Background
Tuberculosis (TB) is the most common cause of infectious disease–related mortality worldwide. The World Health Organization estimates that 2 billion people have latent TB, while another 3 million people worldwide die of TB each year.
Although TB rates are decreasing in the United States, the disease is becoming more common in many parts of the world. In addition, the prevalence of drug-resistant TB is also increasing worldwide. Co-infection with HIV has been an important factor in the emergence and spread of resistance.
New TB treatments are being developed, and new TB vaccines are currently under investigation.
Pathophysiology
Humans are the only known reservoir for Mycobacterium tuberculosis. TB is transmitted by airborne droplet nuclei, which may contain fewer than 10 bacilli. TB exposure occurs by sharing common airspace with an individual who is in the infectious stage of TB. When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. Upon encountering the bacilli, macrophages ingest and transport the bacteria to regional lymph nodes.
The bacilli have 4 potential fates:
(1) They may be killed by the immune system,
(2) they may multiply and cause primary TB,
(3) they may become dormant and remain asymptomatic, or
(4) they may proliferate after a latency period (reactivation disease). Reactivation TB may occur following either (2) or (3) above.
Frequency
United States
The US Centers for Disease Control and Prevention (CDC) has been recording detailed epidemiologic information on TB since 1953. The incidence of TB has been declining since the early 20th century because various factors, including basic infection-control practices (isolation). Beginning in 1985, a resurgence of TB was noted. The increase was observed primarily in ethnic minorities and especially in persons infected with HIV. TB control programs were revamped and strengthened across the United States.
After peaking at 25,287 cases in 1993, the number of reported cases began to fall again. In 2007, 13,293 cases of TB were reported.
This corresponds to a rate of 4.4 cases per 100,000 population. The overall frequency of TB is 7 times higher in foreign-born persons than in native-born persons, accounting for a steadily increasing proportion of all reported TB cases. In 2007, 7,690 cases of TB (58.5% of all US cases) were reported among foreign-born persons. More than half (52%) of TB cases involving foreign-born individuals in 2007 were reported in persons from 4 countries: Mexico (24%), the Philippines (12.4%), India (8%), and Vietnam (7.4%). An estimated 10-15 million people in the United States have latent TB infection.
International
An estimated 20-33% of the world's population is infected with M tuberculosis. Countries with the highest prevalence include Russia, India, Bangladesh, Pakistan, Indonesia, Philippines, Vietnam, Korea, China, Tibet, Hong Kong, Egypt, most sub-Saharan African countries, Brazil, Mexico, Bolivia, Peru, Colombia, Dominican Republic, Ecuador, Puerto Rico, El Salvador, Nicaragua, Haiti, Honduras, and areas undergoing civil war (eg, Balkan countries). The prevalence of TB in countries in Eastern Europe is intermediate. The prevalence of TB is lowest in Costa Rica, western and northern Europe, the United States, Canada, Israel, and most countries in the Caribbean. Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) are becoming increasingly significant.
Genotyping studies have shown that between 63% and 75% of TB cases progress to XDR-TB through acquisition of resistance.
Mortality/Morbidity
The case-fatality rate for TB was 50% for untreated patients before the advent of antibiotic therapy. TB-related deaths worldwide are estimated at 3 million per year. In the United States, the mortality rate of TB dropped from 12.4 deaths per 100,000 population in 1953 to 0.2 deaths per 100,000 population in 2004; this is approximately 4% per newly identified case.
MDR-TB cases are associated with a higher mortality rate. The mortality rate is also higher in patients with underlying diseases that predispose to active TB.
The mortality rate associated with untreated congenital TB is 50%. Congenital TB can mimic congenital syphilis or cytomegalovirus (CMV) infection.
Race
Based on 2007 CDC data, the frequency of TB in Hispanics, blacks, and Asians were 7.6, 8.5, and 23.5 times higher than in whites, respectively.
However, race is not clearly an independent risk factor, as foreign-born persons account for 77% of TB cases among Hispanics and 96% of TB cases among Asians, but only 29% of TB cases among blacks. Risk is best defined based on social, economic, and medical factors.
Sex
Despite the fact that TB rates have declined in both sexes in the United States, certain differences exist. TB rates in women decline with age, but, in men, rates increase with age. Men are more likely to have a positive tuberculin skin test result. The reason for these differences may be social rather than biological in nature.
Age
In the United States, more than 60% of TB cases occur in persons aged 25-64 years; however, the age-specific risk is highest in persons older than 65 years.1
TB infection in infants and young children (≤5 y) always indicates recent transmission. Untreated TB in this age group may result in life-threatening meningitis or disseminated disease.
Elderly individuals with TB may not display typical signs and symptoms of TB infection because they may not mount a good immune response. Active TB infection in this age group may manifest as nonresolving pneumonitis. Obesity in elderly patients has been associated with a lower risk for pulmonary TB.8
History
Pulmonary tuberculosis (TB): Typical symptoms of pulmonary TB include a productive cough, fever, and weight loss. Patients with pulmonary TB occasionally present with hemoptysis or chest pain. Other systemic symptoms include anorexia, fatigue, and night sweats.
Tuberculous meningitis: Patients with tuberculous meningitis may present with a headache that is either intermittent or persistent for 2-3 weeks. Subtle mental status changes may progress to coma over a period of days to weeks. Fever may be low-grade or absent.
Skeletal TB: The most common site of skeletal TB involvement is the spine (Pott disease). Symptoms include back pain or stiffness. Lower-extremity paralysis occurs in up to half of patients with undiagnosed Pott disease. Tuberculous arthritis usually involves only one joint. Although any joint may be involved, the hips and knees are affected most commonly, followed by the ankle, elbow, wrist, and shoulder. Pain may precede radiographic changes by weeks to months.
Genitourinary TB: Reported symptoms of genitourinary TB include flank pain, dysuria, and frequency. In men, genital TB may manifest as epididymitis or a scrotal mass. In women, genital TB may mimic pelvic inflammatory disease. TB is the cause of approximately 10% of sterility cases in women worldwide and approximately 1% in industrialized countries.
Gastrointestinal TB: Any site along the gastrointestinal tract may become infected. Symptoms of gastrointestinal TB are referable to the site infected, including the following: nonhealing ulcers of the mouth or anus; difficulty swallowing with esophageal disease; abdominal pain mimicking peptic ulcer disease with stomach or duodenal infection; malabsorption with infection of the small intestine; and pain, diarrhea, or hematochezia with infection of the colon.
Tuberculous lymphadenitis (scrofula): The most common site of tuberculous lymphadenitis is in the neck along the sternocleidomastoid muscle. It is usually unilateral and causes little or no pain. Advanced cases of tuberculous lymphadenitis may suppurate and form a draining sinus.
Cutaneous TB: Direct inoculation may result in an ulcer or wartlike lesion. Contiguous spread from an infected lymph node typically results in a draining sinus. Hematogenous spread may result in a reddish brown plaque on the face or extremities (lupus vulgaris) or tender nodules or abscesses.
Physical
Physical examination findings associated with TB depend on the organs involved.
Patients with pulmonary TB have abnormal breath sounds, especially over the upper lobes or areas involved.
Signs of extrapulmonary TB differ depending on the tissues involved. Signs may include confusion, coma, neurologic deficit, chorioretinitis, lymphadenopathy, and cutaneous lesions (see History).
Postnatal TB is contracted via the airborne route. The most common findings of postnatal TB include adenopathy and a lung infiltrate. However, the chest radiographic findings may be normal in infants with disseminated disease. Many experts increase the treatment duration to 9 or 12 months because of the possible impaired immune system in children younger than 12 months. Bacille Calmette-Guérin (BCG) vaccine is not recommended in infants in the United States but is commonly used around the world.
Causes
M tuberculosis is a slow-growing organism, requiring 4-8 weeks for visible growth on solid medium. The organism grows in parallel groups called cords (see Image 1). It retains many stains after decoloration with acid-alcohol, which is the basis of acid-fast stains.
Lab Studies
Patients suspected of having tuberculosis (TB) should submit sputum for smear and culture. Sputum should be collected in the early morning on 3 consecutive days. In hospitalized patients, sputum may be collected every 8 hours. In patients without spontaneous sputum production, sputum induction with hypertonic saline should be attempted.
Early-morning gastric aspirate may also produce a good specimen, especially in children. Another option is fiberoptic bronchoscopy with transbronchial biopsy and bronchial washings. Biopsy of bone marrow, liver, or blood cultures is occasionally necessary and may be helpful.
Traditional mycobacterial cultures require weeks for growth and identification. Newer technologies, including ribosomal RNA probes or DNA polymerase chain reaction, allow identification within 24 hours. The DNA probes are approved for direct testing on smear-positive or smear-negative sputa.
However, smear-positive specimens yielded higher sensitivity.
Obtain the following laboratory tests:
CBC count
Chemistries, including alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
Alkaline phosphatase
Total bilirubin
Uric acid
Creatinine
Obtain HIV serology in all patients with TB.
For congenital TB, the best diagnostic test is the examination of the placenta for pathology, histology, and culture. Mycobacterial blood cultures of the newborn may also be helpful. Treatment may be necessary until placental culture results are negative.
Imaging Studies
Chest radiographs may show a patchy or nodular infiltrate (see Images 2-3). TB may be found in any part of the lung, but upper-lobe involvement is most common. The lordotic view may better demonstrate apical abnormalities.
Primary TB is more likely to mimic the appearance of routine community-acquired pneumonia on chest radiography, in contrast to reactivation TB. Studies have shown that either may be associated with pleural effusion or cavitation.
Various patterns may be seen, as follows:
Cavity formation indicates advanced infection and is associated with a high bacterial load.
Noncalcified round infiltrates may be confused with lung carcinoma.
Homogeneously calcified nodules (usually 5-20 mm) are tuberculomas and represent old infection rather than active disease.
Miliary TB is characterized by the appearance of numerous small nodular lesions that resemble millet seeds on chest radiography.
CT scanning of the chest may help to better define abnormalities in patients with vague findings on chest radiography.
Technetium-99m methoxy isobutyl isonitrile single-photon emission CT scanning for solitary pulmonary nodules yields a high predictive value for distinguishing TB from malignancy. Therefore, it has the potential to serve as a low-cost alternative when positron emission tomography is not available, especially in endemic areas.
Other Tests
Tuberculin skin testing (Mantoux test) is the most widely available test for diagnosing tuberculous infection in the absence of active disease (latent infection). The tuberculin skin test involves an intradermal injection of 5 tuberculin units of purified protein derivative. The response is measured as the amount of induration at 48-72 hours. The size of induration, rather than erythema, is diagnostic. Interpretation of skin testing depends on the size of induration, age, and patient risk factors. The tuberculin skin test is not a sensitive test for active TB. Three cutoff points of clinical significance exist; the criteria for each cutoff point are listed below.
Larger than or equal to 5 mm
Close contacts to persons with newly diagnosed TB
Persons with HIV infection
Patients with organ transplant or patients who are taking the equivalent of more than 15 mg/d of prednisone for one month or more
Patients with fibrotic lesions on chest radiography (not granulomas)
Larger than or equal to 10 mm
Patients with medical conditions that increase the risk of TB (eg, diabetes mellitus, hematologic malignancies, carcinoma of the head and neck, intravenous drug use [known to be HIV-negative], end-stage renal disease, silicosis, malnutrition, jejunoileal bypass, gastrectomy)
Recent converter - At least 10-mm increase in skin test in past 2 years (regardless of age)
Recent immigrants (within 5 y) from a high-prevalence country
Children younger than 4 years exposed to adults at high risk for TB
Residents and employees of facilities for long-term care, including correctional institutions, nursing homes, homeless shelters, and mental institutions
Larger than or equal to 15 mm - Persons with none of the above
Whole-blood assay based on interferon-gamma release (IGRA) with ESAT-6 and CFP-10 antigens (QuantiFERON-TB Gold) can also be used to screen for latent TB infection and offers certain advantages over tuberculin skin testing.
Overall, sensitivity and specificity are comparable to those of tuberculin skin testing; however, a second encounter for reading is unnecessary, unlike with tuberculin skin testing. Results are reported as positive, negative, or indeterminate. Patients with an indeterminate result are likely to have evidence of immunosuppression and to be nonreactive on skin testing.
Neither tuberculin skin testing nor IGRA testing is sufficiently sensitive to rule out TB infection.
TREATMENT
Medical Care
For initial empiric treatment of tuberculosis (TB), start patients on a 4-drug regimen: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin. Once the TB isolate is known to be fully susceptible, ethambutol (or streptomycin if used as a fourth drug) can be discontinued.
After 2 months of therapy (for a fully susceptible isolate), pyrazinamide can be stopped. Isoniazid plus rifampin are continued as daily or intermittent therapy for 4 more months.
If isolated isoniazid resistance is documented, discontinue isoniazid and continue treatment with rifampin, pyrazinamide, and ethambutol for the entire 6 months.
Therapy must be extended if the patient has cavitary disease or remains culture-positive after 2 months of treatment.
Directly observed therapy (DOT) is recommended for all patients. Patients on the above regimens as DOT can be switched to 2- to 3-times per week dosing after an initial 2 weeks of daily dosing. Patients on twice-weekly dosing must not miss any doses. Prescribe daily therapy for patients on self-administered medication.
The diagnosis of MDR-TB is established with an isolate that is resistant to both isoniazid and rifampin. Resistance may be initial (no known history of prior treatment) or secondary (acquired during therapy or because of previous inadequate therapy).
Risk factors for initial resistance include exposure to a patient who has MDR-TB or being from a country or region with a high prevalence of resistance. Symptoms and radiographic findings do not differentiate MDR-TB from fully susceptible TB. Suspect MDR-TB if the patient is on DOT with the 4 first-line drugs (no diarrhea) and symptoms do not improve within 1-2 weeks.
Continue treatment for MDR-TB for 18-24 months after sputum culture conversion. The drugs should be prescribed daily (no intermittent therapy), and the patient should always be on DOT. Weekend DOT may not be possible; therefore, giving self-administered oral drugs on Saturdays and Sundays may be reasonable. Consult an expert on MDR-TB. Costs are many times higher for treatment of MDR-TB. Treatment should include an injectable drug together with at least 3 more drugs to which the isolate is susceptible.
The diagnosis of extended drug-resistant TB (XDR-TB) is established with an isolate that is resistant to isoniazid, rifampin, at least one of the quinolones, and at least one injectable drug. Treatment options for XDR-TB are very limited, and XDR-TB carries a very high mortality rate.
Surgical Care
Surgical resection of an infected lung may be considered to reduce the bacillary burden in patients with MDR-TB. Procedures include segmentectomy (rarely used), lobectomy, and pneumonectomy. Pleurectomies for thick pleural peel are rarely indicated. However, intraoperative infection of uninvolved lung tissue has been observed.
Complications include the usual perioperative complications, recurrent disease, and bronchopleural fistulas.
Consultations
Infectious disease specialist
Pulmonologist
General or thoracic surgeon
Activity
Smoking has been shown to be a risk factor for TB; smokers who develop TB should be encouraged to stop smoking to decrease the risk of relapse.14
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Drug Category: Antimycobacterials
The goals of tuberculosis (TB) treatment are to shorten the clinical course, to prevent complications, to prevent the development of latency and/or subsequent recurrences, and to decrease the likelihood of TB transmission. In patients with latent TB, the goal of therapy is to prevent progression of disease.
Drug Name Isoniazid (Laniazid)
Description DOC for preventive therapy and primary drug in combination therapy for active TB. Pyridoxine 25-50 mg PO qd should be coadministered to prevent peripheral neuropathy.
Adult Dose 300 mg PO qd
Pediatric Dose 10 mg/kg/d PO qd; not to exceed 300 mg/d
Contraindications Documented hypersensitivity; previous isoniazid-associated hepatic injury; other severe adverse reactions
Interactions Higher incidence of isoniazid-related hepatitis can occur with daily alcohol ingestion; aluminum salts may decrease isoniazid serum levels (administer 1-2 h before taking aluminum salts); may increase effects of anticoagulants with coadministration; may inhibit metabolic clearance of benzodiazepines
Carbamazepine toxicity or isoniazid hepatotoxicity may result from concurrent use (monitor carbamazepine concentrations and liver function); coadministration with cycloserine may increase adverse CNS effects (eg, dizziness); acute behavioral and coordination changes may occur with coadministration of disulfiram
Coadministration with rifampin after halothane anesthesia may result in hepatotoxicity and hepatic encephalopathy; may inhibit hepatic microsomal enzymes and increase toxicity of hydantoin
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Monitor patients with active chronic liver disease or severe renal dysfunction; periodic ophthalmologic examinations during isoniazid therapy are recommended even when visual symptoms do not occur
Drug Name Rifampin (Rifadin, Rimactane)
Description For use in combination with at least one other antituberculous drug. Inhibits DNA-dependent bacterial but not mammalian RNA polymerase. Cross-resistance may occur.
Treat for 6-9 mo or until 6 mo have elapsed from conversion to sputum culture negativity.
Adult Dose 600 mg PO qd
Pediatric Dose 10-20 mg/kg/d PO qd; not to exceed 600 mg/d
Contraindications Documented hypersensitivity
Interactions Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFTs occur)
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Obtain CBCs and baseline clinical chemistries before and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur
Drug Name Pyrazinamide (PZA)
Description Pyrazine analog of nicotinamide that may be bacteriostatic or bactericidal against M tuberculosis depending on concentration of drug attained at site of infection; mechanism of action is unknown.
Administer for initial 2 mo of a 6-mo or longer treatment regimen for drug-susceptible TB. Treat drug-resistant TB with individualized regimens.
Adult Dose <50>75 kg: 2.5 g PO qd
Pediatric Dose 15-30 mg/kg/d PO qd; not to exceed 2 g/d
Contraindications Documented hypersensitivity; severe hepatic damage; acute gout
Interactions None reported
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Use only in combination with other effective antituberculous agents; inhibits renal excretion of urates; may result in hyperuricemia (usually asymptomatic); perform baseline serum uric acid determinations; discontinue drug if signs of hyperuricemia with acute gouty arthritis occur; perform baseline LFTs (closely monitor in liver disease); discontinue pyrazinamide if signs of hepatocellular damage appear; caution in history of diabetes mellitus
Drug Name Ethambutol (Myambutol)
Description Diffuses into actively growing mycobacterial cells (eg, tubercle bacilli). Impairs cell metabolism by inhibiting synthesis of one or more metabolites, which in turn, causes cell death. No cross-resistance demonstrated.
Mycobacterial resistance is frequent with previous therapy. Use in these patients in combination with second-line drugs that have not been previously administered. Administer q24h until permanent bacteriological conversion and maximal clinical improvement are observed. Absorption is not significantly altered by food.
Adult Dose 15-25 mg/kg PO qd
Pediatric Dose Administer as in adults
Contraindications Documented hypersensitivity; optic neuritis (unless clinically indicated)
Interactions Aluminum salts may delay and reduce absorption (administered several hours before or after ethambutol dose)
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions Reduce dose in impaired renal function; may have reversible adverse visual effects if promptly discontinued
Drug Name Streptomycin sulfate
Description For treatment of susceptible mycobacterial infections. Use in combination with other antituberculous drugs (eg, isoniazid, ethambutol, rifampin). Total period of treatment for TB is a minimum of 1 y; however, indications for terminating streptomycin therapy may occur at any time. Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.
Adult Dose 15 mg/kg IM qd; can be administered 3-5 d/wk
Pediatric Dose 20-30 mg/kg IM qd
Contraindications Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions Narrow therapeutic index; not intended for long-term therapy; caution in renal failure, patient not taking dialysis; caution with myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission
Drug Name Levofloxacin (Levaquin)
Description Second-line drug. Useful in the treatment of TB in combination with rifampin and other antituberculous agents. Useful in treating most cases of MDR-TB.
Adult Dose 500-1000 mg PO qd
Pediatric Dose <18 years: Not recommended unless no alternates available
Contraindications Documented hypersensitivity
Interactions Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy
Drug Name Rifapentine (Priftin)
Description Used in once-weekly regimens along with isoniazid. Should not be used in individuals with HIV or with positive cultures after 2 mo of treatment.
Adult Dose 600 mg PO qwk during the continuation phase of treatment for TB; given in combination with isoniazid for susceptible organism
Pediatric Dose Not established
Contraindications Documented hypersensitivity Interactions Induces cytochrome P 4503 A 4 and P 4502 C 8/9, thereby decreasing levels of other drugs that are metabolized by these enzymes; may decrease plasma concentration of calcium channel blockers (verapamil, nifedipine, diltiazem), methadone, oral anticoagulants, oral contraceptives, benzodiazepines, acetaminophen, dapsone, clofibrate, doxycycline, levothyroxine, nortriptyline, tacrolimus, zidovudine, protease inhibitors, hydantoins, sulfa drugs, or enalapril; toxicity may increase when taken concurrently with halothane or isoniazid
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Adverse effects include serious hepatic events, including hepatitis and liver failure; Clostridium difficile-associated colitis; hyperbilirubinemia; urticaria; thrombocytopenia; hyperkalemia; fatigue; gout; may cause red-orange discoloration of body fluids (eg, tears, urine, sweat, CSF)
Drug Name Para-aminosalicylic acid (Sodium PAS)
Description Second-line drug. Bacteriostatic agent useful against M tuberculosis. Inhibits the onset of bacterial resistance to streptomycin and isoniazid. Administer aminosalicylate sodium with other antituberculous drugs.
Adult Dose 4-6 g PO bid
Pediatric Dose 75 mg/kg PO bid
Contraindications Documented hypersensitivity
Interactions PO absorption of digoxin may be reduced, causing a reduction in serum levels when administered concurrently with PAS; increase in digoxin dosing may be necessary; a deficiency in vitamin B-12 (PO) may be induced because of PAS interference of its GI absorption; parenteral vitamin B-12 supplementation may be required
Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Caution in gastric ulcer and history of congestive heart failure; avoid situations in which excess sodium is potentially harmful
Drug Name Ethionamide (Trecator-SC)
Description Second-line drug. Bacteriostatic against M tuberculosis. Recommended if treatment with first-line drugs (isoniazid, rifampin) is unsuccessful. Treats any form of active TB. However, should only be used with other effective antituberculous agents.
Adult Dose 250-500 mg PO bid
Pediatric Dose 15-20 mg/kg PO bid
Contraindications Documented hypersensitivity; severe hepatic damage Interactions Hepatotoxicity increases when used concurrently with rifampin
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Make determinations of serum transaminase (AST, ALT) prior to therapy and q2-4wk thereafter; perform in vitro susceptibility tests of recent cultures of M tuberculosis from patient, with ethionamide and usual first-line antituberculous drugs; management of diabetes mellitus may be more difficult, and hepatitis may occur more frequently
Drug Name Amikacin (Amikin)
Description Second-line drug. Irreversibly binds to 30S subunit of bacterial ribosomes; blocks recognition step in protein synthesis; causes growth inhibition. Use patient's IBW for dosage calculation.
Adult Dose 15 mg/kg IM qd; can administer 3-5 d/wk
Pediatric Dose 15-30 mg/kg IM qd Contraindications Documented hypersensitivity Interactions
Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B (increases nephrotoxicity); enhances effects of neuromuscular-blocking agents; causes respiratory depression; irreversible hearing loss may occur with coadministration of loop diuretics
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Not intended for long-term therapy; caution in patients with renal failure (patient not taking dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission
Drug Name Cycloserine (Seromycin)
Description Second-line drug. Inhibits cell wall synthesis in susceptible strains of gram-positive and gram-negative bacteria and in M tuberculosis. Structural analogue of D-alanine, which antagonizes role of D-alanine in bacterial cell wall synthesis, inhibiting growth.
Adult Dose 250-500 mg PO bid
Pediatric Dose 10-20 mg/kg PO bid
Contraindications Documented hypersensitivity; severe anxiety or psychosis; epilepsy; depression; severe renal insufficiency; alcoholism; severe neurologic impairments
Interactions Incompatible with alcohol consumption because may increase possibility and risk of epileptic episodes; isoniazid in combination with cycloserine may result in increased adverse cycloserine CNS effects (eg, dizziness)
Pregnancy D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus Precautions Discontinue drug or reduce dosage if allergic dermatitis or symptoms of CNS toxicity (eg, convulsions, headache, tremor, depression, confusion, psychosis, somnolence, hyperreflexia, vertigo, paresis, or dysarthria) develop; risk of convulsions is increased in long-term alcoholism; administration has been associated with vitamin B-12 and folic acid deficiency, megaloblastic anemia, and sideroblastic anemia; monitor blood levels weekly in reduced renal function, patients receiving >500 mg/d, and patients with symptoms of toxicity
Drug Name Capreomycin (Capastat)
Description A second-line drug. Obtained from Streptomyces capreolus for coadministration with other antituberculous agents in pulmonary infections caused by capreomycin-susceptible strains of M tuberculosis. For use only when first-line agents (eg, isoniazid, rifampin) have been ineffective or cannot be used because of toxicity or presence of resistant tubercle bacilli.
Adult Dose 15 mg/kg IM qd; also administered as IV infusion
Pediatric Dose 15-30 mg/kg IM qd
Contraindications Documented hypersensitivity
Interactions Coadministration with aminoglycosides may increase risk of respiratory paralysis and renal dysfunction; with nondepolarizing neuromuscular-blocking agents, has synergistic effects on myoneural function
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Assess vestibular auditory function prior to therapy and regularly while treating; monitor renal function throughout treatment (reduce dose in renal impairment); monitor serum potassium levels
Drug Name Rifabutin (Mycobutin)
Description Ansamycin antibiotic derived from rifamycin S. Inhibits DNA-dependent RNA polymerase, preventing chain initiation. Used in treatment for TB in individuals on specific HIV medications, when rifampin is contraindicated (most protease inhibitors).
Adult Dose 300 mg PO daily; as part of an intermittent regimen, 300 mg PO 3 times/wk
Pediatric Dose Not established; suggested dose is 5 mg/kg/d PO
Contraindications Documented hypersensitivity; WBC count <1000/μL or platelet count <50,000/μL
Interactions Decreases plasma concentration of methadone, verapamil, cyclosporine, digoxin, corticosteroids, oral anticoagulants, barbiturates, theophylline, quinidine, halothane, protease inhibitors, non-nucleoside reverse transcriptase inhibitors, oral contraceptives, ketoconazole, and chloramphenicol; toxicity of rifabutin increases when administered concurrently with indinavir, ketoconazole, itraconazole, ritonavir, erythromycin, or protease inhibitors
Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions Perform hematologic studies periodically due to association with neutropenia, and more rarely thrombocytopenia
Further Inpatient Care
Hospitalized patients with suspected or documented tuberculosis (TB) must be placed in appropriate isolation. This includes a private room with negative pressure and adequate air exchanges. Persons entering the room must wear masks or respirators capable of filtering droplet nuclei.
Worldwide, TB rates are consistently higher among health care workers than in the general population; infection-control measures yield a significant impact in high-income countries but less impact in low- and middle-income countries.
Patients with TB should remain in isolation until sputum becomes smear-negative; however, patients should not ordinarily be kept in the hospital for the sole purpose of providing isolation. Special arrangements are necessary for patients with TB who live with children, individuals infected with HIV, or patients returning to a closed-group setting (eg, nursing home, correctional facilities, residential facility, homeless shelter).
Further Outpatient Care
Patients diagnosed with active TB should undergo sputum analysis for M tuberculosis weekly until sputum conversion is documented. Monitoring for toxicity includes baseline and periodic liver enzymes, CBC count, and serum creatinine.
In addition, patients with TB who are receiving pyrazinamide should undergo baseline or periodic serum uric acid assessments, and patients with TB who are receiving long-term ethambutol therapy should undergo baseline or periodic visual acuity and red-green color perception testing. The latter can be performed with a standard test such as the Ishihara test for color blindness.
Deterrence/Prevention
Patients with a clinically significant result on tuberculin skin testing or positive IGRA result (see Other Tests) should receive a course of therapy once active infection and disease is ruled out. Guidelines published by the CDC in 2000 now refer to this as treatment of latent TB. The recommended regimens are listed below:
Isoniazid daily for 9 months
Isoniazid twice weekly for 9 months (administered as DOT)
Isoniazid daily for 6 months (should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children)
Isoniazid twice weekly for 6 months (administered as DOT; should not be used in patients with fibrotic lesions on chest radiography, patients with HIV, or children)
Rifampin daily for 4 months
Rifampin plus pyrazinamide daily for 2 months (This regimen is no longer recommended because of an increased risk for liver toxicity.)
Children should receive isoniazid for 9 months. In addition, children younger than 5 years who have close contact with a person who has active TB should be started on isoniazid, even if results on skin testing are negative; preventive therapy can be stopped if results on repeat skin testing are negative 2-3 months after last contact with a culture-positive source case.
Patients exposed to MDR-TB may be administered ethambutol plus pyrazinamide for 6-12 months or pyrazinamide plus levofloxacin for 6-12 months; the index isolate should be susceptible to all drugs used.
Recommended regimens in patients with HIV infection include rifampin alone daily for 4 months or isoniazid, daily or twice weekly, for 9 months. Patients on antiretroviral therapy may need rifabutin instead of rifampin because of potential drug interactions. The 2-month combination of pyrazinamide plus rifampin is no longer recommended.
The BCG vaccine continues to be used throughout much of the world and provides protection mostly until early childhood. Immunity begins to wane as early as 3 months after administration.
Complications
Late complications of pulmonary TB include relapse, aspergilloma, bronchiectasis, broncholithiasis, fibrothorax, and possibly carcinoma. A copy of the chest radiograph at the time of completion of therapy should be provided to the patient to facilitate the diagnosis of late complications.
The relapse rate following appropriate completed therapy is only 0-4% and occurs within the first 2 years after completion. Therefore, re-treatment is usually unnecessary, especially after DOT.
Aspergilloma is a fungus ball that develops in a residual lung abnormality (eg, pneumatocele, bulla, bleb, cyst). It may appear as a crescent sign on chest radiographs. Other superinfections may manifest with an air-fluid level and often contain mixed bacteria, including anaerobes.
Hemoptysis is the most common late complication. Broncholithiasis is the result of spontaneous lymph node migration into the bronchial tree and may be associated with postobstructive pneumonia or esophageal perforation. Bronchiectasis may progress to chronic bronchitis; bleeding from submucosal bronchial veins is usually self-limited.
Fibrothorax is the development of trapped lung due to pleural fibrosis and scarring.
The risk of carcinoma is controversial but should be considered with newly developing clubbing.
Prognosis
Among published studies involving DOTS treatment, the rate of recurrence ranges from 0-14%.17 In countries with low TB rates, recurrences usually occur within 12 months of treatment completion and are due to relapse.18 In countries with higher TB rates, most recurrences after appropriate treatment are probably due to reinfection rather than relapse.19
Patient Education
For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Tuberculosis.
edical/Legal Pitfalls
Laws vary from state to state, but communicable-disease laws typically empower public health officials to investigate suspected cases of tuberculosis (TB), including potential contacts. In addition, patients may be incarcerated for noncompliance with therapy. For example, in the Denver Metro Tuberculosis Clinic from 1984-1994, 5% of patients were incarcerated for noncompliance and an additional 5% who were lost to follow-up before completing therapy would have been candidates for incarceration.
Special Concerns
Pregnancy
Pregnancy provides an opportunity to screen for TB; all pregnant women can undergo tuberculin skin testing. If skin-testing results are positive, chest radiography can be performed with lead shielding (the amount of radiation exposure of a single chest radiograph has been compared to that incurred on a regular flight from New York to Los Angeles). Chest radiography should not be delayed during the first 3 months of pregnancy in patients with suggestive symptoms.
Active TB should be treated, even in women in the first stage of pregnancy. Isoniazid, rifampin, and ethambutol may be used. In the United States, pyrazinamide is reserved for women with suspected MDR-TB. Elsewhere in the world, pyrazinamide is commonly used in pregnant women with TB.
Preventive treatment is recommended during pregnancy, especially in the following situations:
Pregnant women with a positive tuberculin skin test result who are HIV seropositive or who have behavioral risk factors for HIV infection but decline HIV testing
Pregnant women with a positive tuberculin skin test result who have been in close contact with a patient who is smear-positive for pulmonary TB
Pregnant women who have had a documented tuberculin skin test conversion in the past 2 years
Pregnant women are at an increased risk for isoniazid-induced hepatotoxicity and should undergo monthly ALT monitoring while on treatment. This risk continues 2-3 months into the postpartum period. Pyridoxine should also be administered to pregnant women receiving isoniazid. Breastfeeding can be continued during preventive therapy. Many experts recommend supplemental pyridoxine to the breastfed infant.
Tuberculosis in children
TB in a child is a sentinel event indicating recent transmission, and contacts should be evaluated to find the source case as soon as possible. Children do not commonly infect other children because they rarely develop cough and sputum production is scant. However, cases of child-child and child-adult TB transmission are well-documented.
Chest radiographs in children with TB may show only hilar lymphadenopathy or a patchy infiltrate. Most children with TB can be treated with isoniazid and rifampin for 6 months, along with pyrazinamide for the first 2 months if the culture from the source case is fully susceptible. Gastric aspirates or biopsies are not necessary if positive cultures have been obtained from the source case.
In children younger than 5 years, the potential for development of fatal miliary TB or meningeal TB is a significant concern. TB disease is uncommon in children aged 5-15 years (the golden age of childhood).
Isoniazid tablets may be crushed and added to food. Isoniazid liquid without sorbitol should be used to avoid osmotic diarrhea, causing decreased absorption. Rifampin capsules may be opened and the powder added to food. If rifampin is not tolerated, it may be taken in divided doses 20 minutes after light meals.
Ethambutol is often avoided in young children because of difficulties monitoring visual acuity and color perception. However, studies show that ethambutol (15 mg/kg) is well tolerated and can prevent further resistance if the child is infected with a resistant strain.
Human immunodeficiency virus
Individuals infected with HIV are at an increased risk for TB, beginning within the first year of HIV infection.20 Based on historical data, the initiation of antiretroviral therapy decreases the risk of developing TB in these patients.
Patients with TB must be tested for HIV, and patients with HIV need periodic evaluation for TB with tuberculin skin testing and/or chest radiography. Patients with HIV and a positive tuberculin skin test result develop active TB at a rate of 3-16% per year.
Patients with TB and HIV are more likely to have disseminated disease and less likely to have upper-lobe infiltrates or classic cavitary pulmonary disease. Patients with a CD4 count of less than 200/μL may have mediastinal adenopathy with infiltrates.
Treatment regimens for active or latent TB in patients with HIV infection are similar to the treatment of individuals who are HIV negative, but dose adjustments may be necessary.
The most significant differences involve the avoidance of rifampin in patients who are on protease inhibitors. Rifabutin may be used in place of rifampin in such patients.
Patients with HIV and TB may develop a paradoxical response when starting antiretroviral therapy. This response has been attributed to a stronger immune response to M tuberculosis. Clinical findings include fever, worsening pulmonary infiltrates, and lymphadenopathy.
Tumor necrosis factor-alpha (TNF-a) antagonists have been associated with a significantly increased risk for TB.
Reports have included atypical presentations, extrapulmonary and disseminated disease, and deaths. Patients scheduled to begin therapy with a TNF-α antagonist should be screened for latent TB and counseled regarding the risk of TB.
Monday, November 24, 2008
DIPHTHERIA
WHAT IS IT?
Diphtheria is an acute infectious illness caused by a bacterium called corynebacterium diphtheriae (C diphtheriae). It often begins with a sore throat, after which there can be serious complications involving the heart and other organs. Thanks to immunization, the disease is now rare in Western world, but it is a growing problem in many parts of the world, so travellers in particular should be aware of the threat.
HOW DOES IT OCCUR?
Diphtheria spreads from person to person by direct contact and in germ-laden droplets in the air which form when talking, sneezing or coughing. Raw (unpasteurised) milk and inanimate objects may also spread the bacteria.
The incubation period is from one to 7 days, usually around two days. However, people can carry the disease without necessarily becoming ill.
Diphtheria has been eliminated from many developed countries but it is still common in other areas, such as Somalia and other African countries, South America, Vietnam and other parts of SE Asia, and the Indian Subcontinent. In 1990 there was an epidemic in Russia. This was poorly controlled and led to the resurgence of diphtheria in many countries of the former Soviet Union.
WHY DOES IT OCCUR?
C diphtheriae invades the throat first, where it causes symptoms. The bacteria also produce a chemical or toxin which can spread through the blood-stream and affect more distant organs.
WHAT ARE THE SYMPTOMS?
The disease often starts with a sore throat, fever, headache and feeling generally unwell. The throat may not be particularly painful, but there is often a typical greyish membrane visible on one or both tonsils. Lymph nodes in the neck can be very large, giving an appearance of "bull-neck", especially in severe cases. This throat phase can last several days, and the membrane can be thick enough to obstruct breathing. Alternatively, the initial site of infection may be the nose, resulting in a bloodstained discharge from one nostril.
In the tropics, sometimes the only symptom is a skin ulcer which is very slow to heal and is covered by a tough grey membrane.
WHAT ARE THE COMPLICATIONS?
Complications can set in a week or two after the initial symptoms. Involvement of the heart muscle causes low blood pressure and a variety of abnormal heart rhythms. This typically occurs 10 to 20 days after the onset of a sore throat, and it can kill, usually because of heart rate irregularities.
Diphtheria toxin can also attack the nervous system, causing paralysis of the palate (roof of the mouth) and therefore trouble speaking and swallowing. The eye muscles may also be affected. Less often, other nerves are involved, for instance those that control breathing, which can be fatal. Nerve involvement can continue to develop up to three months from the start of the illness.
WHAT TESTS ARE DONE?
Swabs are taken from nose and throat (or any skin ulcers) and are sent to the laboratory to look for C diphtheriae. Basic blood tests are also done to monitor liver and kidney function.
WHAT IS THE TREATMENT?
Prompt specialist treatment is essential. Infection control is an important part of the management of diphtheria. Suspected cases are isolated, under the guidance of the local infection control team.
Injections of diphtheria anti-toxin are given to neutralise circulating toxin in the blood-stream. Anti-toxin must be given as soon as possible because it has no effect on toxin which is already bound to nerves or other tissues. Diphtheria anti-toxin originates from horses, so severe allergic reactions sometimes occur. To reduce the risk of these, a small test dose of anti-toxin is given first.
Antibiotics help eliminate the diphtheria bacteria. They are also given to close contacts of the patient.
Heart monitoring is usual. Depending on the condition of the patient, other measures may be needed, such as treatment for breathing and heart complications. These can include artificial ventilation, tracheostomy and insertion of a temporary pacemaker to regulate the heart rate.
WHAT HAPPENS AFTER TREATMENT?
The traditional thinking was that survivors of diphtheria could expect a full recovery, but this is not always so and there may be long-term heart complications.
After recovery from diphtheria, the patient needs an injection of diphtheria toxoid (diphtheria vaccine, see below). This is because having the disease does not necessarily produce immunity to future infections.
HOW CAN DIPHTHERIA BE PREVENTED?
Immunisation with diphtheria toxoid gives effective protection against the disease. In the Western world, routine immunisation has almost eradicated diphtheria. The lack of a vaccination programme is one reason why the disease is widespread in certain countries.
The vaccine, diphtheria toxoid, is made from part of the diphtheria toxin. Giving it stimulates the body to produce its own diphtheria anti-toxin. The basic three-dose course of diphtheria toxoid injections is given to babies at two, three and four months of age as part of the triple vaccine. A reinforcing dose is given before school entry and again before leaving school.
Travellers to a diphtheria area should have had the full basic course of vaccine. If it has been over 10 years since the last injection, a booster of low-dose diphtheria toxoid is given before travel. The low-dose preparation is used in such cases to minimise the possibility of a reaction, which can even happen if a person is already immune to the disease. Those likely to come into contact with diphtheria should continue to have low-dose boosters at 10-year intervals.
WHAT ARE THE COMPLICATIONS OF IMMUNISATION AGAINST DIPHTHERIA?
Swelling and redness at the site of injection (usually the upper arm in adults) are common, as is headache, feeling unwell, and a transient fever. Serious reactions are very rare, but should be reported to the doctor if they occur.
Diphtheria is an acute infectious illness caused by a bacterium called corynebacterium diphtheriae (C diphtheriae). It often begins with a sore throat, after which there can be serious complications involving the heart and other organs. Thanks to immunization, the disease is now rare in Western world, but it is a growing problem in many parts of the world, so travellers in particular should be aware of the threat.
HOW DOES IT OCCUR?
Diphtheria spreads from person to person by direct contact and in germ-laden droplets in the air which form when talking, sneezing or coughing. Raw (unpasteurised) milk and inanimate objects may also spread the bacteria.
The incubation period is from one to 7 days, usually around two days. However, people can carry the disease without necessarily becoming ill.
Diphtheria has been eliminated from many developed countries but it is still common in other areas, such as Somalia and other African countries, South America, Vietnam and other parts of SE Asia, and the Indian Subcontinent. In 1990 there was an epidemic in Russia. This was poorly controlled and led to the resurgence of diphtheria in many countries of the former Soviet Union.
WHY DOES IT OCCUR?
C diphtheriae invades the throat first, where it causes symptoms. The bacteria also produce a chemical or toxin which can spread through the blood-stream and affect more distant organs.
WHAT ARE THE SYMPTOMS?
The disease often starts with a sore throat, fever, headache and feeling generally unwell. The throat may not be particularly painful, but there is often a typical greyish membrane visible on one or both tonsils. Lymph nodes in the neck can be very large, giving an appearance of "bull-neck", especially in severe cases. This throat phase can last several days, and the membrane can be thick enough to obstruct breathing. Alternatively, the initial site of infection may be the nose, resulting in a bloodstained discharge from one nostril.
In the tropics, sometimes the only symptom is a skin ulcer which is very slow to heal and is covered by a tough grey membrane.
WHAT ARE THE COMPLICATIONS?
Complications can set in a week or two after the initial symptoms. Involvement of the heart muscle causes low blood pressure and a variety of abnormal heart rhythms. This typically occurs 10 to 20 days after the onset of a sore throat, and it can kill, usually because of heart rate irregularities.
Diphtheria toxin can also attack the nervous system, causing paralysis of the palate (roof of the mouth) and therefore trouble speaking and swallowing. The eye muscles may also be affected. Less often, other nerves are involved, for instance those that control breathing, which can be fatal. Nerve involvement can continue to develop up to three months from the start of the illness.
WHAT TESTS ARE DONE?
Swabs are taken from nose and throat (or any skin ulcers) and are sent to the laboratory to look for C diphtheriae. Basic blood tests are also done to monitor liver and kidney function.
WHAT IS THE TREATMENT?
Prompt specialist treatment is essential. Infection control is an important part of the management of diphtheria. Suspected cases are isolated, under the guidance of the local infection control team.
Injections of diphtheria anti-toxin are given to neutralise circulating toxin in the blood-stream. Anti-toxin must be given as soon as possible because it has no effect on toxin which is already bound to nerves or other tissues. Diphtheria anti-toxin originates from horses, so severe allergic reactions sometimes occur. To reduce the risk of these, a small test dose of anti-toxin is given first.
Antibiotics help eliminate the diphtheria bacteria. They are also given to close contacts of the patient.
Heart monitoring is usual. Depending on the condition of the patient, other measures may be needed, such as treatment for breathing and heart complications. These can include artificial ventilation, tracheostomy and insertion of a temporary pacemaker to regulate the heart rate.
WHAT HAPPENS AFTER TREATMENT?
The traditional thinking was that survivors of diphtheria could expect a full recovery, but this is not always so and there may be long-term heart complications.
After recovery from diphtheria, the patient needs an injection of diphtheria toxoid (diphtheria vaccine, see below). This is because having the disease does not necessarily produce immunity to future infections.
HOW CAN DIPHTHERIA BE PREVENTED?
Immunisation with diphtheria toxoid gives effective protection against the disease. In the Western world, routine immunisation has almost eradicated diphtheria. The lack of a vaccination programme is one reason why the disease is widespread in certain countries.
The vaccine, diphtheria toxoid, is made from part of the diphtheria toxin. Giving it stimulates the body to produce its own diphtheria anti-toxin. The basic three-dose course of diphtheria toxoid injections is given to babies at two, three and four months of age as part of the triple vaccine. A reinforcing dose is given before school entry and again before leaving school.
Travellers to a diphtheria area should have had the full basic course of vaccine. If it has been over 10 years since the last injection, a booster of low-dose diphtheria toxoid is given before travel. The low-dose preparation is used in such cases to minimise the possibility of a reaction, which can even happen if a person is already immune to the disease. Those likely to come into contact with diphtheria should continue to have low-dose boosters at 10-year intervals.
WHAT ARE THE COMPLICATIONS OF IMMUNISATION AGAINST DIPHTHERIA?
Swelling and redness at the site of injection (usually the upper arm in adults) are common, as is headache, feeling unwell, and a transient fever. Serious reactions are very rare, but should be reported to the doctor if they occur.
Tuesday, November 11, 2008
Diarrhea
WHAT IS GASTROENTERITIS?
Strictly speaking the word "gastroenteritis" means inflammation of the stomach and bowel. Inflammation can be caused by a number of diseases including infection. Doctors tend to use the term gastroenteritis to mean an infection causing inflammation of the lining of the gut resulting in diarrhea and vomiting. It can affect both adults and children although it is most common in children, especially those between the ages of 6 and 24 months.
WHAT CAUSES IT?
Many types of infection can cause gastroenteritis including viruses, bacteria and parasites. The most common type of infections to cause gastroenteritis are viruses that are passed from person to person either in the air or by transmission on the hand to the mouth. There is one particular virus called rotavirus that is responsible for outbreaks of diarrhea in children usually under the age of 5. It tends to cause a more severe type of diarrhea than other kinds of viral gastroenteritis and it often lasts longer than the usual 2-3 days. Outbreaks of rotavirus infection tend to be seasonal and are thought to be transmitted by airborne spread from one child to another.
Diarrhea and vomiting can also be caused by the so-called "food poisoning" germs such as the bacteria Campylobacter, Salmonella or Shigella amongst others. These are picked up from food contaminated with these organisms which enters the gut in the food and then causes inflammation, spasm of the intestinal muscles and other symptoms as described below.
Some types of gastroenteritis are caused by parasites such as one called Giardia and another called Amoeba both of which are usually contracted by eating contaminated food or drinking unsterile water (often abroad).
WHAT ARE THE SYMPTOMS?
The main symptoms of gastroenteritis are diarrhea and/ or vomiting. How much diarrhea or vomiting each sufferer experiences varies from person to person. It also alters according to the age of the individual and which germ is the cause of the illness. However, in addition to the diarrhea and vomiting some infections can cause other symptoms such as stomach cramps, a fever, blood in the motions and a general feeling of illness. As a general rule simple viral gastroenteritis tends to cause diarrhea and vomiting without the other symptoms. Food poisoning infections (from bacteria and parasites) often lead to more severe symptoms such as stomach cramps and the passage of blood from the rectum.
If the diarrhea and vomiting are severe and/or prolonged, symptoms of dehydration may set in. In an adult this shows itself as a dramatic reduction in the production of urine associated with a significant feeling of thirst, general lethargy, a dryness of the tongue and loss of elasticity of the skin. In babies and children dehydration shows itself in a similar way to adults except babies may have a sunken fontanelle (soft spot on the top of the head). Children sometimes become sunken-eyed when significantly dehydrated. As a general rule the younger the child the more quickly they are likely to become dehydrated because their fluid reserves are less than an adults so medical advice should be sought early if dehydration is suspected.
HOW IS INFECTION CAUGHT?
The different types of infection are caught in different ways. Bottle fed babies can develop diarrhea and vomiting by picking up a germ from an unsterile teat or milk that has not been properly sterilised. As children reach an age where they start to mix with other people they may then contract a viral gastroenteritis from another child. Transmission from person to person remains the most common method of transmission of the illness either by airborne spread or what is called the "faeco-oral route" i.e. spread from unclean hands to mouth.
The other frequent method of contracting diarrhea and vomiting is due to foreign travel. Exotic locations for holidays are becoming more frequent resulting in the number of people returning from abroad with diarrhea doubling in the past decade. It has been estimated that about 18 million adults travel abroad each year and of these 39% develop diarrhea whilst they are away. The diarrhea is generally caused either by viruses or bacteria new to the body's defences (so-called "traveller's diarrhea") or by food poisoning germs such as Campylobacter mentioned above. The risk of gastroenteritis obviously varies according to the part of the world being visited; Northern Europe tends to be low risk whereas the risk increases to about 40% in areas such as Central America.
HOW IS IT DIAGNOSED?
Diarrhea and vomiting caused by gastroenteritis is such a common problem in both adults and children that most cases are diagnosed by the family doctor purely on the history (symptoms) of the illness and an examination of the patient. However, if the symptoms are severe or lasting longer than the usual few days the doctor may organise the sending of a stool sample from the individual to the local hospital laboratory. There the stool is examined under the microscope for evidence of parasites of certain food poisoning organisms. It is then cultured on a culture plate for any type of gastroenteritis infection. If the patient is a child it may also be tested for rotavirus as mentioned above.
The doctor will also assess the patient to see how dehydrated they are in case hospital admission is required for rehydration.
HOW IS IT TREATED?
The majority of cases of diarrhea and vomiting can be successfully treated by encouraging the sufferer to drink small amounts of fluid frequently. The type of fluid is generally not important although it is usually best to stick to water or juice and on the whole milk is not recommended (although see below for advice in small babies). However, special rehydration preparations exist which are available over the counter at chemists and you should seek the advice of the pharmacist. These are sachets containing a small amount of sugar and a mixture of salts and minerals. They are made up with water into a rehydration solution to replace the salts and minerals lost in the diarrhea and vomit. Although these are very useful they are only important in the more severe cases. The most important thing is to replace any fluid loss.
Resting the stomach by stopping food for about 24 hours is said to help to stop any vomiting or diarrhea, but there is little published evidence for this. However, prolonged fasting, especially in children, can become unhelpful since hunger itself can begin to make the individual feel unwell. A good guide is to feed them if they are hungry and not if they are not hungry. In other words, trust the stomach itself to know best. Small babies who are being mainly bottle fed can be tried on what is called half-strength or quarter-strength milk. This means making up the milk with the same amount of water as normal but with only a half or a quarter the number of "scoops" of milk powder in the bottle. This has the effect of resting the stomach but still providing some substance. As the baby gets better the milk can be made more concentrated until they are back onto full strength milk. If even quarter-strength milk is vomited back than 12 or 24 hours of water or juice alone can be helpful in settling any vomiting before gradually returning to full strength. In very young babies or if any problems arise medical advice should be sought.
Drug and other treatment: Occasionally antibiotic treatment may be prescribed by the doctor if the type of infection causing the illness is thought to require it. For instance some types of food poisoning bacteria may need treatment with antibiotics. In most cases of gastroenteritis antibiotics are very unlikely to help and may even lead to unwanted side effects. Anti-diarrhea medication may be helpful to treat the symptoms of diarrhea in adults. Similar medication is not usually recommended in children because it may conceal the fact that the child is still unwell and may still be becoming dehydrated. Similarly, anti-diarrhea medication may cause problems in adults with severe diarrhea where there are other symptoms such as severe abdominal pain or blood in the motions in which case medical advice should be obtained.
Finally, if the patient is significantly dehydrated the doctor may think it best to admit them to hospital for intravenous rehydration where fluid is replaced via a "drip" i.e. a tube leading into a vein in the arm. This treatment usually works extremely well and often the sufferer is discharged from hospital within a day or two depending on their progress.
WHAT ARE THE OTHER CAUSES?
There are many causes of diarrhea and vomiting in adults and children; far to numerous to mention in this factsheet, but gastroenteritis is by far the most common cause of short-lasting diarrhea and vomiting. However, if other symptoms exist or the vomiting and/or diarrhea persist then a medical opinion should be obtained to establish a diagnosis.
HOW CAN IT BE PREVENTED?
It is not always possible to prevent gastroenteritis because it is so easily spread from one person to another, especially amongst children. However, many cases can be prevented by practising good general hygiene i.e. washing after going to the toilet and before and during food preparation. For those people travelling abroad it is particularly important for them to be careful what they eat and drink. In high risk areas only bottled water should be drunk (and only ice made from bottled water) and food should only be eaten when prepared by the person themselves or by a reputable kitchen. Those in the catering trade should stay off work if they develop diarrhea and vomiting. They should only return to work once they have provided a normal stool result from the laboratory or on advice of their doctor.
In future it may be possible to vaccinate against certain types of gastroenteritis. For instance, dysentery (caused by an organism called Shigella) may in future be preventable with a vaccine, as may Cholera.
Strictly speaking the word "gastroenteritis" means inflammation of the stomach and bowel. Inflammation can be caused by a number of diseases including infection. Doctors tend to use the term gastroenteritis to mean an infection causing inflammation of the lining of the gut resulting in diarrhea and vomiting. It can affect both adults and children although it is most common in children, especially those between the ages of 6 and 24 months.
WHAT CAUSES IT?
Many types of infection can cause gastroenteritis including viruses, bacteria and parasites. The most common type of infections to cause gastroenteritis are viruses that are passed from person to person either in the air or by transmission on the hand to the mouth. There is one particular virus called rotavirus that is responsible for outbreaks of diarrhea in children usually under the age of 5. It tends to cause a more severe type of diarrhea than other kinds of viral gastroenteritis and it often lasts longer than the usual 2-3 days. Outbreaks of rotavirus infection tend to be seasonal and are thought to be transmitted by airborne spread from one child to another.
Diarrhea and vomiting can also be caused by the so-called "food poisoning" germs such as the bacteria Campylobacter, Salmonella or Shigella amongst others. These are picked up from food contaminated with these organisms which enters the gut in the food and then causes inflammation, spasm of the intestinal muscles and other symptoms as described below.
Some types of gastroenteritis are caused by parasites such as one called Giardia and another called Amoeba both of which are usually contracted by eating contaminated food or drinking unsterile water (often abroad).
WHAT ARE THE SYMPTOMS?
The main symptoms of gastroenteritis are diarrhea and/ or vomiting. How much diarrhea or vomiting each sufferer experiences varies from person to person. It also alters according to the age of the individual and which germ is the cause of the illness. However, in addition to the diarrhea and vomiting some infections can cause other symptoms such as stomach cramps, a fever, blood in the motions and a general feeling of illness. As a general rule simple viral gastroenteritis tends to cause diarrhea and vomiting without the other symptoms. Food poisoning infections (from bacteria and parasites) often lead to more severe symptoms such as stomach cramps and the passage of blood from the rectum.
If the diarrhea and vomiting are severe and/or prolonged, symptoms of dehydration may set in. In an adult this shows itself as a dramatic reduction in the production of urine associated with a significant feeling of thirst, general lethargy, a dryness of the tongue and loss of elasticity of the skin. In babies and children dehydration shows itself in a similar way to adults except babies may have a sunken fontanelle (soft spot on the top of the head). Children sometimes become sunken-eyed when significantly dehydrated. As a general rule the younger the child the more quickly they are likely to become dehydrated because their fluid reserves are less than an adults so medical advice should be sought early if dehydration is suspected.
HOW IS INFECTION CAUGHT?
The different types of infection are caught in different ways. Bottle fed babies can develop diarrhea and vomiting by picking up a germ from an unsterile teat or milk that has not been properly sterilised. As children reach an age where they start to mix with other people they may then contract a viral gastroenteritis from another child. Transmission from person to person remains the most common method of transmission of the illness either by airborne spread or what is called the "faeco-oral route" i.e. spread from unclean hands to mouth.
The other frequent method of contracting diarrhea and vomiting is due to foreign travel. Exotic locations for holidays are becoming more frequent resulting in the number of people returning from abroad with diarrhea doubling in the past decade. It has been estimated that about 18 million adults travel abroad each year and of these 39% develop diarrhea whilst they are away. The diarrhea is generally caused either by viruses or bacteria new to the body's defences (so-called "traveller's diarrhea") or by food poisoning germs such as Campylobacter mentioned above. The risk of gastroenteritis obviously varies according to the part of the world being visited; Northern Europe tends to be low risk whereas the risk increases to about 40% in areas such as Central America.
HOW IS IT DIAGNOSED?
Diarrhea and vomiting caused by gastroenteritis is such a common problem in both adults and children that most cases are diagnosed by the family doctor purely on the history (symptoms) of the illness and an examination of the patient. However, if the symptoms are severe or lasting longer than the usual few days the doctor may organise the sending of a stool sample from the individual to the local hospital laboratory. There the stool is examined under the microscope for evidence of parasites of certain food poisoning organisms. It is then cultured on a culture plate for any type of gastroenteritis infection. If the patient is a child it may also be tested for rotavirus as mentioned above.
The doctor will also assess the patient to see how dehydrated they are in case hospital admission is required for rehydration.
HOW IS IT TREATED?
The majority of cases of diarrhea and vomiting can be successfully treated by encouraging the sufferer to drink small amounts of fluid frequently. The type of fluid is generally not important although it is usually best to stick to water or juice and on the whole milk is not recommended (although see below for advice in small babies). However, special rehydration preparations exist which are available over the counter at chemists and you should seek the advice of the pharmacist. These are sachets containing a small amount of sugar and a mixture of salts and minerals. They are made up with water into a rehydration solution to replace the salts and minerals lost in the diarrhea and vomit. Although these are very useful they are only important in the more severe cases. The most important thing is to replace any fluid loss.
Resting the stomach by stopping food for about 24 hours is said to help to stop any vomiting or diarrhea, but there is little published evidence for this. However, prolonged fasting, especially in children, can become unhelpful since hunger itself can begin to make the individual feel unwell. A good guide is to feed them if they are hungry and not if they are not hungry. In other words, trust the stomach itself to know best. Small babies who are being mainly bottle fed can be tried on what is called half-strength or quarter-strength milk. This means making up the milk with the same amount of water as normal but with only a half or a quarter the number of "scoops" of milk powder in the bottle. This has the effect of resting the stomach but still providing some substance. As the baby gets better the milk can be made more concentrated until they are back onto full strength milk. If even quarter-strength milk is vomited back than 12 or 24 hours of water or juice alone can be helpful in settling any vomiting before gradually returning to full strength. In very young babies or if any problems arise medical advice should be sought.
Drug and other treatment: Occasionally antibiotic treatment may be prescribed by the doctor if the type of infection causing the illness is thought to require it. For instance some types of food poisoning bacteria may need treatment with antibiotics. In most cases of gastroenteritis antibiotics are very unlikely to help and may even lead to unwanted side effects. Anti-diarrhea medication may be helpful to treat the symptoms of diarrhea in adults. Similar medication is not usually recommended in children because it may conceal the fact that the child is still unwell and may still be becoming dehydrated. Similarly, anti-diarrhea medication may cause problems in adults with severe diarrhea where there are other symptoms such as severe abdominal pain or blood in the motions in which case medical advice should be obtained.
Finally, if the patient is significantly dehydrated the doctor may think it best to admit them to hospital for intravenous rehydration where fluid is replaced via a "drip" i.e. a tube leading into a vein in the arm. This treatment usually works extremely well and often the sufferer is discharged from hospital within a day or two depending on their progress.
WHAT ARE THE OTHER CAUSES?
There are many causes of diarrhea and vomiting in adults and children; far to numerous to mention in this factsheet, but gastroenteritis is by far the most common cause of short-lasting diarrhea and vomiting. However, if other symptoms exist or the vomiting and/or diarrhea persist then a medical opinion should be obtained to establish a diagnosis.
HOW CAN IT BE PREVENTED?
It is not always possible to prevent gastroenteritis because it is so easily spread from one person to another, especially amongst children. However, many cases can be prevented by practising good general hygiene i.e. washing after going to the toilet and before and during food preparation. For those people travelling abroad it is particularly important for them to be careful what they eat and drink. In high risk areas only bottled water should be drunk (and only ice made from bottled water) and food should only be eaten when prepared by the person themselves or by a reputable kitchen. Those in the catering trade should stay off work if they develop diarrhea and vomiting. They should only return to work once they have provided a normal stool result from the laboratory or on advice of their doctor.
In future it may be possible to vaccinate against certain types of gastroenteritis. For instance, dysentery (caused by an organism called Shigella) may in future be preventable with a vaccine, as may Cholera.
Tuesday, October 28, 2008
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.
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.
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