HPV

Background

Papillomaviruses affect a wide variety of animals. They cause tumors that erupt from DNA mutations in humans, monkeys, deer, horses, cattle, dogs, birds, and rabbits. The Los Alamos National Laboratory in the United States maintains a database of papillomavirus genomic sequences and a phylogenic tree, both of which are available at HPV Sequence Database.

Human papillomaviruses (HPVs) produce epithelial tumors of the skin and mucous membranes. More than 100 HPV types have been detected, and the genomes of more than 80 have been completely sequenced. The current classification system, which is based on similarities in their genomic sequences, generally correlates with the 3 categories used to describe HPV clinically: anogenital and/or mucosal, nongenital cutaneous, and epidermodysplasia verruciformis (EV).

The mucosal HPV infections are classified further as latent (asymptomatic), subclinical, or clinical. Clinical lesions are grossly apparent, whereas latent infections are detected only with tests for viral DNA. Subclinical lesions are identified by application of 3-5% acetic acid and inspection under magnification. Most HPV infections are latent; clinically apparent infections usually result in warts rather than malignancies.

HPV types 6 and 11 are typically labeled as low risk because infection with these types has low oncogenic potential and usually results in the formation of condylomata and low-grade precancerous lesions. HPV types 16 and 18 have emerged as the high-risk types of HPV because they are responsible for most high-grade intraepithelial lesions that may progress to carcinomas, particularly those in the anogenital and/or mucosal category.

HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression have been implicated in this process. The table lists a variety of diseases and the associated HPV subtypes.

Diseases and Associated HPV SubtypesNongenital Cutaneous Disease HPV Type
Common warts (verrucae vulgaris)
Warts (Nongenital) 1, 2, 4, 26, 27, 29, 41, 57, 65
Plantar warts (myrmecias)
Warts, Plantar 1, 2, 4, 63
Flat warts (verrucae plana) 3, 10, 27, 28, 38, 41, 49
Butcher's warts (common warts of people who handle meat, poultry, and fish)
1, 2, 3, 4, 7, 10, 28
Mosaic warts 2, 27, 57
Ungual squamous cell carcinoma 16
Epidermodysplasia verruciformis (benign)
Epidermodysplasia Verruciformis 2, 3, 10, 12, 15, 19, 36, 46, 47, 50
Epidermodysplasia verruciformis (malignant or benign)
Epidermodysplasia Verruciformis 5, 8, 9, 10, 14, 17, 20, 21, 22, 23, 24, 25, 37, 38
Nonwarty skin lesions 37, 38
Nongenital Mucosal Disease HPV Type
Respiratory papillomatosis
Recurrent Respiratory Papillomatosis 6, 11
Squamous cell carcinoma of the lung 6, 11, 16, 18
Laryngeal papilloma 6, 11, 30
Laryngeal carcinoma 16, 18
Maxillary sinus papilloma 57
Squamous cell carcinoma of the sinuses 16, 18
Conjunctival papillomas 6, 11
Conjunctival carcinoma 16
Oral focal epithelial hyperplasia (Heck disease) 13, 32
Oral carcinoma 16, 18
Oral leukoplakia 16, 18
Squamous cell carcinoma of the esophagus 16, 18
Anogenital Disease HPV Type
Condylomata acuminata 6, 11, 30, 42, 43, 44, 45, 51, 52, 54
Bowenoid papulosis
Bowenoid Papulosis 16, 18, 34, 39, 42, 45
Bowen disease 16, 18, 31, 34
Giant condylomata (Buschke-Löwenstein tumors)
Giant Condylomata Acuminata of Buschke and Löwenstein 6, 11
Unspecified intraepithelial neoplasia 30, 34, 39, 40, 53, 57, 59, 61, 62, 64, 66, 67, 68, 69
Low-grade intraepithelial neoplasia 6, 11, 43
Intermediate intraepithelial neoplasia 31, 33, 35, 42, 44, 45, 51, 52
High-grade intraepithelial neoplasia 16, 18, 56, 58
Carcinoma of vulva
Malignant Vulvar Lesions 6, 11, 16, 18
Carcinoma of vagina 16
Carcinoma of cervix
Cervical Cancer 16, 18, 31
Carcinoma of anus 16, 31, 32, 33
Carcinoma in situ of penis (erythroplasia of Queyrat) 16
Carcinoma of penis 16, 18



Pathophysiology

Papillomaviruses are highly species specific and do not infect other species, even under laboratory conditions. Humans are the only known reservoir for HPV. Papillomaviruses are nonenveloped viruses of icosahedral symmetry with 72 capsomeres that surround a genome containing double-stranded circular DNA with approximately 8000 base pairs.

Papillomaviruses are thought to have 2 modes of replication. One is stable replication of the episomal genome in basal cells; the other is runaway, or vegetative, replication in more differentiated cells to generate progeny virus. Although all cells of a lesion contain the viral genome, the expression of viral genes is tightly linked to the state of cellular differentiation. Most viral genes are not activated until the infected keratinocyte leaves the basal layer. Production of virus particles can occur only in highly differentiated keratinocytes; therefore, virus production only occurs at the epithelial surface where the cells are ultimately sloughed into the environment.

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic, rather viral particles are released as a result of degeneration of desquamating cells. The HPV virus can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot.

Virus multiplication is confined to the nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis (from the Greek koilos, meaning empty) describes a combination of perinuclear clearing (halo) with a pyknotic or shrunken (rasinoid) nucleus and is a characteristic feature of productive papillomavirus infection.

The HPV genome exists as a circular episomal DNA separate from the host cell nucleus in benign or low-risk HPV lesions, such as those typically associated with HPV types 6 and 11. The genomes of high-risk HPV types 16 and 18 are typically integrated into the host cell DNA in malignant lesions. Integration of the viral genome into the host cell genome is considered a hallmark of malignant transformation. HPV proteins E6 and E7 of high-risk serotypes have been shown to inactivate the host's tumor suppressor proteins p53 and Rb, thereby resulting in unregulated host cell proliferation and malignant transformation.

Frequency

United States

The number of patients identified with HPV disease has increased markedly during the past 20 years because of heightened awareness of the various manifestations of HPV disease and because of increased use of HPV DNA testing.

Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with the human immunodeficiency virus (HIV), are especially susceptible to developing HPV infections.

In the United States, 2.5 million women are estimated to have an annual cytological diagnosis of a low-grade cervical cancer precursor.

The incidence of Cervical Cancer has decreased dramatically during the last century because of implementation of the Papanicolaou test (Pap Test, or Pap smear) beginning in the 1930s and 1940s. However, from 1990-2001 the annual number of estimated new invasive cervical cancers has remained relatively constant, ie, 13,500 and 12,900, respectively.

Anogenital warts, or condylomata acuminata, are the most commonly diagnosed viral sexually transmitted disease (STD) in the United States and the United Kingdom. The annual incidence is estimated between 500,000 and 1 million cases. From 1966-1986, the incidence of genital warts has increased 5-fold.

Approximately 7-10% of the population has nongenital cutaneous warts.

International

The worldwide prevalence of HPV in cervical carcinoma is 95-99.7% and in anal cancer is 88%.

In many lesser-developed countries, cervical cancer is the most common cancer among women because of the lack of effective screening programs that monitor cervical cytology by Pap smear.

In many developing nations, cervical cancer is the leading cause of cancer mortality among women. Worldwide, it is the second most common cause of cancer mortality among women.

Mortality/Morbidity

Anogenital/mucosal disease: A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners. Women with a history of a cervical high-grade squamous intraepithelial lesion (HGSIL) or invasive squamous cell carcinoma (SCC) of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma. In these patients, the relative risk of vaginal carcinoma is 5.6, and the risk of anal carcinoma is 4. Anal cancer has been strongly associated with male homosexuality and specific male practices, such as engaging in receptive anal intercourse. Relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.
Nongenital cutaneous warts: Cutaneous lesions typically produce benign self-limited warts (see Warts [Nongenital]).
EV: Patients who are immunosuppressed, particularly those with cutaneous malignant lesions, have a much higher incidence of EV-HPV infection than the general population. These lesions can undergo malignant transformation. Ten percent of patients with EV originate from consanguineous marriages, suggesting an autosomal recessive mode of inheritance (see Epidermodysplasia Verruciformis).
Race

From 1987-1991, the age-adjusted Cervical Cancer death rate reported by the US National Cancer Institute was higher among black women compared to white women, with a ratio of 6:1.
Nongenital cutaneous warts are more common in whites than in people of African descent.

Sex

The overall prevalence of HPV in women is 22-35%.
In men, the prevalence is 2-35% depending on the sexual practices of the population being studied.

Age

Anogenital mucosal HPV infections are highest among college-aged women and men.
Nongenital cutaneous warts are more common among teenagers and adults who work as meat, poultry, and fish handlers. The incidence approaches 10% in child and young adult populations. However, nongenital cutaneous warts rarely occur in people younger than 5 years and usually regress within 2 years.
EV develops at an average age of onset of 6 years, and, beginning in the fourth decade of life, the lesions can undergo malignant transformation into invasive SCC.

CLINICAL

History

Anogenital warts
Condylomata acuminata are exophytic cauliflowerlike lesions that are usually found near moist surfaces. They may be observed in the perianal area, vaginal introitus, vagina, labia, and vulva. Genital warts may also be found on dry surfaces, such as the shaft of the penis.
Genital warts include smooth papular warts and keratotic warts, the latter of which resemble nongenital cutaneous warts because of their thickened bumpy surface.
Genital flat warts are subclinical lesions that typically appear on the cervix. Colposcopic examination with 3% acetic acid solution is required for identification.
Cervical disease
Most cervical infections are either latent or subclinical and, as such, are asymptomatic. These infections are detected on Pap smear and are reported as either a low-grade squamous intraepithelial lesion (LGSIL) or a high-grade squamous intraepithelial lesion (HGSIL). Further examination with 3-5% acetic acid and colposcopy shows characteristic acetowhite changes and abnormal blood vessels indicative of HPV-triggered dysplasia.
Patients who have neglected to obtain annual Pap testing for several years or more and who have an HGSIL that has progressed to invasive cancer of the cervix may report vaginal bleeding between periods or after sexual intercourse, dyspareunia, and fullness in the pelvis.
Anal cancer
The most common presenting symptoms of SCC of the anus are rectal bleeding and sensation of a mass. This may be attributed mistakenly to hemorrhoids.
Fifty percent of men who are homosexual and have SCC of the anus have a history of anorectal warts; however, only 20% of women with SCC and men who are not homosexual have this history.

Nonanogenital mucosal disease

HPV types 6 and 11 have been isolated on nonanogenital mucosal surfaces. Warts have been discovered in the nares, mouth, larynx, and conjunctiva.
HPV types 6 and 11 are associated with respiratory papillomas that are probably the result of intrapartum transmission when the infant passes through the birth canal of a mother who is infected with HPV. However, isolated case reports exist of respiratory papillomatosis after cesarean delivery. Patients with laryngeal papillomas present at an average age of 3 years, most frequently with hoarseness.

Nongenital cutaneous HPV

Cutaneous lesions typically produce benign self-limited warts.
Deep plantar warts occur most commonly as solitary lesions that may become black and painful prior to spontaneous regression. They may contain small black "seeds," which are thrombosed capillaries.
Common warts can occur on any skin surface but are usually found on the hands and fingers. They appear as skin-colored, exophytic, rough papules and nodules that have minimal scaling. Autoinoculation from a wart on one finger may cause the occurrence of warts on an adjacent finger or other skin surface, so-called kissing warts.
Warts that occur in people who handle meat and fish often have large cauliflowerlike plaques.
Flat warts most often occur in groups of small plaques less than 5 mm in diameter on the face and hands. Regression usually occurs spontaneously after several years, and pruritus or erythema occur several weeks prior to their disappearance.

Epidermodysplasia verruciformis

The malignant conversion of skin lesions usually begins in the fourth and fifth decades of life. Premalignant lesions usually first arise on the forehead and other sun-exposed areas. The tumors are either benign papillomas and seborrheic keratoses or premalignant actinic keratoses and SCC.
EV tumors are locally destructive. They develop slowly and have weak metastatic potential if no cocarcinogens, such as x-ray or ultraviolet B irradiation, are applied. Polymorphic, plane wart–like, and red-to-brownish plaques can be distributed widely over the skin. The lymph nodes and oral mucosa are not involved.
Physical

The findings on physical examination depend on the tissues involved. They include a variety of cutaneous lesions with characteristic appearances noted above. Images 1-4 demonstrate extensive anogenital condyloma acuminata.
Causes

Types of HPV demonstrate a high degree of site specificity, with some HPV types only found on certain parts of the skin or mucous membranes.
HPV infection alone does not cause malignant transformation of infected tissue. Cofactors, such as tobacco use, ultraviolet radiation, pregnancy, folate deficiency, and immune suppression, have been implicated in this process. Patients receiving immunosuppressive drugs and patients with defects in cell-mediated immunity, including those infected with HIV are especially susceptible to developing HPV infections.
A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.

DIFFERENTIALS

Benign Cervical Lesions
Benign Vulvar Lesions
Carbon Dioxide Laser Surgery of the Lower Genital Tract
Cervical Cancer
Conization of Cervix
Gynecologic Cryosurgery
Hemorrhoids
Hidradenitis Suppurativa
Malignant Vulvar Lesions
Molluscum Contagiosum
Penile Cancer
Recurrent Respiratory Papillomatosis
Surgical Treatment of Vaginal Cancer
Surgical Treatment of Vulvar Cancer
Urethral Warts

Other Problems to be Considered

Actinic keratoses
Carbon dioxide laser surgery for intraepithelial cervical neoplasms
Cervical polyp
Condyloma lata
Dermatitis papillaris
Nevi
Oropharyngeal SCC
Pityriasis versicolor
Sinonasal Papillomas, Treatment
Warts (Nongenital)
Pap Test
Recurrent Respiratory Papillomatosis
Squamous Cell Carcinoma
Warts, Plantar
Bowenoid Papulosis
Warts
Epidermodysplasia Verruciformis
Squamous Cell Carcinoma, Eyelid
Warts (Genital)
Giant Condylomata Acuminata of Buschke and Löwenstein
Acanthosis Nigricans
Acrochordon
Corns and Calluses
Keloid and Hypertrophic Scar
Keratoacanthoma
Lichen Planus
Psoriasis (Plaque)
Seborrheic Keratosis
Malignant Tumors of the Mobile Tongue

WORKUP

Lab Studies

Cytologic testing

Cervical cytologic testing using the Pap test is the standard screening procedure for cervical neoplasia. It should be performed annually in all women beginning 3 years after they become sexually active or when they have reached age 21 years if they have remained abstinent. Once a woman has had findings within the reference range on 3 or more consecutive annual Pap smears, the Pap smear may be performed less frequently if the patient is at low risk for developing cervical dysplasia.
Pap smears should contain samples of cells from the ectocervix, transformation zone, and endocervical canal. Perform the test when the patient is not menstruating so that the cytologic specimen is not occluded with blood. Furthermore, if the patient has a cervicovaginal infection with a mucopurulent vaginal discharge, consider performing the test after the bacterial infection has resolved. If the test must be performed, the discharge should be gently cleared with a saline-moistened cotton swab.
This test may be modified as required to sample tissues of the vagina, vulva, or perianal region that are suspicious for intraepithelial neoplasia. Although not an established routine, consider performing annual anal Pap smears on men who have high risk and who participate in receptive anal intercourse. See Cervical Cancer for guidelines on how often to perform the Pap smear when abnormalities result.
Liquid-based Pap smears improve the diagnostic sensitivity of cervical cytology screening. They have the additional benefit of enabling easy testing for HPV. Thin Prep and SurePath are the 2 methods currently approved by the US Food and Drug Administration (FDA).

HPV DNA typing

The 2 common methods for HPV DNA testing include the Hybrid Capture II (HC II) and the polymerase chain reaction (PCR) enzyme immunosorbent assay. Both of these methods have similarly high sensitivities and are suitable tools for detection of HPV and posttreatment follow-up of cervical intraepithelial neoplasia (CIN).
HPV DNA testing is the preferred approach in the treatment of women whose Pap test results show atypical squamous cells of undetermined significance (ASC-US) whenever liquid-based cytology is used or co-collection is available. HPV DNA testing is also useful in the management of CIN in certain situations. Detailed consensus guidelines for management of abnormal Pap test results and management of CIN are available at American Society for Colposcopic and Cervical Pathology.

Procedures

Tissue biopsy
Tissue biopsy can be used to confirm HPV infection if the diagnosis is uncertain, particularly if warts are abnormally pigmented, ulcerated, or indurated.
Obtain a biopsy of a warty lesion if the patient is immunocompromised, if the lesions worsen during treatment, or if they do not respond to standard therapy. In addition, biopsy is recommended to clarify the diagnosis in older patients who are at risk for genital carcinoma.

Histologic Findings

Virus multiplication is confined to the host cell nucleus. Consequently, infected cells exhibit a high degree of nuclear atypia. Koilocytosis describes a combination of perinuclear clearing with a pyknotic or shrunken nucleus and is a characteristic feature of productive papillomavirus infection. Other cytologic markers of HPV infection include acanthosis, dyskeratosis, and multinucleation.

TREATMENT

Medical Care

Eradication or reduction of symptoms is the primary goal of treating warts, but elimination of dysplastic lesions is the goal in treating squamous intraepithelial lesions (SILs). Treatment is not recommended for subclinical anogenital and/or mucosal HPV infection in the absence of coexistent dysplasia. No evidence demonstrates that treatment eliminates HPV infection or that it decreases infectivity. In fact, warts may recur after treatment because of activation of latent virus present in healthy skin adjacent to the lesion.

Superiority of any single treatment modality has not been demonstrated, nor is one modality ideal for all types of warts. Factors that influence treatment of HPV disease include the size, morphology, number, and anatomic site of lesions, as well as cost, adverse effects, patient preference, and provider experience.

Most patients with warts require multiple treatments over a course of several weeks or months. If substantial improvements have not occurred after 3 physician-administered treatments or if complete clearance has not occurred after 6 treatments, a different treatment modality should be used.

Treatment

All medicines used to treat HPV disease are applied topically on cutaneous surfaces. Local skin reactions and pain are common adverse effects. Do not apply any of these medications to mucosal surfaces and do not use them to treat dysplastic lesions, SCC, verrucous carcinomas, or Bowenoid Papulosis.

Two broad categories of medications are effective in treating HPV disease. The first category, the immune response modifiers (ie, imiquimod, interferon alfa), is primarily used in treatment of external anogenital warts or condylomata acuminata. The second category consists of the cytotoxic agents, which include the antiproliferative drugs podofilox, podophyllin, and 5-fluorouracil, as well as the chemodestructive or keratolytic agents salicylic acid, trichloroacetic acid (TCA), and bichloroacetic acid (BCA).

None of these medicines has been shown to be uniformly effective or directly antiviral. The keratolytics are the only agents that are recommended for treatment of nongenital cutaneous warts.

Imiquimod

This immune response modifier has no direct antiviral activity; however, it is a powerful cytokine inducer, which stimulates production of interferon alfa, tumor necrosis factor, and interleukin (IL)-1, IL-6, and IL-8.
This patient-applied treatment is used for the treatment of external anogenital warts and condyloma acuminatum. It is applied 3 times per week, with application approximating an every-other-day routine (eg, Monday, Wednesday, Friday). Remove the cream by washing with mild soap and water 6-10 hours after application.
Treatment continues until the warts have completely cleared, up to a maximum of 16 weeks.
Local skin reactions are common, especially following contact with mucosal surfaces.

Interferon alfa

This naturally occurring cytokine is produced by recombinant DNA technology or by collection from pooled human leukocytes. It has potent immunomodulatory, as well as direct antiviral, effects.
This physician-applied medicine is used for intralesional treatment of external anogenital warts and condyloma acuminatum. It is injected into the base of each wart, preferably using a 30-gauge needle. For large warts, it may be injected at several points around the periphery of the wart, using a total dose of 250,000 IU per wart. Direct the needle at the center of the base of the wart and at an angle almost parallel to the plane of the skin (approximating that in the commonly used purified protein derivative [PPD] test).
The maximum response usually occurs 4-8 weeks after initiation of the first treatment course. If results at 12-16 weeks following the initial treatment course with interferon alfa-2b are not satisfactory, a second course of treatment using the same dosage schedule may be instituted, providing that clinical symptoms and signs or changes in laboratory parameters (eg, liver function tests, WBC count, platelet count) do not preclude such a course of action.
Patients with 6-10 condylomata may receive a second (sequential) course of treatment using the same dosage schedule to treat up to 5 additional condylomata per course of treatment. Patients with more than 10 condylomata may receive additional sequences depending on how many condylomata are present.

Podofilox

This antimitotic drug is either chemically synthesized or purified from naturally occurring podophyllin resin. Application stimulates visible necrosis of wart tissue.
This patient-applied medicine is used in the treatment of external genital warts or condyloma acuminatum. It is applied twice a day for 3 days, followed by 4 days of no therapy. This cycle can be repeated for a maximum of 4 cycles.
To ensure that the patient is fully aware of the correct method of therapy and to identify which specific warts should be treated, the prescriber should demonstrate the technique for initial application of the medication.
No more than 0.5 g of gel per day should be used. Limit the total wart tissue treated to 10 cm2 or less.

Podophyllin

This resin derived from the Mayapple (Podophyllum peltatum Linné) contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase.
Podophyllin is a physician-applied medicine used in the treatment of external genital warts and condyloma acuminatum. It can be applied weekly for up to 6 weeks.
Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly.
Initial application should be for 30-40 minutes. Subsequent applications can be for 1-4 hours. Remove dried podophyllin with alcohol or with soap and water. Do not treat large areas or numerous warts at once.

5-Fluorouracil

This antimetabolite interferes with the synthesis of DNA and RNA. This action creates a thymine deficiency, resulting in unbalanced growth and death of a cell.
This patient-applied treatment is not formally indicated for treatment of HPV disease; however, the 5% cream formulation can be helpful in the treatment of some genital warts. It is applied 1-3 times per week for several weeks as needed.
Prior to application, thoroughly cleanse the affected area. Avoid contact with healthy tissue. Apply the medicine sparingly and allow to dry thoroughly. Remove dried cream 3-10 hours after application.

Keratolytics

TCA and BCA are extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. The cauterizing effect is comparable to cryotherapy or electrodesiccation. These physician-applied agents can be used on all types of cutaneous warts.
An 80-90% solution is applied directly on a weekly basis. As the acid dries, a white frosting develops and should be powdered with sodium bicarbonate to remove any unreacted acid.
Salicylic acid is a milder keratolytic that is typically purchased in nonprescription formulations. This patient-applied medicine is used primarily to treat nongenital cutaneous warts.

Surgical Care

Various surgical techniques are available for the treatment of HPV disease. With the exception of cryosurgery, these modalities usually have the common advantage of complete treatment following one application. However, surgical modalities typically require local anesthesia and more time and equipment to implement. Consequently, they are often used when a large number of warts is present or a large area is affected or on patients with refractory disease. Recurrence of HPV disease is less common following surgical treatment as opposed to medical therapy.

Primary surgical therapy can often be accomplished in the office and includes cryosurgery; electrosurgery with either electrodesiccation or loop electrosurgical excision procedure (LEEP); or simple surgical excision with a scalpel, scissors, or curette.

Alternative surgical procedures requiring more advanced equipment and training include carbon dioxide laser ablation, Cavitron Ultrasonic Surgical Aspiration (CUSA), or Mohs surgery.

Cryosurgery (see Gynecologic Cryosurgery for further discussion)
This physically ablative method is a rapid and effective means of treating simple HPV disease. It works by freezing the intracellular water, resulting in cellular destruction.
Although it is somewhat painful, local anesthesia is not usually used. After 2-4 treatments in a 6- to 12-week period, 75-80% of patients experience a complete clearing of warts.
This method is effective for most simple cutaneous warts and for low-grade cervical intraepithelial neoplasia (CIN I). It is not recommended for use in the vagina because the depth of ablation cannot be controlled and damage to adjacent structures, such as the bladder and rectum, is possible.
Liquid nitrogen is applied to the wart using a cotton-tipped applicator, a cryoprobe, or a fine spray. Gases, such as nitrous oxide and carbon dioxide, can also be used.
The freeze-thaw-freeze method is considered more effective than a single freeze. Application is continued until up to a 5-mm margin of surrounding skin or mucosa is frozen. After the skin turns white, freezing is continued for 30 seconds and then the skin is allowed to thaw. If the patient can tolerate the pain, a second cycle is applied.
Within 24 hours after treatment, a bulla forms over the treated area. An additional course of treatment can be applied in 1-2 weeks as needed. This treatment modality is safe for use in women who are pregnant because it is not systemically absorbed.
Electrosurgery
These modalities use high-frequency current to cut and coagulate warts. Electrodesiccation using a bipolar needle can be used to coagulate wart tissue deeply. This is most effective with external genital warts.
LEEP uses a bipolar loop to vaporize and fulgurate affected tissue. It is primarily used to treat cervical SILs; however, it may also be used to remove large external genital warts.
Electrosurgical methods usually require only local anesthesia and may be employed in an outpatient setting if the appropriate equipment is available.
HPV DNA has been found in smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.
Surgical removal
Simple surgical excision with a scalpel, scissors, or curette can be performed under local anesthesia to remove warts and treat SILs of the genital tract.
Mohs surgery can be performed by specially trained dermatologists to excise tissue in areas where maximum conservation is required. This method uses dermatopathology in conjunction with conservative excision of malignant lesions. It may be of particular assistance in managing verrucous carcinomas.
Laser surgery (see Complications of Dermatologic Laser Surgery for further discussion)
Carbon dioxide laser vaporization is an alternative surgical procedure that is typically used for treatment of refractory HPV disease or extensive warts of the anogenital/mucosal category. This precisely controlled modality conserves normal adjacent tissue. It is particularly useful in treatment of periurethral and vaginal warts and vaginal SILs.
HPV DNA has been found in laser smoke plumes; therefore, procedures to evacuate the smoke and prevent inhalation must be used.
Cavitron Ultrasonic Surgical Aspirator
This device vibrates at a frequency of 23 kHz, which is an order of magnitude lower than the frequency of a diagnostic ultrasound. It destroys tissue through heat and cavitation.
CUSA has been used extensively for cytoreduction of intra-abdominal tumors because of the ability to remove epithelium without damage to underlying tissue. Consequently, it has been employed as an alternative therapy for extensive anogenital warts.
Consultations

Consult a gynecologic oncologist for assistance in management of genital tract SILs and carcinomas, as well as exophytic cervical warts and giant condylomata.
Consult a urologist or a urogynecologist for assistance with surgical management of urethral warts, penile condylomata, SILs, or carcinomas.
Consult a colorectal surgeon for assistance with the surgical management of perianal condylomata or anal SILs or carcinomas.
Consult an otolaryngologist for assistance with management of oropharyngeal papillomas or SCC.
Consult a dermatologist in the following cases:
Consult a dermatologist for assistance with management of EV.
Bleeding warts, moles, birthmarks, or unusual warts with hair growing from them can be confused with HPV disease. Refer these types of lesions to a dermatologist for diagnostic clarification.
Dermatologists who specialize in Mohs surgery, which uses dermatopathology in conjunction with the conservative excision of malignant lesions, may be of particular assistance in managing verrucous carcinomas.
Consult an infectious disease specialist for assistance in management of HPV disease in patients who are immunocompromised.
Diet

Folate deficiency is the only dietary factor that has been shown to play a role in early cervical carcinogenesis. Folate deficiency apparently facilitates incorporation of HPV DNA at a fragile chromosomal site, thereby establishing a basis for malignant transformation.
Activity

Certain activities are associated with an increased risk of HPV malignant transformation, particularly in the anogenital/mucosal category.

Sexual activity

A direct correlation exists between anogenital HPV infection and measures of sexual activity, such as the age of first intercourse and the lifetime number of sexual partners.
Women with a history of cervical HGSIL or invasive SCC of the cervix are at increased risk for subsequent development of invasive cancer in other tissues of the anogenital/mucosal category, particularly vaginal and anal carcinoma, with relative risks of 5.6 and 4 respectively.
Anal cancer has been strongly associated with male homosexuality and with specific male practices, such as engaging in receptive anal intercourse; relative risk is 33. However, the overall disease prevalence is higher in women than in men, with a female-to-male ratio of 1.5:1.
Tobacco smoking
Women who smoke tobacco have an increased risk of developing cervical neoplasia.
Measurable amounts of a potent carcinogen, as well as several compounds from cigarette smoke, have been identified in the cervical mucus of females who smoke. These agents are likely to play a role in the increased prevalence of HPV malignant transformation of patients who smoke tobacco.
Oral contraceptive use
Women who use oral contraceptives for longer than 5 years have an increased relative risk of developing cervical carcinoma.
This risk declines after stopping oral contraceptives, and no risk is demonstrated in users of less than 5 years duration.
Chewing Indian betel quid
A high incidence of oral cancer associated with HPV infection has been demonstrated in India among patients who chew betel quid.
This stimulant is made from the leaves of the betel plant and is used in a manner similar to chewing tobacco.
Ultraviolet and x-ray irradiation: EV is particularly susceptible to UV and x-ray irradiation; therefore, patients with EV should avoid activities that unnecessarily expose them to these forms of radiation.


MEDICATION


The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Immune response modifiers

These agents have immunomodulatory effects and are used for treatment of external anogenital warts or condyloma acuminatum.

Drug Name Imiquimod (Aldara)

Description Induces secretion of interferon alfa and other cytokines. Mechanisms of action are unknown.
Adult Dose Apply 3 times per wk, leave on skin for 6-10 h, remove by washing; treatment not to exceed 16 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Not recommended for treatment of rectal, cervical, intravaginal, urethral, and intra-anal HPV infection; following surgery or drug treatment, do not use until genital/perianal tissue is healed; avoid sexual (ie, genital, anal, oral) and eye contact while the cream is on the skin; may weaken vaginal diaphragms and condoms, concurrent use is not recommended

Drug Name Interferon alfa-n3 (Alferon N) and interferon alfa-2b (Intron A)

Description Protein product manufactured from either a single-species recombinant DNA process or from pooled units of donated human leukocytes that have been induced by incomplete infection with a murine virus. Mechanisms by which it exerts antiviral activity are not understood clearly. However, modulation of the host immune response may play an important role. Indicated for intralesional treatment of refractory or recurring external condyloma acuminatum. Particularly useful for patients who have not responded satisfactorily to other treatment modalities (eg, podophyllin resin, surgery, laser, cryotherapy).
Adult Dose Interferon alfa-n3: 0.05 mL (250,000 IU) per wart 2 times/wk for up to 8 wk; maximum recommended dose per treatment session is 0.5 mL (2.5 million IU)
Interferon alfa-2b: 1 million IU injected into each lesion 3 times/wk on alternate d for 3 wk; maximum recommended dose per treatment session is 5 million IU
Pediatric Dose Not established
Contraindications Documented hypersensitivity to mouse IgG, egg protein, or neomycin
Interactions Potential risk of renal failure when administered concurrently with IL-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Depression and suicidal ideation may be adverse effects of treatment; infrequently, severe or fatal GI hemorrhage has been reported; prior to initiation of therapy, perform tests to quantitate peripheral blood hemoglobin, platelets, granulocytes, hairy cells, and bone marrow hairy cells; monitor periodically (eg, monthly) during treatment to determine response to treatment; if no response within 6 mo, discontinue treatment; if a response occurs, continue treatment until no further improvement is observed and laboratory parameters have been stable for about 3 mo; not known whether continued treatment after that time is beneficial; because the manufacturing process, strength, and type of interferon (eg, natural human leukocyte interferon versus single-species recombinant interferon) may vary for different interferon formulations, changing brands may require a change in dosage (do not change interferon product without considering these factors); fever and other flulike symptoms associated with thisproduct;
caution in debilitating medical conditions (eg, unstable angina, uncontrolled congestive heart failure, chronic obstructive pulmonary disease, diabetes mellitus with ketoacidosis, coagulation disorders, severe myelosuppression, seizure disorders)



Drug Category: Antimitotic agents

Interfere with mitosis. Many are chemotherapeutic agents. The drugs listed below are used specifically for treatment of external anogenital warts or condyloma acuminatum.

Drug Name Podofilox (Condylox)

Description Topical antimitotic that can be synthesized chemically or purified from plant families Coniferae and Berberidaceae (eg, species of Juniperus and Podophyllum).
Treatment results in necrosis of visible wart tissue. Exact mechanism of action unknown.
Adult Dose 0.5% gel or solution applied to anogenital warts bid for 3 consecutive d, then discontinue; repeat cycle until no visible wart tissue or maximum of 4 cycles
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Avoid contact with eyes; if eye contact occurs, immediately flush eye with copious quantities of water and seek medical advice; not for use on mucous membranes of genital area, including urethra, rectum, and vagina; not to exceed frequency of application or duration of usage

Drug Name Podophyllin (Podocon-25, Podofin)

Description Derived from Mayapple (Podophyllum peltatum Linné) and contains the active agent podophyllotoxin, which is a cytotoxic agent that arrests mitosis in metaphase. American podophyllum contains one fourth the amount of Indian source.
Adult Dose 25% podophyllin in benzoin tincture applied only by a physician and never dispensed to a patient; reapply each wk for up to 6 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity; diabetes; impaired peripheral circulation
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions Powerful caustic and severe irritant; do not use if surrounding tissue is swollen or irritated; do not apply 25% solution near mucous membranes; do not use large amounts; avoid contact with cornea (if contact occurs, flush with copious amounts of warm water); avoid use on mucous membranes, eyes, bleeding warts, moles, birthmarks, or unusual warts with hair



Drug Category: Antimetabolites

Interfere with nucleic acid synthesis. Chemotherapeutic agents not formally approved for use against warts. Some studies have demonstrated a benefit against external anogenital warts or condyloma acuminatum.

Drug Name Fluorouracil (Efudex)
Description Interferes with synthesis of DNA and RNA, which creates thymine deficiency resulting in unbalanced growth and cell death.
Adult Dose 5% strength applied as thin layer 1-3 times/wk; therapy may be required for up to 10-12 wk
Pediatric Dose Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy X - Contraindicated in pregnancy
Precautions Incidence of inflammatory reactions may occur with occlusive dressings; reports of vaginal ulcerations and vaginal adenosis with clear cell carcinoma following treatment; not recommended for treatment of vaginal condyloma; increased absorption through ulcerated or inflamed skin; minimize ultraviolet irradiation exposure during and immediately following treatment (reaction intensity may increase); only the 5% strength is recommended



Drug Category: Keratolytics

Used to aid in removal of keratin in hyperkeratotic skin disorders, including corns, ichthyoses, common warts, flat warts, and other benign verrucae.

Drug Name Trichloroacetic acid and bichloracetic acid (TCA & BCA)

Description Extremely powerful keratolytic agents that rapidly penetrate and chemically cauterize skin, keratin, and other tissues. Can be used to treat nongenital cutaneous warts, as well as external anogenital warts or condyloma acuminatum.
Adult Dose 80-90% solution applied directly by physician per wk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions External use only; restrict use to treatment areas only; avoid contact with eyes (if eye contact occurs, immediately flush with copious quantities of water and seek medical advice); not for use on premalignant or malignant lesions

Drug Name Salicylic acid (Compound W)

Description By dissolving the intercellular cement substance, salicylic acid produces desquamation of the horny layer of skin, while not affecting structure of viable epidermis. For removal of nongenital cutaneous warts, particularly common or plantar warts.
Prior to application, wash affected area. May soak wart in warm water for 5 min. Dry area thoroughly.
Adult Dose 17% by weight solution or gel: Apply to wart and let dry bid/tid prn until wart removed for up to 12 wk
40% by weight solution adsorbed to medicated discs: Apply over wart and cover for 48 h, replace prn until wart removed for up to 12 wk
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity
Interactions Use of this medication with other topical drying agents (eg, tretinoin, sulfur, resorcinol, benzoyl peroxide) or topical medicated or alcohol-containing preparations (eg, aftershave, toiletries, skin cleansers, cosmetics) may have a cumulative drying or irritating effect, leading to desquamation and skin erosion
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Avoid contact with mucous membranes, normal skin surrounding warts, and eyes; immediately flush with water for 15 min if contact with eyes or mucous membranes occurs; avoid inhaling vapors; prolonged use in infants, people with diabetes, and patients with impaired circulation is contraindicated; not for use on moles, birthmarks, warts with hair growing from them, genital or facial warts, warts on mucous membranes, irritated skin, or any area that is infected or reddened



Drug Category: Vaccines

A human papillomavirus vaccine is now available for the prevention of HPV-associated dysplasias and neoplasia, including cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions. Girls and young women aged 9-26 years should receive the complete immunization series.

Drug Name Papillomavirus vaccine (Gardasil)

Description Quadrivalent HPV recombinant vaccine. First vaccine indicated to prevent cervical cancer, genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3; vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy mediated by humoral immune responses following immunization series.
Adult Dose < 26 years: 0.5 mL IM administered as 3 separate doses; administer second and third doses 2 and 6 mo after first dose, respectively
>26 years: Not established
Pediatric Dose <9 years: Not established
>9 years: Administer as in adults
Contraindications Documented hypersensitivity
Interactions Immunosuppressive therapies (eg, irradiation, antineoplastic agents, corticosteroids) may decrease immune response to vaccine
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Shake well before administering; administer in deltoid region of upper arm or in higher anterolateral thigh; individuals with impaired immune responsiveness (eg, HIV infection, neoplastic disease, currently taking immunosuppressive drugs) may not elicit antibody response; because of IM administration, do not administer to individuals with bleeding disorders (eg, thrombocytopenia, coagulation disorders, anticoagulant therapy); common adverse effects include pain, swelling, erythema, and/or pruritus at injection site and fever



Drug Category: Miscellaneous topical ointment

Kunecatechins is another topical product that has gain FDA approval for genital warts.Drug Name Kunecatechins (Veregen)
Description Botanical drug product for topical use that consists of extract from green tea leaves. Mode of action unknown but does elicit antioxidant activity in vitro. Indicated for topical treatment of external genital and perianal warts (condylomata acuminatum) in immunocompetent patients.
Adult Dose Apply topically tid; use approximately a 0.5-cm strand of ointment topically for each external genital or perianal wart
Pediatric Dose <18 years: Not established
Contraindications Documented hypersensitivity
Interactions None reported
Pregnancy C - Safety for use during pregnancy has not been established
Precautions Not evaluated for urethral, intravaginal, cervical, rectal, or intra-anal HPV disease and should not be used to treat these conditions; avoid application to open wounds, eyes, and nose; wash hands before and after application; avoid sexual contact while ointment is on skin; may cause application-site reactions, phimosis, inguinal lymphadenitis, urethral meatal stenosis, dysuria, genital herpes simplex, vulvitis, hypersensitivity, pruritus, pyodermitis, skin ulcer, erosions in the urethral meatus, and superinfection of warts and ulcers



FOLLOW-UP

Deterrence/Prevention

The FDA has recently approved a vaccine for HPV.

Complications

Complications of wart treatment are rare. Complications are generally confined to the treatment site and include scarring and, in the case of genital warts, vulvodynia or hyperesthesia.
Surgical complications of treating SILs are discussed in the articles involving those diseases. See the following articles for discussion of complications:
Benign Vulvar Lesions
Carbon Dioxide Laser Surgery of the Lower Genital Tract
Complications of Dermatologic Laser Surgery
Cervical Cancer
Conization of Cervix
Gynecologic Cryosurgery
Urethral Warts
Surgical Treatment of Vulvar Cancer
Malignant Vulvar Lesions
Penile Cancer
Surgical Treatment of Vaginal Cancer

Prognosis

Approximately two thirds of patients with nongenital cutaneous warts experience a spontaneous regression within 2 years; however, some new warts may appear.
Most patients with EV experience progression of their disease in the third or forth decades of life. Malignant transformation usually arises from actinic keratoses, particularly in patients who are exposed to irradiation. Patients who remain protected from x-rays and sun exposure generally have satisfactory health.
Genital warts may spontaneously regress, remain unchanged, or increase in size. Treatment of these lesions does not affect the development of cervical cancer.
Histologic evidence of HPV infection on a cervical Pap smear is similar to mild dysplasia. This subclinical disease often spontaneously regresses.

Patient Education

Educating women, particularly those who are socially and economically disadvantaged, about behaviors that enhance sexual risk reduction has a proven benefit in reducing the incidence of STDs. Reducing the incidence of STDs potentially could decrease HPV transmission and, consequently, the incidence of cervical carcinoma.
For excellent patient education resources, visit eMedicine's Women's Health Center, Pregnancy and Reproduction Center, Cancer and Tumors Center, and Warts Center. Also, see eMedicine's patient education articles Birth Control Overview, Birth Control FAQs, Cervical Cancer, Warts, Genital Warts, Plantar Warts, and Pap Smear.





Medical/Legal Pitfalls

The United States Centers for Disease Control (CDC) has specified Clinical Laboratory Improvement Amendments (CLIA) standards for cytologists to participate successfully in a cytology proficiency testing program to ensure the accuracy of interpretation of Pap smears. These guidelines can be found on the CDC Web site under the CLIA section for Gynecologic Cytology Standards. In order for laboratories in the United States to maintain certification for assessment of Pap smears and other laboratory testing, these standards must be followed.

Special Concerns

Pregnancy

The risk of perinatal HPV transmission to the oropharyngeal mucosa of the neonate is low for mothers with latent infections or genital warts. The time between rupture of the amnion and delivery may be a critical factor in predicting transmission.
Infants with HPV-positive nasopharyngeal aspirates in the immediate postpartum period are considered contaminated rather than infected with HPV because the virus generally clears from the neonate over several months after birth. Cesarean delivery for the prevention of vertical HPV transmission to the newborn is not indicated. However, in rare cases, cesarean delivery may be indicated if the pelvic outlet is obstructed by large genital warts.

Sex partners

Although a high prevalence of HPV-associated penile SILs exists in the male sex partners of women with cervical SILs, examination of these men is not necessary for management of HPV disease. Nevertheless, sex partners of patients with HPV disease may benefit from examination and a detailed evaluation for STDs.
Condom use may reduce the transmission of HPV to uninfected sex partners, but it does not eliminate the risk. Furthermore, caution patients that treatment does not eliminate the possibility of HPV transmission because latent virus still may be present in tissues adjacent to treated areas.

Colds and the flu

Highlights

Vaccine News:

• On September 28, 2007, the U.S. Food and Drug Administration (FDA) approved a new brand of inactivated influenza ("flu") vaccine, Alfuria, for adults aged 18 years or older. This vaccine is given by injection.

• On September 19, 2007, the FDA approved the use of the live flu vaccine (FluMist) in healthy children as young as 2 years of age. This vaccine, given in the form of a nose spray, was previously approved for healthy children and non-pregnant adults aged 5 - 49.

Drug Resistance:
• The World Health Organization reports that resistance to the anti-viral drug oseltamivir (Tamiflu) can develop with extensive use. Oseltamivir is one of two drugs the CDC recommends for treating the flu. It is also the current recommended treatment for the H5N1 avian flu virus.

Drug Recalls:
• In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse. The U.S. Food and Drug Administration (FDA) recommends against using these products to treat children under age 2. The FDA is currently reviewing the safety of cough and cold medicines in children ages 2 - 11 years.

Emerging Virus:
• A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections, pneumonia, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths.

Introduction

Upper respiratory tract infections affect the airways in the nose, ears, and throat.
Structures of the throat include the esophagus, trachea, epiglottis, and tonsils.
The infections can be caused by viruses, bacteria, or other microscopic organisms. In most cases, these infections lead to colds or mild influenza (flu) and are temporary and harmless. In rare cases, flu can be severe, or the infections may turn into pneumonia.
Organisms that cause these upper respiratory tract infections are generally spread by:
• Direct contact (such as hand-to-mouth)
• Coughing or sneezing

The Common Cold

The common cold (medically known as infectious nasopharyngitis) is the most common upper respiratory tract infection. More than 200 viruses can cause colds. The most common cause is the rhinovirus, which is responsible for about half of all colds. Symptoms usually develop 1 - 3 days after being exposed to the virus.

A cold usually progresses in the following manner:

• It nearly always starts rapidly with throat irritation and stuffiness in the nose.
• Within hours, full-blown cold symptoms usually develop, which can include sneezing, mild sore throat, fever, minor headaches, muscle aches, and coughing.
• Fever is low-grade or absent. In small children, however, fever may be as high as 103F for 1 or 2 days. The fever should go down after that time, and be back to normal by the 5th day.
• Nasal discharge is usually clear and runny the first 1 - 3 days. It then thickens and becomes yellow to greenish.
• The sore throat is usually mild and lasts only about a day. A runny nose usually lasts 2 - 7 days, although coughing and nasal discharge can persist for more than 2 weeks.
A new, more virulent strain of adenovirus has reportedly emerged in the United States in 2006. The adenovirus family causes upper respiratory infections (it is one of the many viruses that cause the common cold). It also causes pneumonia, conjunctivitis, and several other diseases. The new strain of adenovirus 14 causes severe respiratory illness that has resulted in several deaths. Some patients who contracted this new viral disease had to be hospitalized, sometimes in intensive care units.

Influenza ("The Flu")

Every year, influenza strikes millions of people worldwide. Influenza epidemics are most serious when they involve a new strain, against which most people around the world are not immune. Such global epidemics (pandemics) can rapidly infect more than one fourth of the world's population. For example, the Spanish flu in 1918 and 1919 killed an estimated 20 million people in the U.S. and Europe and 17 million people in India. With modern society's dependence on air travel, an influenza pandemic could potentially inflict catastrophic damage on human lives, and disrupt the global economy.

The influenza virus mutates (changes) rapidly as it moves from species to species. Most Type A influenza strains (the most common strains) first develop in migratory waterfowl populations. While most avian influenza (bird flu) virus strains are relatively harmless, a few develop into "highly pathogenic avian influenza," which can be very deadly for domesticated poultry and livestock. As recent events have shown, these strains can also be deadly to humans. People can become infected by these bird flu strains through contact with contaminated chickens and pigs. The medical community is now greatly concerned about the H5N1 bird flu virus, which has infected and even killed people in several countries.

Symptoms of influenza.
Patients usually feel sick 1 - 4 days after exposure to the influenza (flu) virus. The flu usually involves:
• Abrupt onset of severe symptoms, which include headache, muscle aches, fatigue, and high
   fever (up to 104F).
• Cough (which is usually dry but can be severe) and sometimes a runny nose and sore throat.
• Children may experience vomiting, diarrhea, and ear infections, as well as other flu symptoms.
• The symptoms usually resolve in 4 - 5 days, although some people can experience coughing and feelings of illness for more than 2 weeks. In some cases, flu can become more severe or make other conditions worse.

Transmitting the Virus. The flu virus is spread primarily when a person with the flu coughs or sneezes near someone else. Adults with flu typically spread it to someone else from 1 day before symptoms start to about 5 days after symptoms develop. Children can spread the infection for more than 10 days after symptoms begin, and young children can transmit the virus 6 days or even earlier before the onset of symptoms. People with severely compromised immune systems can transmit the virus for weeks or months.
Flu Strains. A virus is a cluster of genes wrapped in a protein membrane, which is coated with a fatty substance that contains molecules called glycoproteins. Strains of the flu are identified according to the number of membranes and type of glycoproteins present.

The two major flu strains are referred to as A and B:

• Influenza A is the most widespread and can infect animals and humans. Influenza A is the cause of the major pandemics (worldwide epidemics) of influenza that have occurred so far. It is usually further categorized by two subtypes based on two substances that occur on the surface of the viruses: hemagglutinin (H) and neuraminidase (N).

• Influenza B infects only humans. It is less common than type A, but is often associated with specific outbreaks, such as in nursing homes.
The vast majority of flu cases are type A. Influenza A usually causes more severe disease than type B. There is some concern, however, that since influenza B has been less common in the past few years, some people, particularly small children, may have fewer antibodies to it and so may be at higher risk for severe infection.

Avian Influenza (Bird Flu)

Although the risk of lethal viruses is generally low, scientists are greatly concerned about a particular virus called H5N1, which causes avian influenza. Since 1997, the H5N1 virus has triggered deadly outbreaks in poultry across Southeast Asia. As of Janaury 15, 2008, 350 people had been infected with the bird flu in 12 countries. Of these people, 217 have died, according to the World Health Organization. No cases have been seen in the United States.

So far, the virus has spread from birds to humans. The virus does not seem to be easily spread from person to person. However, scientists and public health officials are monitoring the spread of H5N1 and working to contain it. Efforts include slaughtering infected birds, developing new vaccines, and stockpiling antiviral drugs such as oseltamivir (Tamiflu). Many poor nations have limited resources and already contend with other serious health problems, including HIV-AIDS. If H5N1 does mutate and spread, the consequences could be especially severe for these countries.
In April 2007, the FDA approved a vaccine to protect humans from avian influenza. Currently this vaccine is not being used for routine immunization. However, if the avian flu develops the ability to spread fairly easily from human to human, this vaccine may be made available.

Diagnosis

Differentiating between a cold and flu may be difficult. Cold symptoms are nearly always less severe than those of the flu.
Comparing Colds and Flus
Symptoms Cold Flu
Fever Rare Common and high (102-104F); lasts 3 - 4 days
Headache Rare Almost always present
General aches and pains Mild, if they occur at all Often severe
Fatigue, exhaustion, and weakness Mild, it they occur at all Extreme exhaustion is early and severe; can last 2 - 3 weeks
Stuffy nose Nearly always Sometimes
Sneezing Very common Sometimes
Sore throat Common Sometimes
Chest discomfort and cough Mild-to-moderate, hacking cough Common, can be severe
Source: National Institute of Allergy and Infectious Disease

Diagnosing the Flu

Several available tests can isolate and identify the viruses responsible for some respiratory infections. They are generally not needed, since most cases of the flu are self-evident. However, such tests can be very helpful in confirming or ruling out the flu. If a doctor believes a diagnosis would help, samples using a swab should be taken from the nasal passages or throat within 4 days of the first symptoms.

A nasopharyngeal culture is a test used to identify disease-causing organisms in nasal secretions. Nasopharyngeal cultures are useful in identifying Bordetella pertussis and Neisseria meningitidis (types of bacteria). The culture may help determine appropriate antibiotic therapy.
Several rapid tests for the flu can produce results in less than 30 minutes, but vary on the specific strain or strains that they can detect. They are not as accurate as a viral culture, however, in which the virus is reproduced in the laboratory. Culture results can take 3 - 10 days. Blood tests can also document the infection several weeks after symptoms appear.

Diagnosing Avian Influenza

In February 2006, the U.S. Food and Drug Administration approved a new, faster test for diagnosing H5 strains of avian influenza in people suspected of having the virus. The test is called the Influenza A/H5 (Asian lineage) Virus Real-time RT-PCR Primer and Probe Set. The test gives preliminary results within 4 hours. Older tests required 2 - 3 days. It checks for the presence of the Influenza A H5 strain. If the presence of this strain is confirmed through the rapid test, further testing will be needed to determine the exact subtype of the virus. For example, the current strain of concern is H5, subtype N1, designated as H5N1 for short.

Other Causes of Congestion

Ruling out Allergic Rhinitis. Symptoms of allergic rhinitis include nasal obstruction and congestion, which are similar to the symptoms of a cold. People with allergies, however, are likely to have the following:
• Thin, clear, and runny nasal discharge
• An itchy nose, eyes, or throat
• Recurrent sneezing
There are two forms of allergic rhinitis:
• Symptoms that appear only during allergy season are called allergic rhinitis, commonly known as hay or rose fever. [For more information, see In-Depth Report #77: Allergic rhinitis.]
• Allergens in the house, such as house dust mites, molds, and pet dander, can cause year-long allergic rhinitis, referred to as perennial rhinitis.
Ruling out Sinusitis. The signs and symptoms suggestive of true acute sinusitis include the following:

• A return of congestion and discomfort after initial improvement in a cold (called double
   sickening)
• Purulent (pus-filled) nasal secretion
• A lack of response to decongestant or antihistamine
• Pain in the upper teeth or pain on one side of the head
• Pain above or below both eyes when leaning over
Children with sinusitis are less likely to have facial pain and headache and may only develop a high fever or prolonged upper respiratory symptoms (such as a daytime cough that does not improve for 11 - 14 days). When the diagnosis is unclear or complications are suspected, further tests may be required. [For more information, see In-Depth Report #62: Sinusitis.]

Other Causes of Coughing

Acute Bronchitis. Acute bronchitis is usually caused by a virus and in most cases is self-limiting. The cough it causes typically lasts for about 7 - 10 days, but in about half of patients, coughing can last for up to 3 weeks, and 25% of patients continue to cough for over 1 month.
Atypical Pneumonia. Pneumonia caused by atypical organisms (for example, Mycoplasma pneumonia, chlamydia, Legionella) can cause symptoms similar to the flu. Only laboratory tests can diagnose the difference. [For more information, see In-Depth Report #64: Pneumonia.]
Ruling out More Serious Viral Infections. Respiratory syncytial virus (RSV) and, possibly human parainfluenza viruses (HPV), are proving to be important causes of serious respiratory infections in infants, the elderly, and people with damaged immune systems. (Both also cause mild conditions.) RSV may be a much more common cause of flu-like symptoms than previously thought.

Pertussis.
Pertussis (whooping cough) was a very common childhood illness throughout the first half of the century. Although immunizations caused a decline in cases to only 1,700 in the U.S. in 1980, the incidence has risen recently, with almost 30,000 cases reported between 1997 and 2000 (17 infants died of the disease in 2000). Many more cases are reported worldwide.
Nearly half of pertussis cases now occur in people 10 years of age or older, perhaps due to waning immunity in adolescents and adults. Such cases may be greatly underreported. Up to 25% of adults who see a doctor for persistent cough may actually have pertussis. It may go undiagnosed, however, because symptoms are usually mild, and adults are unlikely to have the classic "whooping" cough. This is of some concern because such adults may unknowingly infect unvaccinated children. The younger the patient, the higher the risk for severe complications, including pneumonia, seizures, and even death. Children younger than 6 months are at particular risk because protection is incomplete, even with vaccination.

Other Causes of Sore Throat

In addition to common cold viruses, other, less frequent causes of sore throat include the following:
• Strep throat
• Foodborne and waterborne infections (Streptococcus C and G)
• An uncommon organism called Arcanobacterium haemolyticum (infection with this bacterium
   can mimic strep throat and may even cause a rash)
• Infectious mononucleosis ("mono")
• Herpesvirus 1

What is Strep Throat?

Group A Streptococcal bacteria is the most common bacterial cause of the severe sore throat known commonly as "strep throat." It occurs mostly in school age children, but people of all ages are susceptible. (Strep throat constitutes about 12% of all sore throat cases seen by doctors.)

The symptoms of strep throat include the following:
• A sudden onset of severe sore throat
• Difficulty in swallowing
• Fever
• Headache
• Stomach pain
• Vomiting

Only about half of patients with strep throat have such clear-cut symptoms. Furthermore, half of people who have these symptoms do not actually have strep throat.
How Is Strep Throat Diagnosed? Most cold-related sore throats are caused by viruses and require no treatment. They usually do not last more than a day. When the sore throat persists and is very painful the doctor will want to rule out or confirm the presence of the strep bacteria.

• The doctor will look for redness and pus-filled patches on the tonsils and back of the throat.
  Enlarged tonsils are less likely to indicate a strep throat.
• The doctor will feel the sides of the neck for swollen lymph nodes. If the lymph nodes are not
  swollen, it is less likely to be a strep throat.
• A cotton swab is used to take a sample of pus in the throat for a throat culture.
A throat culture is the most effective and least expensive test for confirming the presence of strep throat. It takes 24 - 48 hours to obtain a result.
Rapid Antigen-Detection Test for Strep Throat. A faster test, called the rapid strep antigen test, uses chemicals to detect the presence of bacteria in a few minutes. A positive result nearly always means that streptococcal bacteria is the cause of the infection. The test, however, fails to detect 10 - 20% of cases, so a culture may still be necessary to catch any missed infections, particularly in children.

How Serious is Strep Throat?

The use of antibiotics has removed the threat of most complications from streptococcus infection in the throat (strep throat). However, untreated strep throat could lead to the following complications:
• Abscess in the tonsils
• Scarlet fever
• Rheumatic fever (rare in the U.S.)

How Is Strep Throat Treated? Strep throat infections require antibiotics. Antibiotics prevent a serious complication called rheumatic fever, which can result in permanent damage to the heart. Fortunately, this complication occurs rarely in United States anymore. If started on time, antibiotic treatment of strep throat will almost always prevent this complication. In addition, antibiotics shorten the recovery time from strep throat.

The following antibiotics are generally used to treat strep throat:

• Penicillin is usually the antibiotic of choice unless the patient is allergic. A full 10 days may be
  necessary. Amoxicillin, a form of penicillin, is proving to be effective when taken in a single daily
  dose for 10 days.
• Macrolide antibiotics. Erythromycin is known as a macrolide antibiotic and is the first choice for
  patients with penicillin allergies. A 10-day regimen is needed. Another macrolide, azithromycin,   can be given as a single daily dose and may be effective in 5 days. It is expensive, however, and   bacterial resistance to macrolides is growing, so it should not be given as a first choice.
• Cephalosporins are very effective in eradicating the bacteria.
   Antibiotics are very commonly inappropriately prescribed for non-strep sore throats. One    study reported that an estimated 6.7 million American adults visited their doctors because of    sore throat between 1989 and 1999, with 73% of them receiving antibiotics. Studies indicate,    however, that fewer than half of adults and far fewer children with even strong signs and    symptoms for strep throat actually have strep infections.
   Parents should be comforted that a delay in antibiotic treatment while waiting for lab results   does not increase the risk that the child will develop serious long-term complications, including    acute rheumatic fever. If a patient is severely ill, however, it is reasonable to begin    administering antibiotics before the results are back. If the culture is negative (there is no     evidence of bacteria), the doctor should call the family to make certain the patient stops taking   the antibiotics and any remaining pills are discarded.

Children who have a sore throat and who have had rheumatic fever in the past should receive antibiotics immediately, even before culture results are back. Children with a sore throat who have a family member with strep throat or rheumatic fever should also receive immediate antibiotic treatment.

Complications

Colds rarely cause serious complications. In about 1% of cases, a cold can lead to other complications, such as sinus or ear infections. It can also aggravate asthma and, in uncommon situations, increase the risk for lower respiratory tract infections.
Ear Infections. The rhinovirus infection, a major cause of colds, also commonly predisposes children to ear infections, possibly by obstructing the Eustachian tube, which leads to the middle ear. Viruses may even attack the ear directly.

Sinusitis.

Between 0.5 - 5% of people with colds develop sinusitis, an infection in the sinus cavities (air-filled spaces in the skull). Sinusitis is usually mild, but if it becomes severe, antibiotics generally eliminate further problems. In rare cases, however, sinusitis can be serious.
Lower Respiratory Tract Infections. The common cold poses a risk for bronchitis and pneumonia in nursing home patients, and in other people who may be vulnerable to infection. Some experts believe that the rhinovirus may play a more significant role than the flu in causing lower respiratory infections in the vulnerable population.

Aggravation of Asthma.
Rhinovirus infections can aggravate asthma in both children and adults. In fact, rhinovirus has been reported to be the most common infectious organism associated with asthma attacks. Colds may promote allergic inflammation of the airways, and increase the intensity their responsiveness for weeks.

Complications of Influenza

The flu is usually self-limited and not serious. However, each year in the United States, more than 200,000 people are hospitalized due to complications of the flu. An estimated 36,000 people die each year of influenza-related complications. People at highest risk for serious complications are those over 65 years old and those with chronic medical conditions. Influenza A is the most severe strain. Influenza B tends to be milder.

Pneumonia.
Pneumonia is the major serious complication of influenza and can be very serious. It can develop about 5 days after viral influenza. More than 90% of the deaths caused by influenza and pneumonia occur among older adults. Flu-related pneumonia nearly always occurs in high-risk individuals, such as the following:

• People with weakened immune systems, such as AIDS patients
• Elderly patients, particularly patients in nursing home
• Very young children -- [it may be difficult to tell whether pneumonia is related to influenza or
   caused by respiratory syncytial virus (RSV)]
• Hospitalized patients and anyone with serious medical conditions, such as diabetes, heart,    circulation, or lung disorders, particularly chronic lung disease
• Drug abusers who use needles

Combinations of these factors further increase the risk. It should be noted that pneumonia is an uncommon outcome of influenza in healthy adults.
Complications in the Central Nervous System in Children. Influenza increases the risk for complications in the central nervous system of small children. Febrile seizures are the most common neurologic complication in children The risks decline after a child turns 1 year old, but are still high in children aged 3 - 5 years old.

Risk Factors

Age

The very young and the very old are at higher risk for upper respiratory tract infections and their associated complications.

Children.  
Young children are prone to colds and may have 8 to 12 of them every year. Millions of cases of influenza develop in American children and adolescents each year.
Before the immune system matures, all infants are susceptible to uppper respiratory infections, with a possible frequency of one cold every 1 - 2 months. Smaller nasal and sinus passages also make younger children more vulnerable to colds than older children and adults. Upper respiratory infections gradually diminish as children grow, until at school age their rate of such infections is about the same as an adult's. There is almost never cause for concern when a child has frequent colds, unless the colds become unusually severe or more frequent than usual.
The Elderly. The elderly have diminished cough and gag reflexes, and their immune systems are often weaker. They are therefore at greater risk for serious respiratory infections than the young and middle-aged adults.

Exposure to Smoke and Environmental Pollutants
The risk of respiratory infections is increased by exposure to cigarette smoke, which can injure airways and damage the cilia (tiny hair-like structures that help keep the airways clear). Toxic fumes, industrial smoke, and other air pollutants are also risk factors. Parental smoking increases the risk of respiratory infections in their children.

Medical Conditions

People with AIDS and other medical conditions that damage the immune system are extremely susceptible to serious infections.
Cancers, especially leukemia and Hodgkin's disease, put patients at risk. Patients who are on corticosteroid (steroid) treatments, chemotherapy, or other medications that suppress the immune system are also prone to infection.

People with diabetes are at a higher risk for the flu.
Certain genetic disorders predispose people to respiratory infections. They include sickle-cell disease, cystic fibrosis, and Kartagener syndrome (which results in malfunctioning cilia).

People under Stress
Much evidence suggests that stress increases one's susceptibility to a cold. In one study, people with high stress levels averaged 2.7 upper respiratory infections during a 6-month period and those reporting low stress averaged 1.5 infections. Another study found the duration of colds in children with chronic, year-round colds decreased with help of a stress management program. Stress appears to increase the risk for a cold regardless of lifestyle or other health habits. And once a person catches a cold or flu, stress can make symptoms worse.

It is not clear why these events occur. Some experts believe that stress alters specific immune factors, which cause inflammation in the airways. One study reported that the only people who got sick after experiencing short stress were those whose body responded to stress with high levels of cortisol, a stress hormone, coupled with a low immune response.

Excessive Exercise
In people who already have colds, exercise has no effect on the illness' severity or duration of the infection. High-intensity or endurance exercises, however, appear to suppress the immune system while they are being performed. Some highly trained athletes, for instance, report being susceptible to colds after strenuous events. People should avoid strenuous physical activity when they have high fevers or widespread viral illnesses. Note: Very low fat diets appear to worsen this dampening effect on the immune system. A higher fat-diet may help correct this imbalance (omega-3 fatty acids, found in fish and canola oil, are preferred). Whether carbohydrate loading provides much additional value is not clear.

Seasonal Incidence
Colds and flus occur predominantly in the winter. Flu season typically starts in October and lasts into mid March.
The reasons for this seasonal bias are not due to the cold itself, but to other factors. Certainly, flus and colds are more likely to be transmitted in winter because people spend more time indoors and are exposed to higher concentrations of airborne viruses. Dry winter weather also dries up nasal passages, making them more susceptible to viruses. Some experts theorize that the high rates of viral infections in winter may be due to certain immune factors, which react to light and dark and affect a person's susceptibility to viruses.

Traveling in Trains, Buses, and Planes
Traveling in close contact with people, whether on trains, planes, or buses, can increase the risk for respiratory infections.

Day Care Centers
Children who attend day care may have an increased risk of colds. However, one study suggested that although children in day care centers incur higher rates of the common cold in the preschool years, they have lower cold rates in their first years of regular school. The colds they catch in day care, then, may bestow some immunity to future colds for a few years. By age 13, such protection has worn off. There is also some evidence that frequent colds in young children may help protect against future allergies and asthma.

Prevention

Because colds and flus are easily spread, everyone should always wash their hands before eating and after going outside. Ordinary soap is sufficient. Waterless hand cleaners that contain an alcohol-based gel are also effective for every day use and may even kill cold viruses. (They are less effective, however, if extreme hygiene is required. In such cases, alcohol-based rinses are needed.)

Antibacterial Products

Antibacterial soaps add little protection, particularly against viruses. In fact, one study suggests that common liquid dish washing soaps are up to 100 times more effective than antibacterial soaps in killing respiratory syncytial virus (RSV), which is known to cause pneumonia. Wiping surfaces with a solution that contains one part bleach to 10 parts water is very effective in killing viruses.

Temperature

Colds are not caused by insufficiently warm clothes or by going outside with wet hair.

Dietary Factors

Foods Containing Lactobacilli (Good Bacteria). Researchers are also studying the possible protective value of certain strains of lactobacilli bacteria found in the intestines. Some of these strains, particularly acidophilus, are used to make yogurt. According to one Finnish study, children attending day care who ate milk containing the strain lactobacilli GG 10 - 20% fewer respiratory infections. (The strain used was not the kind found in most commercial yogurt products.)

Vitamins.
Studies are mixed whether vitamin supplements protect against upper respiratory infections. Large doses of vitamin C, for example, may help reduce the duration of a cold, but they do not appear to protect against one in the first place, even after exposure to a cold virus. Two studies on multivitamins reported opposite results, with one finding fewer infections and one finding no difference. It is possible that vitamin C or multivitamin supplements may be helpful in specific people, such those who are vitamin deficient or have medical problems that impair their immune systems.

Treatment

The following are some food and fluid recommendations. Most will not cure a cold, but they may help a person deal better with the symptoms:

• Drinking plenty of fluids and getting lots of rest when needed is still the best bit of advice to ease the discomforts of the common cold. Water is the best fluid and helps lubricate the mucous membranes. (There is no evidence that drinking milk will increase or worsen mucus, although milk is a food and should not serve as fluid replacement.)

• Chicken soup does indeed help congestion and body aches. The hot steam from the soup may be its chief advantage, although laboratory studies have actually reported that ingredients in the soup may have anti-inflammatory effects. In fact, any hot beverage may have similar soothing effects from steam. Ginger tea, fruit juice, and hot tea with honey and lemon may all be helpful.
• Spicy foods that contain hot peppers or horseradish may help clear sinuses.
• Foods rich in vitamins A and C are always recommended and may be helpful during a respiratory infection. They include oranges, kiwi, and tomatoes for vitamin C, and sweet potatoes, spinach, and broccoli for vitamin A.

Vitamins
Different studies have found that large doses of vitamin C may reduce the duration of a cold. Some precautions against taking high doses of vitamin C include the following:
• High doses of vitamin C may cause headaches, intestinal and urinary problems, and even kidney stones.
• Because vitamin C increases iron absorption, people with certain blood disorders, such as hemochromatosis, thalassemia, or sideroblastic anemia, should avoid high doses of this vitamin.
• Large doses of vitamin C can also interfere with anticoagulant medications ("blood thinners"), blood tests used in diabetes, and stool tests.
• Vitamin E or multivitamin supplements do not appear to be helpful in reducing symptoms of the cold.

Zinc

Zinc appears to have certain important effects on the immune system and it may have a direct effect on viruses. How it works is not entirely clear, however. Zinc preparations in lozenge or nasal gel form are now available as cold treatments. Studies are very mixed on the effects of zinc on colds. The variance may be due to different zinc preparations. A review of available studies comparing zinc treatment to placebo ("sugar pill") found only one high-quality study, which showed that zinc nasal gels might provide a benefit. The overall benefit of zinc in the prevention of colds remains unproven. In any case, no one with an adequate diet and a healthy immune system should take zinc for prolonged periods, for the purpose of preventing colds.

Side Effects.

Side effects, particularly of the lozenges form, include the following:
• Dry mouth
• Constipation
• Nausea
• Bad taste (possibly only with zinc gluconate lozenges)
• Severe vomiting, dehydration, and restlessness (signs of overdose, seek medical help)
• Allergic response (rare)
  Food and Drug Interactions. Zinc may also interact with drugs or other elements:
• It may reduce absorption of certain antibiotics.
• Foods high in calcium or phosphorus may reduce zinc absorption.
• In high doses and for long periods of time, zinc can cause copper deficiencies.

Medications for Mild Pain and Fever Reduction

Many people take medications to reduce mild pain and fever. Adults most often choose aspirin, ibuprofen (Advil), or acetaminophen (Tylenol).

The following are recommendations for children:

• Acetaminophen (Tylenol) or ibuprofen (usually Advil or Motrin) are the typical pain-relievers parents give their children. Most pediatricians advise such medications for children who run fevers over 101F. Some suggest alternating the two agents, although there is no evidence that this regimen offers any benefits, and it might be harmful.
• Aspirin and aspirin-containing products are virtually never recommended for children or adolescents. Reye syndrome, a very serious condition, has been associated with aspirin use in children who have flu symptoms or chicken pox.

Nasal Strips

Nasal strips (such as Breathe Right) are placed across the lower part of the nose and pull the nostrils open. These strips may open the nasal passages and ease congestion due to a cold, sinusitis, or hay fever. As of yet, there is no scientific evidence that they offer such benefits.

Nasal Wash
A nasal wash can be helpful for removing mucus from the nose. A saline solution can be purchased at a drug store or made at home. One study reported that neither a homemade solution (using one teaspoon of salt and one pinch of baking soda in a pint of warm water) nor a commercial hypertonic saline nasal wash had any effect on symptoms. Further, one preliminary study found that over-the-counter saline nasal sprays that contain benzalkonium chloride as a preservative may actually worsen symptoms and infection.

Some physicians, however, advocate a traditional nasal wash that has been used for centuries and is different from that used in most studies. It contains no baking soda and uses more fluid for each dose and less salt. The nasal wash should be performed several times a day.

A simple method for administering a nasal wash:
• Lean over the sink head down.
• Pour some solution into the palm of the hand and inhale it through the nose, one nostril at a   time.
• Spit the remaining solution out.
• Gently blow the nose.

The solution may also be inserted into the nose using a large rubber ear syringe, available at a pharmacy. In this case, the process is the following:
• Lean over the sink head down.
• Insert only the tip of the syringe into one nostril.
• Gently squeeze the bulb several times to wash the nasal passage.
• Then press the bulb firmly enough so that the solution passes into the mouth.
• The process should be repeated in the other nostril.

Nasal-Delivery Decongestants
Nasal-delivery decongestants are applied directly into the nasal passages with a spray, gel, drops, or vapors. Nasal forms work faster than oral decongestants and have fewer side effects. They often require frequent administration, although long-acting forms are now available. Ingredients and brands of nasal decongestants include the following:
Long Acting Nasal-Delivery Decongestants. They are effective in a few minutes and remain so for 6 - 12 hours.
 The primary ingredient in long-acting decongestant is:
• Oxymetazoline: Brands include Vicks Sinex (12-hour brands), Afrin (12-hour brands), Dristan 12-Hour, Good Sense, Nostrilla, Neo-Synephrine 12-Hour
• Xylometazoline: Inspire, Otrivin, Natru-vent
 
Short-Acting Nasal-Delivery Decongestants. The effects usually last about 4 hours. The primary ingredients in short-acing decongestants are:
• Phenylephrine: Neo-Synephrine (mild, regular, high-potency), 4-Way, Dristan Mist Spray,   Vicks  Sinex
• Naphazoline (Naphcon Forte, Privine)
Dependency and Rebound. The major hazard with nasal-delivery decongestants, particularly long-acting forms, is a cycle of dependency and rebound effects. The 12-hour brands pose a particular risk for this effect.

This effect works in the following way:
• With prolonged use (more than 3 - 5 days), nasal decongestants lose effectiveness and even cause swelling in the nasal passages.
• The patient then increases the frequency of their dose. The congestion worsens, and the patient   responds with even more frequent doses, in some cases as often as every hour.
• Individuals then become dependent on them.
Tips for Use. The following precautions are important for people taking nasal decongestants:
• When using a nasal spray, spray each nostril once. Wait a minute to allow absorption into the mucosal tissues, and then spray again.
• Keep the nasal passages moist. All forms of nasal decongestants can cause irritation and stinging. They also may dry out the affected areas and damage tissues.
• Do not share droppers and inhalators with other people.
• Use decongestants only for conditions requiring short-term use, such as before air travel or for a single-allergy attack. Do not take them more than 3 days in a row. With prolonged use, nasal decongestants become ineffective and result in the so-called rebound effect and dependence.
• Discard sprayers, inhalators, or other decongestant delivery devices when the medication is no longer needed. Over time, these devices can become reservoirs for bacteria.
• Discard the medicine if it becomes cloudy or unclear.

Oral Decongestants
Oral decongestants also come in many brands, which mainly differ in their ingredients. The most common active ingredient is pseudoephedrine (Sudafed, Actifed, Drixoral).
Side Effects of Decongestants. Decongestants have certain adverse effects, which are more apt to occur in oral than nasal decongestants and include the following:
• Agitation and nervousness
• Drowsiness (particularly with oral decongestants and in combination with alcohol)
• Changes in heart rate and blood pressure

Avoid combinations of oral decongestants with alcohol or certain drugs, including monoamine oxidase inhibitors (MAOI) and sedatives
Individuals at Risk for Complications from Decongestants. People who may be at higher risk for complications are those with certain medical conditions, including disorders that make blood vessels highly susceptible to contraction. Such conditions include the following:
• Heart disease
• High blood pressure
• Thyroid disease
• Diabetes
• Prostate problems that cause urinary difficulties
• Migraines
• Raynaud's phenomenon
• High sensitivity to cold
• Emphysema or chronic bronchitis

Anyone with the above conditions should not use either oral or nasal decongestants without a doctor's guidance. In addition, people taking medications that increase serotonin levels, such as certain antidepressants, anti-migraine agents, diet pills, St. John's wort, and methamphetamine, should avoid decongestants. The combinations can cause blood vessels in the brain to narrow suddenly, causing severe headaches and even stroke.
Others who should use these drugs with caution are the following (consult your health care provider):
• Anyone who is pregnant.
• Children: Children appear to metabolize decongestants differently than adults. Decongestants should not be used at all in infants and small children under the age of 2, according to a new recommendation from an advisory panel of the Food and Drug Administration. These children are at particular risk for side effects that depress the central nervous system. Such symptoms cause changes in blood pressure, drowsiness, deep sleep, and, rarely, coma. Studies have also shown that these cough and cold products generally are not effective in the treatment of children under 6 years of age.
In October 2007, drug manufacturers voluntarily withdrew from the market all oral cough and cold products, including decongestants, aimed at children under 2, due to potential harm from misuse.

Cough Remedies
Major studies have indicated that over-the-counter cough medicines are not very effective, but they are also not harmful.
• For thick phlegm, patients may try cough medications that contain guaifenesin (Robitussin, Scot-Tussin Expectorant), which loosens mucus. Patients should not suppress coughs that produce mucus and phlegm. It is important to expel this substance. To loosen phlegm, patients should drink plenty of fluids and use a humidifier or steamer.
• For patients with a dry cough, a suppressant may be useful, such as one that contains dextromethorphan (Drixoral Cough, Robitussin Maximum Strength Cough Suppressant).
Medications that contain both a cough suppressant and an expectorant are not useful and should be avoided. Medicated cough drops that contain dextromethorphan are not very useful. A patient is just as likely to find relief from hard candy or lozenges.
Prescription cough medications with small doses of narcotics are available. They are usually reserved for lower respiratory infections with significant coughs.

Remedies for Sore Throat Associated with Colds
Sore throats that are associated with colds are generally mild. The following may be helpful:
• Cough drops, throat sprays, or gargling warm salt water may help relieve sore throat and reduce coughing.
• Throat sprays that contain phenol (for example, Vicks Chloraseptic) may be particularly helpful. Phenol has antibacterial properties. In one study, patients with sore throat who used the spray experienced faster resolution of the cold itself, including fever, headache, and other symptoms compared to a placebo. The patients were not taking antibiotics.
• Cough drops that contain menthol and mild anesthetics, such as benzocaine, hexylrescorincol, phenol, and dyclonine (the most potent), may soothe a mild sore throat.
• People with sore throats from postnasal drip might try taking a teaspoon of liquid antacid. They shouldn't drink anything afterward, since the intention is to coat the throat and help neutralize the acid in the mucus that might be causing pain.
If soreness in the throat is very severe and does not respond to mild treatments, the patient or parent should check with the physician to see if a strep throat is present, which would require antibiotics. [See What is Strep Throat? in the Diagnosis section.]

Combination Cold and Flu Remedies and Antihistamines
Dozens of remedies are available that combine ingredients aimed at more than one cold or flu symptom. In general, they do no harm, but they have the following problems:
• Some ingredients may produce side effects without even helping a cold.
• In some cases, the ingredients conflict (such as a cough expectorant and a cough suppressant).
• In other cases, a patient may wish to increase the dosage to improve one symptom, which serves to increase other ingredients that do no good and, in higher doses, may cause side effects.
Note on Antihistamines. Many combination remedies contain antihistamines. Antihistamines are used for allergies and are not generally recommended to relieve the symptoms of the common cold. Some evidence suggests, however, that they may have some value.
First-generation antihistamines may reduce cold symptoms. Their benefits for the cold are likely to be due to the drowsiness they cause. Such antihistamines include Benadryl, Tavist, and Chlor-Trimeton. The newer, second-generation antihistamines (Claritin, Allegra, Zyrtec) do not have these effects and also appear to have no benefits against colds.
Herbs and Supplements
Herbal remedies and dietary supplements are not regulated by the FDA. This means that manufacturers and distributors do not need FDA approval to sell their products. In addition, any substance that affects the body's chemistry can, like any drug, produce side effects that may be harmful. There have been numerous reported cases of serious and even deadly side effects from herbal products.
The following are special concerns for people taking natural remedies for colds or influenza:
• Echinacea is commonly taken to prevent onset and ease symptoms of cold or flu. A rigorous study, published in 2005 in the New England Journal of Medicine, determined that this herb does not help to prevent or treat colds. In addition, some people are allergic to echinacea. People who have autoimmune diseases or plant allergies should avoid it. There have been a few reports of people experiencing a skin reaction called erythema nodosum, which is characterized by tender, red nodules under the skin.
• Chinese herbal cold and allergy products can contain trace amounts of aristolochic acid, a chemical that causes kidney damage and cancer. Many herbal remedies imported from Asia may contain potent pharmaceuticals, such as phenacetin and steroids, as well as toxic metals.

Medications

Vaccines are available to prevent influenza (See section on Viral Influenza Vaccines).
For mild influenza, symptom relief is similar to that for colds.
Two classes of antiviral agents have been developed to treat influenza: neuraminidase inhibitors and M2 inhibitors.
Anti-Viral Drugs: Neuraminidase Inhibitors
Brands and Benefits. Zanamivir (Relenza) and oseltamivir (Tamiflu) are neuraminidase inhibitors. They are newer agents that have been designed to block a key viral enzyme, neuraminidase, which is involved with viral replication. According to a major review of over 50 studies published in 2006, these drugs are effective against the flu in about 60% of cases.

Important points about the use of these drugs:
• Neuraminidase inhibitors are effective for treating both A and B strains of influenza. (M2 inhibitors are effective only against type A.) However, their main benefit has been to reduce the length of symptoms by about one day, and only when started within 48 hours after symptoms become evident.
• They may help reduce transmission of the virus.
• They have a lower risk than M2 inhibitors for emerging viral strains that are resistant to their effects. However, The World Health Organization reports that viral resistance to oseltamivir (Tamiflu) can develop with extensive use. The level of resistance averaged 0.3% over 3 flu seasons surveyed in Japan (2003 - 2006). During that time, 35 million Japanese patients used the drug.
• They have fewer serious side effects than the M2 inhibitors.
• Both show some benefits for preventing influenza. Only oseltamivir has been approved for this purpose, however, and only in people over 13.
• They may reduce complications of influenza, although this needs to be confirmed. It is not yet known if they have any effect on overall survival rates.
• Oseltamivir is the only drug studied in avian flu cases. Although it is active in lab experiments, it has not been successful clinically. Experience is very limited, however, and it is not clear whether people infected with avian flu received the drug in time for it to be useful.
Limitations and Side Effects. Although they have many advantages compared to the M2 inhibitors, neuraminidase inhibitors are much more expensive. They also need to be taken within 2 days of the start of symptoms to be effective. Neither neuraminidase inhibitor is effective against influenza-like illness (one that is not caused by an influenza virus). There are also some differences between the two drugs that could be significant for some individuals:
• Zanamivir is administered as a nasal spray or inhaler. People with asthma or other lung disorders may experience airway spasms and should use this drug with caution. Side effects are generally minor in most patients. It is important to make sure that elderly patients are able to properly use the zanamivir inhaler device.
• Oseltamivir comes in capsule and liquid form. Side effects are also minor, but about 10 - 15% of patients experience nausea and vomiting. Patients with kidney dysfunction should take lower doses.
The current use of neuraminidase inhibitors in different age and patient groups is as follows:
• Adults: Both drugs are approved for treatment in adult patients.
• Children: Oseltamivir is approved for use in children age one and older. Studies report significant reduction in symptoms and in the incidence of ear infections in this population. However, studies from Japan point to the possibility of psychiatric side effects in children under 16 using oseltamivir. Zanamivir is approved for children over age 7, and studies are currently underway to determine its safety in younger children.
• High-Risk Patients. Recent studies indicate neuraminidase inhibitors are safe and effective in patients with serious medical problems or other conditions that put them at risk for complications of flu.

Anti-Viral Drugs: M2 Inhibitors
Brands and Benefits. Amantadine (Symmetrel) and rimantadine (Flumadine) are M2 inhibitors. The following benefits may apply to the minority of strains of influenza A that remain sensitive to the drugs:
• Both offer protection against influenza A and prevent severe illness if a person contracts the infection. (To be effective it must be administered within 2 days of onset.)
• They may shorten the duration and lessen the severity of the flu if given within 48 hours of onset of symptoms.

Limitations.
Drawbacks of M2 inhibitors include:
• Viral resistance to these agents is rapidly emerging. For this reason, the Centers for Disease Control and Prevention Does not recommends M2 inhibitors for use during the 2007 - 2008 flu season in the United States.
• M2 inhibitors are not effective against influenza B.
• Neither drug has proven to reduce the risk for complications of the flu, including pneumonia and bronchitis.

Side Effects.
Both M2 inhibitors occasionally cause nausea, vomiting, indigestion, insomnia, and hallucinations. Amantadine affects the nervous system and about 10% of people experience nervousness, depression, anxiety, difficulty concentrating, and lightheadedness. Rimantadine is less likely to do so. Rarely, amantadine can cause seizures, usually in elderly people already at risk for psychiatric symptoms.
Note: Amantadine is a standard treatment for Parkinson's disease and should be continued for that condition.

Viral Influenza Vaccines
Flu Shots. These vaccines use inactivated (not live) viruses. They are designed to provoke the immune system to attack antigens contained on the surface of the virus. (Antigens are foreign molecules that the immune system specifically recognizes as alien and targets for attack.)
Unfortunately, the antigens in these influenza viruses undergo genetic changes (called antigenic drift) over time, so they are likely to become resistant to a vaccine that worked in the previous year.

Vaccines are then redesigned annually to match the current strain.
• Influenza A. The influenza A virus is further categorized by primary molecular antigens (hemagglutinin and neuraminidase), which serve as the targets for the vaccines. Influenza A is a particular problem, because it can infect other species, such as pigs or chicken, and undergo major genetic changes.
• Influenza B viruses tend to be more stable than influenza A viruses, but they too vary. Although influenza B has been far less common than A, a vaccine for type B is important because experts are concerned that small children will not have developed any immunity to the virus, and will experience severe flu if they are exposed to type B viruses.
Intranasal (inside the nose) vaccine. A live but weakened intranasal vaccine (FluMist) is proving to be effective and safe in healthy, non-pregnant people aged 2 - 49 years and has been approved by the FDA. It is known as a live, attenuated, intranasal influenza vaccine (LAIV). The vaccine is engineered to grow only in the cooler temperatures of the nasal passages, not in the warmer lungs and lower airways. It boosts the specific immune factors in the mucous membranes of the nose that fight off the actual viral infections. FluMist is given using a nasal spray.

Timing and Effectiveness of the Vaccine. Ideally, people should be vaccinated every October or November. However, it may take longer for a full supply of the vaccine to reach certain locations. In such cases, the high-risk groups should be served first.
Antibodies to the influenza virus usually develop within 2 weeks of vaccination, and immunity peaks within 4 - 6 weeks, then gradually wanes.
• Because children under age 8 do not develop strong immune responses to one dose, the CDC recommends two vaccinations given 1 month apart on the first year they receive the vaccine. If children under 8 received only 1 dose of the vaccine on their first immunization year, they should receive 2 doses the following year. Children under 8 who have received single doses for 3 or more years should continue to receive single doses.
• It should be noted that if an individual develops influenza symptoms and is accurately diagnosed in time, vaccination of the other members of the household within 36 - 48 hours affords effective protection to those individuals.
In healthy adults, immunization typically reduces the chance of illness by about 70 - 90%. The current flu vaccines may be slightly less effective in certain patients, such as the elderly and those with certain chronic diseases. Even in people with a weaker response, however, the vaccine is usually protective against serious flu complications, particularly pneumonia. In fact, among the elderly, interesting studies are now suggesting that influenza vaccination may help protect against stroke, adverse heart events, and death from all causes.
Children Who Should Be Vaccinated. The following children over 6 months should be vaccinated against influenza:
• The American Academy of Pediatrics (AAP) and the CDC recommend influenza vaccination in all healthy children between ages 6 months and 18 years old.
• In addition, any child over the age of 2 years with a condition that requires regular medical care or who has been hospitalized for a serious illness (particularly lung or kidney disease, diabetes, sickle-cell, or immune deficiencies). If parents are concerned about vaccines that contain the mercury preservative thimerosal, they can ask their doctor about reduced-thimerosal flu vaccine.
• Children who come in direct contact with a person vulnerable to complications from influenza should also be vaccinated.
• Children who are receiving long-term aspirin therapy should also be immunized against the flu because they are at higher risk for Reye syndrome, a life-threatening disease, if they get the flu.
• Children over age 5 who have a higher risk for serious illness.
Adults Who Should Be Vaccinated. The following, in order of priority, are the population groups who should be vaccinated each year. The first two groups have the highest need for influenza vaccinations and are given top priority:
• All adults 50 years and older. Vaccinated older adults have lower hospitalization rates than unvaccinated peers. Evidence now suggests that vaccination may help protect against adverse heart events (including those after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two thirds of the people in this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.
• People of any age at high risk for serious complications from influenza. Such people include those with heart disease, lung problems, immune deficiencies, diabetes, kidney disease, or chronic blood disease. Those with any condition that may compromise respiratory function or the handling of respiratory secretions, including people with cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders, are included in this group. (There have been concerns about the safety of the vaccinations in certain high-risk patients such as those with HIV or asthma. Studies now suggest that the vaccine is generally safe in these patient groups. Furthermore, their risk for serious complications from influenza outweighs any potential adverse effects from the vaccines.)
• All health care workers should be vaccinated, according to the ACIP's recommendations.
• Household members in contact with individuals who are at high-risk for complications from influenza should be vaccinated. (Breast-feeding women may receive the vaccine.)
Others who should be vaccinated:
• People at risk for complications for influenza and who are traveling to the tropics at any time or to the Southern Hemisphere between April and September.
• Pregnant women and women who will become pregnant during flu season.
• Police officers, firefighters, and other public safety officials.
Negative Effects. Possible negative responses to the vaccines include:
• Allergic Reaction. Newer vaccines contain very little egg protein, but an allergic reaction still may occur in people with strong allergies to eggs.
• Soreness at the Injection Site. Up to two thirds of people who receive the influenza vaccine develop redness or soreness at the injection site for 1 - 2 days afterward.
• Flu-like Symptoms. Some people actually experience flu-like symptoms, called oculo-respiratory syndrome, which include cough, wheezing, tightness in the chest, sore throat, or a combination. Such symptoms tend to occur 2 - 24 hours after the vaccination and generally last up to 2 days. These symptoms are not influenza itself but an immune response to the virus proteins in the vaccine. (Anyone with a fever at the time the vaccination is scheduled, however, should wait to be immunized until the ailment has subsided.)
• Guillain-Barre Syndrome. Although isolated cases of a paralytic illness known as Guillain-Barre syndrome occurred in about one of every 100,000 people vaccinated with the swine-flu vaccine in 1976, it has not been a problem with subsequent vaccines. The risk is far outweighed by the number of severe flu cases prevented by immunization.
• There has been some question concerning influenza vaccinations because of some reports that vaccines may worsen asthma. Recent and major studies have been reporting, however, that the vaccination is safe for children with asthma. It is also very important for these patients to reduce their risk for respiratory diseases.

Avian Influenza Vaccine
The FDA approved the first vaccine for humans against H5NI influenza virus in April 2007. The vaccine, which is made from a human strain of the virus, could be used in people ages 18 - 64 to prevent the spread of the virus from human to human. The vaccine requires two shots, given about a month apart. It will not be sold commercially, but instead is being purchased by the U.S. government to be stockpiled and distributed to public health officials in the event of an outbreak of avian flu.
In a study, 103 healthy adults received two g shots of the virus, 28 days apart. An additional group of 300 adults received the vaccine at a lower dose, while 48 people received placebo injections. The study showed that 45% of those who received the higher dose developed antibodies that may reduce their risk of getting the avian flu. The most common side effects reported were pain at the injection site, headache, and muscle pain. Research on the vaccine is continuing.

Antibiotic Resistance
The intense and widespread use of antibiotics is leading to a serious global problem of antibiotic resistance. The inappropriate use of powerful newer antibiotics for conditions such as colds or sore throats poses a particular risk for resistant strains of bacteria. For example, the number of cases of methicillin-resistant Staphylococcus aureus (MRSA) is increasing in people who have no known risk factors. (MRSA causes sometimes-fatal skin infections.) In 2006, rates of Neisseria gonorrhoeae resistance to the fluoroquinolone antibiotics family exceeded 10%. The CDC no longer recommends treating gonorrhea infections with fluoroquinolone first.
When Antibiotics Are Needed for Upper Respiratory Infections.
Antibiotics do not affect viruses and, in healthy individuals, these drugs are almost never necessary or helpful for influenza or colds, even with persistent cough and thick, green mucus. In one disturbing study, antibiotics were prescribed for nearly half of children who went to the doctor for a common cold.

Antibiotics may be required for upper respiratory tract infections only under certain situations, such as the following:
• Patients, particularly small children or elderly people, who have medical conditions that put them at high risk for complications from any respiratory tract infections, should usually be given antibiotics.
• Patients with severe sinusitis that does not clear up within 7 days (some experts say 10 days) and whose symptoms include one or more of the following: green and thick nasal discharge, facial pain, or tooth pain or tenderness.
• Some children with middle ear infections, although experts differ on who will benefit. Some experts recommend that only children under the age of 2 years should be treated with antibiotics, and children over 2 should be treated on a case-by-case basis.
• Patients with strep throat or severe sore throat that involves fever, swollen lymph nodes, and absence of cough. (Strep throat makes up only 10 - 15% of all sore throat cases.)
• Patients who have an acute cough that is caused by pneumonia (but in few other cases, regardless of the duration of the cough). Experts estimate that, outside the hospital setting, less than 20% of prescriptions for persistent coughing are necessary.
Patients at Highest Risk for Infection with Resistant Bacteria Strains. Some patients are at greater risk for developing an infection resistant to common antibiotics. At this time, the average person is not endangered by this problem. Risk factors include:
• Very old or very young age
• Exposure to patients with drug-resistant infection
• Hospitalization in intensive care
• History of an invasive surgical procedure
• Staying in the hospital
• Prolonged course of antibiotics, particularly within the past 4 - 6 weeks
• Serious wounds
• Tubes down the throat, catheters, or intravenous (I.V.) lines
• Immunosuppression
Children at higher risk for antibiotic resistance are those who attend day care, who are exposed to cigarette smoke, who were bottle-fed, and who had siblings with recurrent ear infections.
What the Health Care Community Is Doing. Prescribing antibiotics only when necessary is the most important step in restoring bacterial strains that are susceptible to antibiotics. Encouraging studies are reporting that inappropriate antibiotic prescriptions are on the decline. Prescriptions for other common respiratory infections, such as otitis media, sore throat, acute bronchitis, and colds and flus have been decreasing.
What Patients and Parents Can Do. Patients and parents can also help with the following tips:
• Use home or over-the-counter remedies to relieve symptoms of mild upper respiratory tract infections.
• Realize that antibiotics will not shorten the course of a viral infection. It is important for patients and parents to understand that although antibiotics may bring a sense of security, they provide no significant benefit for a person with viral infection, and overuse can contribute to the growing problem of resistant bacteria.
• Don't pressure a doctor into prescribing an antibiotic if it is clearly inappropriate. The doctor very often will give in.
• If a child needs an antibiotic, ask the doctor whether it is appropriate to use high-dose short-term antibiotics, which may lower the risk for developing resistant strains.
• If an antibiotic is prescribed, take the full course, even if you feel better before finishing it.
Resources
• www.cdc.gov/flu -- U.S. Centers for Disease Control and Prevention
• www.niaid.nih.gov -- National Institute for Allergy and Infectious Diseases
• www.who.int/csr/disease/influenza/en -- World Health Organization
• www.cdc.gov/vaccines -- National Immunization Program
• www.immunize.org -- Immunization Action Coalition
• www.entnet.org -- American Academy of Otolaryngology -- Head and Neck Surgery
• www.cdc.gov/flu/avian -- Avian Influenza Information

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