Describe the differences between hepatitis A, B, and C, including treatment and disease course.

Identify candidates for vaccination against hepatitis A.

Explain how hepatitis C is transmitted.

Diagnose a urinary tract infection (UTI).

Manage an elderly patient with UTI.

Hepatitis A, B, and C
Coleman I. Smith, MD, Associate Professor of Medicine, University of Minnesota Medical School, Minneapolis

Hepatitis A virus (HAV): RNA virus

Epidemiology: low prevalence in United States, Australia, and Western Europe; spread through fecal-oral transmission; usually through household or sexual contact, or daycare centers; also spread by food handlers (especially those handling raw shellfish), and those who have traveled to endemic areas; bloodborne spread possible, but rare; sexual transmission more likely in men who have sex with men

Typical course: virus usually absent from stool by time symptoms and elevated transaminases appear; IgM anti- HAV antibody subsequently appears; virus spread during incubation phase (2-3 wk), often before patient aware of infection; antibody disappears within 6 mo, but immunity lifelong; young children and young adults usually have mild disease; older children and older adults have clinical disease; ≈90% of infected children <6 yr of age have subclinical disease, then remain immune for life

Vaccination: 2 products available (both excellent, with high seroconversion rates and few side effects); 2 injections, 6 mo apart; candidates—anyone traveling to areas with intermediate to high prevalence rates of HIV or HAV; men who have sex with men; users of injection drugs; anyone with chronic liver disease (likelihood of contracting HAV not higher, but severity of disease greater); residents of communities with high rates of hepatitis infection (eg, American Indians); children at 2 yr of age; persistence of immunity—>20 yr; antibody levels occasionally too low for detection by standard commercial assays, but vaccination “successful in the vast majority of cases”; combination hepatitis A and B vaccine (Twinrix) recommended for anyone susceptible to both viruses

Hepatitis B virus (HBV): DNA virus; has surface antigen; complex internal structure with characteristic E antigen, which acts as serologic marker; geographic distribution—low prevalence in United States, Australia, and Western Europe; high prevalence in sub-Saharan Africa, Asia, and parts of South America; also high among Alaskan Natives; 33.5 million US residents foreign-born, many from areas with high prevalence of HBV; represent major source of HBV cases in United States

Transmission routes: blood-borne, sexual, maternal-child (likely via blood during birth); nearly 50% of cases involve risk factor (eg, injection drug use, multiple sexual partners, men having sex with men, sex with infected partner, blood transfusion [rare], hemodialysis or needlestick [rare]); no specific cause identified in slightly >50% of cases (however, most patients immigrants from endemic areas)

Clinical features: incubation period 60 to 90 days; clinical illness usually occurs in individuals >5 yr of age; mortality low, but higher than that associated with HAV; 30% to 90% of patients in newborn to 5-yr-old age group have chronic HBV (body will not clear virus; responsible for most clinical cases); of those who become infected with HBV at older age (ie, older children or adults), only 2% [adults] to 10% develop chronic liver disease; however, high mortality associated with chronic infection

Serology: acute—HBV surface antigen (HbsAg) appears, then disappears; no virus detected during incubation period; E antigen marker of whole virus in blood and ongoing replication; usually clears eventually; HBV anti-core antibody appears at same time as HbsAg, but remains in blood; marker of exposure (no association with immunity); anti-core antibody appears first as IgM antibody, which disappears in ≤32 wk; subsequently switches to IgG; presence of IgG anti-core antibody indicates patient previously exposed to HBV; IgM indicates exposure more recent (patient may still have virus or is currently recovering); eventually, patient develops HBV surface antibody (HbsAb), which is marker of immunity

Transmission: patient infected by time symptoms appear; patient likely to have already transmitted virus

Chronic infection: patient does not make HbsAb; HBsAg persists; viral replication may continue for years; E antigen also persists; only IgG anti-core antibody seen; patient not immune

Clinical progression: liver disease may be minimal, requiring little treatment and attention; patients should be followed for possible hepatocellular carcinoma (may occur before chronic liver disease develops); patient may develop cirrhosis and require transplantation; some patients may have intervals of good health interspersed with flare-ups that exacerbate liver damage; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/ Cancer-In HBV (REVEAL-HBV) study showed association between viral load, mortality, and risk for cancer

Treatment: recommended for patients with high levels of HBV DNA and liver damage; goal to lower viral DNA as much as possible, improve liver histology (in clinical trials), normalize liver enzyme levels, and eliminate E antigen and HbsAg (if possible); recent mutations block formation of E antigen; in those cases, HBV DNA only measure of replication; E antigen-negative patients respond less well to treatment and may require lifelong therapy (some E antigen-positive patients can discontinue treatment 6-12 mo after seroconversion); take- home message—viral replication may be occurring even if patient does not have E antigen; E antigen-negative patients outnumber antigen-positive patients in many regions, including southern Europe (Mediterranean region); patients with cirrhosis—treat for life, regardless of E antigen status

Drugs: interferons (rarely used); lamivudine (no longer used as monotherapy, due to high risk [70% at 2-3 yr] of developing resistant viral strains); speaker recommends entecavir (Baraclude) and tenofovir (PMPA; Viread); speaker does not recommend telbivudine

Vaccine: safe and effective (prevents cancer)

Hepatitis C virus (HCV): RNA virus; replicates in liver cells; 12 trillion virions produced daily, resulting in many “quasi-species” of virus; several genotypes also identified (hinders vaccine development)

Natural history: after exposure, 15% of patients clear virus; remaining patients develop chronic disease; in some patients, liver damage progresses to cirrhosis over 20 to 30 yr; among this subgroup, some also develop liver cancer (usually occurs only with cirrhosis; requires transplantation); risk factors for rapid progression—infection at older age; male sex; coinfection with HIV or HBV; fatty liver disease; white ethnicity; more than 2 to 3 alcoholic drinks/day; obesity; use of cannabis or heroin (may hasten fibrosis); level of alanine aminotransferase, viral load, viral genotype, or mode of transmission do not affect progression of disease

Clinical manifestations: patients often asymptomatic; symptoms often nonspecific (malaise, fatigue, weakness); more advanced disease associated with jaundice; virus spreads through blood; risk factors—injection drug use (perhaps intranasal drug use as well); transfusion of clotting factors (before use of recombinant technology); long-term hemodialysis (rarer today than formerly); organ transplantation or transfusion of blood products before 1992, when testing for HCV introduced; sexual transmission—rare; risk higher with multiple partners; maternal-fetal transmission—risk <5%

Advice to patients: do not donate blood; donate organs only to other HCV-positive people; recommend testing for sexual partners (however, barrier precautions not recommended, due to low risk for sexual transmission)

Patient evaluation: antibody good screen for exposure; does not confer immunity; measure HCV RNA and liver function; however, liver damage may occur even with normal liver function tests (biopsy to assess degree of inflammation and fibrosis)

Treatment: goals—clear virus; prevent disease progression; regimen—pegylated interferon weekly or ribavirin daily, for 24 to 48 wk; both treatments associated with serious side effects; ribavirin teratogenic (neither patient nor partner should become pregnant until 6 mo after treatment); success defined as sustained viral response (ie, virus not detectable at end of treatment, or 6 mo thereafter); improvement in histology also often seen

Urinary Tract Infections: To Treat or Not to Treat?
Gary R. Kravitz, MD, Adjunct Assistant Professor of Medicine, University of Minnesota Medical School, Minneapolis

Sample case: 80-yr-old man admitted with acute aphasia and left-sided weakness; patient afebrile, but experiencing chills and distress; urinalysis shows 10 to 25 white blood cells (WBCs) per high-power field (HPF); urine culture shows >105 colony-forming units (CFU) of Escherichia coli per milliliter

Diagnosis: standard criterion of >105 CFU/mL incorrect; chosen from studies in young girls as number unlikely to be due to skin or urethral contamination; does not always denote infection; similarly, <105 CFU/mL does not count out infection; diagnosis made on presence of symptoms as well as bacteriuria

Pyuria: 5-10 WBCs/HPF upper limit of normal; >10 WBCs/HPF indicates abnormal pyuria in healthy person, but often persists chronically in elderly people with asymptomatic bacteriuria (ASB), so >10 WBCs/HPF not, by itself, indicative of infection in absence of symptoms

Cystitis: most common symptomatic urinary tract infection (UTI); usually self-limited (resolves in ≤10 days); recurs due to infection with new bacteria, making prolonged courses of antibiotic to eradicate pathogen unnecessary; in young women, preferred treatment is antibiotics for 3 days; trimethoprim-sulfamethoxazole (TMP/SMZ; eg, Bactrim) rarely used today because many E coli strains now resistant; however, resistance to quinolones also increasing; oral third-generation cephalosporin (cefpodoxime) “can come in handy”

Pyelonephritis: β-lactams kill organism more slowly than TMP/SMZ, aminoglycosides, or quinolones; speaker prescribes third-generation cephalosporin or piperacillin plus tazobactam; may take 2 to 5 days to see improvement; can then switch patient to oral antibiotics and treat as outpatient; imaging studies recommended only if patient unduly septic or unresponsive to treatment; if using β-lactam, treat patient for 2 wk

Nosocomial UTI: almost always due to urinary catheters; only 8% are symptomatic; microbiology becoming more complex (Pseudomonas, extended-spectrum β-lactamase [ESBL]-producing E coli, Klebsiella; methicillin-resistant Staphylococcus aureus; vancomycin-resistant enterococci; yeast)

Asymptomatic bacteriuria: defined as >105 CFU/mL in 2 urine specimens (women) or single specimen (men); >100 CFU/mL in specimen from catheterized patient; prevalence increases with age (≈20% among people >70 yr); may be 40% to 50% among people in long-term care facilities (LTCFs); virtually 100% among people with long-term indwelling catheters; most common reason for antibiotic prescriptions in LTCFs; ASB estimated to outnumber symptomatic cases by 100 to 1; in febrile patients with Foley catheter, bacteriuria causes fever only 12% of time; difficult to ask demented or aphasic patient about symptoms; Foley catheter major risk factor for serious symptomatic infection; pyuria—common in people with ASB; may persist for years; cannot distinguish ASB from true UTI, but absence means infection unlikely

Treatment: several studies show that treating elderly patients with ASB has no impact on incidence of symptomatic UTI, urinary incontinence, or survival; however, treated patients did have higher incidence of adverse drug reactions and recolonization with resistant organisms; findings similar in patients with Foley catheters; conclusion— do not screen for or treat ASB

Clostridium difficile infection (CDI): common in LTCFs; infection rates climbing; new strains more severe; “don’t trade ASB for CDI”; antibiotics most likely to produce resistance include imipenem-cilastatin and clindamycin; moxifloxacin, ceftazidime, and ceftriaxone also “up there;” safest drugs include cephalexin, TMP-SMZ, amoxicillin, metronidazole, and doxycycline (lowest risk for resistance)

Candidates for ASB treatment: pregnant patients; patients about to undergo urologic surgery; patients with duplication of urinary system (rare), polycystic kidneys, or recurring infections; diabetes, prosthetic joints or heart valves, and immunosuppression or transplantation no longer indications for treatment; in noncatheterized patients, treatment most appropriate for those with acute symptoms (urinalysis indicated only in presence of symptoms); catheterized patients—very high risk for UTI; symptoms may be nonspecific; look for fever, new delirium, rigors, and new tenderness of costovertebral angle; delirium characterized by rambling, hallucinations, and change of consciousness or cognition; do not automatically ascribe to UTI (may result from adverse drug reaction, metabolic disturbances, or fluctuating course of Alzheimer’s disease)

Conclusion: treat only symptomatic UTI

Asymptomatic candiduria (ASC): risk factors for colonization similar to those for ASB; diabetes, urinary catheters, previous antibiotic use prominent; one-third to two-thirds of cases resolve spontaneously; candidemia rare (almost exclusive to neutropenic patients or those who have undergone urologic surgery); evidence suggests therapy does not alter clinical outcome; recurrence common; resistance may develop; no established value to treatment