 1980, in many of whom primary vaccination failed. The measles–mumps–rubella (MMR) vaccine is typically used; its coverage


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InternalMed_Harrison. Health maintenance recommendations are based not only on the travof rubella also addresses a growing concern in some areas of Eastern eler’s destination but also on assessment of risk, which is determined Europe and Asia. by such variables as health status, specific itinerary, purpose of travel, season, and lifestyle during travel. Detailed information regarding influenza Influenza (Chap. 224)—possibly the most common vaccinecountry-specific risks and recommendations may be obtained from the preventable infection in travelers—occurs year-round in the tropicsCenters for Disease Control and Prevention (CDC) publication Health and during the summer months in the Southern Hemisphere (coin-Information for International Travel (available at www.cdc.gov/travel).


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InternalMed_Harrison. ciding with the winter months in the Northern Hemisphere). OneFitness for travel is an issue of growing concern in view of the prospective study showed that influenza developed in 1% of travelersincreased numbers of elderly and chronically ill individuals journeying to Southeast Asia per month of stay. Annual vaccination should beto exotic destinations (see “Travel and Special Hosts,” below). Since considered for all travelers who do not have a contraindication. Travel-most commercial aircraft are pressurized to 2500 m (8000 ft) above related influenza continues to occur during summer months in Alaska sea level (corresponding to a Pa02 of ~55 mmHg), individuals with seri-and the Northwest Territories of Canada among cruise-ship passenous cardiopulmonary problems or anemia should be evaluated before gers and staff. The speed of global spread of the pandemic H1N1 virustravel. In addition, those who have recently had surgery, a myocardial once again illustrates why influenza immunization


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InternalMed_Harrison. before gers and staff. The speed of global spread of the pandemic H1N1 virustravel. In addition, those who have recently had surgery, a myocardial once again illustrates why influenza immunization is so important forinfarction, a cerebrovascular accident, or a deep-vein thrombosis may travelers. be at high risk for adverse events during flight. A summary of current recommendations regarding fitness to fly has been published by the pneumococcal infection Regardless of travel, pneumococcal vaccine Aerospace Medical Association Air Transport Medicine Committee (Chap. 171) should be administered routinely to persons over the age (www.asma.org/publications/medical-publications-for-airline-travel). of 65 and to persons at high risk of serious infection, including those A pretravel health assessment may be advisable for individuals consid-with chronic heart, lung, or kidney disease; those who have been spleering particularly adventurous recreational activities, such as moun-nectomized; and


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InternalMed_Harrison. may be advisable for individuals consid-with chronic heart, lung, or kidney disease; those who have been spleering particularly adventurous recreational activities, such as moun-nectomized; and those who have sickle cell disease. tain climbing and scuba diving.


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InternalMed_Harrison. Required Immunizations • yellow fever Documentation of vaccina-IMMUNIZATIONS FOR TRAVEL tion against yellow fever (Chap. 233) may be required or recom-Immunizations for travel fall into three broad categories: mended as a condition for entry into or passage through countries of routine (childhood/adult boosters that are necessary regardless of sub-Saharan Africa and equatorial South America, where the disease travel), required (immunizations that are mandated by international is endemic or epidemic, or (by the International Health Regulations) regulations for entry into certain areas or for border crossings), and for entry into countries at risk of having the infection introduced. This aCross-protects against enterotoxigenic Escherichia coli and provides 30–50% protection against travelers’ diarrhea.


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InternalMed_Harrison. vaccine is given only by state-authorized yellow fever centers, and its administration must be documented on an official International Certificate of Vaccination. A registry of U.S. clinics that provide the vaccine is available from the CDC (www.cdc.gov/travel). Recent data suggest that fewer than 50% of travelers entering areas endemic for yellow fever are immunized; this lack of coverage is a serious problem, as 13 countries in Central and South America and 30 countries in Africa harbor the illness. Severe adverse events associated with this vaccine have recently increased in incidence. First-time vaccine recipients may present with a syndrome characterized as either neurotropic (1 case per 125,000 doses) or viscerotropic (overall, 1 case per 250,000 doses; among persons 60–69 years of age, 1 case per 100,000 doses; and among persons ≥ 70 years of age, 1 case per 40,000 doses). Immunosuppression and thymic disease increase the risk of these adverse events


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InternalMed_Harrison. persons 60–69 years of age, 1 case per 100,000 doses; and among persons ≥ 70 years of age, 1 case per 40,000 doses). Immunosuppression and thymic disease increase the risk of these adverse events (www.cdc.gov/vaccines/hcp/vis/vis-statements/yf.pdf).


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InternalMed_Harrison. meningococcal meningitis Protection against meningitis with one of the quadrivalent (preferably conjugate) vaccines is required for entry into Saudi Arabia during the Hajj (Chap. 180). influenza Both seasonal and pandemic H1N1 vaccines (the latter, where available) were required for entry into Saudi Arabia during the Hajj in 2013.


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InternalMed_Harrison. influenza Both seasonal and pandemic H1N1 vaccines (the latter, where available) were required for entry into Saudi Arabia during the Hajj in 2013. Recommended Immunizations • Hepatitis a and b Hepatitis A (Chap. 795 360) is one of the most common vaccine-preventable infections of travelers. The risk is six times greater for travelers who stray from the usual tourist routes. The mortality rate for hepatitis A increases with age, reaching almost 2% among individuals over age 50. Of the four hepatitis A vaccines currently available in North America (two in the United States), all are interchangeable and have an efficacy of >95%. Hepatitis A vaccine is currently given to all children in the United States. Since the most frequently identified risk factor for hepatitis A in the United States is international travel, and since morbidity and mortality increase with age, it seems appropriate that all adults be immune prior to travel.


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InternalMed_Harrison. Long-stay overseas workers appear to be at considerable risk for hepatitis B infection (Chap. 360). The recommendation that all travelers be immunized against hepatitis B before departure is supported by two studies showing that 17% of the assessed travelers who received health care abroad had some type of injection; according to the World Health Organization, nonsterile equipment is used for up to 75% of all injections given in parts of the developing world. A 3-week accelerated schedule of the combined hepatitis A and B vaccine has been approved in the United States. Although no data are available on the specific risk of infection with hepatitis B virus among U.S. travelers, ~240 million people in the world have chronic infection. All children and adolescents in the United States are immunized against this illness. Hepatitis B vaccination should be considered for all travelers.


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InternalMed_Harrison. typHoid fever Most cases of typhoid fever in North America are due to travel, with ~300 cases seen per year in the United States. The attack rate for typhoid fever (Chap. 190) is 1 case per 30,000 travelers per month of travel to the developing world. However, attack rates in India, Senegal, and North Africa are tenfold higher; rates are especially high among travelers to relatively remote destinations and among immigrants and their families who have returned to their homelands to visit friends or relatives (VFRs). Between 1999 and 2006 in the United States, 66% of imported cases involved the latter group. Unfortunately, data show that the causative organism has become increasingly resistant to fluoroquinolone antibiotics (especially in those cases acquired on the Indian subcontinent). Both of the available vaccines—one oral (live) and the other injectable (polysaccharide)— have efficacy rates of ~70%. In some countries, a combined hepatitis A/typhoid vaccine is available.


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InternalMed_Harrison. meningococcal meningitis Although the risk of meningococcal disease among travelers has not been quantified, it is likely to be higher among travelers who live with poor indigenous populations in overcrowded conditions (Chap. 180). Because of its enhanced ability to prevent nasal carriage (compared with the older polysaccharide vaccine), a quadrivalent conjugate vaccine is the product of choice (regardless of age) for immunization of persons traveling to sub-Saharan Africa during the dry season or to areas of the world where there are epidemics. The vaccine, which protects against serogroups A, C, Y, and W-135, has an efficacy rate of >90%.


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InternalMed_Harrison. Japanese encepHalitis The risk of Japanese encephalitis (Chap. 233), an infection transmitted by mosquitoes in rural Asia and Southeast Asia, can be as high as ~1 case per 5000 travelers per month of stay in an endemic area. Most infections are asymptomatic, with a very small proportion of infected persons becoming ill. However, among those who do become ill, severe neurologic sequelae are common. Most symptomatic infections among U.S. residents have involved military personnel or their families. The vaccine efficacy rate is >90%. The vaccine is recommended for persons staying >1 month in rural endemic areas or for shorter periods if their activities (e.g., camping, bicycling, hiking) in these areas will increase exposure risk.


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InternalMed_Harrison. cHolera The risk of cholera (Chap. 193) is extremely low, with ~1 case per 500,000 journeys to endemic areas. Cholera vaccine, not currently available in the United States, was rarely recommended but was considered for aid and health care workers in refugee camps or in disaster-stricken/war-torn areas. A more effective oral cholera vaccine is available in other countries.