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InternalMed_Harrison. The burden of HPV-related cancers is expected to increase in HIV-infected patients, given the prolonged life expectancies made possible by ART. For women living in developing countries where cervical cancer screening is not widely available, this situation may have significant consequences. Thus, elucidating the interactions of HIV infection and cervical cancer with cofactors such as diet, other sexually transmitted infections, and environmental exposures is a research focus with potentially enormous implications for women living in lowand middle-income countries.


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InternalMed_Harrison. Similar to that of cervical cancer, the incidence of anal cancer is strongly influenced by HIV infection. HIV-infected men who have sex with men (MSM) and HIV-infected women have much higher rates of anal cancer than HIV-uninfected populations. Specifically, the incidence has been found to be as high as 130 cases/100,000 among HIV-positive MSM as opposed to only 5 cases/100,000 among HIV-negative MSM. The advent of ART has not impacted the incidence of anal cancer and high-grade anal intraepithelial neoplasia in the HIV-infected population. More information on screening, prevention, and treatment in the HIV-infected population can be found at the Department of Health and Human Services website (aidsinfo.nih.gov/guidelines).


InternalMed_Harrison

InternalMed_Harrison. HPV infects the female vulva, vagina, and cervix and the male urethra, penis, and scrotum. Perianal, anal, and oropharyngeal infections occur in both genders. Figures 222-1, 222-2, and 222-3 show vulvar, penile, and perianal warts, respectively. Genital warts are caused primarily by HPV-6 or HPV-11; their surface is either smooth or rough. Penile genital warts are usually 2–5 mm in diameter and often occur in groups. A second type of penile lesion, keratotic plaques, is slightly raised above the normal epithelium and has a rough, often pigmented surface. Vulvar warts are soft, whitish papules that either are sessile or have multiple fine, finger-like projections. These lesions are most often located in the introitus and on the labia. In nonmucosal areas, lesions are similar in appearance to those in men: dry and keratotic. Vulvar lesions can appear as smooth, sometimes pigmented papules that may coalesce. Vaginal lesions appear as multiple areas of elongated papillae. Biopsy of vulvar


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InternalMed_Harrison. those in men: dry and keratotic. Vulvar lesions can appear as smooth, sometimes pigmented papules that may coalesce. Vaginal lesions appear as multiple areas of elongated papillae. Biopsy of vulvar or vaginal lesions may reveal malignancy, which is not always reliably identified by clinical examination.


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InternalMed_Harrison. FIGuRE 222-1 Vulvar warts. (Downloaded from http://www2a.cdc .gov/stdtraining/ready-to-use/Manuals/HPV/hpv-slides-2013.pdf.) Subclinical cervical HPV infections are common, and the cervix may appear normal on examination. Cervical lesions often appear as papillary proliferations near the transformation zone. Irregular vascular loops are present beneath the surface epithelium. Patients who develop cervical cancer arising from HPV infection may present with a variety of symptoms. Early carcinomas appear eroded and bleed easily. More advanced carcinomas present as ulcerated lesions or as an exophytic cervical mass. Some cervical carcinomas are located in the cervical canal and may be difficult to see. Bleeding, symptoms of a mass lesion in late stages, and metastatic disease that may manifest as bowel or bladder obstruction due to direct extension of the tumor have also been described. FIGuRE 222-2 Condyloma acuminata of the shaft of the penis.


InternalMed_Harrison

InternalMed_Harrison. FIGuRE 222-2 Condyloma acuminata of the shaft of the penis. FIGuRE 222-3 Perianal warts. (Reprinted from K Wolff, RA Johnson, AP Saavedra: Fitzpatrick’s Color Atlas & Synopsis of Clinical Dermatology, 7th ed. New York, McGraw-Hill, 2013.) Patients with squamous cell cancer of the anus have more variable presentations. The most common presentations include rectal bleeding and pain or a mass sensation. Of patients who are diagnosed with anal cancer, 20% may present with no specific symptoms at the time of diagnosis; rather, the lesion is found fortuitously. PREVENTION OF HPV INFECTION: HPV VACCINES


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InternalMed_Harrison. PREVENTION OF HPV INFECTION: HPV VACCINES Vaccines effective in preventing HPV infection and HPV-associated disease represent a major development in the last decade. The vaccines use virus-like particles (VLPs) that consist of the HPV L1 major capsid protein. The L1 protein self-assembles into VLPs when expressed in eukaryotic cells (i.e., yeast for the Merck vaccine or insect cells for the GlaxoSmithKline vaccine; see below). These VLPs contain the same epitopes as the HPV virion. However, they do not contain genetic material and cannot transmit infection. The immunogenicity of HPV vaccines relies on the development of conformational neutralizing antibodies to epitopes displayed on viral capsids.


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InternalMed_Harrison. Several large trials have demonstrated the high degree of safety and efficacy of HPV vaccines. The evidence to date has shown high and sustained efficacy against disease caused by those HPV types represented in the vaccines (HPV-6, -11, -16, and -18 in the Merck vaccine and HPV-16 and -18 in the GlaxoSmithKline vaccine). However, no therapeutic effect against active infection or disease has been found for either vaccine.


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InternalMed_Harrison. Bivalent Vaccine (Cervarix) A bivalent L1 VLP vaccine (HPV-16 and -18), marketed under the name Cervarix (GlaxoSmithKline), is administered by IM injection at months 0, 1, and 6. This vaccine was tested in 18,644 women 15–25 years of age who were residing in the United States, South America, Europe, and Asia. The primary endpoints of the study included vaccine efficacy against persistent infections with HPV16 and -18. Investigators also assessed the vaccine’s efficacy against CIN of grade 2 or higher due to HPV-16 and -18 in women who had no evidence of infection with these HPV types at baseline; in these women, vaccine efficacy was 94.9% (95% confidence interval [CI], 87.7 to 98.4) against CIN ≥2 related to HPV-16 or HPV-18, 91.7% (95% CI, 66.6 to 99.1) against CIN ≥3, and 100% (95% CI, –8.6 to 100) against adenocarcinoma in situ.


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InternalMed_Harrison. Adverse events were evaluated in phase 3 trials in a subset of 3077 women who received the bivalent vaccine and 3080 women (controls) who received hepatitis A vaccine. Injection-site adverse events (pain, redness, and swelling) and systemic adverse events (fatigue, headache, and myalgia) were reported more frequently in the HPV vaccine group than in the control group. Serious adverse events (mainly injection-site reactions), new-onset chronic disease, or medically significant conditions occurred in 3.5% of HPV vaccine recipients and in 3.5% of women receiving the control vaccine. 1200 The bivalent vaccine is approved in the United States for prevention of cervical cancer, CIN ≥2, adenocarcinoma in situ, and CIN 1 caused by HPV-16 and -18. This vaccine is approved for administration to girls and women 9–25 years of age.


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InternalMed_Harrison. Quadrivalent Vaccine (Gardasil) A quadrivalent L1 VLP (HPV-6, -11, -16, and -18) vaccine, marketed under the name Gardasil (Merck), is administered IM at months 0, 2, and 6. A combined efficacy analysis based on data from four randomized double-blind clinical studies including more than 20,000 participants demonstrated that the vaccine’s efficacy against external genital warts was 98.9% (95% CI, 93.7 to 100). Its efficacy was 95.2% (95% CI, 87.2 to 98.7) in protecting against CIN, 100% (95% CI, 92.9 to 100) against HPV-16or HPV-18-related CIN 2/3 or adenocarcinoma in situ, and 100% (95% CI, 55.5 to 100.0) against HPV-16or HPV-18-related vulvar intraepithelial neoplasia grades 2 and 3 (VIN 2/3) and vaginal intraepithelial neoplasia grades 2 and 3 (VaIN 2/3).


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InternalMed_Harrison. Safety data on the quadrivalent HPV vaccine are available from seven clinical trials including nearly 12,000 girls and women 9–26 years of age who received the vaccine and ~10,000 who received placebo. A larger proportion of young women reported injection-site adverse events in the vaccine groups than in the aluminum-containing or saline placebo groups. Systemic adverse events were reported by similar proportions of vaccine and placebo recipients and were described as mild or moderate by most participants. The types of serious adverse events reported were similar for the two groups. Ten persons who received the quadrivalent vaccine and seven persons who received placebo died during the course of the trials; no deaths were considered to be vaccine related.


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InternalMed_Harrison. During the course of the quadrivalent vaccine trials, surveillance data on the development of new medical conditions were collected for up to 4 years after vaccination. No statistically significant differences in the incidence of any medical conditions between vaccine and placebo recipients were found; this result indicated a very good safety profile. A recent safety review by the U.S. Food and Drug Administration and the Centers for Disease Control and Prevention (CDC) examined events related to Gardasil that had been reported to the Vaccine Adverse Events Reporting System. Adverse events were consistent with those seen in previous safety studies of the vaccine. It is noteworthy that rates of syncope and venous thrombotic events were higher with Gardasil than those that have usually been documented for other vaccines.


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InternalMed_Harrison. The quadrivalent vaccine is approved for (1) vaccination of girls and women 9–26 years of age to prevent genital warts and cervical cancer caused by HPV-6, -11, -16, and -18; (2) vaccination of the same population to prevent precancerous or dysplastic lesions, including cervical adenocarcinoma in situ, CIN 2/3, VIN 2/3, VaIN 2/3, and CIN 1; (3) vaccination of boys and men 9–26 years of age to prevent genital warts caused by HPV-6 and -11; and (4) vaccination of individuals 9–26 years of age to prevent anal cancer and associated precancerous lesions due to HPV-6, -11, -16, and -18.


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InternalMed_Harrison. Cross-Protection of HPV Vaccines Women vaccinated with either of the available vaccines produce neutralizing antibodies against types related to HPV-16 or -18. Analyses of data from clinical trials suggest that both vaccines may offer cross-protection against nonvaccine types. The bivalent vaccine appears more efficacious against HPV-31, -33, and -45 than the quadrivalent vaccine, but differences in study design make direct comparisons difficult. In addition, vaccine efficacy against persistent infections with HPV-31 and -45 appeared to wane over time in the bivalent vaccine trials, whereas efficacy against persistent infection with HPV-16 or -18 remained stable.


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InternalMed_Harrison. Second-Generation Vaccines While HPV-16 and -18 cause the majority of cervical cancers worldwide, global data have shown that HPV-31, -33, -35, -45, -52, and -58 are the next most frequently detected types in invasive cervical cancers. Second-generation vaccines that are in development incorporate VLPs of additional oncogenic HPV types (other than HPV-16 and -18), including HPV-31, -33, -45, -52, and -58; efficacy studies are ongoing. If vaccines with these five additional oncogenic types prove to be effective, mathematical models estimate that the level of protection could be raised to 90% of all squamous cell cervical cancers worldwide.


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InternalMed_Harrison. Recommendations for Vaccination The CDC’s Advisory Committee for Immunization Practice recommends administration of the quadrivalent HPV vaccine—with the schedule used in the vaccine trials—to all boys and girls 11–12 years of age as well as to boys/men and girls/ women 13–26 years of age who have not previously been vaccinated or who have not completed the full series. For women, Papanicolaou (Pap) smear testing and screening for HPV DNA are not recommended before vaccination. After vaccination, Pap testing is recommended to detect disease caused by other oncogenic HPV types.


InternalMed_Harrison

InternalMed_Harrison. After HPV infection occurs, prevention of HPV-associated disease relies on screening. Women residing in developing countries who lack access to cervical screening programs have a higher rate of cervical cancer and a lower rate of cancer-specific survival. Approximately 75% of women living in developed countries have been screened in the past 5 years, whereas the figure is only ~5% among women living in developing countries. Economic and logistic obstacles likely impede routine screening of these populations for cervical cancer.


InternalMed_Harrison

InternalMed_Harrison. The primary method used for cancer screening is cervical cytology via Pap smear. The guidelines of the American Society of Colposcopy and Cervical Pathology recommend initiation of cervical cancer screening at age 21, regardless of the age of sexual debut. Women 21–29 years old with a normal Pap smear should have the test repeated every 3 years. Although adolescent and young women often test positive for HPV DNA, they are at very low risk of cervical cancer. Co-testing, or testing for HPV DNA at the time of the Pap smear, is not recommended for women in this age group because the presence of HPV DNA does not correlate with the presence of high-grade squamous intraepithelial neoplasia. Women 30–65 years of age should have a Pap smear every 3 years if testing for HPV DNA is not performed. The screening interval for women in this age group can be extended to every 5 years if co-testing results are negative. HPV testing is not recommended for partners of women with HPV or for screening


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InternalMed_Harrison. The screening interval for women in this age group can be extended to every 5 years if co-testing results are negative. HPV testing is not recommended for partners of women with HPV or for screening for conditions other than cervical cancer.


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InternalMed_Harrison. Currently, there is no clear consensus regarding screening for anal cancer and its precursors, including high-grade anal intraepithelial lesions. This lack of clarity is due to an inadequate understanding of optimal treatment for lowor high-grade anal dysplasia found during cytologic screening. The current HIV treatment guidelines suggest that there may be a benefit to screening, but an effect on the associated morbidity and mortality of anal squamous cell cancer has not been consistently demonstrated.


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InternalMed_Harrison. A variety of treatment modalities are available for various HPV infections, but none has been proven to eliminate HPV from tissue adjacent to the destroyed and infected tissue. Treatment efficacies are limited by frequent recurrences (presumably due to reinfection acquired from an infected partner), reactivation of latent virus, or autoinoculation from nearby infected cells. The goals of treatment include prevention of virus transmission, eradication of premalignant lesions, and reduction of symptoms. Treatment is generally successful in eliminating visible lesions and grossly diseased tissue. Different therapies are indicated for genital warts, vaginal and cervical disease, and perianal and anal disease.


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InternalMed_Harrison. An optimal therapy for HPV-related genital tract disease that combines high efficacy, low toxicity, low cost, and low recurrence rate is not available. For genital warts of the penis or vulva, cryotherapy (see below) is safest, least expensive, and most effective. Guidelines for the treatment of genital warts can be found on the CDC website (www .cdc.gov/std/treatment/2010/genital-warts.htm). Women with vaginal lesions should be referred to a gynecologist experienced in colposcopy and treatment of these lesions. Treatment of cervical disease involves careful inspection, biopsy, and histopathologic grading to determine the severity and extent of disease. Women with evidence of cervical HPV infection should be referred to a gynecologist familiar with HPV and experienced in colposcopy. Optimal follow-up of these patients includes colposcopic examination of the cervix and vagina on a yearly basis. Guidelines from the American College of Gynecology and Obstetrics are available for the


InternalMed_Harrison

InternalMed_Harrison. follow-up of these patients includes colposcopic examination of the cervix and vagina on a yearly basis. Guidelines from the American College of Gynecology and Obstetrics are available for the treatment of cervical dysplasia and cancer.


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InternalMed_Harrison. For anal or perianal lesions, cryotherapy or surgical removal is safest and most effective. Anoscopy and/or sigmoidoscopy should be performed when patients have perianal lesions, and suspicious lesions should be biopsied to rule out malignancy. Tables 222-1 and 222-2 list the available patient-administered and physician-administered treatments, respectively. Podophyllotoxin Podophyllotoxin (0.05% solution or gel and 0.15% cream) induces necrosis of genital wart tissue that heals within a few days. It is relatively effective and can be self-administered. Podophyllotoxin is applied twice daily on three consecutive days of the week for a maximum of 4 weeks. Adverse effects are common and include pain, inflammation, erosion, and burning or itching. Podophyllotoxin should not be used to treat vaginal, cervical, or anal lesions. The safety of podophyllotoxin during pregnancy has not been established.


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InternalMed_Harrison. Sinecatechins Sinecatechins (15% ointment) is used to treat genital warts but should not be used to treat vaginal, cervical, or anal lesions. Sinecatechins causes an inflammatory response when applied topically three times a day for up to 4 months. Clearance rates approach 60% in some studies, and recurrence rates are 6–9%. Adverse effects (redness, burning, itching, and pain at the site of application) are generally mild. The safety of sinecatechins during pregnancy is unknown.


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InternalMed_Harrison. Imiquimod Imiquimod (5% or 3.75% cream) is a patient-applied topical immunomodulatory agent thought to activate immune cells by binding to a Toll-like receptor—an event that leads to an inflammatory response. Imiquimod 5% cream is applied to genital warts at bedtime three times per week for up to 16 weeks. Warts are cleared in ~56% of patients, more often in women than in men; recurrence rates approach 13%. Local inflammatory side effects are common. Rates of clearance of genital warts with the 3.75% formulation are not as high, but the duration of treatment is shorter (i.e., daily application for a maximum of 8 weeks), and fewer local and systemic adverse reactions occur. Imiquimod should not be used to treat vaginal, cervical, or anal lesions. The safety of imiquimod during pregnancy has not been established.


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InternalMed_Harrison. Cryotherapy Cryotherapy (liquid nitrogen) for HPV-associated lesions causes cellular death. Genital warts usually disappear after two or three weekly sessions but often recur. Cryotherapy, which Availability Cost Good Frequent Frequent, is nontoxic and is not associated with significant adverse reactions, can also be used for diseased cervical tissue. Local pain occurs frequently. Surgical Methods Exophytic lesions can be surgically removed after intradermal injection of 1% lidocaine. This treatment is well tolerated but can cause scarring and requires hemostasis. Genital warts can also be destroyed by electrocautery, in which no additional hemostasis is required.


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InternalMed_Harrison. Laser Therapy Laser treatment affords destruction of exophytic lesions and other HPV-infected tissue while preserving normal tissue. Local anesthetics are generally adequate. Efficacy for genital lesions is at least equal to that of other therapies (60–90%), with low recurrence rates (5–10%). Complications include local pain, vaginal discharge, periurethral swelling, and penile or vulvar swelling. Laser therapy has also been used successfully to treat cervical dysplasia and anal disease caused by HPV.


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InternalMed_Harrison. Interferon (IFN) Recombinant IFN-α is used for intralesional treatment of genital warts, including perianal lesions. The recommended dosage is 1.0 × 106 IU of IFN injected into each lesion three times weekly for 3 weeks. IFN therapy causes clearance of infected cells by immune-boosting effects. Adverse events include headache, nausea, vomiting, fatigue, and myalgia. IFN therapy is costly and should be reserved for severe cases that do not respond to cheaper treatments. IFN should not be used to treat vaginal, cervical, or anal lesions. Other Therapies Both trichloroacetic acid and bichloroacetic acid are caustic agents that destroy warts by coagulation of proteins. Neither of these agents is recommended for treatment.


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InternalMed_Harrison. Most sexually active adults will be infected with HPV during their lives. For all patients (vaccinated or unvaccinated), certain behavioral interventions can reduce the risk of acquiring HPV. Physicians can provide their patients with measures that can reduce this risk. The only way to avoid acquiring an HPV infection is to abstain from sexual activity, including intimate touching and oral sex. Practicing safe sex (partner reduction, condom use) may lower the likelihood of HPV transmission. Most HPV infections are controlled by the immune system and cause no symptoms or disease. Some infections lead to genital warts and cervical precancers. Genital warts can be treated for cosmetic reasons and to prevent spread of infection to others. Even after resolution of genital warts, latent virus can persist in normal-appearing skin or mucosa and thus theoretically can be transmitted to uninfected partners. Precancerous cervical lesions should be treated to prevent progression to cancer.


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InternalMed_Harrison. human diseases, accounting for one-half or more of all acute illnesses. The incidence of acute respiratory disease in the United States is 3–5.6 cases per person per year. The rates are highest among children <1 year old (6.1–8.3 cases per year) and remain high until age 6, when a progressive decrease begins. Adults have 3–4 cases per person per year. Morbidity from acute respiratory illnesses accounts for 30–50% of time lost from work by adults and for 60–80% of time lost from school by children. The use of antibacterial agents to treat viral respiratory infections represents a major source of abuse of that category of drugs.


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InternalMed_Harrison. It has been estimated that two-thirds to three-fourths of cases of acute respiratory illness are caused by viruses. More than 200 antigenically distinct viruses from 10 genera have been reported to cause acute respiratory illness, and it is likely that additional agents will be described in the future. The vast majority of these viral infections involve the upper respiratory tract, but lower respiratory tract disease can also develop, particularly in younger age groups, in the elderly, and in certain epidemiologic settings.


InternalMed_Harrison

InternalMed_Harrison. The illnesses caused by respiratory viruses traditionally have been divided into multiple distinct syndromes, such as the “common cold,” pharyngitis, croup (laryngotracheobronchitis), tracheitis, bronchiolitis, bronchitis, and pneumonia. Each of these general categories of illness has a certain epidemiologic and clinical profile; for example, croup occurs exclusively in very young children and has a characteristic clinical course. Some types of respiratory illness are more likely to be associated with certain viruses (e.g., the common cold with rhinoviruses), whereas others occupy characteristic epidemiologic niches (e.g., adenovirus infections in military recruits). The syndromes most commonly associated with infections with the major respiratory virus groups are summarized in Table 223-1. Most respiratory viruses clearly have the potential to cause more than one type of respiratory illness, and features of several types of illness may be found in the same patient. Moreover, the


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InternalMed_Harrison. 223-1. Most respiratory viruses clearly have the potential to cause more than one type of respiratory illness, and features of several types of illness may be found in the same patient. Moreover, the clinical illnesses induced by these viruses are rarely sufficiently distinctive to permit an etiologic diagnosis on clinical grounds alone, although the epidemiologic setting increases the likelihood that one group of viruses rather than another is involved. In general, laboratory methods must be relied on to establish a specific viral diagnosis.


InternalMed_Harrison

InternalMed_Harrison. This chapter reviews viral infections caused by six of the major groups of respiratory viruses: rhinoviruses, coronaviruses, respiratory syncytial viruses, metapneumoviruses, parainfluenza viruses, and adenoviruses. The extraordinary outbreaks of lower respiratory tract disease associated with coronaviruses (severe acute respiratory syndrome [SARS] in 2002– 2003 and Middle East respiratory syndrome [MERS] in 2012–2013) are also discussed. Influenza viruses, which are a major cause of death as well as morbidity, are reviewed in Chap. 224. Herpesviruses, which occasionally cause pharyngitis and which also cause lower respiratory tract disease in immunosuppressed patients, are reviewed in Chap. 216. Enteroviruses, which account for occasional respiratory illnesses during the summer months, are reviewed in Chap. 228.


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InternalMed_Harrison. Rhinoviruses are members of the Picornaviridae family—small (15to 30-nm) nonenveloped viruses that contain a single-stranded RNA genome. Human rhinoviruses were first classified by immunologic serotype and are now divided into three genetic species: HRV-A, HRV-B, and HRV-C. The 102 serotypes described initially are encompassed by HRV-A and HRV-B species, whereas HRV-C encompasses more than 60 previously unrecognized serotypes. In contrast to other members of the picornavirus family, such as enteroviruses, rhinoviruses are acid-labile and are almost completely inactivated at pH ≤3. HRV-A and HRV-B species grow preferentially at 33°–34°C (the temperature of the human nasal passages) rather


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InternalMed_Harrison. Frequency of Respiratory Syndromes aSevere acute respiratory syndrome–associated coronavirus (SARS-CoV) caused epidemics of pneumonia from November 2002 to July 2003 (see text). bMiddle East respiratory syndrome coronavirus (MERS-CoV) has caused severe respiratory illnesses from 2012 to the time of this writing (2014); see text. cSerotypes 4 and 7 most commonly; also serotypes 14 and 21. dFever, cough, myalgia, malaise. eMay or may not have a respiratory component. than at 37°C (the temperature of the lower respiratory tract), whereas HRV-C viruses replicate well at either temperature. Of the 101 initially recognized serotypes of rhinovirus, 88 use intercellular adhesion molecule 1 (ICAM-1) as a cellular receptor and constitute the “major” receptor group, 12 use the low-density lipoprotein receptor (LDLR) and constitute the “minor” receptor group, and 1 uses decay-accelerating factor.


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InternalMed_Harrison. Rhinovirus infections are worldwide in distribution. They are a prominent cause of the common cold and have been detected in up to 50% of common cold–like illnesses by tissue culture and polymerase chain reaction (PCR) techniques. Overall rates of rhinovirus infection are higher among infants and young children and decrease with increasing age. Rhinovirus infections occur throughout the year, with seasonal peaks in early fall and spring in temperate climates. These infections are most often introduced into families by preschool or grade-school children <6 years old. Of initial illnesses in family settings, 25–70% are followed by secondary cases, with the highest attack rates among the youngest siblings at home. Attack rates also increase with family size.


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InternalMed_Harrison. Rhinoviruses appear to spread through direct contact with infected secretions, usually respiratory droplets. In some studies of volunteers, transmission was most efficient by hand-to-hand contact, with subsequent self-inoculation of the conjunctival or nasal mucosa. Other studies demonstrated transmission by largeor small-particle aerosol. Virus can be recovered from plastic surfaces inoculated 1–3 h previously; this observation suggests that environmental surfaces contribute to transmission. In studies of married couples in which neither partner had detectable serum antibody, transmission was associated with prolonged contact (≥122 h) during a 7-day period. Transmission was infrequent unless (1) virus was recoverable from the donor’s hands and nasal mucosa, (2) at least 1000 TCID50 (50% tissue culture infectious dose) of virus was present in nasal washes from the donor, and (3) the donor was at least moderately symptomatic with the “cold.” Despite anecdotal observations, exposure to


InternalMed_Harrison

InternalMed_Harrison. tissue culture infectious dose) of virus was present in nasal washes from the donor, and (3) the donor was at least moderately symptomatic with the “cold.” Despite anecdotal observations, exposure to cold temperatures, fatigue, and sleep deprivation have not been associated with increased rates of rhinovirus-induced illness in volunteers, although some studies have suggested that psychologically defined “stress” may contribute to development of symptoms.


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InternalMed_Harrison. By adulthood, nearly all individuals have neutralizing antibodies to multiple rhinovirus serotypes, although the prevalence of antibody to any one serotype varies widely. Multiple serotypes circulate simultaneously, and generally no single serotype or group of serotypes has been more prevalent than the others.


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InternalMed_Harrison. Rhinoviruses infect cells through attachment to specific cellular receptors; as mentioned above, most serotypes attach to ICAM-1, while a few use LDLR. Relatively limited information is available on the histopathology and pathogenesis of acute rhinovirus infections in humans. Examination of biopsy specimens obtained during experimentally induced and naturally occurring illness indicates that the nasal mucosa is edematous, is often hyperemic, and—during acute illness—is covered by a mucoid discharge. There is a mild infiltrate with inflammatory cells, including neutrophils, lymphocytes, plasma cells, and eosinophils. Mucus-secreting glands in the submucosa appear hyperactive; the nasal turbinates are engorged, a condition that may lead to obstruction of nearby openings of sinus cavities. Several mediators—e.g., bradykinin; lysylbradykinin; prostaglandins; histamine; interleukins 1β, 6, and 8; interferon γ–induced protein 10; and tumor necrosis factor α—have been linked to the


InternalMed_Harrison

InternalMed_Harrison. Several mediators—e.g., bradykinin; lysylbradykinin; prostaglandins; histamine; interleukins 1β, 6, and 8; interferon γ–induced protein 10; and tumor necrosis factor α—have been linked to the development of signs and symptoms in rhinovirus-induced colds.


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InternalMed_Harrison. The incubation period for rhinovirus illness is short, generally 1–2 days. Virus shedding coincides with the onset of illness or may begin shortly before symptoms develop. The mechanisms of immunity to rhinovirus infection are not well worked out. In some studies, the presence of homotypic antibody has been associated with significantly reduced rates of subsequent infection and illness, but data conflict regarding the relative importance of serum and local antibody in protection from rhinovirus infection.


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InternalMed_Harrison. The most common clinical manifestations of rhinovirus infections are those of the common cold. Illness usually begins with rhinorrhea and sneezing accompanied by nasal congestion. The throat is frequently sore, and in some cases sore throat is the initial complaint. Systemic signs and symptoms, such as malaise and headache, are mild or absent, and fever is unusual in adults but may occur in up to one-third of children. Illness generally lasts for 4–9 days and resolves spontaneously without sequelae. In children, bronchitis, bronchiolitis, and bronchopneumonia have been reported; nevertheless, it appears that rhinoviruses are not major causes of lower respiratory tract disease in children. Rhinoviruses may cause exacerbations of asthma and chronic pulmonary disease in adults. The vast majority of rhinovirus infections resolve without sequelae, but complications related to obstruction of the eustachian tubes or sinus ostia, including otitis media or acute sinusitis, can develop. In


InternalMed_Harrison

InternalMed_Harrison. majority of rhinovirus infections resolve without sequelae, but complications related to obstruction of the eustachian tubes or sinus ostia, including otitis media or acute sinusitis, can develop. In immunosuppressed patients, particularly bone marrow transplant recipients, severe and even fatal pneumonias have been associated with rhinovirus infections.


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InternalMed_Harrison. Although rhinoviruses are the most frequently recognized cause of the common cold, similar illnesses are caused by a variety of other viruses, and a specific viral etiologic diagnosis cannot be made on clinical grounds alone. Rather, rhinovirus infection is diagnosed by isolation of the virus from nasal washes or nasal secretions in tissue culture. In practice, this procedure is rarely undertaken because of the benign, self-limited nature of the illness. In most settings, detection of rhino-virus RNA is more sensitive and easier by PCR than by tissue culture. Accordingly, PCR has generally become the standard for detection of rhinoviruses in clinical specimens. Given the many serotypes of rhinovirus, diagnosis by serum antibody tests is currently impractical. Likewise, common laboratory tests, such as white blood cell count and erythrocyte sedimentation rate, are not helpful.


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InternalMed_Harrison. Because rhinovirus infections are generally mild and self-limited, treatment is not usually necessary. Therapy in the form of first-generation antihistamines and nonsteroidal anti-inflammatory drugs may be beneficial in patients with particularly pronounced symptoms, and an oral decongestant may be added if nasal obstruction is particularly troublesome. Reduction of activity is prudent in instances of significant discomfort or fatigability. Antibacterial agents should be used only if bacterial complications such as otitis media or sinusitis develop. Specific antiviral therapy is not available.


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InternalMed_Harrison. Intranasal application of interferon sprays has been effective in the prophylaxis of rhinovirus infections but is also associated with local irritation of the nasal mucosa. Studies of prevention of rhinovirus infection by blocking of ICAM-1 or by binding of drug (pleconaril) to parts of the viral capsid have yielded mixed results. Experimental vaccines to certain rhinovirus serotypes have been generated, but their usefulness is questionable because of the myriad serotypes involved and the uncertainty about mechanisms of immunity. Thorough hand washing, environmental decontamination, and protection against autoinoculation may help to reduce rates of transmission of infection.


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InternalMed_Harrison. Coronaviruses are pleomorphic, single-stranded RNA viruses that measure 100–160 nm in diameter. The name derives from the crown-like appearance produced by the club-shaped projections that stud the viral envelope. Coronaviruses infect a wide variety of animal species and have been divided into four genera. Coronaviruses that infect humans (HCoVs) fall into two genera: Alphacoronavirus 1204 and Betacoronavirus. Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are betacoronaviruses. In general, human coronaviruses have been difficult to cultivate in vitro, and some strains grow only in human tracheal organ cultures rather than in tissue culture. SARS-CoV and MERS-CoV are exceptions whose ready growth in African green monkey kidney (Vero E6) cells greatly facilitates their study.


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InternalMed_Harrison. Human coronavirus infections are present throughout the world. Seroprevalence studies of strains HCoV-229E and HCoV-OC43 have demonstrated that serum antibodies are acquired early in life and increase in prevalence with advancing age, so that >80% of adult populations have antibodies detectable by enzyme-linked immunosorbent assay (ELISA). Overall, coronaviruses account for 10–35% of common colds, depending on the season. Coronavirus infections appear to be particularly prevalent in late fall, winter, and early spring—times when rhinovirus infections are less common.


InternalMed_Harrison

InternalMed_Harrison. An extraordinary outbreak of the coronavirus-associated illness known as SARS occurred in 2002–2003. The outbreak apparently began in southern China and eventually resulted in 8096 recognized cases in 28 countries in Asia, Europe, and North and South America; ~90% of cases occurred in China and Hong Kong. The natural reservoir of SARS-CoV appeared to be the horseshoe bat, and the outbreak may have originated from human contact with infected semidomesticated animals such as the palm civet. In most cases, however, the infection was transmitted from human to human. Case–fatality rates varied among outbreaks, with an overall figure of ~9.5%. The disease appeared to be somewhat milder in cases in the United States and was clearly less severe among children. The outbreak ceased in 2003; 17 cases were detected in 2004, mostly in laboratory-associated settings, and no cases have been reported subsequently.


InternalMed_Harrison

InternalMed_Harrison. The mechanisms of transmission of SARS are incompletely understood. Clusters of cases suggest that spread may occur via both large-and small-droplet aerosols and perhaps via the fecal–oral route as well. The outbreak of illness in a large apartment complex in Hong Kong suggested that environmental sources, such as sewage or water, may also play a role in transmission. Some ill individuals (“super-spreaders”) appeared to be hyperinfectious and were capable of transmitting infection to 10–40 contacts, although most infections resulted in spread either to no one or to three or fewer individuals.


InternalMed_Harrison

InternalMed_Harrison. Since it began in June 2012, another extraordinary outbreak of serious respiratory illness, MERS, has been linked with a coronavirus (MERS-CoV). Through May 2014, a total of 536 cases and 145 deaths (27%) have been reported. All cases have been associated with contact or travel to six countries in or near the Arabian Peninsula: Jordan, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates. Cases have also been reported in France, Italy, Tunisia, Germany, Spain, and the United Kingdom. Person-to-person transmission has been documented, but sustained spread in communities has not. The source of MERS-CoV has not been established, but it is suspected that bats may be the animal reservoir and that camels serve as an intermediate host.


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InternalMed_Harrison. Coronaviruses that cause the common cold (e.g., strains HCoV-229E and HCoV-OC43) infect ciliated epithelial cells in the nasopharynx via the aminopeptidase N receptor (group 1) or a sialic acid receptor (group 2). Viral replication leads to damage of ciliated cells and induction of chemokines and interleukins, with consequent common-cold symptoms similar to those induced by rhinoviruses.


InternalMed_Harrison

InternalMed_Harrison. SARS-CoV infects cells of the respiratory tract via the angiotensinconverting enzyme 2 receptor. The result is a systemic illness in which virus is also found in the bloodstream, in the urine, and (for up to 2 months) in the stool. Virus persists in the respiratory tract for 2–3 weeks, and titers peak ~10 days after the onset of systemic illness. Pulmonary pathology consists of hyaline membrane formation, desquamation of pneumocytes in alveolar spaces, and an interstitial infiltrate made up of lymphocytes and mononuclear cells. Giant cells are frequently seen, and coronavirus particles have been detected in type II pneumocytes. Elevated levels of proinflammatory cytokines and chemokines have been detected in sera from patients with SARS. Because MERS-CoV was so recently detected, little is known at present about its pathogenesis. However, it may well be similar to that of SARS-CoV.


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InternalMed_Harrison. After an incubation period that generally lasts 2–7 days (range, 1–14 days), SARS usually begins as a systemic illness marked by the onset of fever, which is often accompanied by malaise, headache, and myalgias and is followed in 1–2 days by a nonproductive cough and dyspnea. Approximately 25% of patients have diarrhea. Chest x-rays can show a variety of infiltrates, including patchy areas of consolidation—most frequently in peripheral and lower lung fields—or interstitial infiltrates, which can progress to diffuse involvement. In severe cases, respiratory function may worsen during the second week of illness and progress to frank adult respiratory distress syndrome accompanied by multiorgan dysfunction. Risk factors for severe disease include an age of >50 years and comorbidities such as cardiovascular disease, diabetes, and hepatitis. Illness in pregnant women may be particularly severe, but SARS-CoV infection appears to be milder in children than in adults.


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InternalMed_Harrison. Information regarding the clinical manifestations of MERS-CoV is limited. The case–fatality rate has been high in the initial cases, but this may represent an ascertainment bias, and it is clear that mild cases occur as well. The median incubation period has been estimated to be 5.2 days, and a secondary case was estimated to have an incubation period of 9–12 days. Cases have been reported that begin with cough and fever and progress to acute respiratory distress and respiratory failure within a week. Other cases have manifested as mild upper respiratory symptoms only. Renal failure has been noted, and DPP-4, the host cell receptor for MERS-CoV, is expressed at high levels in the kidney; these findings suggest that direct viral infection of the kidney may lead to renal dysfunction. Diarrhea and vomiting are also common in MERS, and pericarditis has been reported.


InternalMed_Harrison

InternalMed_Harrison. The clinical features of common colds caused by human coronaviruses are similar to those of illness caused by rhinoviruses. In studies of volunteers, the mean incubation period of colds induced by corona-viruses (3 days) is somewhat longer than that of illness caused by rhinoviruses, and the duration of illness is somewhat shorter (mean, 6–7 days). In some studies, the amount of nasal discharge was greater in colds induced by coronaviruses than in those induced by rhinoviruses. Coronaviruses other than SARS-CoV have been recovered occasionally from infants with pneumonia and from military recruits with lower respiratory tract disease and have been associated with worsening of chronic bronchitis. Two novel coronaviruses, HCoV-NL63 and HCoVHKU1, have been isolated from patients hospitalized with acute respiratory illness. Their overall role as causes of human respiratory disease remains to be determined.


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InternalMed_Harrison. Laboratory abnormalities in SARS include lymphopenia, which is documented in ~50% of cases and which mostly affects CD4+ T cells but also involves CD8+ T cells and natural killer cells. Total white blood cell counts are normal or slightly low, and thrombocytopenia may develop as the illness progresses. Elevated serum levels of aminotransferases, creatine kinase, and lactate dehydrogenase have been reported.


InternalMed_Harrison

InternalMed_Harrison. A rapid diagnosis of SARS-CoV infection can be made by reverse-transcription PCR (RT-PCR) of respiratory tract samples and plasma early in the illness and of urine and stool later on. SARS-CoV can also be grown from respiratory tract samples by inoculation into Vero E6 tissue culture cells, in which a cytopathic effect is seen within days. RT-PCR appears to be more sensitive than tissue culture, but only around one-third of cases are positive by PCR at initial presentation. Serum antibodies can be detected by ELISA or immunofluorescence, and nearly all patients develop detectable serum antibodies within 28 days after the onset of illness.


InternalMed_Harrison

InternalMed_Harrison. Laboratory abnormalities in MERS-CoV infection include lymphopenia with or without neutropenia, thrombocytopenia, and elevated levels of lactate dehydrogenase. MERS-CoV can be isolated in tissue culture in Vero and LLC-MK2 cells, but PCR techniques are more sensitive and rapid and are the standard for laboratory diagnosis. Serologic tests using ELISA and immunofluorescence techniques have also been developed. Laboratory diagnosis of coronavirus-induced colds is rarely required. Coronaviruses that cause those illnesses are frequently difficult to cultivate in vitro but can be detected in clinical samples by ELISA or immunofluorescence assays or by RT-PCR for viral RNA. These research procedures can be used to detect coronaviruses in unusual clinical settings.


InternalMed_Harrison

InternalMed_Harrison. There is no specific therapy for SARS with established efficacy. Although ribavirin has frequently been used, it has little if any activity against SARS-CoV in vitro, and no beneficial effect on the course of illness has been demonstrated. Because of suggestions that immunopathology may contribute to the disease, glucocorticoids have also been widely used, but their benefit, if any, likewise remains to be established. Supportive care to maintain pulmonary and other organ-system functions remains the mainstay of therapy. Similarly, there is no established antiviral therapy for MERS. Interferon α2b and ribavirin have displayed activity against MERS-CoV in vitro and in a rhesus macaque model, but data are not available on its use in human cases of MERS. The approach to the treatment of common colds caused by coronaviruses is similar to that discussed above for rhinovirus-induced illnesses.


InternalMed_Harrison

InternalMed_Harrison. The recognition of SARS led to a worldwide mobilization of public health resources to apply infection control practices to contain the disease. Case definitions were established, travel advisories were proposed, and quarantines were imposed in certain locales. As of this writing, no additional cases of SARS have been reported since 2004. However, it remains unknown whether the disappearance of cases is a result of control measures, whether it is part of a seasonal or otherwise unexplained epidemiologic pattern of SARS, or when or whether SARS might reemerge. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) maintain recommendations for surveillance and assessment of potential cases of SARS (www.cdc.gov/sars/). The frequent transmission of the disease to health care workers makes it mandatory that strict infection-control practices be employed by health care facilities to prevent airborne, droplet, and contact transmission from any


InternalMed_Harrison

InternalMed_Harrison. of the disease to health care workers makes it mandatory that strict infection-control practices be employed by health care facilities to prevent airborne, droplet, and contact transmission from any suspected cases of SARS. Health care workers who enter areas in which patients with SARS may be present should don gowns, gloves, and eye and respiratory protective equipment (e.g., an N95 filtering facepiece respirator certified by the National Institute for Occupational Safety and Health).


InternalMed_Harrison

InternalMed_Harrison. Similarly, the WHO and the CDC have issued recommendations for identification, prevention, and control of MERS-CoV infections (www.cdc.gov/coronavirus/mers/index.html). Isolation precautions against airborne spread of infection should be instituted for patients hospitalized for suspected MERS, as described above for SARS. Vaccines have been developed against several animal coronaviruses but not against known human coronaviruses. The emergence of SARS-CoV and MERS-CoV has stimulated interest in the development of vaccines against such agents.


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InternalMed_Harrison. Human respiratory syncytial virus (HRSV) is a member of the Paramyxoviridae family (genus Pneumovirus). It is an enveloped virus ~150–350 nm in diameter and is so named because its replication in vitro leads to the fusion of neighboring cells into large multinucleated 1205 syncytia. The single-stranded RNA genome codes for 11 virus-specific proteins. Viral RNA is contained in a helical nucleocapsid surrounded by a lipid envelope bearing two glycoproteins: the G protein, by which the virus attaches to cells, and the F (fusion) protein, which facilitates entry of the virus into the cell by fusing host and viral membranes. HRSV is considered to be of a single antigenic type, but two distinct subgroups (A and B) and multiple subtypes within each subgroup have now been described. Antigenic diversity is reflected by differences in the G protein, whereas the F protein is relatively conserved. Both antigenic groups can circulate simultaneously in outbreaks, although there are typically


InternalMed_Harrison

InternalMed_Harrison. diversity is reflected by differences in the G protein, whereas the F protein is relatively conserved. Both antigenic groups can circulate simultaneously in outbreaks, although there are typically alternating patterns in which one subgroup predominates over 1to 2-year periods.


InternalMed_Harrison

InternalMed_Harrison. HRSV is a major respiratory pathogen of young children and the foremost cause of lower respiratory disease in infants. Infection with HRSV is seen throughout the world in annual epidemics that occur in late fall, winter, or spring and last up to 5 months. The virus is rarely encountered during the summer. Rates of illness are highest among infants 1–6 months of age, peaking at 2–3 months of age. The attack rates among susceptible infants and children are extraordinarily high, approaching 100% in settings such as daycare centers where large numbers of susceptible infants are present. By age 2, virtually all children will have been infected with HRSV. HRSV accounts for 20–25% of hospital admissions of young infants and children for pneumonia and for up to 75% of cases of bronchiolitis in this age group. It has been estimated that more than half of infants who are at risk will become infected during an HRSV epidemic.


InternalMed_Harrison

InternalMed_Harrison. In older children and adults, reinfection with HRSV is frequent, but disease is milder than in infancy. A common cold–like syndrome is the illness most commonly associated with HRSV infection in adults. It has been increasingly appreciated that severe lower respiratory tract disease with pneumonitis can occur in elderly (often institutionalized) adults, in individuals with cardiopulmonary disease, and in patients with immunocompromising disorders or treatment, including recipients of hematopoietic stem cell transplants (HSCTs) and solid-organ transplants (SOTs). HRSV is also an important nosocomial pathogen; during an outbreak, it can infect pediatric patients and up to 25–50% of the staff on pediatric wards. The spread of HRSV among families is efficient: up to 40% of siblings may become infected when the virus is introduced into the family setting.


InternalMed_Harrison

InternalMed_Harrison. HRSV is transmitted primarily by close contact with contaminated fingers or fomites and by self-inoculation of the conjunctiva or anterior nares. Virus may also be spread by coarse aerosols produced by coughing or sneezing, but it is inefficiently spread by fine-particle aerosols. The incubation period is ~4–6 days, and virus shedding may last for ≥2 weeks in children and for shorter periods in adults. In immunosuppressed patients, shedding can continue for weeks.


InternalMed_Harrison

InternalMed_Harrison. Little is known about the histopathology of minor HRSV infection. Severe bronchiolitis or pneumonia is characterized by necrosis of the bronchiolar epithelium and a peribronchiolar infiltrate of lymphocytes and mononuclear cells. Interalveolar thickening and filling of alveolar spaces with fluid can also be found. The correlates of protective immunity to HRSV are incompletely understood. Because reinfection occurs frequently and is often associated with illness, the immunity that develops after single episodes of infection clearly is not complete or long-lasting. However, the cumulative effect of multiple reinfections is to temper subsequent disease and to provide some temporary measure of protection against infection. Studies of experimentally induced disease in healthy volunteers indicate that the presence of nasal IgA neutralizing antibody correlates more closely with protection than does the presence of serum antibody. Studies in infants, however, suggest that maternally acquired


InternalMed_Harrison

InternalMed_Harrison. that the presence of nasal IgA neutralizing antibody correlates more closely with protection than does the presence of serum antibody. Studies in infants, however, suggest that maternally acquired antibody provides some protection from lower respiratory tract disease, although illness can be severe even in infants who have moderate levels of maternally derived serum antibody. The relatively severe disease observed in immunosuppressed 1206 patients and experimental animal models indicates that cell-mediated immunity is an important mechanism of host defense against HRSV. Evidence suggests that major histocompatibility class I–restricted cytotoxic T cells may be particularly important in this regard.


InternalMed_Harrison

InternalMed_Harrison. HRSV infection leads to a wide spectrum of respiratory illnesses. In infants, 25–40% of infections result in lower respiratory tract involvement, including pneumonia, bronchiolitis, and tracheobronchitis. In this age group, illness begins most frequently with rhinorrhea, low-grade fever, and mild systemic symptoms, often accompanied by cough and wheezing. Most patients recover gradually over 1–2 weeks. In more severe illness, tachypnea and dyspnea develop, and eventually frank hypoxia, cyanosis, and apnea can ensue. Physical examination may reveal diffuse wheezing, rhonchi, and rales. Chest radiography shows hyperexpansion, peribronchial thickening, and variable infiltrates ranging from diffuse interstitial infiltrates to segmental or lobar consolidation. Illness may be particularly severe in children born prematurely and in those with congenital cardiac disease, bronchopulmonary dysplasia, nephrotic syndrome, or immunosuppression. One study documented a 37% mortality rate among


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InternalMed_Harrison. severe in children born prematurely and in those with congenital cardiac disease, bronchopulmonary dysplasia, nephrotic syndrome, or immunosuppression. One study documented a 37% mortality rate among infants with HRSV pneumonia and congenital cardiac disease.


InternalMed_Harrison

InternalMed_Harrison. In adults, the most common symptoms of HRSV infection are those of the common cold, with rhinorrhea, sore throat, and cough. Illness is occasionally associated with moderate systemic symptoms such as malaise, headache, and fever. HRSV has also been reported to cause lower respiratory tract disease with fever in adults, including severe pneumonia in the elderly—particularly in nursing-home residents, among whom its impact can rival that of influenza. HRSV pneumonia can be a significant cause of morbidity and death among patients undergoing stem cell and solid organ transplantation, in whom case– fatality rates of 20–80% have been reported. Sinusitis, otitis media, and worsening of chronic obstructive and reactive airway disease have also been associated with HRSV infection.


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of HRSV infection can be suspected on the basis of a suggestive epidemiologic setting—that is, severe illness among infants during an outbreak of HRSV in the community. Infections in older children and adults cannot be differentiated with certainty from those caused by other respiratory viruses. The specific diagnosis is established by detection of HRSV in respiratory secretions, such as sputum, throat swabs, or nasopharyngeal washes. Virus can be isolated in tissue culture, but this method has been largely supplanted by rapid viral diagnostic techniques consisting of immunofluorescence or ELISA of nasopharyngeal washes, aspirates, and (less satisfactorily) nasopharyngeal swabs. With specimens from children, these techniques have sensitivities and specificities of 80–95%; they are somewhat less sensitive with specimens from adults. RT-PCR detection techniques have shown even higher rates of sensitivity and specificity, particularly in adults. Serologic diagnosis may be


InternalMed_Harrison

InternalMed_Harrison. are somewhat less sensitive with specimens from adults. RT-PCR detection techniques have shown even higher rates of sensitivity and specificity, particularly in adults. Serologic diagnosis may be made by comparison of acuteand convalescent-phase serum specimens by ELISA or by neutralization or complement-fixation tests. These tests may be useful in older children and adults but are less sensitive in children <4 months of age.


InternalMed_Harrison

InternalMed_Harrison. Treatment of upper respiratory tract HRSV infection is aimed primarily at the alleviation of symptoms and is similar to that for other viral infections of the upper respiratory tract. For lower respiratory tract infections, respiratory therapy, including hydration, suctioning of secretions, and administration of humidified oxygen and antibronchospastic agents, is given as needed. In severe hypoxia, intubation and ventilatory assistance may be required. Studies of infants with HRSV infection who were given aerosolized ribavirin, a nucleoside analogue active in vitro against HRSV, demonstrated a modest beneficial effect on the resolution of lower respiratory tract illness, including alleviation of blood-gas abnormalities, in some studies. The American Academy of Pediatrics does not recommend routine use of ribavirin but states that treatment with aerosolized ribavirin “may be considered” for infants who are severely ill or who are at high risk for complications of HRSV infection;


InternalMed_Harrison

InternalMed_Harrison. routine use of ribavirin but states that treatment with aerosolized ribavirin “may be considered” for infants who are severely ill or who are at high risk for complications of HRSV infection; included are premature infants and those with bronchopulmonary dysplasia, congenital heart disease, or immunosuppression. The efficacy of ribavirin against HRSV pneumonia in older children and adults, including those with immunosuppression, has not been established. No benefit has been found in the treatment of HRSV pneumonia with standard immunoglobulin; immunoglobulin with high titers of antibody to HRSV (RSVIg), which is no longer available; or chimeric mouse–human monoclonal IgG antibody to HRSV (palivizumab). Combined therapy with aerosolized ribavirin and palivizumab is being evaluated in immunosuppressed patients with HRSV pneumonia.


InternalMed_Harrison

InternalMed_Harrison. Monthly administration of RSVIg (no longer available) or palivizumab has been approved as prophylaxis against HRSV for children <2 years of age who have bronchopulmonary dysplasia or cyanotic heart disease or who were born prematurely. Considerable interest exists in the development of vaccines against HRSV. Inactivated whole-virus vaccines have been ineffective; in one study, they actually potentiated disease in infants. Other approaches include immunization with purified F and G surface glycoproteins of HRSV or generation of stable live attenuated virus vaccines. In settings where rates of transmission are high (e.g., pediatric wards), barrier methods for the protection of hands and conjunctivae may be useful in reducing the spread of virus.


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InternalMed_Harrison. Human metapneumovirus (HMPV) is a viral respiratory pathogen that has been assigned to the Paramyxoviridae family (genus Metapneumovirus). Its morphology and genomic organization are similar to those of avian metapneumoviruses, which are recognized respiratory pathogens of turkeys. HMPV particles may be spherical, filamentous, or pleomorphic in shape and measure 150–600 nm in diameter. Particles contain 15-nm projections from the surface that are similar in appearance to those of other Paramyxoviridae. The single-stranded RNA genome codes for nine proteins that, except for the absence of nonstructural proteins, generally correspond to those of HRSV. HMPV is of only one antigenic type; two closely related genotypes (A and B), four subgroups, and two sublineages have been described.


InternalMed_Harrison

InternalMed_Harrison. HMPV infections are worldwide in distribution, are most frequent during the winter in temperate climates, and occur early in life, so that serum antibodies to the virus are present in 50% of children by age 2 and in nearly all children by age 5. HMPV infections have been detected in older age groups, including elderly adults, and in both immunocompetent and immunosuppressed hosts. This virus accounts for 1–5% of childhood upper respiratory tract infections and for 10–15% of respiratory tract illnesses requiring hospitalization of children. In addition, HMPV causes 2–4% of acute respiratory illnesses in ambulatory adults and elderly patients. HMPV has been detected in a few cases of SARS, but its role (if any) in these illnesses has not been established.


InternalMed_Harrison

InternalMed_Harrison. The spectrum of clinical illnesses associated with HMPV is similar to that associated with HRSV and includes both upper and lower respiratory tract illnesses, such as bronchiolitis, croup, and pneumonia. Reinfection with HMPV is common among older children and adults and has manifestations ranging from subclinical infections to common cold syndromes and occasionally pneumonia, which is seen primarily in elderly patients and those with cardiopulmonary diseases. Serious HMPV infections occur in immunocompromised patients, including those with neoplasia, recipients of HSCTs, and children with HIV infection. HMPV can be detected in nasal aspirates and respiratory secretions by immunofluorescence, by PCR (the most sensitive technique), or by growth in rhesus monkey kidney (LLC-MK2) tissue cultures. A serologic diagnosis can be made by ELISA, which uses HMPV-infected tissue culture lysates as sources of antigens.


InternalMed_Harrison

InternalMed_Harrison. Treatment for HMPV infections is primarily supportive and symptom-based. Ribavirin is active against HMPV in vitro, but its efficacy in vivo is unknown. Vaccines against HMPV are in the early stages of development. Parainfluenza viruses belong to the Paramyxoviridae family (genera Respirovirus and Rubulavirus). They are 150–200 nm in diameter, are enveloped, and contain a single-stranded RNA genome. The envelope is studded with two glycoproteins: one possesses both hemagglutinin and neuraminidase activity, and the other contains fusion activity. The viral RNA genome is enclosed in a helical nucleocapsid and codes for six structural and several accessory proteins. All types of parainfluenza virus (1, 2, 3, 4A, and 4B) share certain antigens with other members of the Paramyxoviridae family, including mumps and Newcastle disease viruses.


InternalMed_Harrison

InternalMed_Harrison. Parainfluenza viruses are distributed throughout the world; infection with serotypes 4A and 4B has been reported less widely, probably because these types are more difficult than the other three to grow in tissue culture. Infection is acquired in early childhood; by 5 years of age, most children have antibodies to serotypes 1, 2, and 3. Types 1 and 2 cause epidemics during the fall, often occurring in an alternate-year pattern. Type 3 infection has been detected during all seasons, but epidemics have occurred annually in the spring.


InternalMed_Harrison

InternalMed_Harrison. The contribution of parainfluenza infections to respiratory disease varies with both the location and the year. In studies conducted in the United States, parainfluenza virus infections have accounted for 4.3–22% of respiratory illnesses in children. The major importance of these viruses is as a cause of lower respiratory illness in young children, in whom they rank second only to HRSV in that regard. Parainfluenza virus type 1 is the most common cause of croup (laryngotracheobronchitis) in children, whereas serotype 2 causes similar, although generally less severe, disease. Type 3 is an important cause of bronchiolitis and pneumonia in infants, whereas illnesses associated with types 4A and 4B have generally been mild. Unlike types 1 and 2, type 3 frequently causes illness during the first month of life, when passively acquired maternal antibody is still present. Parainfluenza viruses are spread through infected respiratory secretions, primarily by person-to-person contact and/or by


InternalMed_Harrison

InternalMed_Harrison. month of life, when passively acquired maternal antibody is still present. Parainfluenza viruses are spread through infected respiratory secretions, primarily by person-to-person contact and/or by large droplets, and by contact with fomites contaminated with respiratory secretions. The incubation period has varied from 3 to 6 days in experimental infections but may be somewhat shorter for naturally occurring disease in children.


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InternalMed_Harrison. In adults, parainfluenza virus infections are generally mild and account for fewer than 10% of respiratory illnesses. The advent of contemporary laboratory methods for diagnosis has increased awareness of the impact of parainfluenza infections in adults. In a recent study, parainfluenza virus was the third most common viral isolate from patients 16–64 years old who required hospitalization (0.7 isolate/1000 population). In the 2009 influenza pandemic, parainfluenza virus type 3 was the second most common cause of illness after influenza virus.


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InternalMed_Harrison. Immunity to parainfluenza viruses is incompletely understood, but evidence suggests that immunity to infections with serotypes 1 and 2 is mediated by local IgA antibodies in the respiratory tract. Passively acquired serum neutralizing antibodies also confer some protection against infection with types 1, 2, and (to a lesser degree) 3. Studies in experimental animal models and in immunosuppressed patients suggest that T cell–mediated immunity may also be important in parainfluenza virus infections. Lack of cellular immune responses is associated with an increased risk of progressive and fatal disease in HSCT recipients.


InternalMed_Harrison

InternalMed_Harrison. Parainfluenza virus infections occur most frequently among children, in whom initial infection with serotype 1, 2, or 3 is associated with an acute febrile illness in 50–80% of cases. Children may present with coryza, sore throat, hoarseness, and cough that may or may not be croupy. In severe croup, fever persists, with worsening coryza and sore throat. A brassy or barking cough may progress to frank stridor. Most children recover over the next 1 or 2 days, although progressive airway obstruction and hypoxia ensue occasionally. If bronchiolitis or pneumonia develops, progressive cough accompanied by wheezing, tachypnea, and intercostal retractions may occur. In this setting, sputum production increases modestly. Physical examination documents nasopharyngeal discharge and oropharyngeal injection, along with rhonchi, wheezes, or coarse breath sounds. Chest x-rays can show air trapping and occasionally interstitial infiltrates.


InternalMed_Harrison

InternalMed_Harrison. In older children and adults, parainfluenza infections tend to be milder, presenting most frequently as a common cold or as hoarseness, with or without cough. Lower respiratory tract involvement in older children and adults is uncommon, although tracheobronchitis and community-acquired pneumonia have been reported in adults. Parainfluenza viruses, most frequently type 3, are important pathogens in immunosuppressed patients—particularly in HSCT recipients but also in SOT recipients (especially recipients of lung transplants). Patients receiving cancer chemotherapy are also at risk for severe parainfluenza infection. Severe, prolonged, and even fatal parainfluenzaassociated respiratory illnesses have been reported in children and adults with severe immunosuppression.


InternalMed_Harrison

InternalMed_Harrison. The clinical syndromes caused by parainfluenza viruses (with the possible exception of croup in young children) are not sufficiently distinctive to be diagnosed on clinical grounds alone. A specific diagnosis is established by detection of virus in respiratory tract secretions, throat swabs, or nasopharyngeal washings. Growth of the virus in tissue culture is detected either by hemagglutination or by a cytopathic effect. A rapid diagnosis may be made by identification of parainfluenza antigens in exfoliated cells from the respiratory tract with immunofluorescence or ELISA, although these techniques appear to be less sensitive than tissue culture. Highly specific and sensitive PCR assays have also been developed and have now become the standard for viral diagnosis. Serologic diagnosis can be established by hemagglutinationinhibition, complement-fixation, or neutralization testing of acuteand convalescent-phase specimens. However, because frequent heterotypic responses occur among the


InternalMed_Harrison

InternalMed_Harrison. be established by hemagglutinationinhibition, complement-fixation, or neutralization testing of acuteand convalescent-phase specimens. However, because frequent heterotypic responses occur among the parainfluenza serotypes, the serotype causing illness often cannot be identified by serologic techniques alone.


InternalMed_Harrison

InternalMed_Harrison. Acute epiglottitis caused by Haemophilus influenzae type b must be differentiated from viral croup. Influenza A virus is also a common cause of croup during epidemic periods.


InternalMed_Harrison

InternalMed_Harrison. For upper respiratory tract illness, symptoms can be treated as discussed for other viral respiratory tract illnesses. If complications such as sinusitis, otitis, or superimposed bacterial bronchitis develop, appropriate antibacterial drugs should be administered. Mild cases of croup should be treated with bed rest and moist air generated by vaporizers. More severe cases require hospitalization 1208 and close observation for the development of respiratory distress. If acute respiratory distress develops, humidified oxygen and intermittent racemic epinephrine are usually administered. Aerosolized or systemically administered glucocorticoids are beneficial; systemic administration has a more profound effect. No specific antiviral therapy has been established. Ribavirin is active against parainfluenza viruses in vitro, and anecdotal reports describe its use clinically, particularly in immunosuppressed patients, but its efficacy, if any, is unclear. DAS181, a sialidase with activity


InternalMed_Harrison

InternalMed_Harrison. parainfluenza viruses in vitro, and anecdotal reports describe its use clinically, particularly in immunosuppressed patients, but its efficacy, if any, is unclear. DAS181, a sialidase with activity against parainfluenza viruses, is undergoing evaluation in immunosuppressed patients.


InternalMed_Harrison

InternalMed_Harrison. Vaccines against parainfluenza viruses are under development.


InternalMed_Harrison

InternalMed_Harrison. Adenoviruses are complex DNA viruses that measure 70–80 nm in diameter. Human adenoviruses belong to the genus Mastadenovirus, which includes 51 serotypes. Adenoviruses have a characteristic morphology consisting of an icosahedral shell composed of 20 equilateral triangular faces and 12 vertices. The protein coat (capsid) consists of hexon subunits with group-specific and type-specific antigenic determinants and penton subunits at each vertex primarily containing group-specific antigens. A fiber with a knob at the end projects from each penton; this fiber contains type-specific and some group-specific antigens. Human adenoviruses have been divided into seven subgroups (A through G) on the basis of the homology of DNA genomes and other properties. Revised criteria for classifying human adenoviruses have been proposed; reflecting recent approaches to the characterization of novel adenoviruses, the revised criteria include genome sequence and computational analysis in addition to


InternalMed_Harrison

InternalMed_Harrison. adenoviruses have been proposed; reflecting recent approaches to the characterization of novel adenoviruses, the revised criteria include genome sequence and computational analysis in addition to traditional serologic criteria. The adenovirus genome is a linear double-stranded DNA that codes for structural and nonstructural polypeptides. The replicative cycle of adenovirus may result either in lytic infection of cells or in the establishment of a latent infection (primarily involving lymphoid cells). Some adenovirus types can induce oncogenic transformation, and tumor formation has been observed in rodents; however, despite intensive investigation, adenoviruses have not been associated with tumors in humans.


InternalMed_Harrison

InternalMed_Harrison. Adenovirus infections most frequently affect infants and children. Infections occur throughout the year but are most common from fall to spring. In the United States, adenoviruses account for ~10% of acute respiratory infections in children but for <2% of respiratory illnesses in civilian adults. Nearly 100% of adults have serum antibody to multiple serotypes—a finding indicating that infection is common in childhood. Types 1, 2, 3, and 5 are the most common isolates from children. Certain adenovirus serotypes—particularly 4 and 7 but also 3, 14, and 21—are associated with outbreaks of acute respiratory disease in military recruits. Clusters of particularly severe disease have been seen with adenovirus 14.


InternalMed_Harrison

InternalMed_Harrison. Adenovirus infection can be transmitted by inhalation of aerosolized virus, by inoculation of virus into conjunctival sacs, and probably by the fecal-oral route as well. Type-specific antibody generally develops after infection and is associated with protection—albeit incomplete—against infection with the same serotype.


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InternalMed_Harrison. In children, adenoviruses cause a variety of clinical syndromes. The most common is an acute upper respiratory tract infection, with prominent rhinitis. On occasion, lower respiratory tract disease, including bronchiolitis and pneumonia, also develops. Adenoviruses, particularly types 3 and 7, cause pharyngoconjunctival fever, a characteristic acute febrile illness of children that occurs in outbreaks, most often in summer camps. The syndrome is marked by bilateral conjunctivitis in which the bulbar and palpebral conjunctivae have a granular appearance. Low-grade fever is frequently present for the first 3–5 days, and rhinitis, sore throat, and cervical adenopathy develop. The illness generally lasts for 1–2 weeks and resolves spontaneously. Febrile pharyngitis without conjunctivitis has also been associated with adenovirus infection. Adenoviruses have been isolated from cases of whooping cough with or without Bordetella pertussis; the significance of adenovirus in that disease is


InternalMed_Harrison

InternalMed_Harrison. also been associated with adenovirus infection. Adenoviruses have been isolated from cases of whooping cough with or without Bordetella pertussis; the significance of adenovirus in that disease is unknown.


InternalMed_Harrison

InternalMed_Harrison. In adults, the most frequently reported illness has been acute respiratory disease caused by adenovirus types 4 and 7 in military recruits. This illness is marked by a prominent sore throat and the gradual onset of fever, which often reaches 39°C (102.2°F) on the second or third day of illness. Cough is almost always present, and coryza and regional lymphadenopathy are frequently seen. Physical examination may show pharyngeal edema, injection, and tonsillar enlargement with little or no exudate. If pneumonia has developed, auscultation and x-ray of the chest may indicate areas of patchy infiltration.


InternalMed_Harrison

InternalMed_Harrison. Adenoviruses have been associated with a number of non–respiratory tract diseases, including acute diarrheal illness caused by types 40 and 41 in young children and hemorrhagic cystitis caused by types 11 and 21. Epidemic keratoconjunctivitis, caused most frequently by types 8, 19, and 37, has been associated with contaminated common sources such as ophthalmic solutions and roller towels. Adenoviruses have also been implicated in disseminated disease and pneumonia in immunosuppressed patients, including recipients of SOTs or HSCTs. In HSCT recipients, adenovirus infections have manifested as pneumonia, hepatitis, nephritis, colitis, encephalitis, and hemorrhagic cystitis. In SOT recipients, adenovirus infection may involve the organ transplanted (e.g., hepatitis in liver transplants, nephritis in renal transplants) but can disseminate to other organs as well. In patients with AIDS, high-numbered and intermediate adenovirus serotypes have been isolated, usually in the setting of low


InternalMed_Harrison

InternalMed_Harrison. in renal transplants) but can disseminate to other organs as well. In patients with AIDS, high-numbered and intermediate adenovirus serotypes have been isolated, usually in the setting of low CD4+ T cell counts, but their isolation often has not been clearly linked to disease manifestations. Adenovirus nucleic acids have been detected in myocardial cells from patients with “idiopathic” myocardiopathies, and adenoviruses have been suggested as causative agents in some cases.


InternalMed_Harrison

InternalMed_Harrison. Adenovirus infection should be suspected in the epidemiologic setting of acute respiratory disease in military recruits and in certain clinical syndromes (such as pharyngoconjunctival fever or epidemic keratoconjunctivitis) in which outbreaks of characteristic illnesses occur. In most cases, however, illnesses caused by adenovirus infection cannot be differentiated from those caused by a number of other viral respiratory agents and Mycoplasma pneumoniae. A definitive diagnosis of adenovirus infection is established by detection of the virus in tissue culture (as evidenced by cytopathic changes) and by specific identification with immunofluorescence or other immunologic techniques. Rapid viral diagnosis can be established by immunofluorescence or ELISA of nasopharyngeal aspirates, conjunctival or respiratory secretions, urine, or stool. Highly sensitive and specific PCR assays and nucleic acid hybridization are available and have become the standard for diagnosis based on clinical


InternalMed_Harrison

InternalMed_Harrison. or respiratory secretions, urine, or stool. Highly sensitive and specific PCR assays and nucleic acid hybridization are available and have become the standard for diagnosis based on clinical specimens. Adenovirus types 40 and 41, which have been associated with diarrheal disease in children, require special tissue-culture cells for isolation, and these serotypes are most commonly detected by direct ELISA of stool or by PCR. Serum antibody rises can be demonstrated by complement-fixation or neutralization tests, ELISA, radioimmunoassay, or (for those adenoviruses that hemagglutinate red cells) hemagglutination-inhibition tests.


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InternalMed_Harrison. Only symptom-based treatment and supportive therapy are available for adenovirus infections, and clinically useful antiviral therapy has not been established. Ribavirin and cidofovir are active in vitro against certain adenoviruses. Retrospective studies and anecdotes describe the use of these agents in disseminated adenovirus infections, but definitive efficacy data from controlled studies are not available. An oral liposomal form of cidofovir (CMX001) is being evaluated for adenovirus infections in immunosuppressed patients.


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InternalMed_Harrison. Live vaccines have been developed against adenovirus types 4 and 7 and have been highly efficacious in control of acute respiratory disease among military recruits. These vaccines consist of live, unattenuated virus administered in enteric-coated capsules. Infection of the gastrointestinal tract with types 4 and 7 does not cause disease but stimulates local and systemic antibodies that are protective against subsequent acute respiratory disease due to those serotypes. These vaccines were not produced from 1999 to 2011 but are now available again and are being used effectively in military recruits. Adenoviruses are also being studied as live-virus vectors for the delivery of vaccine antigens and Yehuda Z. Cohen, Raphael Dolin


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InternalMed_Harrison. Yehuda Z. Cohen, Raphael Dolin Influenza is an acute respiratory illness caused by infection with influenza viruses. The illness affects the upper and/or lower respiratory tract and is often accompanied by systemic signs and symptoms such as fever, headache, myalgia, and weakness. Outbreaks of illness of variable extent and severity occur nearly every year. Such outbreaks result in significant morbidity rates in the general population and in increased mortality rates among certain high-risk patients, mainly as a result of pulmonary complications.


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InternalMed_Harrison. Influenza viruses are members of the Orthomyxoviridae family, of which influenza A, B, and C viruses constitute three separate genera. The designation of influenza viruses as type A, B, or C is based on antigenic characteristics of the nucleoprotein (NP) and matrix (M) protein antigens. Influenza A viruses are further subdivided (subtyped) on the basis of the surface hemagglutinin (H) and neuraminidase (N) antigens; individual strains are designated according to the site of origin, isolate number, year of isolation, and subtype—for example, influenza A/California/07/2009 (H1N1). Influenza A has 18 distinct H subtypes and 11 distinct N subtypes, of which only H1, H2, H3, N1, and N2 have been associated with epidemics of disease in humans. Avian influenza A viruses have been associated with small outbreaks and sporadic cases in humans (see below). Influenza B and C viruses are designated similarly to influenza A viruses, but H and N antigens from these viruses do not receive subtype


InternalMed_Harrison

InternalMed_Harrison. small outbreaks and sporadic cases in humans (see below). Influenza B and C viruses are designated similarly to influenza A viruses, but H and N antigens from these viruses do not receive subtype designations because intratypic variations in influenza B antigens are less extensive than those in influenza A viruses and may not occur with influenza C virus.


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InternalMed_Harrison. Influenza A and B viruses are major human pathogens and the most extensively studied of the Orthomyxoviridae. Type A and type B viruses are morphologically similar. The virions are irregularly shaped spherical particles, measure 80–120 nm in diameter, and have a lipid envelope from the surface of which the H and N glycoproteins project (Fig. 224-1). The hemagglutinin is the site by which the virus binds to sialic acid cell receptors, whereas the neuraminidase degrades the receptor and plays a role in the release of the virus from infected cells after replication has taken place. Influenza viruses enter cells by receptor-mediated endocytosis, forming a virus-containing endosome. The viral hemagglutinin mediates fusion of the endosomal membrane with the virus envelope, and viral nucleocapsids are subsequently released into the cytoplasm. Immune responses to the H antigen are the major determinants of protection against infection with influenza virus, whereas those to the N antigen limit


InternalMed_Harrison

InternalMed_Harrison. are subsequently released into the cytoplasm. Immune responses to the H antigen are the major determinants of protection against infection with influenza virus, whereas those to the N antigen limit viral spread and contribute to reduction of the infection. The lipid envelope of influenza A virus also contains the M proteins M1 and M2, which are involved in stabilization of the lipid envelope and in virus assembly. The virion also contains the NP antigen, which is associated with the viral genome, as well as three polymerase (P) proteins that are essential for transcription


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InternalMed_Harrison. FIGuRE 224-1 An electron micrograph of influenza A virus (×40,000). and synthesis of viral RNA. Two nonstructural proteins function as an interferon antagonist and posttranscriptional regulator (NS1) and a nuclear export factor (NS2 or NEP). The genomes of influenza A and B viruses consist of eight single-strand RNA segments, which code for the structural and nonstructural proteins. Because the genome is segmented, the opportunity for gene reassortment during infection is high; reassortment often takes place during infection of cells with more than one influenza A virus.


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InternalMed_Harrison. Influenza outbreaks occur virtually every year, although their extent and severity vary widely. Localized outbreaks take place at variable intervals, usually every 1–3 years. Global pandemics have occurred at variable intervals, but much less frequently than interpandemic outbreaks (Table 224-1). The most recent pandemic emerged in March of 2009 and was caused by an influenza A/H1N1 virus that rapidly spread worldwide over the next several months.


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InternalMed_Harrison. Influenza A Virus • antigenic variation and inflUenza oUtbreaks and pandemics The most extensive and severe outbreaks of influenza are caused by influenza A viruses, in part because of the remarkable propensity of the H and N antigens of these viruses to undergo periodic antigenic variation. Major antigenic variations, called antigenic shifts, are seen only with influenza A viruses and may be associated with pandemics. Minor variations are called antigenic drifts. Antigenic variation may involve the hemagglutinin alone or both the hemagglutinin and the neuraminidase. An example of an antigenic shift involving both the hemagglutinin and the neuraminidase is that of 1957, when the predominant influenza A virus subtype shifted from H1N1 to H2N2; this shift resulted in a severe pandemic, with an estimated 70,000 excess deaths (i.e., deaths in excess of the number expected without an influenza epidemic) in the United States alone. This excess mortality was significantly greater than that


InternalMed_Harrison

InternalMed_Harrison. an estimated 70,000 excess deaths (i.e., deaths in excess of the number expected without an influenza epidemic) in the United States alone. This excess mortality was significantly greater than that during interpandemic influenza seasons.


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InternalMed_Harrison. a As determined by retrospective serologic survey of individuals alive during those years (“seroarchaeology”). b Hemagglutinins formerly designated as Hsw and H0 are now classified as variants of H1. c From this time until 2008–2009, viruses of the H1N1 and H3N2 subtypes circulated either in alternating years or concurrently. d A novel influenza A/H1N1 virus emerged to cause this pandemic.


InternalMed_Harrison

InternalMed_Harrison. 1210 In 1968, an antigenic shift involving only the hemagglutinin occurred (H2N2 to H3N2); the subsequent pandemic was less severe than that of 1957. In 1977, an H1N1 virus emerged and caused a pandemic that primarily affected younger individuals (i.e., those born after 1957). As shown in Table 224-1, H1N1 viruses circulated from 1918 to 1956; thus, individuals born prior to 1957 would be expected to have some degree of immunity to H1N1 viruses. The pandemic of 2009–2010 was caused by an A/H1N1 virus against which little immunity was present in the general population, although approximately one-third of individuals born before 1950 had some apparent immunity to related H1N1 strains. During most outbreaks of influenza A, a single subtype has circulated at a time. However, since 1977, H1N1 and H3N2 viruses have circulated simultaneously, resulting in outbreaks of varying severity. In some outbreaks, influenza B viruses have also circulated simultaneously with influenza A viruses. In


InternalMed_Harrison

InternalMed_Harrison. and H3N2 viruses have circulated simultaneously, resulting in outbreaks of varying severity. In some outbreaks, influenza B viruses have also circulated simultaneously with influenza A viruses. In 2009–2010, the pandemic A/H1N1 virus appeared to circulate nearly exclusively.


InternalMed_Harrison

InternalMed_Harrison. featUres of pandemic and interpandemic inflUenza a Pandemics provide the most dramatic evidence of the impact of influenza A. However, illnesses occurring between pandemics (interpandemic disease) also account for extensive mortality and morbidity, albeit over a longer period. In the United States, influenza was associated with an average of 23,000 excess deaths per season in 1976–2007 and with a maximum of 48,600 excess deaths during the 2003–2004 season.


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InternalMed_Harrison. Influenza A viruses that circulate between pandemics demonstrate antigenic drifts in the H antigen. These antigenic drifts result from point mutations in the RNA segment that codes for the hemagglutinin and occur most frequently in five hypervariable regions. Epidemiologically significant strains—that is, those with the potential to cause widespread outbreaks—exhibit changes in amino acids in at least two of the major antigenic sites in the hemagglutinin molecule. Because two point mutations are unlikely to occur simultaneously, it is believed that antigenic drifts result from point mutations occurring sequentially during the spread of virus from person to person. Antigenic drifts have been reported nearly annually since 1977 for H1N1 viruses and since 1968 for H3N2 viruses.


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InternalMed_Harrison. Interpandemic influenza A outbreaks usually begin abruptly, peak over a 2to 3-week period, generally last for 2–3 months, and often subside almost as rapidly as they began. In contrast, pandemic influenza may begin with rapid transmission at multiple locations, have high attack rates, and extend beyond the usual seasonality, with multiple waves of attack before or after the main outbreak. In interpandemic outbreaks, the first indication of influenza activity is an increase in the number of children with febrile respiratory illnesses who present for medical attention. This increase is followed by increases in rates of influenza-like illnesses among adults and eventually by an increase in hospital admissions for patients with pneumonia, worsening of congestive heart failure, and exacerbations of chronic pulmonary disease. Rates of absence from work and school also rise at this time. An increase in the number of deaths caused by pneumonia and influenza is generally a late observation in


InternalMed_Harrison

InternalMed_Harrison. of chronic pulmonary disease. Rates of absence from work and school also rise at this time. An increase in the number of deaths caused by pneumonia and influenza is generally a late observation in an outbreak. Attack rates have been highly variable from outbreak to outbreak in interpandemic influenza but most commonly are in the range of 10–20% of the general population.


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InternalMed_Harrison. Although pandemic influenza may occur throughout the year, interpandemic influenza occurs almost exclusively during the winter months in the temperate zones of the Northern and Southern hemispheres. In those locations, it is highly unusual to detect influenza A virus at other times, although rises in serum antibody titer or even outbreaks have been noted rarely during warm-weather months. In contrast, influenza virus infections occur throughout the year in the tropics. Where or how influenza A viruses persist between outbreaks in temperate zones is unknown. It is possible that the viruses are maintained in the human population on a worldwide basis by person-to-person transmission and that large population clusters support a low level of interepidemic transmission. Alternatively, human strains may persist in animal reservoirs. Convincing evidence to support either explanation is not available. In the modern era, rapid transportation may contribute to the transmission of viruses among


InternalMed_Harrison

InternalMed_Harrison. may persist in animal reservoirs. Convincing evidence to support either explanation is not available. In the modern era, rapid transportation may contribute to the transmission of viruses among widespread geographic locales.


InternalMed_Harrison

InternalMed_Harrison. The factors that result in the inception and termination of outbreaks of influenza A are incompletely understood. A major determinant of the extent and severity of an outbreak is the level of immunity in the population at risk. With the emergence of an antigenically novel influenza virus to which little or no immunity is present in a community, extensive outbreaks may occur. When the absence of immunity is worldwide, epidemic disease may spread around the globe, resulting in a pandemic. Such pandemic waves can continue for several years, until immunity in the population reaches a high level. In the years following pandemic influenza, antigenic drifts among influenza viruses result in outbreaks of variable severity in populations with high levels of immunity to the pandemic strain that circulated earlier. This situation persists until another antigenically novel pandemic strain emerges. On the other hand, outbreaks sometimes end despite the persistence of a large pool of susceptible


InternalMed_Harrison

InternalMed_Harrison. earlier. This situation persists until another antigenically novel pandemic strain emerges. On the other hand, outbreaks sometimes end despite the persistence of a large pool of susceptible individuals in the population. It has been suggested that certain influenza A viruses may be intrinsically less virulent and cause less severe disease than other variants, even in immunologically virgin subjects. If so, then other (undefined) factors besides the level of preexisting immunity must play a role in the epidemiology of influenza.


InternalMed_Harrison

InternalMed_Harrison. Avian and Swine Influenza Viruses Aquatic birds are the largest reservoir of influenza A viruses, harboring 16 hemagglutinin (H1–H16) and nine neuraminidase (N1–N9) subtypes. (In addition, H17N10 and H18N11 viruses are found in bats.) Influenza A pandemic strains in 1957 (A/H2N2) and in 1968 (A/H3N2) resulted from reassortment of gene segments between human and avian viruses. The influenza A/ H1N1 virus that caused the most severe pandemic of modern times (1918–1919) appears to have been an adaptation of an avian virus to human infection. Thus, there is concern that avian influenza viruses with novel hemagglutinin and neuraminidase antigens have the potential to emerge as pandemic strains.


InternalMed_Harrison

InternalMed_Harrison. Avian influenza A viruses have been reported to cause spo radic cases and small outbreaks in humans, usually after direct contact with birds (most commonly poultry). Sustained person-to-person transmission in the community has not been observed. Avian influenza A/H5N1 virus has been noted to cause illness in humans since 1997, with 648 cases reported to the World Health Organization as of January 2014. It is not clear whether the high observed case–fatality rate (59%) reflects preferential detection of severe cases. A/H7N7 infections have been noted in poultry industry workers; conjunctivitis was the most prominent feature, although a minority of individuals also had respiratory illness. More than 333 cases of avian A/H7N9 infection have been reported in China, with case–fatality rates of 36% among the infected patients admitted to the hospital. Most H7N9 isolates are sensitive to neuraminidase inhibitors, but a few isolates have exhibited high-level resistance to oseltamivir and


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InternalMed_Harrison. of 36% among the infected patients admitted to the hospital. Most H7N9 isolates are sensitive to neuraminidase inhibitors, but a few isolates have exhibited high-level resistance to oseltamivir and diminished sensitivity to zanamivir. Infections with avian H9N2 viruses have been reported primarily among children in Hong Kong and have consisted largely of mild respiratory illnesses. Mild cases of illness due to influenza H10N7 virus in Egypt and Australia have also been reported. In 2013, the first cases of human infection with avian A/ H10N8 and H6N1 viruses were described.