A 35-year-old man who was born in Vietnam presents to the emergency department of a local hospital because he has had jaundice for 5 days and fatigue, malaise, and anorexia for 2 weeks. He also has nausea and mild epigastric and right upper quadrant abdominal pain. He denies having fevers, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss.

His medical history is remarkable only for perinatally acquired hepatitis B virus (HBV) infection, for which he never received antiviral therapy. He does not take any prescribed, over-the-counter, or herbal medications.

He lives in the Midwest region of the United States and works full-time as a physician in private practice. He is married and has two children.

He has not travelled recently. He has no pets at home and has not been exposed to any.

He has never smoked. He drinks alcohol socially but has never used recreational drugs.

In a laboratory evaluation performed a year ago for insurance purposes, his liver function tests—serum albumin, total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels—were all normal. He was positive for HBV surface antigen and HBV e antigen and negative for antibodies against these antigens.

PHASES OF HBV INFECTION

1. Which of the following best describes the status of HBV infection in this patient before his current symptoms developed?

• Resolved HBV infection
• Chronic inactive HBV infection
• Chronic active HBV infection
• Immune-tolerant chronic HBV infection

The correct answer is immune-tolerant chronic HBV infection.

Resolved infection. In immunocompetent adults, most primary HBV infections are self-limited: people clear the virus and gain lasting immunity (defined as the loss of HBV surface antigen, the development of antibody against surface antigen, no detectable HBV DNA in the serum, and normal alanine and aspartate aminotransferase levels). However, a minority of primary HBV infections persist and become chronic.

Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients with chronic HBV infection can be broadly classified as having either inactive disease (the inactive surface antigen carrier state) or chronic active hepatitis B (Figure 1).^1–9

Chronic inactive HBV infection. Carriers of inactive HBV infection have low serum levels of HBV DNA (< 2,000 IU/mL), persistently normal aminotransferase levels, and no HBV e antigen; if a liver biopsy is performed, no significant hepatitis is found.

Chronic active HBV infection. Patients with chronic active HBV infection, in contrast, have high serum HBV DNA levels (> 20,000 IU/mL) and persistently or intermittently high aminotransferase levels; they do have HBV e antigen, and a liver biopsy shows moderate or severe necroinflammation.

A small group of patients with chronic active hepatitis B may be negative for e antigen but still have high aminotransferase levels, high HBV DNA levels, and continued necroinflammation in the liver.⁴ The virus in these patients has a mutation in its precore or core promoter gene that prevents the production of e antigen.

Patients with chronic active HBV infection (whether positive or negative for e antigen) are at a significantly greater risk of progressive liver injury and developing cirrhosis and hepatocellular carcinoma than are inactive carriers of HBV.

Immune-tolerant chronic HBV infection. Patients who acquired HBV at birth (eg, our patient) may have immune-tolerant HBV infection, which is characterized by significant HBV replication manifested by the presence of HBV e antigen and high levels of HBV DNA in the serum. However, these patients have no clinical or pathologic evidence of active liver disease (no symptoms, normal serum alanine aminotransferase levels, and minimal changes on liver biopsy).⁵ This was obviously the case in our patient, based on his history and laboratory results before his current symptoms developed.

Case continues: Liver function abnormalities

On physical examination, the patient’s temperature is 99.9°F (37.7°C), heart rate 106 per minute, blood pressure 98/54 mm Hg, respiratory rate 18 per minute, and oxygen saturation 100% while breathing ambient air. He is alert and oriented to time, place, and person.

He has icteric sclera, and his skin is jaundiced. His lymph nodes are not palpable. His cardiac examination is normal except for tachycardia. His lungs are clear to auscultation and percussion. He has mild epigastric and right upper quadrant abdominal tenderness with no peritoneal signs, hepatosplenomegaly, or masses.

His basic laboratory values on admission are listed in Table 1. His amylase and lipase levels are normal. A urine dipstick test is positive for bilirubin.

WHAT IS THE LEAST LIKELY DIAGNOSIS?

2. Which one of the following is the least likely diagnosis in this patient?

• Reactivation of hepatitis B
• Drug-associated liver injury
• Acute viral hepatitis
• Acute alcoholic hepatitis
• Ischemic hepatitis

The degree and pattern of liver function abnormalities in our patient reflect hepatocellular injury rather than cholestatic liver disease, because his aminotransferase levels are elevated much higher than his alkaline phosphatase level (Table 1). Bilirubin elevation does not help differentiate the two conditions.

The degree and pattern of aminotransferase elevations are also helpful in narrowing the differential diagnosis. Serum aminotransferase levels of more than 1,000 U/L are mainly seen in patients with ischemic, viral, and toxininduced liver injury. Other rare causes of such high levels include Budd-Chiari syndrome, Wilson disease, and autoimmune hepatitis.

Ischemic hepatitis. Our patient has mild hypotension, but it does not seem to have been severe enough or of long enough duration to have caused ischemic hepatitis.

Drug-associated liver injury. Hepatotoxicity associated with drugs (most commonly acetaminophen [Tylenol]), herbal therapy, or mushroom poisoning should be considered in any patient whose aminotransferase levels are this high. However, our patient denies taking any medications (prescribed or over-the-counter), herbal remedies, or illicit drugs.

Acute viral hepatitis can certainly explain the patient’s clinical picture. Infection with hepatitis A virus, hepatitis D virus, hepatitis E virus, cytomegalovirus, Epstein-Barr virus, herpes simplex viruses types 1 and 2, and varicella zoster virus have all been implicated in severe acute hepatitis. Although hepatitis E virus infection is more common in developing countries, it has been reported in the United States.⁶ It is unlikely that acute hepatitis C virus infection is producing this degree of elevation in aminotransferase levels.

Reactivation of the patient’s chronic HBV infection can also account for his clinical presentation.

Acute alcoholic hepatitis should be suspected clinically if a patient has a history of heavy alcohol use and clinical and laboratory findings that are compatible with the diagnosis. However, the absolute values of serum aspartate aminotransferase and alanine aminotransferase in acute alcoholic hepatitis are almost always less than 500 IU/L (and typically less than 300 IU/L). Our patient’s values are much higher, and he says he does not drink very much. Although people sometimes underestimate their alcohol intake, alcoholic hepatitis is the least likely diagnosis in our patient.

Case continues: The patient is hospitalized

The patient is admitted with a diagnosis of acute hepatitis. Given his history of chronic hepatitis B, he is empirically started on lamivudine (Epivir-HBV).

• Antinuclear antibody negative
• Autoimmune liver disease panel negative
• Serum ceruloplasmin 30 mg/dL (normal range 15–60)
• Alpha fetoprotein 35.1 μg/L (< 10).

Abdominal ultrasonography is performed and reveals a small stone in the gallbladder with no evidence of biliary dilatation; otherwise, the gallbladder appears normal. Doppler ultrasonography shows the liver vessels to be patent; the liver is normal in appearance. The abdomen and pelvis appear to be normal on computed tomography without intravenous contrast.

On the third hospital day, the patient’s blood test results are:

• Aspartate aminotransferase 199 U/L (normal range 7–40)
• Alanine aminotransferase 735 U/L (0–45)
• Total bilirubin 22.9 mg/dL (0–1.5)
• International normalized ratio 6.0 (0.77–1.17)
• White blood cell count 5.1 × 10⁹/L (4–11)
• Hemoglobin 11.7 g/dL (12–16)
• Platelet count 166 × 10⁹/L (150–400)
• Blood and urine cultures negative.

WHAT IS CAUSING HIS ACUTE HEPATITIS?

3. On the basis of the new data, which of the following statements about the cause of acute hepatitis in this patient is the most accurate?

• Herpetic hepatitis is the most likely cause, given his positive test for immunoglobulin M (IgM) against herpes simplex virus
• Hepatitis C cannot be excluded with the available data
• Negative HBV e antigen does not exclude the diagnosis of acute exacerbation of HBV infection
• Hepatocellular carcinoma is the likely diagnosis, given the elevated alpha fetoprotein level

The third answer above is correct: a negative test for hepatitis B e antigen does not exclude the diagnosis of acute exacerbation of HBV infection

Herpetic hepatitis. Although not common, hepatitis due to herpes simplex virus infection should be considered in the differential diagnosis of any patient presenting with severe acute hepatitis, particularly when fever is present. Common features of herpetic hepatitis on presentation include high fever, leukopenia, markedly elevated aminotransferases, and mild cholestasis. Vesicular rash occurs in only less than half of cases of herpetic hepatitis.¹⁰

Serologic testing is of limited value because it has high rates of false-positive and false-negative results. The diagnosis can be confirmed only by viral polymerase chain reaction testing or by identifying herpes simplex viral inclusions in the liver biopsy.

However, the death rate is high in this disease, and since herpetic hepatitis is one of the few treatable causes of acute liver failure, parenteral acyclovir (Zovirax) should be considered empirically in patients presenting with acute liver failure. Our patient was started on acyclovir when his tests for IgM against herpes simplex virus came back positive.

Hepatitis C. Antibodies against hepatitis C virus do not develop immediately after this virus is contracted; they may take up to 12 weeks to develop after exposure. For this reason, about 30% to 50% of patients with acute hepatitis C virus infection are negative for these antibodies initially. In those patients, hepatitis C virus RNA in the blood is the most sensitive test to detect acute hepatitis C virus infection.

Our patient has neither antibodies against hepatitis C virus nor hepatitis C virus RNA by polymerase chain reaction testing, which rules out hepatitis C virus infection.

Disappearance of e antigen in HBV infection. The disappearance of HBV e antigen is usually associated with a decrease in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease and high levels of HBV DNA despite e antigen seroconversion. This is due to a stop codon mutation in the precore region of the viral genome that decreases or prevents production of HBV e antigen.⁴ In other words, even though HBV e antigen is a good marker of HBV replication in general, a subgroup of patients with chronic HBV infection are negative for e antigen but still have a high rate of viral replication as evidenced by high serum HBV DNA levels.

Patients with perinatally acquired chronic HBV infection most often have immune-tolerant chronic HBV infection. Among those patients (mostly Asian),^5,7 the virus is spontaneously cleared at a rate of approximately 2% to 3% per year,⁸ most often during the second and third decades of age.

Transition from the immune-tolerant phase to the immune clearance phase is frequently associated with mild transient worsening of the liver function profile.^9,11,12 However, in a small percentage of patients, hepatic decompensation and even (rarely) death from hepatic failure may occur secondary to a sudden activation of the immune system as it attempts to clear the virus. This may result in an increase in immune-mediated lysis of infected hepatocytes.

Hepatocellular carcinoma. Exacerbation of hepatitis B may be associated with an elevation of alpha fetoprotein, which may falsely raise concerns about the possibility of hepatocellular carcinoma. However, our patient had abdominal imaging with both ultrasonography and computed tomography, which showed no evidence of hepatocellular carcinoma.

Comment. The most likely cause of the patient’s acute liver failure is an acute exacerbation of hepatitis B. However, herpetic hepatitis should be ruled out by testing for herpes simplex virus by polymerase chain reaction, performing a liver biopsy, or both.

Case continues: His condition worsens

A transjugular liver biopsy shows changes associated with chronic hepatitis B, severe acute hepatitis with extensive confluent and submassive hepatic necrosis, and no intracellular viral inclusions. Subsequently, acyclovir is stopped.

On the 6th hospital day, he develops progressive metabolic acidosis and hypotension, with worsening hypoxemia. A chest radiograph is obtained to look for pneumonia, but it is indeterminate; computed tomography of the chest without contrast medium is likewise unremarkable. Duplex ultrasonography of the four extremities is negative for venous thrombosis.

The patient becomes more lethargic and difficult to arouse. He is transferred to the intensive care unit and intubated. His prothrombin and partial thromboplastin times continue to rise, the prothrombin time reaching values of more than 50 seconds. In addition, progressive renal insufficiency develops.

WHAT IS THE NEXT STEP?

4. Which of the following is the most appropriate next step in the management of this patient?

• Liver transplantation
• HBV immunoglobulin only
• Interferon and a nucleoside analogue
• Liver-assist devices
• Continue supportive care only

Liver transplantation. Since the patient’s severe acute hepatitis is accompanied by coagulopathy and encephalopathy, he meets the definition of having acute liver failure. Liver transplantation remains the only definitive therapy.

HBV immune globulin immunoprophylaxis is indicated in patients with HBV infection undergoing liver transplantation, to prevent recurrence of hepatitis B after the transplant, particularly in those with a high pretransplant viral load.¹⁷ The use of pretransplant antiviral therapy and the posttransplant combination of antiviral therapy and HBV immune globulin has reduced the rate of hepatitis B recurrence to less than 10%. However, immune globulin is by no means the best single next step in managing this patient, who clearly needs a new liver.

Interferon, nucleoside analogues. Options for antiviral treatment are interferon alfa and nucleoside analogues. Interferon therapy is contraindicated in patients such as ours, who have decompensated liver disease, because it can exacerbate the disease.¹⁸

Liver-assist devices. Because liver allografts are in short supply, there has been a strong interest in developing a device that would provide the same benefits for patients with liver failure as hemodialysis does for patients with renal failure. Trials are under way to determine the efficacy and safety of these devices.²⁰

Case continues: He receives a liver

The patient undergoes liver transplantation. He is given HBV immune globulin during and after the surgery.

Pathologic review. Under the microscope, his old liver has widespread necrosis and hemorrhage as well as inflammatory changes suggesting a chronic viral process. Regenerative nodules are present in the small amount of surviving liver parenchyma, consistent with early cirrhosis. Iron staining shows +3 depositions in areas of hepatic collapse (a nonspecific finding). Periodic acid-Schiff staining after diastase (used to detect alpha-1 antitrypsin deficiency) is negative. Herpetic viral inclusions are not present.

An immunoassay for herpes simplex virus antigen is negative. Immunostaining with antibodies to the HBV core antigen is negative. HBV surface antigen is strongly and diffusely positive in the cytoplasm of 80% to 90% of hepatocytes. The immunohistologic staining pattern is consistent with integration of HBV DNA into the DNA of hepatic tissue.

Postoperative course. Lamivudine is continued after surgery, and the patient is sent home. He has resumed the level of functioning he had before becoming ill.

Comment. The outcome of liver transplantation for hepatitis B has notably improved since HBV immune globulin and nucleoside analogues were introduced. The results of liver transplantation for hepatitis B, particuarly patient and graft survival rates, are now better than those in transplant patients with hepatitis C and similar to those in transplant patients with other types of liver disease.²¹ The combination of HBV immune globulin and lamivudine has cut the rate of HBV reinfection after liver transplantation to approximately 10% and increased the 5-year survival rate after transplantation to about 80%.^17,22

KEY POINTS

• In immunocompetent adults, most primary HBV infections are self-limited.
• Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients having chronic HBV infection can be broadly classified as inactive carriers or having chronic active disease.
• Most patients with chronic active HBV infection are positive for HBV e antigen, except patients in whom the virus has a mutation in the precore or core region of its genome that prevents the production of e antigen.
• Patients who carry inactive HBV or who are immune-tolerant require serial measurements of aminotransferase and HBV DNA levels. Treatment can be considered if the patient has a high viral load (> 2,000 IU/mL), elevated aminotransferases, or active disease on liver biopsy.
• Carriers of chronic active HBV (whether positive or negative for HBV e antigen) should be referred to a hepatologist for consideration of liver biopsy and treatment.
• Interferon should not be used in immunocompromised patients or those with decompensated liver disease because it can further exacerbate the liver disease.
• Liver transplantation should be considered in patients with acute liver failure who have a poor prognosis according to the King’s College Hospital criteria.

A 35-year-old man who was born in Vietnam presents to the emergency department of a local hospital because he has had jaundice for 5 days and fatigue, malaise, and anorexia for 2 weeks. He also has nausea and mild epigastric and right upper quadrant abdominal pain. He denies having fevers, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss.

His medical history is remarkable only for perinatally acquired hepatitis B virus (HBV) infection, for which he never received antiviral therapy. He does not take any prescribed, over-the-counter, or herbal medications.

He lives in the Midwest region of the United States and works full-time as a physician in private practice. He is married and has two children.

He has not travelled recently. He has no pets at home and has not been exposed to any.

He has never smoked. He drinks alcohol socially but has never used recreational drugs.

In a laboratory evaluation performed a year ago for insurance purposes, his liver function tests—serum albumin, total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels—were all normal. He was positive for HBV surface antigen and HBV e antigen and negative for antibodies against these antigens.

PHASES OF HBV INFECTION

1. Which of the following best describes the status of HBV infection in this patient before his current symptoms developed?

• Resolved HBV infection
• Chronic inactive HBV infection
• Chronic active HBV infection
• Immune-tolerant chronic HBV infection

The correct answer is immune-tolerant chronic HBV infection.

Resolved infection. In immunocompetent adults, most primary HBV infections are self-limited: people clear the virus and gain lasting immunity (defined as the loss of HBV surface antigen, the development of antibody against surface antigen, no detectable HBV DNA in the serum, and normal alanine and aspartate aminotransferase levels). However, a minority of primary HBV infections persist and become chronic.

Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients with chronic HBV infection can be broadly classified as having either inactive disease (the inactive surface antigen carrier state) or chronic active hepatitis B (Figure 1).^1–9

Chronic inactive HBV infection. Carriers of inactive HBV infection have low serum levels of HBV DNA (< 2,000 IU/mL), persistently normal aminotransferase levels, and no HBV e antigen; if a liver biopsy is performed, no significant hepatitis is found.

Chronic active HBV infection. Patients with chronic active HBV infection, in contrast, have high serum HBV DNA levels (> 20,000 IU/mL) and persistently or intermittently high aminotransferase levels; they do have HBV e antigen, and a liver biopsy shows moderate or severe necroinflammation.

A small group of patients with chronic active hepatitis B may be negative for e antigen but still have high aminotransferase levels, high HBV DNA levels, and continued necroinflammation in the liver.⁴ The virus in these patients has a mutation in its precore or core promoter gene that prevents the production of e antigen.

Patients with chronic active HBV infection (whether positive or negative for e antigen) are at a significantly greater risk of progressive liver injury and developing cirrhosis and hepatocellular carcinoma than are inactive carriers of HBV.

Immune-tolerant chronic HBV infection. Patients who acquired HBV at birth (eg, our patient) may have immune-tolerant HBV infection, which is characterized by significant HBV replication manifested by the presence of HBV e antigen and high levels of HBV DNA in the serum. However, these patients have no clinical or pathologic evidence of active liver disease (no symptoms, normal serum alanine aminotransferase levels, and minimal changes on liver biopsy).⁵ This was obviously the case in our patient, based on his history and laboratory results before his current symptoms developed.

Case continues: Liver function abnormalities

On physical examination, the patient’s temperature is 99.9°F (37.7°C), heart rate 106 per minute, blood pressure 98/54 mm Hg, respiratory rate 18 per minute, and oxygen saturation 100% while breathing ambient air. He is alert and oriented to time, place, and person.

He has icteric sclera, and his skin is jaundiced. His lymph nodes are not palpable. His cardiac examination is normal except for tachycardia. His lungs are clear to auscultation and percussion. He has mild epigastric and right upper quadrant abdominal tenderness with no peritoneal signs, hepatosplenomegaly, or masses.

His basic laboratory values on admission are listed in Table 1. His amylase and lipase levels are normal. A urine dipstick test is positive for bilirubin.

WHAT IS THE LEAST LIKELY DIAGNOSIS?

2. Which one of the following is the least likely diagnosis in this patient?

• Reactivation of hepatitis B
• Drug-associated liver injury
• Acute viral hepatitis
• Acute alcoholic hepatitis
• Ischemic hepatitis

The degree and pattern of liver function abnormalities in our patient reflect hepatocellular injury rather than cholestatic liver disease, because his aminotransferase levels are elevated much higher than his alkaline phosphatase level (Table 1). Bilirubin elevation does not help differentiate the two conditions.

The degree and pattern of aminotransferase elevations are also helpful in narrowing the differential diagnosis. Serum aminotransferase levels of more than 1,000 U/L are mainly seen in patients with ischemic, viral, and toxininduced liver injury. Other rare causes of such high levels include Budd-Chiari syndrome, Wilson disease, and autoimmune hepatitis.

Ischemic hepatitis. Our patient has mild hypotension, but it does not seem to have been severe enough or of long enough duration to have caused ischemic hepatitis.

Drug-associated liver injury. Hepatotoxicity associated with drugs (most commonly acetaminophen [Tylenol]), herbal therapy, or mushroom poisoning should be considered in any patient whose aminotransferase levels are this high. However, our patient denies taking any medications (prescribed or over-the-counter), herbal remedies, or illicit drugs.

Acute viral hepatitis can certainly explain the patient’s clinical picture. Infection with hepatitis A virus, hepatitis D virus, hepatitis E virus, cytomegalovirus, Epstein-Barr virus, herpes simplex viruses types 1 and 2, and varicella zoster virus have all been implicated in severe acute hepatitis. Although hepatitis E virus infection is more common in developing countries, it has been reported in the United States.⁶ It is unlikely that acute hepatitis C virus infection is producing this degree of elevation in aminotransferase levels.

Reactivation of the patient’s chronic HBV infection can also account for his clinical presentation.

Acute alcoholic hepatitis should be suspected clinically if a patient has a history of heavy alcohol use and clinical and laboratory findings that are compatible with the diagnosis. However, the absolute values of serum aspartate aminotransferase and alanine aminotransferase in acute alcoholic hepatitis are almost always less than 500 IU/L (and typically less than 300 IU/L). Our patient’s values are much higher, and he says he does not drink very much. Although people sometimes underestimate their alcohol intake, alcoholic hepatitis is the least likely diagnosis in our patient.

Case continues: The patient is hospitalized

The patient is admitted with a diagnosis of acute hepatitis. Given his history of chronic hepatitis B, he is empirically started on lamivudine (Epivir-HBV).

• Antinuclear antibody negative
• Autoimmune liver disease panel negative
• Serum ceruloplasmin 30 mg/dL (normal range 15–60)
• Alpha fetoprotein 35.1 μg/L (< 10).

Abdominal ultrasonography is performed and reveals a small stone in the gallbladder with no evidence of biliary dilatation; otherwise, the gallbladder appears normal. Doppler ultrasonography shows the liver vessels to be patent; the liver is normal in appearance. The abdomen and pelvis appear to be normal on computed tomography without intravenous contrast.

On the third hospital day, the patient’s blood test results are:

• Aspartate aminotransferase 199 U/L (normal range 7–40)
• Alanine aminotransferase 735 U/L (0–45)
• Total bilirubin 22.9 mg/dL (0–1.5)
• International normalized ratio 6.0 (0.77–1.17)
• White blood cell count 5.1 × 10⁹/L (4–11)
• Hemoglobin 11.7 g/dL (12–16)
• Platelet count 166 × 10⁹/L (150–400)
• Blood and urine cultures negative.

WHAT IS CAUSING HIS ACUTE HEPATITIS?

3. On the basis of the new data, which of the following statements about the cause of acute hepatitis in this patient is the most accurate?

• Herpetic hepatitis is the most likely cause, given his positive test for immunoglobulin M (IgM) against herpes simplex virus
• Hepatitis C cannot be excluded with the available data
• Negative HBV e antigen does not exclude the diagnosis of acute exacerbation of HBV infection
• Hepatocellular carcinoma is the likely diagnosis, given the elevated alpha fetoprotein level

The third answer above is correct: a negative test for hepatitis B e antigen does not exclude the diagnosis of acute exacerbation of HBV infection

Herpetic hepatitis. Although not common, hepatitis due to herpes simplex virus infection should be considered in the differential diagnosis of any patient presenting with severe acute hepatitis, particularly when fever is present. Common features of herpetic hepatitis on presentation include high fever, leukopenia, markedly elevated aminotransferases, and mild cholestasis. Vesicular rash occurs in only less than half of cases of herpetic hepatitis.¹⁰

Serologic testing is of limited value because it has high rates of false-positive and false-negative results. The diagnosis can be confirmed only by viral polymerase chain reaction testing or by identifying herpes simplex viral inclusions in the liver biopsy.

However, the death rate is high in this disease, and since herpetic hepatitis is one of the few treatable causes of acute liver failure, parenteral acyclovir (Zovirax) should be considered empirically in patients presenting with acute liver failure. Our patient was started on acyclovir when his tests for IgM against herpes simplex virus came back positive.

Hepatitis C. Antibodies against hepatitis C virus do not develop immediately after this virus is contracted; they may take up to 12 weeks to develop after exposure. For this reason, about 30% to 50% of patients with acute hepatitis C virus infection are negative for these antibodies initially. In those patients, hepatitis C virus RNA in the blood is the most sensitive test to detect acute hepatitis C virus infection.

Our patient has neither antibodies against hepatitis C virus nor hepatitis C virus RNA by polymerase chain reaction testing, which rules out hepatitis C virus infection.

Disappearance of e antigen in HBV infection. The disappearance of HBV e antigen is usually associated with a decrease in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease and high levels of HBV DNA despite e antigen seroconversion. This is due to a stop codon mutation in the precore region of the viral genome that decreases or prevents production of HBV e antigen.⁴ In other words, even though HBV e antigen is a good marker of HBV replication in general, a subgroup of patients with chronic HBV infection are negative for e antigen but still have a high rate of viral replication as evidenced by high serum HBV DNA levels.

Patients with perinatally acquired chronic HBV infection most often have immune-tolerant chronic HBV infection. Among those patients (mostly Asian),^5,7 the virus is spontaneously cleared at a rate of approximately 2% to 3% per year,⁸ most often during the second and third decades of age.

Transition from the immune-tolerant phase to the immune clearance phase is frequently associated with mild transient worsening of the liver function profile.^9,11,12 However, in a small percentage of patients, hepatic decompensation and even (rarely) death from hepatic failure may occur secondary to a sudden activation of the immune system as it attempts to clear the virus. This may result in an increase in immune-mediated lysis of infected hepatocytes.

Hepatocellular carcinoma. Exacerbation of hepatitis B may be associated with an elevation of alpha fetoprotein, which may falsely raise concerns about the possibility of hepatocellular carcinoma. However, our patient had abdominal imaging with both ultrasonography and computed tomography, which showed no evidence of hepatocellular carcinoma.

Comment. The most likely cause of the patient’s acute liver failure is an acute exacerbation of hepatitis B. However, herpetic hepatitis should be ruled out by testing for herpes simplex virus by polymerase chain reaction, performing a liver biopsy, or both.

Case continues: His condition worsens

A transjugular liver biopsy shows changes associated with chronic hepatitis B, severe acute hepatitis with extensive confluent and submassive hepatic necrosis, and no intracellular viral inclusions. Subsequently, acyclovir is stopped.

On the 6th hospital day, he develops progressive metabolic acidosis and hypotension, with worsening hypoxemia. A chest radiograph is obtained to look for pneumonia, but it is indeterminate; computed tomography of the chest without contrast medium is likewise unremarkable. Duplex ultrasonography of the four extremities is negative for venous thrombosis.

The patient becomes more lethargic and difficult to arouse. He is transferred to the intensive care unit and intubated. His prothrombin and partial thromboplastin times continue to rise, the prothrombin time reaching values of more than 50 seconds. In addition, progressive renal insufficiency develops.

WHAT IS THE NEXT STEP?

4. Which of the following is the most appropriate next step in the management of this patient?

• Liver transplantation
• HBV immunoglobulin only
• Interferon and a nucleoside analogue
• Liver-assist devices
• Continue supportive care only

Liver transplantation. Since the patient’s severe acute hepatitis is accompanied by coagulopathy and encephalopathy, he meets the definition of having acute liver failure. Liver transplantation remains the only definitive therapy.

HBV immune globulin immunoprophylaxis is indicated in patients with HBV infection undergoing liver transplantation, to prevent recurrence of hepatitis B after the transplant, particularly in those with a high pretransplant viral load.¹⁷ The use of pretransplant antiviral therapy and the posttransplant combination of antiviral therapy and HBV immune globulin has reduced the rate of hepatitis B recurrence to less than 10%. However, immune globulin is by no means the best single next step in managing this patient, who clearly needs a new liver.

Interferon, nucleoside analogues. Options for antiviral treatment are interferon alfa and nucleoside analogues. Interferon therapy is contraindicated in patients such as ours, who have decompensated liver disease, because it can exacerbate the disease.¹⁸

Liver-assist devices. Because liver allografts are in short supply, there has been a strong interest in developing a device that would provide the same benefits for patients with liver failure as hemodialysis does for patients with renal failure. Trials are under way to determine the efficacy and safety of these devices.²⁰

Case continues: He receives a liver

The patient undergoes liver transplantation. He is given HBV immune globulin during and after the surgery.

Pathologic review. Under the microscope, his old liver has widespread necrosis and hemorrhage as well as inflammatory changes suggesting a chronic viral process. Regenerative nodules are present in the small amount of surviving liver parenchyma, consistent with early cirrhosis. Iron staining shows +3 depositions in areas of hepatic collapse (a nonspecific finding). Periodic acid-Schiff staining after diastase (used to detect alpha-1 antitrypsin deficiency) is negative. Herpetic viral inclusions are not present.

An immunoassay for herpes simplex virus antigen is negative. Immunostaining with antibodies to the HBV core antigen is negative. HBV surface antigen is strongly and diffusely positive in the cytoplasm of 80% to 90% of hepatocytes. The immunohistologic staining pattern is consistent with integration of HBV DNA into the DNA of hepatic tissue.

Postoperative course. Lamivudine is continued after surgery, and the patient is sent home. He has resumed the level of functioning he had before becoming ill.

Comment. The outcome of liver transplantation for hepatitis B has notably improved since HBV immune globulin and nucleoside analogues were introduced. The results of liver transplantation for hepatitis B, particuarly patient and graft survival rates, are now better than those in transplant patients with hepatitis C and similar to those in transplant patients with other types of liver disease.²¹ The combination of HBV immune globulin and lamivudine has cut the rate of HBV reinfection after liver transplantation to approximately 10% and increased the 5-year survival rate after transplantation to about 80%.^17,22

KEY POINTS

• In immunocompetent adults, most primary HBV infections are self-limited.
• Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients having chronic HBV infection can be broadly classified as inactive carriers or having chronic active disease.
• Most patients with chronic active HBV infection are positive for HBV e antigen, except patients in whom the virus has a mutation in the precore or core region of its genome that prevents the production of e antigen.
• Patients who carry inactive HBV or who are immune-tolerant require serial measurements of aminotransferase and HBV DNA levels. Treatment can be considered if the patient has a high viral load (> 2,000 IU/mL), elevated aminotransferases, or active disease on liver biopsy.
• Carriers of chronic active HBV (whether positive or negative for HBV e antigen) should be referred to a hepatologist for consideration of liver biopsy and treatment.
• Interferon should not be used in immunocompromised patients or those with decompensated liver disease because it can further exacerbate the liver disease.
• Liver transplantation should be considered in patients with acute liver failure who have a poor prognosis according to the King’s College Hospital criteria.

A 35-year-old man who was born in Vietnam presents to the emergency department of a local hospital because he has had jaundice for 5 days and fatigue, malaise, and anorexia for 2 weeks. He also has nausea and mild epigastric and right upper quadrant abdominal pain. He denies having fevers, chills, night sweats, vomiting, diarrhea, melena, hematochezia, or weight loss.

His medical history is remarkable only for perinatally acquired hepatitis B virus (HBV) infection, for which he never received antiviral therapy. He does not take any prescribed, over-the-counter, or herbal medications.

He lives in the Midwest region of the United States and works full-time as a physician in private practice. He is married and has two children.

He has not travelled recently. He has no pets at home and has not been exposed to any.

He has never smoked. He drinks alcohol socially but has never used recreational drugs.

In a laboratory evaluation performed a year ago for insurance purposes, his liver function tests—serum albumin, total bilirubin, alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase levels—were all normal. He was positive for HBV surface antigen and HBV e antigen and negative for antibodies against these antigens.

PHASES OF HBV INFECTION

1. Which of the following best describes the status of HBV infection in this patient before his current symptoms developed?

• Resolved HBV infection
• Chronic inactive HBV infection
• Chronic active HBV infection
• Immune-tolerant chronic HBV infection

The correct answer is immune-tolerant chronic HBV infection.

Resolved infection. In immunocompetent adults, most primary HBV infections are self-limited: people clear the virus and gain lasting immunity (defined as the loss of HBV surface antigen, the development of antibody against surface antigen, no detectable HBV DNA in the serum, and normal alanine and aspartate aminotransferase levels). However, a minority of primary HBV infections persist and become chronic.

Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients with chronic HBV infection can be broadly classified as having either inactive disease (the inactive surface antigen carrier state) or chronic active hepatitis B (Figure 1).^1–9

Chronic inactive HBV infection. Carriers of inactive HBV infection have low serum levels of HBV DNA (< 2,000 IU/mL), persistently normal aminotransferase levels, and no HBV e antigen; if a liver biopsy is performed, no significant hepatitis is found.

Chronic active HBV infection. Patients with chronic active HBV infection, in contrast, have high serum HBV DNA levels (> 20,000 IU/mL) and persistently or intermittently high aminotransferase levels; they do have HBV e antigen, and a liver biopsy shows moderate or severe necroinflammation.

A small group of patients with chronic active hepatitis B may be negative for e antigen but still have high aminotransferase levels, high HBV DNA levels, and continued necroinflammation in the liver.⁴ The virus in these patients has a mutation in its precore or core promoter gene that prevents the production of e antigen.

Patients with chronic active HBV infection (whether positive or negative for e antigen) are at a significantly greater risk of progressive liver injury and developing cirrhosis and hepatocellular carcinoma than are inactive carriers of HBV.

Immune-tolerant chronic HBV infection. Patients who acquired HBV at birth (eg, our patient) may have immune-tolerant HBV infection, which is characterized by significant HBV replication manifested by the presence of HBV e antigen and high levels of HBV DNA in the serum. However, these patients have no clinical or pathologic evidence of active liver disease (no symptoms, normal serum alanine aminotransferase levels, and minimal changes on liver biopsy).⁵ This was obviously the case in our patient, based on his history and laboratory results before his current symptoms developed.

Case continues: Liver function abnormalities

On physical examination, the patient’s temperature is 99.9°F (37.7°C), heart rate 106 per minute, blood pressure 98/54 mm Hg, respiratory rate 18 per minute, and oxygen saturation 100% while breathing ambient air. He is alert and oriented to time, place, and person.

He has icteric sclera, and his skin is jaundiced. His lymph nodes are not palpable. His cardiac examination is normal except for tachycardia. His lungs are clear to auscultation and percussion. He has mild epigastric and right upper quadrant abdominal tenderness with no peritoneal signs, hepatosplenomegaly, or masses.

His basic laboratory values on admission are listed in Table 1. His amylase and lipase levels are normal. A urine dipstick test is positive for bilirubin.

WHAT IS THE LEAST LIKELY DIAGNOSIS?

2. Which one of the following is the least likely diagnosis in this patient?

• Reactivation of hepatitis B
• Drug-associated liver injury
• Acute viral hepatitis
• Acute alcoholic hepatitis
• Ischemic hepatitis

The degree and pattern of liver function abnormalities in our patient reflect hepatocellular injury rather than cholestatic liver disease, because his aminotransferase levels are elevated much higher than his alkaline phosphatase level (Table 1). Bilirubin elevation does not help differentiate the two conditions.

The degree and pattern of aminotransferase elevations are also helpful in narrowing the differential diagnosis. Serum aminotransferase levels of more than 1,000 U/L are mainly seen in patients with ischemic, viral, and toxininduced liver injury. Other rare causes of such high levels include Budd-Chiari syndrome, Wilson disease, and autoimmune hepatitis.

Ischemic hepatitis. Our patient has mild hypotension, but it does not seem to have been severe enough or of long enough duration to have caused ischemic hepatitis.

Drug-associated liver injury. Hepatotoxicity associated with drugs (most commonly acetaminophen [Tylenol]), herbal therapy, or mushroom poisoning should be considered in any patient whose aminotransferase levels are this high. However, our patient denies taking any medications (prescribed or over-the-counter), herbal remedies, or illicit drugs.

Acute viral hepatitis can certainly explain the patient’s clinical picture. Infection with hepatitis A virus, hepatitis D virus, hepatitis E virus, cytomegalovirus, Epstein-Barr virus, herpes simplex viruses types 1 and 2, and varicella zoster virus have all been implicated in severe acute hepatitis. Although hepatitis E virus infection is more common in developing countries, it has been reported in the United States.⁶ It is unlikely that acute hepatitis C virus infection is producing this degree of elevation in aminotransferase levels.

Reactivation of the patient’s chronic HBV infection can also account for his clinical presentation.

Acute alcoholic hepatitis should be suspected clinically if a patient has a history of heavy alcohol use and clinical and laboratory findings that are compatible with the diagnosis. However, the absolute values of serum aspartate aminotransferase and alanine aminotransferase in acute alcoholic hepatitis are almost always less than 500 IU/L (and typically less than 300 IU/L). Our patient’s values are much higher, and he says he does not drink very much. Although people sometimes underestimate their alcohol intake, alcoholic hepatitis is the least likely diagnosis in our patient.

Case continues: The patient is hospitalized

The patient is admitted with a diagnosis of acute hepatitis. Given his history of chronic hepatitis B, he is empirically started on lamivudine (Epivir-HBV).

• Antinuclear antibody negative
• Autoimmune liver disease panel negative
• Serum ceruloplasmin 30 mg/dL (normal range 15–60)
• Alpha fetoprotein 35.1 μg/L (< 10).

Abdominal ultrasonography is performed and reveals a small stone in the gallbladder with no evidence of biliary dilatation; otherwise, the gallbladder appears normal. Doppler ultrasonography shows the liver vessels to be patent; the liver is normal in appearance. The abdomen and pelvis appear to be normal on computed tomography without intravenous contrast.

On the third hospital day, the patient’s blood test results are:

• Aspartate aminotransferase 199 U/L (normal range 7–40)
• Alanine aminotransferase 735 U/L (0–45)
• Total bilirubin 22.9 mg/dL (0–1.5)
• International normalized ratio 6.0 (0.77–1.17)
• White blood cell count 5.1 × 10⁹/L (4–11)
• Hemoglobin 11.7 g/dL (12–16)
• Platelet count 166 × 10⁹/L (150–400)
• Blood and urine cultures negative.

WHAT IS CAUSING HIS ACUTE HEPATITIS?

3. On the basis of the new data, which of the following statements about the cause of acute hepatitis in this patient is the most accurate?

• Herpetic hepatitis is the most likely cause, given his positive test for immunoglobulin M (IgM) against herpes simplex virus
• Hepatitis C cannot be excluded with the available data
• Negative HBV e antigen does not exclude the diagnosis of acute exacerbation of HBV infection
• Hepatocellular carcinoma is the likely diagnosis, given the elevated alpha fetoprotein level

The third answer above is correct: a negative test for hepatitis B e antigen does not exclude the diagnosis of acute exacerbation of HBV infection

Herpetic hepatitis. Although not common, hepatitis due to herpes simplex virus infection should be considered in the differential diagnosis of any patient presenting with severe acute hepatitis, particularly when fever is present. Common features of herpetic hepatitis on presentation include high fever, leukopenia, markedly elevated aminotransferases, and mild cholestasis. Vesicular rash occurs in only less than half of cases of herpetic hepatitis.¹⁰

Serologic testing is of limited value because it has high rates of false-positive and false-negative results. The diagnosis can be confirmed only by viral polymerase chain reaction testing or by identifying herpes simplex viral inclusions in the liver biopsy.

However, the death rate is high in this disease, and since herpetic hepatitis is one of the few treatable causes of acute liver failure, parenteral acyclovir (Zovirax) should be considered empirically in patients presenting with acute liver failure. Our patient was started on acyclovir when his tests for IgM against herpes simplex virus came back positive.

Hepatitis C. Antibodies against hepatitis C virus do not develop immediately after this virus is contracted; they may take up to 12 weeks to develop after exposure. For this reason, about 30% to 50% of patients with acute hepatitis C virus infection are negative for these antibodies initially. In those patients, hepatitis C virus RNA in the blood is the most sensitive test to detect acute hepatitis C virus infection.

Our patient has neither antibodies against hepatitis C virus nor hepatitis C virus RNA by polymerase chain reaction testing, which rules out hepatitis C virus infection.

Disappearance of e antigen in HBV infection. The disappearance of HBV e antigen is usually associated with a decrease in serum HBV DNA and remission of liver disease. However, some patients continue to have active liver disease and high levels of HBV DNA despite e antigen seroconversion. This is due to a stop codon mutation in the precore region of the viral genome that decreases or prevents production of HBV e antigen.⁴ In other words, even though HBV e antigen is a good marker of HBV replication in general, a subgroup of patients with chronic HBV infection are negative for e antigen but still have a high rate of viral replication as evidenced by high serum HBV DNA levels.

Patients with perinatally acquired chronic HBV infection most often have immune-tolerant chronic HBV infection. Among those patients (mostly Asian),^5,7 the virus is spontaneously cleared at a rate of approximately 2% to 3% per year,⁸ most often during the second and third decades of age.

Transition from the immune-tolerant phase to the immune clearance phase is frequently associated with mild transient worsening of the liver function profile.^9,11,12 However, in a small percentage of patients, hepatic decompensation and even (rarely) death from hepatic failure may occur secondary to a sudden activation of the immune system as it attempts to clear the virus. This may result in an increase in immune-mediated lysis of infected hepatocytes.

Hepatocellular carcinoma. Exacerbation of hepatitis B may be associated with an elevation of alpha fetoprotein, which may falsely raise concerns about the possibility of hepatocellular carcinoma. However, our patient had abdominal imaging with both ultrasonography and computed tomography, which showed no evidence of hepatocellular carcinoma.

Comment. The most likely cause of the patient’s acute liver failure is an acute exacerbation of hepatitis B. However, herpetic hepatitis should be ruled out by testing for herpes simplex virus by polymerase chain reaction, performing a liver biopsy, or both.

Case continues: His condition worsens

A transjugular liver biopsy shows changes associated with chronic hepatitis B, severe acute hepatitis with extensive confluent and submassive hepatic necrosis, and no intracellular viral inclusions. Subsequently, acyclovir is stopped.

On the 6th hospital day, he develops progressive metabolic acidosis and hypotension, with worsening hypoxemia. A chest radiograph is obtained to look for pneumonia, but it is indeterminate; computed tomography of the chest without contrast medium is likewise unremarkable. Duplex ultrasonography of the four extremities is negative for venous thrombosis.

The patient becomes more lethargic and difficult to arouse. He is transferred to the intensive care unit and intubated. His prothrombin and partial thromboplastin times continue to rise, the prothrombin time reaching values of more than 50 seconds. In addition, progressive renal insufficiency develops.

WHAT IS THE NEXT STEP?

4. Which of the following is the most appropriate next step in the management of this patient?

• Liver transplantation
• HBV immunoglobulin only
• Interferon and a nucleoside analogue
• Liver-assist devices
• Continue supportive care only

Liver transplantation. Since the patient’s severe acute hepatitis is accompanied by coagulopathy and encephalopathy, he meets the definition of having acute liver failure. Liver transplantation remains the only definitive therapy.

HBV immune globulin immunoprophylaxis is indicated in patients with HBV infection undergoing liver transplantation, to prevent recurrence of hepatitis B after the transplant, particularly in those with a high pretransplant viral load.¹⁷ The use of pretransplant antiviral therapy and the posttransplant combination of antiviral therapy and HBV immune globulin has reduced the rate of hepatitis B recurrence to less than 10%. However, immune globulin is by no means the best single next step in managing this patient, who clearly needs a new liver.

Interferon, nucleoside analogues. Options for antiviral treatment are interferon alfa and nucleoside analogues. Interferon therapy is contraindicated in patients such as ours, who have decompensated liver disease, because it can exacerbate the disease.¹⁸

Liver-assist devices. Because liver allografts are in short supply, there has been a strong interest in developing a device that would provide the same benefits for patients with liver failure as hemodialysis does for patients with renal failure. Trials are under way to determine the efficacy and safety of these devices.²⁰

Case continues: He receives a liver

The patient undergoes liver transplantation. He is given HBV immune globulin during and after the surgery.

Pathologic review. Under the microscope, his old liver has widespread necrosis and hemorrhage as well as inflammatory changes suggesting a chronic viral process. Regenerative nodules are present in the small amount of surviving liver parenchyma, consistent with early cirrhosis. Iron staining shows +3 depositions in areas of hepatic collapse (a nonspecific finding). Periodic acid-Schiff staining after diastase (used to detect alpha-1 antitrypsin deficiency) is negative. Herpetic viral inclusions are not present.

An immunoassay for herpes simplex virus antigen is negative. Immunostaining with antibodies to the HBV core antigen is negative. HBV surface antigen is strongly and diffusely positive in the cytoplasm of 80% to 90% of hepatocytes. The immunohistologic staining pattern is consistent with integration of HBV DNA into the DNA of hepatic tissue.

Postoperative course. Lamivudine is continued after surgery, and the patient is sent home. He has resumed the level of functioning he had before becoming ill.

Comment. The outcome of liver transplantation for hepatitis B has notably improved since HBV immune globulin and nucleoside analogues were introduced. The results of liver transplantation for hepatitis B, particuarly patient and graft survival rates, are now better than those in transplant patients with hepatitis C and similar to those in transplant patients with other types of liver disease.²¹ The combination of HBV immune globulin and lamivudine has cut the rate of HBV reinfection after liver transplantation to approximately 10% and increased the 5-year survival rate after transplantation to about 80%.^17,22

KEY POINTS

• In immunocompetent adults, most primary HBV infections are self-limited.
• Chronic HBV infection is defined as the persistence of HBV surface antigen in the serum for at least 6 months. Patients having chronic HBV infection can be broadly classified as inactive carriers or having chronic active disease.
• Most patients with chronic active HBV infection are positive for HBV e antigen, except patients in whom the virus has a mutation in the precore or core region of its genome that prevents the production of e antigen.
• Patients who carry inactive HBV or who are immune-tolerant require serial measurements of aminotransferase and HBV DNA levels. Treatment can be considered if the patient has a high viral load (> 2,000 IU/mL), elevated aminotransferases, or active disease on liver biopsy.
• Carriers of chronic active HBV (whether positive or negative for HBV e antigen) should be referred to a hepatologist for consideration of liver biopsy and treatment.
• Interferon should not be used in immunocompromised patients or those with decompensated liver disease because it can further exacerbate the liver disease.
• Liver transplantation should be considered in patients with acute liver failure who have a poor prognosis according to the King’s College Hospital criteria.

In spite of some recent studies, or perhaps because of them, we still are unsure about how best to screen for and prevent prostate cancer. Two large trials of screening with prostate-specific antigen (PSA) measurements came to seemingly opposite conclusions.^1,2 Furthermore, a large trial of selenium and vitamin E found that these agents have no value as preventive agents.³

See related editorial

Nevertheless, negative studies also advance science, and steady progress is being made in prostate cancer research. In this paper I briefly summarize and comment on some of the recent findings.

TO SCREEN OR NOT TO SCREEN?

All cases of prostate cancer are clinically relevant in that they can cause anxiety or can lead to treatment-related morbidity. The challenge is to detect the minority of cases of cancer that are biologically significant, ie, those that will cause serious illness or death.

Many men have prostate cancer

In the United States, the lifetime probability of developing prostate cancer is 1 in 6, and the probability increases with age. Prostate cancer is primarily a disease of the Western world, but it is becoming more common in other areas as well.

Risk factors for prostate cancer are age, race, and family history. Clinically apparent disease is very rare in men younger than 40 years; until recently, most guidelines suggested that screening for it should begin at age 50. African American men have the highest risk of developing and dying of prostate cancer, for reasons that are not clear. In the past, this finding was attributed to disparities in access and less aggressive therapy in black men, but recent studies suggest the differences persist even in the absence of these factors, suggesting there is a biological difference in cancers between blacks and whites. Having a father or brother who had prostate cancer increases one’s risk twofold (threefold if the father or brother was affected before the age of 60); having a father and a brother with prostate cancer increases one’s risk fourfold, and true hereditary cancer raises the risk fivefold.⁴

But relatively few men die of it

The Scandinavian Prostate Cancer Group⁵ randomized 695 men with early prostate cancer (mostly discovered by digital rectal examination or by symptoms) to undergo either radical prostatectomy or a program of watchful waiting. In 8.2 years of follow-up, 8.6% of the men in the surgery group and 14.4% of those in the watchful waiting group died of prostate cancer. Thus, we can conclude that surgery is beneficial in this situation.

Adapated from Bill-Axelson A, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352:1977–1984. Copyright 2005 Massachusetts Medical Society. All rights reserved.

Despite these calculations, in contemporary practice in the United States, about 90% of men with newly diagnosed low-grade prostate cancer choose to be treated.⁶ This high level of intervention reflects our current inability to predict which cancers will remain indolent vs which will progress and the lack of validated markers that tell us when to intervene in patients who are managed expectantly and not lose the chance for cure. Most often, patients and their physicians, who are paid to intervene, deal with this uncertainty by choosing the high likelihood of cure with early intervention despite treatment-related morbidity.

What PSA has wrought

When PSA screening was introduced in the late 1980s and early 1990s, it brought about several changes in the epidemiology and clinical profile of this disease that led us to believe that it was making a meaningful difference.

A spike in the apparent incidence of prostate cancer occurred in the late 1980s and early 1990s with the introduction of PSA screening. The spike was temporary, representing detection of preexisting cases. Now, the incidence may have leveled off.⁷

A shift in the stages of cancers detected. In 1982, half of men with newly diagnosed prostate cancer had incurable disease.⁸ Five years after the introduction of PSA testing, 95% had curable disease.⁹

An increase in the rate of cure after radical prostatectomy was seen.

A decrease in the death rate from prostate cancer since the early 1990s has been noted, which is likely due not only to earlier detection but also to earlier and better treatment.

PSA screening has low specificity. PSA is more sensitive than digital rectal examination, but most men with “elevated” PSA do not have prostate cancer. Nevertheless, although it is not a perfect screening test, it is still the best cancer marker that we have.

In the Prostate Cancer Prevention Trial (PCPT),¹⁰ finasteride (Proscar) decreased the incidence of prostate cancer by about 25% over 7 years. But there were also lessons to be learned from the placebo group, which underwent PSA testing every year and prostate biopsy at the end of the study.

We used to think the cutoff PSA level that had high sensitivity and specificity for finding cancer was 4 ng/mL. However, in the PCPT, 6.6% of men with PSA levels below 0.5 ng/mL were found to have cancer, and 12.5% of those cancers were high-grade. Of those with PSA levels of 3.1 to 4.0 ng/mL, 26.9% had cancer, and 25.0% of the cancers were high-grade. These data demonstrate that there is no PSA level below which risk of cancer is zero, and that there is no PSA cutoff with sufficient sensitivity and specificity to be clinically useful.

The PCPT risk calculator (http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp) is a wonderful tool that came out of that study. It uses seven variables—race, age, PSA level, family history of prostate cancer, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride—and calculates the patient’s risk of harboring prostate cancer and, more important, the risk of having high-grade prostate cancer. This tool allows estimation of individual risk and helps identify who is at risk of cancer that may require therapy.

Other factors can affect PSA levels. Men with a higher body mass index have lower PSA levels. The reason is not clear; it may be a hormonal effect, or heavier men may simply have higher blood volume, which may dilute the PSA. Furthermore, there are genetic differences that make some men secrete more PSA, but this effect is probably not clinically important. And a study by Hamilton et al¹¹ suggested that statin drugs lower PSA levels. As these findings are confirmed, in the future it may be necessary to adjust PSA levels to account for their effects before deciding on the need for biopsy.

Two new, conflicting studies

Two large trials of PSA screening, published simultaneously in March 2009, came to opposite conclusions.

The European Randomized Study of Screening for Prostate Cancer² randomized 162,243 men between the ages of 55 and 69 to undergo PSA screening at an average of once every 4 years or to a control group. Most of the participating centers used a PSA level of 3.0 ng/mL as an indication for biopsy. At an average follow-up time of 8.8 years, 214 men had died of prostate cancer in the screening group, compared with 326 in the control group, for an adjusted rate ratio of 0.80 (95% confidence interval [CI] 0.65–0.98, P = .04). In other words, screening decreased the risk of death from prostate cancer by 20%.

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,¹ conducted in the United States, came to the opposite conclusion, ie, that there is no benefit from PSA screening. This study was smaller, with 76,693 men between ages 55 and 74 randomly assigned to receive PSA testing every year for 6 years and digital rectal examination for 4 years, or usual care. A PSA level of more than 4.0 ng/mL was considered to be positive for prostate cancer. At 7 years, of those who reported undergoing no more than one PSA test at baseline, 48 men had died of prostate cancer in the screening group, compared with 41 in the control group (rate ratio 1.16, 95% CI 0.76–1.76).

Why were the findings different? The PLCO investigators offered several possible explanations for their negative results. The PSA threshold of 4 ng/mL that was used in that study may not be effective. More than half the men in the control group actually had a PSA test in the first 6 years of the study, potentially diluting any effect of testing. (This was the most worrisome flaw in the study, in my opinion.) About 44% of the men in the study had already had one or more PSA tests at baseline, which would have eliminated cancers detectable on screening from the study, and not all men who were advised to undergo biopsy actually did so. The follow-up time may not yet be long enough for the benefit to be apparent. Most important, in their opinion, treatment for prostate cancer improved during the time of the trial, so that fewer men than expected died of prostate cancer in both groups.

Improvements to PSA screening

Derivatives of PSA have been used in an attempt to improve its performance characteristics for detecting cancer.

PSA density, defined as serum PSA divided by prostate volume, has some predictive power but requires performance of transrectal ultrasonography. It is therefore not a good screening test in the primary care setting.

PSA velocity or doubling time, based on the rate of change over time, is predictive of prostate cancer, but is highly dependent on the absolute value of PSA and does not add independent information to the variables defined in the PCPT risk calculator or other standard predictive variables.¹²

A PSA level between the ages of 44 and 50 may predict the lifetime risk of prostate cancer, according to a study by Lilja et al¹³ in Sweden. This finding suggests that we should measure PSA early in life and screen men who have higher values more frequently or with better strategies. This recommendation has been adopted by the American Urological Association, which released updated screening guidelines in April 2009 (available at www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf).

New markers under study

A number of new biological markers probably will improve our ability to detect prostate cancer, although they are not yet ready for widespread use.

Urinary PCA3. Prostate cancer gene 3 (PCA3) codes for a messenger RNA that is highly overexpressed in the urine of men with prostate cancer. Urine is collected after prostate massage. Marks et al¹⁴ reported that PCA3 scores predicted biopsy outcomes in men with serum PSA levels of 2.5 ng/mL or higher.

Serum EPCA-2 (early prostate cancer antigen 2) is another candidate marker undergoing study.

Gene fusions, specifically of TRMPSS2 and the ETS gene family, are detectable in high levels in the urine of some men with prostate cancer, and appear to be very promising markers for detection.

Metabolomics is a technique that uses mass spectroscopy to detect the metabolic signature of cancer. Sreekumar et al¹⁵ identified sarcosine as a potential marker of prostate cancer using this technique.

Some data suggest that we can use genetic tests to screen for prostate cancer, but the tests are not yet as good as we would like.

Zheng et al¹⁶ reported that 16 singlenucleotide polymorphisms (SNPs) in five chromosomal regions plus a family history of prostate cancer have a cumulative association with prostate cancer: men who had any five or more of these SNPs had a risk of prostate cancer nearly 10 times as high as men without any of them. However, the number of men who actually fall into this category is so low that routine use in the general population is not cost-effective; it may, however, be useful in men with a family history of prostate cancer.

Other SNPs have been linked to prostate cancer (reviewed by Witte¹⁷). Having any one of these loci increases one’s risk only modestly, however. Only about 2% of the population has five or more of these SNPS, and the sensitivity is about only about 16%.

A commercially available DNA test (Decode Genetics, Reykjavik, Iceland) can detect eight variants that, according to the company, account for about half of all cases of prostate cancer.

Prostate cancer screening: My interpretation

I believe the two new studies of PSA screening suggest there is a modest benefit from screening in terms of preventing deaths from prostate cancer. But I also believe we should be more judicious in recommending treatment for men whom we know have biologically indolent tumors, although we cannot yet identify them perfectly.

In the past, we used an arbitrary PSA cutoff to detect prostate cancer of any grade, and men with high levels were advised to have a biopsy. Currently, we use continuous-risk models to look for any cancer and biologically significant cancers. These involve nomograms, a risk calculator, and new markers.

We use the PCPT risk calculator routinely in our practice. I recommend—completely arbitrarily—that a man undergo biopsy if he has a 10% or higher risk of high-grade cancer, but not if the risk is less. I believe this is more accurate than a simple PSA cutoff value.

CAN WE PREVENT PROSTATE CANCER?

Prostate cancer is a significant public health risk, with 186,000 new cases and 26,000 deaths yearly. Its risk factors (age, race, and genes) are not modifiable. The benefit of screening in terms of preventing deaths is not as good as we would like, and therapy is associated with morbidity. That leaves prevention as a potential way to reduce the morbidity and perhaps mortality of prostate cancer and its therapy.

Epidemiologic studies suggest that certain lifestyle factors may increase the risk, ie, consumption of fat, red meat, fried foods, and dairy; high calcium intake; smoking; total calories; and body size. Other factors may decrease the risk: plant-based foods and vegetables, especially lycopene-containing foods such as tomatoes, cruciferous vegetables, soy, and legumes, specific nutrients such as carotenoids, lycopene, total antioxidants, fish oil (omega-3 fatty acids), and moderate to vigorous exercise. However, there have been few randomized trials to determine if any of these agents are beneficial.

Selenium and vitamin E do not prevent prostate cancer, lung cancer, colorectal cancer, other primary cancers, or deaths. The Selenium and Vitamin E Cancer Prevention Trial (SELECT)³ involved 35,533 men 55 years of age or older (or 50 and older if they were African American). They were randomized to receive one of four treatments: selenium 200 μg/day plus vitamin E placebo, vitamin E 400 IU/day plus selenium placebo, selenium plus vitamin E, or double placebo. At a median follow-up of 5.46 years, compared with the placebo group, the hazard ratio for prostate cancer was 1.04 in the selenium-only group, 1.13 in the vitamin E-only group, and 1.05 in the selenium-plus-vitamin E group. None of the differences was statistically significant.

The Physician’s Health Study¹⁸ also found that vitamin E at the same dose given every other day does not prevent prostate cancer.

Finasteride prevents prostate cancer. The PCPT¹⁹ included 18,882 men, 55 years of age or older, who had PSA levels of 3.0 ng/mL or less and normal findings on digital rectal examination. Treatment was with finasteride 5 mg/day or placebo. At 7 years, prostate cancer had been discovered in 18.4% of the finasteride group vs 24.4% of the placebo group, a 24.8% reduction (95% CI 18.6–30.6, P < .001). Sexual side effects were more common in the men who received finasteride, while urinary symptoms were more common in the placebo group.

At the time of the original PCPT report in 2003,¹⁹ tumors of Gleason grade 7 or higher were more common in the finasteride group, accounting for 37.0% of the tumors discovered, than in the placebo group (22.2%), creating concern that finasteride might somehow cause the tumors that occurred to be more aggressive. However, a subsequent analysis²⁰ found the opposite to be true, ie, that finasteride decreases the risk of high-grade cancers. A companion quality-of-life study showed that chronic use of finasteride had clinically insignificant effects on sexual function, and the PCPT and other studies have shown benefits of finasteride in reducing lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), reducing the risk of acute urinary retention and the need for surgical intervention for BPH, and reducing the risk of prostatitis.

Dutasteride also prevents prostate cancer. A large-scale trial of another 5-alpha reductase inhibitor, dutasteride (Avodart), was reported by Andriole at the annual meeting of the American Urological Association in April 2009.²¹ The Reduction by Dutasteride of Prostate Events (REDUCE) trial included men who were 50 to 75 years old, inclusively, and who had PSA levels between 2.5 and 10 ng/mL, prostate volume less than 80 cc, and one prior negative prostate biopsy within 6 months of enrollment, representing a group at high risk for cancer on a subsequent biopsy. The trial accrued 8,231 men. At 4 years, prostate cancer had occurred in 659 men in the dutasteride group vs 857 in the placebo group, a 23% reduction (P < .0001). Interestingly, no significant increase in Gleason grade 8 to grade 10 tumors was observed in the study.

Preliminary analyses also suggest that dutasteride enhanced the utility of PSA as a diagnostic test for prostate cancer, had beneficial effects on BPH, and was generally well tolerated. The fact that the results of REDUCE were congruent with those of the PCPT with respect to the magnitude of risk reduction, beneficial effects on benign prostatic hypertrophy, minimal toxicity, and no issues related to tumor grade suggests a class effect for 5-alpha reductase inhibitors, and suggests that these agents should be used more liberally for the prevention of prostate cancer.

There is current debate about whether 5-alpha reductase inhibitors should be used by all men at risk of prostate cancer or only by those at high risk. However, the American Urological Association and the American Society of Clinical Oncology have issued guidelines stating that men at risk should consider this intervention.²²

In spite of some recent studies, or perhaps because of them, we still are unsure about how best to screen for and prevent prostate cancer. Two large trials of screening with prostate-specific antigen (PSA) measurements came to seemingly opposite conclusions.^1,2 Furthermore, a large trial of selenium and vitamin E found that these agents have no value as preventive agents.³

See related editorial

Nevertheless, negative studies also advance science, and steady progress is being made in prostate cancer research. In this paper I briefly summarize and comment on some of the recent findings.

TO SCREEN OR NOT TO SCREEN?

All cases of prostate cancer are clinically relevant in that they can cause anxiety or can lead to treatment-related morbidity. The challenge is to detect the minority of cases of cancer that are biologically significant, ie, those that will cause serious illness or death.

Many men have prostate cancer

In the United States, the lifetime probability of developing prostate cancer is 1 in 6, and the probability increases with age. Prostate cancer is primarily a disease of the Western world, but it is becoming more common in other areas as well.

Risk factors for prostate cancer are age, race, and family history. Clinically apparent disease is very rare in men younger than 40 years; until recently, most guidelines suggested that screening for it should begin at age 50. African American men have the highest risk of developing and dying of prostate cancer, for reasons that are not clear. In the past, this finding was attributed to disparities in access and less aggressive therapy in black men, but recent studies suggest the differences persist even in the absence of these factors, suggesting there is a biological difference in cancers between blacks and whites. Having a father or brother who had prostate cancer increases one’s risk twofold (threefold if the father or brother was affected before the age of 60); having a father and a brother with prostate cancer increases one’s risk fourfold, and true hereditary cancer raises the risk fivefold.⁴

But relatively few men die of it

The Scandinavian Prostate Cancer Group⁵ randomized 695 men with early prostate cancer (mostly discovered by digital rectal examination or by symptoms) to undergo either radical prostatectomy or a program of watchful waiting. In 8.2 years of follow-up, 8.6% of the men in the surgery group and 14.4% of those in the watchful waiting group died of prostate cancer. Thus, we can conclude that surgery is beneficial in this situation.

Adapated from Bill-Axelson A, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352:1977–1984. Copyright 2005 Massachusetts Medical Society. All rights reserved.

Despite these calculations, in contemporary practice in the United States, about 90% of men with newly diagnosed low-grade prostate cancer choose to be treated.⁶ This high level of intervention reflects our current inability to predict which cancers will remain indolent vs which will progress and the lack of validated markers that tell us when to intervene in patients who are managed expectantly and not lose the chance for cure. Most often, patients and their physicians, who are paid to intervene, deal with this uncertainty by choosing the high likelihood of cure with early intervention despite treatment-related morbidity.

What PSA has wrought

When PSA screening was introduced in the late 1980s and early 1990s, it brought about several changes in the epidemiology and clinical profile of this disease that led us to believe that it was making a meaningful difference.

A spike in the apparent incidence of prostate cancer occurred in the late 1980s and early 1990s with the introduction of PSA screening. The spike was temporary, representing detection of preexisting cases. Now, the incidence may have leveled off.⁷

A shift in the stages of cancers detected. In 1982, half of men with newly diagnosed prostate cancer had incurable disease.⁸ Five years after the introduction of PSA testing, 95% had curable disease.⁹

An increase in the rate of cure after radical prostatectomy was seen.

A decrease in the death rate from prostate cancer since the early 1990s has been noted, which is likely due not only to earlier detection but also to earlier and better treatment.

PSA screening has low specificity. PSA is more sensitive than digital rectal examination, but most men with “elevated” PSA do not have prostate cancer. Nevertheless, although it is not a perfect screening test, it is still the best cancer marker that we have.

In the Prostate Cancer Prevention Trial (PCPT),¹⁰ finasteride (Proscar) decreased the incidence of prostate cancer by about 25% over 7 years. But there were also lessons to be learned from the placebo group, which underwent PSA testing every year and prostate biopsy at the end of the study.

We used to think the cutoff PSA level that had high sensitivity and specificity for finding cancer was 4 ng/mL. However, in the PCPT, 6.6% of men with PSA levels below 0.5 ng/mL were found to have cancer, and 12.5% of those cancers were high-grade. Of those with PSA levels of 3.1 to 4.0 ng/mL, 26.9% had cancer, and 25.0% of the cancers were high-grade. These data demonstrate that there is no PSA level below which risk of cancer is zero, and that there is no PSA cutoff with sufficient sensitivity and specificity to be clinically useful.

The PCPT risk calculator (http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp) is a wonderful tool that came out of that study. It uses seven variables—race, age, PSA level, family history of prostate cancer, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride—and calculates the patient’s risk of harboring prostate cancer and, more important, the risk of having high-grade prostate cancer. This tool allows estimation of individual risk and helps identify who is at risk of cancer that may require therapy.

Other factors can affect PSA levels. Men with a higher body mass index have lower PSA levels. The reason is not clear; it may be a hormonal effect, or heavier men may simply have higher blood volume, which may dilute the PSA. Furthermore, there are genetic differences that make some men secrete more PSA, but this effect is probably not clinically important. And a study by Hamilton et al¹¹ suggested that statin drugs lower PSA levels. As these findings are confirmed, in the future it may be necessary to adjust PSA levels to account for their effects before deciding on the need for biopsy.

Two new, conflicting studies

Two large trials of PSA screening, published simultaneously in March 2009, came to opposite conclusions.

The European Randomized Study of Screening for Prostate Cancer² randomized 162,243 men between the ages of 55 and 69 to undergo PSA screening at an average of once every 4 years or to a control group. Most of the participating centers used a PSA level of 3.0 ng/mL as an indication for biopsy. At an average follow-up time of 8.8 years, 214 men had died of prostate cancer in the screening group, compared with 326 in the control group, for an adjusted rate ratio of 0.80 (95% confidence interval [CI] 0.65–0.98, P = .04). In other words, screening decreased the risk of death from prostate cancer by 20%.

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,¹ conducted in the United States, came to the opposite conclusion, ie, that there is no benefit from PSA screening. This study was smaller, with 76,693 men between ages 55 and 74 randomly assigned to receive PSA testing every year for 6 years and digital rectal examination for 4 years, or usual care. A PSA level of more than 4.0 ng/mL was considered to be positive for prostate cancer. At 7 years, of those who reported undergoing no more than one PSA test at baseline, 48 men had died of prostate cancer in the screening group, compared with 41 in the control group (rate ratio 1.16, 95% CI 0.76–1.76).

Why were the findings different? The PLCO investigators offered several possible explanations for their negative results. The PSA threshold of 4 ng/mL that was used in that study may not be effective. More than half the men in the control group actually had a PSA test in the first 6 years of the study, potentially diluting any effect of testing. (This was the most worrisome flaw in the study, in my opinion.) About 44% of the men in the study had already had one or more PSA tests at baseline, which would have eliminated cancers detectable on screening from the study, and not all men who were advised to undergo biopsy actually did so. The follow-up time may not yet be long enough for the benefit to be apparent. Most important, in their opinion, treatment for prostate cancer improved during the time of the trial, so that fewer men than expected died of prostate cancer in both groups.

Improvements to PSA screening

Derivatives of PSA have been used in an attempt to improve its performance characteristics for detecting cancer.

PSA density, defined as serum PSA divided by prostate volume, has some predictive power but requires performance of transrectal ultrasonography. It is therefore not a good screening test in the primary care setting.

PSA velocity or doubling time, based on the rate of change over time, is predictive of prostate cancer, but is highly dependent on the absolute value of PSA and does not add independent information to the variables defined in the PCPT risk calculator or other standard predictive variables.¹²

A PSA level between the ages of 44 and 50 may predict the lifetime risk of prostate cancer, according to a study by Lilja et al¹³ in Sweden. This finding suggests that we should measure PSA early in life and screen men who have higher values more frequently or with better strategies. This recommendation has been adopted by the American Urological Association, which released updated screening guidelines in April 2009 (available at www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf).

New markers under study

A number of new biological markers probably will improve our ability to detect prostate cancer, although they are not yet ready for widespread use.

Urinary PCA3. Prostate cancer gene 3 (PCA3) codes for a messenger RNA that is highly overexpressed in the urine of men with prostate cancer. Urine is collected after prostate massage. Marks et al¹⁴ reported that PCA3 scores predicted biopsy outcomes in men with serum PSA levels of 2.5 ng/mL or higher.

Serum EPCA-2 (early prostate cancer antigen 2) is another candidate marker undergoing study.

Gene fusions, specifically of TRMPSS2 and the ETS gene family, are detectable in high levels in the urine of some men with prostate cancer, and appear to be very promising markers for detection.

Metabolomics is a technique that uses mass spectroscopy to detect the metabolic signature of cancer. Sreekumar et al¹⁵ identified sarcosine as a potential marker of prostate cancer using this technique.

Some data suggest that we can use genetic tests to screen for prostate cancer, but the tests are not yet as good as we would like.

Zheng et al¹⁶ reported that 16 singlenucleotide polymorphisms (SNPs) in five chromosomal regions plus a family history of prostate cancer have a cumulative association with prostate cancer: men who had any five or more of these SNPs had a risk of prostate cancer nearly 10 times as high as men without any of them. However, the number of men who actually fall into this category is so low that routine use in the general population is not cost-effective; it may, however, be useful in men with a family history of prostate cancer.

Other SNPs have been linked to prostate cancer (reviewed by Witte¹⁷). Having any one of these loci increases one’s risk only modestly, however. Only about 2% of the population has five or more of these SNPS, and the sensitivity is about only about 16%.

A commercially available DNA test (Decode Genetics, Reykjavik, Iceland) can detect eight variants that, according to the company, account for about half of all cases of prostate cancer.

Prostate cancer screening: My interpretation

I believe the two new studies of PSA screening suggest there is a modest benefit from screening in terms of preventing deaths from prostate cancer. But I also believe we should be more judicious in recommending treatment for men whom we know have biologically indolent tumors, although we cannot yet identify them perfectly.

In the past, we used an arbitrary PSA cutoff to detect prostate cancer of any grade, and men with high levels were advised to have a biopsy. Currently, we use continuous-risk models to look for any cancer and biologically significant cancers. These involve nomograms, a risk calculator, and new markers.

We use the PCPT risk calculator routinely in our practice. I recommend—completely arbitrarily—that a man undergo biopsy if he has a 10% or higher risk of high-grade cancer, but not if the risk is less. I believe this is more accurate than a simple PSA cutoff value.

CAN WE PREVENT PROSTATE CANCER?

Prostate cancer is a significant public health risk, with 186,000 new cases and 26,000 deaths yearly. Its risk factors (age, race, and genes) are not modifiable. The benefit of screening in terms of preventing deaths is not as good as we would like, and therapy is associated with morbidity. That leaves prevention as a potential way to reduce the morbidity and perhaps mortality of prostate cancer and its therapy.

Epidemiologic studies suggest that certain lifestyle factors may increase the risk, ie, consumption of fat, red meat, fried foods, and dairy; high calcium intake; smoking; total calories; and body size. Other factors may decrease the risk: plant-based foods and vegetables, especially lycopene-containing foods such as tomatoes, cruciferous vegetables, soy, and legumes, specific nutrients such as carotenoids, lycopene, total antioxidants, fish oil (omega-3 fatty acids), and moderate to vigorous exercise. However, there have been few randomized trials to determine if any of these agents are beneficial.

Selenium and vitamin E do not prevent prostate cancer, lung cancer, colorectal cancer, other primary cancers, or deaths. The Selenium and Vitamin E Cancer Prevention Trial (SELECT)³ involved 35,533 men 55 years of age or older (or 50 and older if they were African American). They were randomized to receive one of four treatments: selenium 200 μg/day plus vitamin E placebo, vitamin E 400 IU/day plus selenium placebo, selenium plus vitamin E, or double placebo. At a median follow-up of 5.46 years, compared with the placebo group, the hazard ratio for prostate cancer was 1.04 in the selenium-only group, 1.13 in the vitamin E-only group, and 1.05 in the selenium-plus-vitamin E group. None of the differences was statistically significant.

The Physician’s Health Study¹⁸ also found that vitamin E at the same dose given every other day does not prevent prostate cancer.

Finasteride prevents prostate cancer. The PCPT¹⁹ included 18,882 men, 55 years of age or older, who had PSA levels of 3.0 ng/mL or less and normal findings on digital rectal examination. Treatment was with finasteride 5 mg/day or placebo. At 7 years, prostate cancer had been discovered in 18.4% of the finasteride group vs 24.4% of the placebo group, a 24.8% reduction (95% CI 18.6–30.6, P < .001). Sexual side effects were more common in the men who received finasteride, while urinary symptoms were more common in the placebo group.

At the time of the original PCPT report in 2003,¹⁹ tumors of Gleason grade 7 or higher were more common in the finasteride group, accounting for 37.0% of the tumors discovered, than in the placebo group (22.2%), creating concern that finasteride might somehow cause the tumors that occurred to be more aggressive. However, a subsequent analysis²⁰ found the opposite to be true, ie, that finasteride decreases the risk of high-grade cancers. A companion quality-of-life study showed that chronic use of finasteride had clinically insignificant effects on sexual function, and the PCPT and other studies have shown benefits of finasteride in reducing lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), reducing the risk of acute urinary retention and the need for surgical intervention for BPH, and reducing the risk of prostatitis.

Dutasteride also prevents prostate cancer. A large-scale trial of another 5-alpha reductase inhibitor, dutasteride (Avodart), was reported by Andriole at the annual meeting of the American Urological Association in April 2009.²¹ The Reduction by Dutasteride of Prostate Events (REDUCE) trial included men who were 50 to 75 years old, inclusively, and who had PSA levels between 2.5 and 10 ng/mL, prostate volume less than 80 cc, and one prior negative prostate biopsy within 6 months of enrollment, representing a group at high risk for cancer on a subsequent biopsy. The trial accrued 8,231 men. At 4 years, prostate cancer had occurred in 659 men in the dutasteride group vs 857 in the placebo group, a 23% reduction (P < .0001). Interestingly, no significant increase in Gleason grade 8 to grade 10 tumors was observed in the study.

Preliminary analyses also suggest that dutasteride enhanced the utility of PSA as a diagnostic test for prostate cancer, had beneficial effects on BPH, and was generally well tolerated. The fact that the results of REDUCE were congruent with those of the PCPT with respect to the magnitude of risk reduction, beneficial effects on benign prostatic hypertrophy, minimal toxicity, and no issues related to tumor grade suggests a class effect for 5-alpha reductase inhibitors, and suggests that these agents should be used more liberally for the prevention of prostate cancer.

There is current debate about whether 5-alpha reductase inhibitors should be used by all men at risk of prostate cancer or only by those at high risk. However, the American Urological Association and the American Society of Clinical Oncology have issued guidelines stating that men at risk should consider this intervention.²²

In spite of some recent studies, or perhaps because of them, we still are unsure about how best to screen for and prevent prostate cancer. Two large trials of screening with prostate-specific antigen (PSA) measurements came to seemingly opposite conclusions.^1,2 Furthermore, a large trial of selenium and vitamin E found that these agents have no value as preventive agents.³

See related editorial

Nevertheless, negative studies also advance science, and steady progress is being made in prostate cancer research. In this paper I briefly summarize and comment on some of the recent findings.

TO SCREEN OR NOT TO SCREEN?

All cases of prostate cancer are clinically relevant in that they can cause anxiety or can lead to treatment-related morbidity. The challenge is to detect the minority of cases of cancer that are biologically significant, ie, those that will cause serious illness or death.

Many men have prostate cancer

In the United States, the lifetime probability of developing prostate cancer is 1 in 6, and the probability increases with age. Prostate cancer is primarily a disease of the Western world, but it is becoming more common in other areas as well.

Risk factors for prostate cancer are age, race, and family history. Clinically apparent disease is very rare in men younger than 40 years; until recently, most guidelines suggested that screening for it should begin at age 50. African American men have the highest risk of developing and dying of prostate cancer, for reasons that are not clear. In the past, this finding was attributed to disparities in access and less aggressive therapy in black men, but recent studies suggest the differences persist even in the absence of these factors, suggesting there is a biological difference in cancers between blacks and whites. Having a father or brother who had prostate cancer increases one’s risk twofold (threefold if the father or brother was affected before the age of 60); having a father and a brother with prostate cancer increases one’s risk fourfold, and true hereditary cancer raises the risk fivefold.⁴

But relatively few men die of it

The Scandinavian Prostate Cancer Group⁵ randomized 695 men with early prostate cancer (mostly discovered by digital rectal examination or by symptoms) to undergo either radical prostatectomy or a program of watchful waiting. In 8.2 years of follow-up, 8.6% of the men in the surgery group and 14.4% of those in the watchful waiting group died of prostate cancer. Thus, we can conclude that surgery is beneficial in this situation.

Adapated from Bill-Axelson A, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352:1977–1984. Copyright 2005 Massachusetts Medical Society. All rights reserved.

Despite these calculations, in contemporary practice in the United States, about 90% of men with newly diagnosed low-grade prostate cancer choose to be treated.⁶ This high level of intervention reflects our current inability to predict which cancers will remain indolent vs which will progress and the lack of validated markers that tell us when to intervene in patients who are managed expectantly and not lose the chance for cure. Most often, patients and their physicians, who are paid to intervene, deal with this uncertainty by choosing the high likelihood of cure with early intervention despite treatment-related morbidity.

What PSA has wrought

When PSA screening was introduced in the late 1980s and early 1990s, it brought about several changes in the epidemiology and clinical profile of this disease that led us to believe that it was making a meaningful difference.

A spike in the apparent incidence of prostate cancer occurred in the late 1980s and early 1990s with the introduction of PSA screening. The spike was temporary, representing detection of preexisting cases. Now, the incidence may have leveled off.⁷

A shift in the stages of cancers detected. In 1982, half of men with newly diagnosed prostate cancer had incurable disease.⁸ Five years after the introduction of PSA testing, 95% had curable disease.⁹

An increase in the rate of cure after radical prostatectomy was seen.

A decrease in the death rate from prostate cancer since the early 1990s has been noted, which is likely due not only to earlier detection but also to earlier and better treatment.

PSA screening has low specificity. PSA is more sensitive than digital rectal examination, but most men with “elevated” PSA do not have prostate cancer. Nevertheless, although it is not a perfect screening test, it is still the best cancer marker that we have.

In the Prostate Cancer Prevention Trial (PCPT),¹⁰ finasteride (Proscar) decreased the incidence of prostate cancer by about 25% over 7 years. But there were also lessons to be learned from the placebo group, which underwent PSA testing every year and prostate biopsy at the end of the study.

We used to think the cutoff PSA level that had high sensitivity and specificity for finding cancer was 4 ng/mL. However, in the PCPT, 6.6% of men with PSA levels below 0.5 ng/mL were found to have cancer, and 12.5% of those cancers were high-grade. Of those with PSA levels of 3.1 to 4.0 ng/mL, 26.9% had cancer, and 25.0% of the cancers were high-grade. These data demonstrate that there is no PSA level below which risk of cancer is zero, and that there is no PSA cutoff with sufficient sensitivity and specificity to be clinically useful.

The PCPT risk calculator (http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp) is a wonderful tool that came out of that study. It uses seven variables—race, age, PSA level, family history of prostate cancer, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride—and calculates the patient’s risk of harboring prostate cancer and, more important, the risk of having high-grade prostate cancer. This tool allows estimation of individual risk and helps identify who is at risk of cancer that may require therapy.

Other factors can affect PSA levels. Men with a higher body mass index have lower PSA levels. The reason is not clear; it may be a hormonal effect, or heavier men may simply have higher blood volume, which may dilute the PSA. Furthermore, there are genetic differences that make some men secrete more PSA, but this effect is probably not clinically important. And a study by Hamilton et al¹¹ suggested that statin drugs lower PSA levels. As these findings are confirmed, in the future it may be necessary to adjust PSA levels to account for their effects before deciding on the need for biopsy.

Two new, conflicting studies

Two large trials of PSA screening, published simultaneously in March 2009, came to opposite conclusions.

The European Randomized Study of Screening for Prostate Cancer² randomized 162,243 men between the ages of 55 and 69 to undergo PSA screening at an average of once every 4 years or to a control group. Most of the participating centers used a PSA level of 3.0 ng/mL as an indication for biopsy. At an average follow-up time of 8.8 years, 214 men had died of prostate cancer in the screening group, compared with 326 in the control group, for an adjusted rate ratio of 0.80 (95% confidence interval [CI] 0.65–0.98, P = .04). In other words, screening decreased the risk of death from prostate cancer by 20%.

The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial,¹ conducted in the United States, came to the opposite conclusion, ie, that there is no benefit from PSA screening. This study was smaller, with 76,693 men between ages 55 and 74 randomly assigned to receive PSA testing every year for 6 years and digital rectal examination for 4 years, or usual care. A PSA level of more than 4.0 ng/mL was considered to be positive for prostate cancer. At 7 years, of those who reported undergoing no more than one PSA test at baseline, 48 men had died of prostate cancer in the screening group, compared with 41 in the control group (rate ratio 1.16, 95% CI 0.76–1.76).

Why were the findings different? The PLCO investigators offered several possible explanations for their negative results. The PSA threshold of 4 ng/mL that was used in that study may not be effective. More than half the men in the control group actually had a PSA test in the first 6 years of the study, potentially diluting any effect of testing. (This was the most worrisome flaw in the study, in my opinion.) About 44% of the men in the study had already had one or more PSA tests at baseline, which would have eliminated cancers detectable on screening from the study, and not all men who were advised to undergo biopsy actually did so. The follow-up time may not yet be long enough for the benefit to be apparent. Most important, in their opinion, treatment for prostate cancer improved during the time of the trial, so that fewer men than expected died of prostate cancer in both groups.

Improvements to PSA screening

Derivatives of PSA have been used in an attempt to improve its performance characteristics for detecting cancer.

PSA density, defined as serum PSA divided by prostate volume, has some predictive power but requires performance of transrectal ultrasonography. It is therefore not a good screening test in the primary care setting.

PSA velocity or doubling time, based on the rate of change over time, is predictive of prostate cancer, but is highly dependent on the absolute value of PSA and does not add independent information to the variables defined in the PCPT risk calculator or other standard predictive variables.¹²

A PSA level between the ages of 44 and 50 may predict the lifetime risk of prostate cancer, according to a study by Lilja et al¹³ in Sweden. This finding suggests that we should measure PSA early in life and screen men who have higher values more frequently or with better strategies. This recommendation has been adopted by the American Urological Association, which released updated screening guidelines in April 2009 (available at www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/psa09.pdf).

New markers under study

A number of new biological markers probably will improve our ability to detect prostate cancer, although they are not yet ready for widespread use.

Urinary PCA3. Prostate cancer gene 3 (PCA3) codes for a messenger RNA that is highly overexpressed in the urine of men with prostate cancer. Urine is collected after prostate massage. Marks et al¹⁴ reported that PCA3 scores predicted biopsy outcomes in men with serum PSA levels of 2.5 ng/mL or higher.

Serum EPCA-2 (early prostate cancer antigen 2) is another candidate marker undergoing study.

Gene fusions, specifically of TRMPSS2 and the ETS gene family, are detectable in high levels in the urine of some men with prostate cancer, and appear to be very promising markers for detection.

Metabolomics is a technique that uses mass spectroscopy to detect the metabolic signature of cancer. Sreekumar et al¹⁵ identified sarcosine as a potential marker of prostate cancer using this technique.

Some data suggest that we can use genetic tests to screen for prostate cancer, but the tests are not yet as good as we would like.

Zheng et al¹⁶ reported that 16 singlenucleotide polymorphisms (SNPs) in five chromosomal regions plus a family history of prostate cancer have a cumulative association with prostate cancer: men who had any five or more of these SNPs had a risk of prostate cancer nearly 10 times as high as men without any of them. However, the number of men who actually fall into this category is so low that routine use in the general population is not cost-effective; it may, however, be useful in men with a family history of prostate cancer.

Other SNPs have been linked to prostate cancer (reviewed by Witte¹⁷). Having any one of these loci increases one’s risk only modestly, however. Only about 2% of the population has five or more of these SNPS, and the sensitivity is about only about 16%.

A commercially available DNA test (Decode Genetics, Reykjavik, Iceland) can detect eight variants that, according to the company, account for about half of all cases of prostate cancer.

Prostate cancer screening: My interpretation

I believe the two new studies of PSA screening suggest there is a modest benefit from screening in terms of preventing deaths from prostate cancer. But I also believe we should be more judicious in recommending treatment for men whom we know have biologically indolent tumors, although we cannot yet identify them perfectly.

In the past, we used an arbitrary PSA cutoff to detect prostate cancer of any grade, and men with high levels were advised to have a biopsy. Currently, we use continuous-risk models to look for any cancer and biologically significant cancers. These involve nomograms, a risk calculator, and new markers.

We use the PCPT risk calculator routinely in our practice. I recommend—completely arbitrarily—that a man undergo biopsy if he has a 10% or higher risk of high-grade cancer, but not if the risk is less. I believe this is more accurate than a simple PSA cutoff value.

CAN WE PREVENT PROSTATE CANCER?

Prostate cancer is a significant public health risk, with 186,000 new cases and 26,000 deaths yearly. Its risk factors (age, race, and genes) are not modifiable. The benefit of screening in terms of preventing deaths is not as good as we would like, and therapy is associated with morbidity. That leaves prevention as a potential way to reduce the morbidity and perhaps mortality of prostate cancer and its therapy.

Epidemiologic studies suggest that certain lifestyle factors may increase the risk, ie, consumption of fat, red meat, fried foods, and dairy; high calcium intake; smoking; total calories; and body size. Other factors may decrease the risk: plant-based foods and vegetables, especially lycopene-containing foods such as tomatoes, cruciferous vegetables, soy, and legumes, specific nutrients such as carotenoids, lycopene, total antioxidants, fish oil (omega-3 fatty acids), and moderate to vigorous exercise. However, there have been few randomized trials to determine if any of these agents are beneficial.

Selenium and vitamin E do not prevent prostate cancer, lung cancer, colorectal cancer, other primary cancers, or deaths. The Selenium and Vitamin E Cancer Prevention Trial (SELECT)³ involved 35,533 men 55 years of age or older (or 50 and older if they were African American). They were randomized to receive one of four treatments: selenium 200 μg/day plus vitamin E placebo, vitamin E 400 IU/day plus selenium placebo, selenium plus vitamin E, or double placebo. At a median follow-up of 5.46 years, compared with the placebo group, the hazard ratio for prostate cancer was 1.04 in the selenium-only group, 1.13 in the vitamin E-only group, and 1.05 in the selenium-plus-vitamin E group. None of the differences was statistically significant.

The Physician’s Health Study¹⁸ also found that vitamin E at the same dose given every other day does not prevent prostate cancer.

Finasteride prevents prostate cancer. The PCPT¹⁹ included 18,882 men, 55 years of age or older, who had PSA levels of 3.0 ng/mL or less and normal findings on digital rectal examination. Treatment was with finasteride 5 mg/day or placebo. At 7 years, prostate cancer had been discovered in 18.4% of the finasteride group vs 24.4% of the placebo group, a 24.8% reduction (95% CI 18.6–30.6, P < .001). Sexual side effects were more common in the men who received finasteride, while urinary symptoms were more common in the placebo group.

At the time of the original PCPT report in 2003,¹⁹ tumors of Gleason grade 7 or higher were more common in the finasteride group, accounting for 37.0% of the tumors discovered, than in the placebo group (22.2%), creating concern that finasteride might somehow cause the tumors that occurred to be more aggressive. However, a subsequent analysis²⁰ found the opposite to be true, ie, that finasteride decreases the risk of high-grade cancers. A companion quality-of-life study showed that chronic use of finasteride had clinically insignificant effects on sexual function, and the PCPT and other studies have shown benefits of finasteride in reducing lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), reducing the risk of acute urinary retention and the need for surgical intervention for BPH, and reducing the risk of prostatitis.

Dutasteride also prevents prostate cancer. A large-scale trial of another 5-alpha reductase inhibitor, dutasteride (Avodart), was reported by Andriole at the annual meeting of the American Urological Association in April 2009.²¹ The Reduction by Dutasteride of Prostate Events (REDUCE) trial included men who were 50 to 75 years old, inclusively, and who had PSA levels between 2.5 and 10 ng/mL, prostate volume less than 80 cc, and one prior negative prostate biopsy within 6 months of enrollment, representing a group at high risk for cancer on a subsequent biopsy. The trial accrued 8,231 men. At 4 years, prostate cancer had occurred in 659 men in the dutasteride group vs 857 in the placebo group, a 23% reduction (P < .0001). Interestingly, no significant increase in Gleason grade 8 to grade 10 tumors was observed in the study.

Preliminary analyses also suggest that dutasteride enhanced the utility of PSA as a diagnostic test for prostate cancer, had beneficial effects on BPH, and was generally well tolerated. The fact that the results of REDUCE were congruent with those of the PCPT with respect to the magnitude of risk reduction, beneficial effects on benign prostatic hypertrophy, minimal toxicity, and no issues related to tumor grade suggests a class effect for 5-alpha reductase inhibitors, and suggests that these agents should be used more liberally for the prevention of prostate cancer.

There is current debate about whether 5-alpha reductase inhibitors should be used by all men at risk of prostate cancer or only by those at high risk. However, the American Urological Association and the American Society of Clinical Oncology have issued guidelines stating that men at risk should consider this intervention.²²

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

A 29-year-old man presented to the emergency department (ED) with a chief complaint of food stuck in his throat. He reported that he had swallowed a piece of chicken and felt it get stuck. Drinking water to help it go down was unsuccessful.

The patient’s history was positive for childhood asthma and nine years of solid food dysphagia. There was no history of a caustic chemical ingestion or of drug-induced esophagitis. He denied having dyspepsia, heartburn, or chest pain. He was not taking any medications and had no allergies.

When his dysphagia symptoms began nine years ago, he was diagnosed with acid reflux disease, confirmed by an upper gastrointestinal (GI) tract x-ray. Since that time, he reported having to swallow liquid after every bite of food and said he suffered from severe anxiety over fear of choking.

Evaluation in the ED consisted of endoscopic examination by a gastroenterologist. In addition to dislodging a food bolus, the endoscope revealed a narrowed, ringed esophagus with mucosal changes throughout the length of the esophagus (see Figures 1 through 3). Esophageal biopsies were taken, and the esophagus was dilated successfully with a 40-Fr Maloney dilator. The endoscopist detected too much resistance to pass a larger dilator.

Biopsy results revealed eosinophilic esophagitis. The patient was given oral fluticasone propionate. At one-month follow-up, he reported feeling much better. Upper endoscopy revealed some improvement, and the gastroenterologist was able to pass both a 46- and a 48-Fr Maloney dilator with only mild resistance. (The largest Maloney dilator, a 60-Fr dilator, should easily pass through a normal esophagus, according to T. L. Sack, MD, oral communication, June 2009.)

Discussion
Eosinophilic esophagitis (EE) involves the infiltration of the esophageal mucosa with eosinophils, causing edema, inflammation, and eventually, thickening and stenotic changes of the esophageal mucosa.¹

The normal esophageal mucosa contains lymphocytes, mast cells, and dendritic cells, which protect the esophagus from invading toxins and microorganisms. Eosinophils are not usually present, but when they are, they can have toxic effects on the esophageal mucosa.² EE is associated with solid food dysphagia, a direct result of damage to the esophageal mucosa, and other causes that are not clearly understood.

Research findings suggest that symptoms of dysphagia may be caused by degranulating eosinophils and mast cells, which have an antagonistic effect on the muscarinic receptors and cause smooth muscle to contract.^3,4 The proposed triggering mechanism of EE is an immunoglobulin E (IgE) immune–mediated response to an allergen.² Based on results from IgE radioallergosorbent testing (RAST), aeroallergens are more likely than food to act as triggers.⁵

EE in the Adult Patient
Traditionally, EE has been a condition seen in the pediatric population, with symptoms of nausea, vomiting, and failure to thrive; however, it is becoming increasingly recognized among adults. The typical patient is a man in his 20s or 30s (although cases of EE have been reported among women and older adults) with acute and recurrent solid food dysphagia, with or without food impaction.⁴

Often the patient reports a history of environmental or food allergies, asthma, rhinitis, or eczema.^2,4-6 Researchers have reported the presence of allergic symptoms in at least 50% of patients diagnosed with EE,² and many patients experience exacerbations associated with seasonal changes.⁷

GERD may coexist with EE; however, no relationship has been identified between the two.⁸ EE should be considered in patients with gastrointestinal symptoms that persist despite at least four weeks’ treatment with a proton pump inhibitor (PPI).²

Dysphagia: Differential Diagnosis
Adult patients with esophageal dysphagia usually report the feeling of food getting stuck when they try to swallow.⁹ Dysphagia may result from a mechanical obstruction or a neuromuscular/motility condition. Patients with mechanical obstructions usually have difficulty swallowing solids, while those with motility disorders tend to have difficulty with both liquids and solids.^1,9

Mechanical obstructions may include carcinomas (intrinsic and extrinsic), strictures, or Schatzki rings (small thin mucosal rings of unknown etiology located at the gastroesophageal junction).^1,9 Progressive dysphagia to solids over a short period of time is often indicative of esophageal carcinoma. GERD, pill-induced trauma, previous ingestion of a caustic chemical, and radiation are common causes of esophageal stricture formation. For a list of medications that are particularly caustic to the esophageal mucosa, see the table.^9,10

Neuromuscular manifestations of dysphagia include achalasia, diffuse esophageal spasm, nutcracker esophagus, and scleroderma.¹ These are usually associated with progressive difficulty in swallowing.⁹

Evaluating the Patient
A thorough patient history can often reveal potential causes of dysphagia and eliminate others. This should include current medications, chronic medical conditions and details regarding their onset and duration, and symptoms associated with dysphagia.⁹

Physical examination should include palpation of the thyroid because of the potential for a thyroid mass to cause extrinsic compression of the esophagus, palpation of the abdomen for masses or organomegaly, and a complete neurologic evaluation.⁹

Laboratory tests should be ordered based on the information obtained from the history and physical. Testing may include thyroid studies to eliminate hypothyroid or hyperthyroid causes of dysphagia, and complete blood count (CBC) with differential to rule out inflammatory or infectious processes.⁹ While eosinophilia may be present in the differential, it is not a universally accepted marker for establishing the diagnosis of EE.^2,5 Stools should be checked for occult blood, because a positive finding may suggest esophageal carcinoma.⁹

Diagnosis
In the primary care setting, a barium esophagram may be used during the initial workup to evaluate the anatomic structures of the esophagus and to differentiate between a mechanical obstruction and a neuromuscular disorder.^1,9 This noninvasive test requires the patient to swallow a radiopaque liquid as x-rays are taken.

The gold standard for diagnosing EE, however, is upper endoscopy with biopsy of the esophageal mucosa.⁶ Endoscopic findings that indicate EE are atypical of GERD; they may include a narrowed, small-caliber esophagus, concentric mucosal rings, proximal stenosis, linear ulcerations, atrophic changes, and white papules associated with eosinophilic microabscesses.⁶

Although there is no consensus regarding the number of eosinophils that should be present for an accurate diagnosis of EE, microscopic interpretation of the biopsy from both the proximal and the distal esophageal epithelia⁵ usually shows 15 or more eosinophils per high-power field.^2,11 It has been suggested that mucosal biopsies be taken along the entire length of the esophagus, as eosinophilic infiltration may extend from the proximal to the distal esophagus.²

GERD and trauma induced by medication use may also be associated with esophageal eosinophilic infiltration5; however, eosinophils are usually present only in the distal esophageal mucosa³ and are not as abundant as in EE.⁷ If endoscopy reveals persistent eosinophilia despite four to eight weeks’ treatment with a PPI, the diagnosis of EE is confirmed.²

Treatment
Treatment for EE is still under investigation. Research has examined the association between EE and food allergies or aeroallergens.⁴ Evaluation by an allergist using skin prick tests or RAST is recommended in the adult patient to help determine the source of the underlying inflammation.^5,7 Eliminating any identified allergen should help alleviate symptoms.⁴

For patients in whom no source of inflammation can be identified, treatment with 1.0 to 2.0 mg/kg/d of oral prednisone for acute exacerbations has been shown to significantly improve symptoms and histology¹²; however, because of the associated risk for adverse systemic effects, long-term use is not recommended.

In many patients, the inhaled corticosteroid fluticasone has also proved successful in reducing EE—associated inflammation.⁶ Current evidence supports adult dosing between 880 and 1,760 mcg per day for six to eight weeks, administered with a metered-dose inhaler and no spacer. Fluticasone should be sprayed directly into the mouth and swallowed, after which the patient should take nothing by mouth for 30 minutes.¹³ Prolonged fluticasone use has been associated with esophageal candidiasis.² There are currently no recommendations regarding its use as maintenance therapy.

Montelukast, a leukotriene receptor antagonist, has also been shown in some studies to reduce the inflammatory process¹¹; however, one study team recently found it to have no therapeutic effect.¹³

PPIs may be effective for improving EE symptoms even in the absence of GERD because of the reduced gastric acid production,⁷ but they do not usually improve EE’s histologic features.³

Use of esophageal dilation in patients with EE is controversial because of an associated risk for perforation.¹⁴ If this intervention is to be performed, the patient should be treated in advance with oral corticosteroids to reduce esophageal inflammation.^15,16 In addition, the endoscopist should start with small-sized dilators and carefully proceed to larger sizes.¹¹ Critics of esophageal dilation argue that the procedure is only a temporary solution and does nothing for the underlying condition.^4,8

Regarding endoscopic surveillance, an interval of at least four weeks between interventions is recommended.¹³

Role of the Primary Care Clinician
Undiagnosed EE can cause the patient discomfort, frustration, and anxiety, as seen in the case study. Many patients with undiagnosed EE have been exposed to unnecessary medical therapy and antireflux surgery.³ Without proper diagnosis and treatment, EE may worsen, causing complications associated with chronic inflammation (ie, esophageal fibrosis and strictures).^2,6

The long-term prognosis of EE is unknown at this time.⁸ The disease is usually chronic, with periods of remission and exacerbation. With an understanding of EE and appropriate therapies, the primary care practitioner can team with the gastroenterologist to provide effective disease management through endoscopic surveillance and intervention for acute exacerbations. Guidelines recommend that patients be closely followed with regular office visits to reassess symptoms, compliance with therapy, and adverse effects, with the goal of preventing complications associated with EE.¹³

Conclusion
To effectively evaluate the patient who presents with dysphagia, the primary care provider should have a working knowledge of EE, as well as an understanding of the key elements in the history and physical examination to help ensure an accurate diagnosis. This will facilitate timely referral to a gastroenterologist for endoscopic evaluation, when indicated.         

4 years of Tx, but diagnosis was wrong

FOR 4 YEARS, STARTING AT AGE 50, A WOMAN COMPLAINED TO HER INTERNIST of a persistent cough, nasal congestion, muscle and joint pain, and respiratory difficulty on exertion. The doctor treated her with allergy shots, massage therapy, vitamins, and a combination of drugs.

A little more than 4 years after the woman’s first visit to the internist, another physician diagnosed metastatic bone cancer. By then, the disease had spread from the primary mass in the lungs to the brain, legs, liver, and spine. The patient died 2 months later.

PLAINTIFF’S CLAIM The diagnosis should have been made when the patient first visited the internist; prompt treatment could have saved her life.

DOCTOR’S DEFENSE The patient’s respiratory difficulty wasn’t persistent and was judged to arise from seasonal allergies. In addition, the respiratory problems resulted from deconditioning caused by chronic fatigue syndrome.

VERDICT $1.2 million New York verdict.

COMMENT Persistent symptoms should always prompt a reevaluation of the diagnosis.

Negligence case hinges on penicillin allergy

AN 18-MONTH-OLD GIRL WITH AN EAR INFECTION was seen by a pediatrician, who prescribed amoxicillin clavulanate. The next day she developed puffy eyes and a runny nose. Her parents took her to the emergency room, where the physician diagnosed an allergic reaction to amoxicillin clavulanate and changed her medication to azithromycin. The doctor also prescribed diphenhydramine for the allergic reaction and told the parents to bring the child back the next day for follow-up. After the child took azithromycin, the puffiness and redness around her eyes began to go away. It was more prominent on one side than the other.

When the parents and child returned to the ER the following day, the girl was seen by another doctor, who diagnosed orbital cellulitis without reviewing the chart from the previous visit. He ordered intravenous ceftriaxone, a third-generation cephalosporin with a “known” cross-reactivity with penicillin-based drugs.

Despite the note in the chart about the child’s penicillin allergy, the nursing staff administered the drug while the child’s father held her in his arms. Within several minutes, the girl’s eyes were fixed and she wasn’t moving. The mother ran to get the nurses, by which time the child’s face was turning blue and she was limp. Resuscitation efforts failed.

PLAINTIFFS’ CLAIM The ER physician who saw the child on the second day was negligent in failing to note her history of penicillin allergy. Orbital cellulitis was the wrong diagnosis, unsupported by the symptoms. It should have been confirmed with a computed tomography or magnetic resonance imaging scan. The doctor was negligent in prescribing ceftriaxone, which caused an anaphylactic reaction, acute circulatory collapse, and death. The nurse should have asked the doctor to explain the ceftriaxone order before giving the drug to make sure the doctor was aware of the penicillin allergy. Ceftriaxone should have been administered by IV drip rather than gravity. The child should have been given a green allergy ID wrist band when her parents brought her to the ER the second time.

THE DEFENSE No information about the defense is available.

VERDICT $3 million Illinois settlement.

COMMENT A poorly managed handoff with resulting discontinuity of care, alleged misdiagnosis, and a dubious assertion of cross-reactivity between penicillin and ceftriaxone (see www.jfponline.com/Pages.asp?AID=3850&issue=February%202006 for details) make for a $3 million settlement!

Poor follow-up hinders stage 3 cancer Dx

A LUMP IN HER LEFT BREAST prompted a 42-year-old woman to contact her primary care physician. Office staff returned her phone call, advised her to apply warm compresses to the site, and told her that she’d be scheduled for a mammogram and ultrasound examination. The mammogram revealed bilateral asymmetry. An ultrasound wasn’t done. The woman’s primary care physician didn’t perform a physical examination or refer her for surgical consultation.

Eight months after her initial call to her doctor, the woman began to see another physician, who didn’t follow-up on her complaints of a lump and tenderness in her breast or refer her to a surgeon. Six months later, she was diagnosed with stage 3 breast cancer. Her prognosis was poor.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Massachusetts settlement.

COMMENT Yet another example of inadequate follow-up of a breast mass that turned out to be cancer. It’s critical that physicians establish a tickler file to assure appropriate follow-up of all women with breast masses.

Was lack of regular PSA testing to blame?

A 49-YEAR-OLD MAN HAD A PARTIAL PHYSICAL EXAM and a prostate-specific antigen test. He complained of urinary problems, including frequent urination and a weak stream. The patient didn’t complete the second part of the exam.

Five months later, he scheduled a follow-up and acute care visit, at which time he complained of rectal bleeding. The doctor performed a digital rectal exam, which revealed an enlarged prostate. He didn’t discuss further PSA testing or follow-up on the previous urinary complaints. He referred the patient to a gastroenterologist.

Six months after the second visit, the patient called to ask about some blood work, including a test for diabetes. The physician ordered a fasting blood sugar test. About a year after that, the patient saw his doctor for a sore throat. The doctor ordered lipid panels, thyroid-stimulating hormone tests, and liver enzyme tests. He didn’t order or discuss PSA testing.

Seventeen months later, the patient was diagnosed with stage 4 prostate cancer, which had metastasized to the brain, lungs, spine, and bony extremities. Various treatment protocols failed to help. By the time of arbitration, the patient had been given fewer than 2 weeks to live.

PLAINTIFF’S CLAIM The plaintiff should have had more regular PSA testing.

THE DEFENSE The PSA test done at the time of the initial physical examination was sufficient; even if the patient had been diagnosed at the second doctor visit 5 months later, his chance of survival would have been less than 50%.

VERDICT $3.5 million California arbitration award.

COMMENT Evidence? What evidence? Here is an arbitration award of $3.5 million for failure to perform PSA testing regularly in a 49-year-old. Although this account is incomplete, remember that the courts are sometimes impervious to evidence-based medicine.

4 years of Tx, but diagnosis was wrong

FOR 4 YEARS, STARTING AT AGE 50, A WOMAN COMPLAINED TO HER INTERNIST of a persistent cough, nasal congestion, muscle and joint pain, and respiratory difficulty on exertion. The doctor treated her with allergy shots, massage therapy, vitamins, and a combination of drugs.

A little more than 4 years after the woman’s first visit to the internist, another physician diagnosed metastatic bone cancer. By then, the disease had spread from the primary mass in the lungs to the brain, legs, liver, and spine. The patient died 2 months later.

PLAINTIFF’S CLAIM The diagnosis should have been made when the patient first visited the internist; prompt treatment could have saved her life.

DOCTOR’S DEFENSE The patient’s respiratory difficulty wasn’t persistent and was judged to arise from seasonal allergies. In addition, the respiratory problems resulted from deconditioning caused by chronic fatigue syndrome.

VERDICT $1.2 million New York verdict.

COMMENT Persistent symptoms should always prompt a reevaluation of the diagnosis.

Negligence case hinges on penicillin allergy

AN 18-MONTH-OLD GIRL WITH AN EAR INFECTION was seen by a pediatrician, who prescribed amoxicillin clavulanate. The next day she developed puffy eyes and a runny nose. Her parents took her to the emergency room, where the physician diagnosed an allergic reaction to amoxicillin clavulanate and changed her medication to azithromycin. The doctor also prescribed diphenhydramine for the allergic reaction and told the parents to bring the child back the next day for follow-up. After the child took azithromycin, the puffiness and redness around her eyes began to go away. It was more prominent on one side than the other.

When the parents and child returned to the ER the following day, the girl was seen by another doctor, who diagnosed orbital cellulitis without reviewing the chart from the previous visit. He ordered intravenous ceftriaxone, a third-generation cephalosporin with a “known” cross-reactivity with penicillin-based drugs.

Despite the note in the chart about the child’s penicillin allergy, the nursing staff administered the drug while the child’s father held her in his arms. Within several minutes, the girl’s eyes were fixed and she wasn’t moving. The mother ran to get the nurses, by which time the child’s face was turning blue and she was limp. Resuscitation efforts failed.

PLAINTIFFS’ CLAIM The ER physician who saw the child on the second day was negligent in failing to note her history of penicillin allergy. Orbital cellulitis was the wrong diagnosis, unsupported by the symptoms. It should have been confirmed with a computed tomography or magnetic resonance imaging scan. The doctor was negligent in prescribing ceftriaxone, which caused an anaphylactic reaction, acute circulatory collapse, and death. The nurse should have asked the doctor to explain the ceftriaxone order before giving the drug to make sure the doctor was aware of the penicillin allergy. Ceftriaxone should have been administered by IV drip rather than gravity. The child should have been given a green allergy ID wrist band when her parents brought her to the ER the second time.

THE DEFENSE No information about the defense is available.

VERDICT $3 million Illinois settlement.

COMMENT A poorly managed handoff with resulting discontinuity of care, alleged misdiagnosis, and a dubious assertion of cross-reactivity between penicillin and ceftriaxone (see www.jfponline.com/Pages.asp?AID=3850&issue=February%202006 for details) make for a $3 million settlement!

Poor follow-up hinders stage 3 cancer Dx

A LUMP IN HER LEFT BREAST prompted a 42-year-old woman to contact her primary care physician. Office staff returned her phone call, advised her to apply warm compresses to the site, and told her that she’d be scheduled for a mammogram and ultrasound examination. The mammogram revealed bilateral asymmetry. An ultrasound wasn’t done. The woman’s primary care physician didn’t perform a physical examination or refer her for surgical consultation.

Eight months after her initial call to her doctor, the woman began to see another physician, who didn’t follow-up on her complaints of a lump and tenderness in her breast or refer her to a surgeon. Six months later, she was diagnosed with stage 3 breast cancer. Her prognosis was poor.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Massachusetts settlement.

COMMENT Yet another example of inadequate follow-up of a breast mass that turned out to be cancer. It’s critical that physicians establish a tickler file to assure appropriate follow-up of all women with breast masses.

Was lack of regular PSA testing to blame?

A 49-YEAR-OLD MAN HAD A PARTIAL PHYSICAL EXAM and a prostate-specific antigen test. He complained of urinary problems, including frequent urination and a weak stream. The patient didn’t complete the second part of the exam.

Five months later, he scheduled a follow-up and acute care visit, at which time he complained of rectal bleeding. The doctor performed a digital rectal exam, which revealed an enlarged prostate. He didn’t discuss further PSA testing or follow-up on the previous urinary complaints. He referred the patient to a gastroenterologist.

Six months after the second visit, the patient called to ask about some blood work, including a test for diabetes. The physician ordered a fasting blood sugar test. About a year after that, the patient saw his doctor for a sore throat. The doctor ordered lipid panels, thyroid-stimulating hormone tests, and liver enzyme tests. He didn’t order or discuss PSA testing.

Seventeen months later, the patient was diagnosed with stage 4 prostate cancer, which had metastasized to the brain, lungs, spine, and bony extremities. Various treatment protocols failed to help. By the time of arbitration, the patient had been given fewer than 2 weeks to live.

PLAINTIFF’S CLAIM The plaintiff should have had more regular PSA testing.

THE DEFENSE The PSA test done at the time of the initial physical examination was sufficient; even if the patient had been diagnosed at the second doctor visit 5 months later, his chance of survival would have been less than 50%.

VERDICT $3.5 million California arbitration award.

COMMENT Evidence? What evidence? Here is an arbitration award of $3.5 million for failure to perform PSA testing regularly in a 49-year-old. Although this account is incomplete, remember that the courts are sometimes impervious to evidence-based medicine.

4 years of Tx, but diagnosis was wrong

FOR 4 YEARS, STARTING AT AGE 50, A WOMAN COMPLAINED TO HER INTERNIST of a persistent cough, nasal congestion, muscle and joint pain, and respiratory difficulty on exertion. The doctor treated her with allergy shots, massage therapy, vitamins, and a combination of drugs.

A little more than 4 years after the woman’s first visit to the internist, another physician diagnosed metastatic bone cancer. By then, the disease had spread from the primary mass in the lungs to the brain, legs, liver, and spine. The patient died 2 months later.

PLAINTIFF’S CLAIM The diagnosis should have been made when the patient first visited the internist; prompt treatment could have saved her life.

DOCTOR’S DEFENSE The patient’s respiratory difficulty wasn’t persistent and was judged to arise from seasonal allergies. In addition, the respiratory problems resulted from deconditioning caused by chronic fatigue syndrome.

VERDICT $1.2 million New York verdict.

COMMENT Persistent symptoms should always prompt a reevaluation of the diagnosis.

Negligence case hinges on penicillin allergy

AN 18-MONTH-OLD GIRL WITH AN EAR INFECTION was seen by a pediatrician, who prescribed amoxicillin clavulanate. The next day she developed puffy eyes and a runny nose. Her parents took her to the emergency room, where the physician diagnosed an allergic reaction to amoxicillin clavulanate and changed her medication to azithromycin. The doctor also prescribed diphenhydramine for the allergic reaction and told the parents to bring the child back the next day for follow-up. After the child took azithromycin, the puffiness and redness around her eyes began to go away. It was more prominent on one side than the other.

When the parents and child returned to the ER the following day, the girl was seen by another doctor, who diagnosed orbital cellulitis without reviewing the chart from the previous visit. He ordered intravenous ceftriaxone, a third-generation cephalosporin with a “known” cross-reactivity with penicillin-based drugs.

Despite the note in the chart about the child’s penicillin allergy, the nursing staff administered the drug while the child’s father held her in his arms. Within several minutes, the girl’s eyes were fixed and she wasn’t moving. The mother ran to get the nurses, by which time the child’s face was turning blue and she was limp. Resuscitation efforts failed.

PLAINTIFFS’ CLAIM The ER physician who saw the child on the second day was negligent in failing to note her history of penicillin allergy. Orbital cellulitis was the wrong diagnosis, unsupported by the symptoms. It should have been confirmed with a computed tomography or magnetic resonance imaging scan. The doctor was negligent in prescribing ceftriaxone, which caused an anaphylactic reaction, acute circulatory collapse, and death. The nurse should have asked the doctor to explain the ceftriaxone order before giving the drug to make sure the doctor was aware of the penicillin allergy. Ceftriaxone should have been administered by IV drip rather than gravity. The child should have been given a green allergy ID wrist band when her parents brought her to the ER the second time.

THE DEFENSE No information about the defense is available.

VERDICT $3 million Illinois settlement.

COMMENT A poorly managed handoff with resulting discontinuity of care, alleged misdiagnosis, and a dubious assertion of cross-reactivity between penicillin and ceftriaxone (see www.jfponline.com/Pages.asp?AID=3850&issue=February%202006 for details) make for a $3 million settlement!

Poor follow-up hinders stage 3 cancer Dx

A LUMP IN HER LEFT BREAST prompted a 42-year-old woman to contact her primary care physician. Office staff returned her phone call, advised her to apply warm compresses to the site, and told her that she’d be scheduled for a mammogram and ultrasound examination. The mammogram revealed bilateral asymmetry. An ultrasound wasn’t done. The woman’s primary care physician didn’t perform a physical examination or refer her for surgical consultation.

Eight months after her initial call to her doctor, the woman began to see another physician, who didn’t follow-up on her complaints of a lump and tenderness in her breast or refer her to a surgeon. Six months later, she was diagnosed with stage 3 breast cancer. Her prognosis was poor.

PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.

THE DEFENSE No information about the defense is available.

VERDICT $1 million Massachusetts settlement.

COMMENT Yet another example of inadequate follow-up of a breast mass that turned out to be cancer. It’s critical that physicians establish a tickler file to assure appropriate follow-up of all women with breast masses.

Was lack of regular PSA testing to blame?

A 49-YEAR-OLD MAN HAD A PARTIAL PHYSICAL EXAM and a prostate-specific antigen test. He complained of urinary problems, including frequent urination and a weak stream. The patient didn’t complete the second part of the exam.

Five months later, he scheduled a follow-up and acute care visit, at which time he complained of rectal bleeding. The doctor performed a digital rectal exam, which revealed an enlarged prostate. He didn’t discuss further PSA testing or follow-up on the previous urinary complaints. He referred the patient to a gastroenterologist.

Six months after the second visit, the patient called to ask about some blood work, including a test for diabetes. The physician ordered a fasting blood sugar test. About a year after that, the patient saw his doctor for a sore throat. The doctor ordered lipid panels, thyroid-stimulating hormone tests, and liver enzyme tests. He didn’t order or discuss PSA testing.

Seventeen months later, the patient was diagnosed with stage 4 prostate cancer, which had metastasized to the brain, lungs, spine, and bony extremities. Various treatment protocols failed to help. By the time of arbitration, the patient had been given fewer than 2 weeks to live.

PLAINTIFF’S CLAIM The plaintiff should have had more regular PSA testing.

THE DEFENSE The PSA test done at the time of the initial physical examination was sufficient; even if the patient had been diagnosed at the second doctor visit 5 months later, his chance of survival would have been less than 50%.

VERDICT $3.5 million California arbitration award.

COMMENT Evidence? What evidence? Here is an arbitration award of $3.5 million for failure to perform PSA testing regularly in a 49-year-old. Although this account is incomplete, remember that the courts are sometimes impervious to evidence-based medicine.

Background Studies have shown that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, but alcohol pads are used infrequently used and not always available.

Methods We conducted a prospective, single-blinded study to investigate whether simultaneously scrubbing hands and stethoscope head with alcohol-based hand foam would significantly reduce bacterial counts on the stethoscope. Using their own stethoscope, participants imprinted the stethoscope head onto a chocolate agar plate, then used alcohol-based hand foam to cleanse their hands while simultaneously rubbing the stethoscope head. Once the stethoscope heads were dry, the participants imprinted their stethoscope heads onto a second plate. After 48 hours’ incubation, we determined the bacterial counts for the prewash and post-wash plates, and compared the 2.

Results We analyzed a total of 184 cultures (from 92 stethoscopes). Both the mean (28 prewash vs 3 post-wash, P=.001) and median (11 prewash vs 1 post-wash, P=.001) colony counts were significantly greater before being cleansed. Three methicillin-resistant Staphylococcus aureus (MRSA) colonies were identified in the prewash period; all were destroyed by the foam. The estimated number of hand washes needed to prevent 1 MRSA colony is 31 (95% confidence interval [CI], 18-89).

Conclusion Simultaneously using hand foam to clean hands and stethoscope heads reduces bacterial counts on stethoscopes. Further research is needed to determine whether this intervention can reduce morbidity and mortality associated with bacterial infection.

More than 160 years after a Hungarian physician introduced a protocol of strict handwashing and instrument sterilization to hospital wards,¹ many clinicians still don’t wash their hands regularly or properly sterilize their medical equipment.^2,3 The lack of stringent infection control, both in inpatient and office settings, is exacerbated by the rise in antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, including community-acquired MRSA, accounts for infections ranging from severe skin lesions to sepsis, and an estimated 18,650 deaths annually.^4,5

Waterless hand cleansers, such as alcohol-based foams and gels, improve handwashing compliance.^6-8 These products are effective in reducing both bacterial and viral agents, are convenient to use, and may even be good for caregivers’ skin.⁹ But would they work on stethoscopes? Our study was designed to find out.

An often-neglected source of bacteria

Infection can spread from patient to patient, not only on hands, but also via fomites such as ventilators, computer keyboards, pagers, and stethoscopes.^10-14 Antimicrobial stethoscope covers, including those impregnated with silver ions, do not decrease bacterial colonization; evidence suggests that their use may actually increase it.¹⁵ Studies indicate that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, and it has been suggested that cleansing of stethoscopes daily may be as effective as more frequent cleaning.¹⁶ Unfortunately, many clinicians do not clean their stethoscopes on a regular basis.¹⁷ In addition, alcohol pads are not always available, and using them requires an extra step and produces waste.

An earlier study by a member of our research team (A.S., unpublished data, 2007) indicated that rubbing stethoscopes exposed to nonpathogenic Staphylococcus epidermidis with alcohol-based hand foam was comparable to using alcohol wipes in reducing bacterial counts. The primary objective of this study was to determine whether clinicians can simultaneously reduce bacteria on stethoscope heads and clean their hands with alcohol-based foam.

Methods

This study was a prospective, single-blinded, “before-and-after” trial—a design in which each participant served as his or her own control and used foam that was already available on site. The study was conducted at 1 community-based hospital and 1 satellite family health center; the study was approved by the hospital Institutional Review Board. A grant from St. Margaret’s Foundation covered the cost of the agar plates.

We began by asking the attending physicians, faculty, nurses, residents, and medical students who attended a grand rounds program to participate; we visited the satellite health facility to recruit participants, as well. We started with 93 participants, but 1 stethoscope was damaged during the study, so we ended up with 92 participants and 184 cultures.

Interventions

In the prewash, or “before” portion of the study, all participants imprinted the head of their stethoscope onto a chocolate agar plate. The clinicians then used a 62.5% ethyl alcohol-based foam to cleanse their hands, simultaneously rubbing the stethoscope head between their hands. After a brief drying time, the clinicians imprinted their stethoscope head onto a separate agar plate (the post-wash, or “after” component).

We did not tell participants how to wash their hands or for how long. We simply told them to cleanse their hands as they normally would and to rub the foam onto the stethoscope head, as well.

Randomization and measurement

Prior to data collection, randomly assigned ID numbers were recorded on the bottom of 200 agar plates, which were then placed in a box. One member of our research team gave each clinician 2 plates. Participants imprinted their stethoscope head onto the first plate and handed it to another investigator, who recorded the prewash ID numbers. Participants then performed the handwashing and stethoscope rub and repeated the imprinting procedure with the second plate. This time, the investigator recorded the professional role of each participant (eg, resident, attending, nurse, faculty) as well as the post-wash ID numbers.

After 48 hours at 35°C incubation, the plates were arranged in numerical order. A member of the research team then counted the number and identified the type of bacterial colonies on each plate and recorded the findings on a data sheet by ID number.

Validation

In order to validate the bacterial counts, the supervisor of the hospital laboratory—who had 20 years’ experience in examining cultures and served as the gold standard—independently examined a random sample of plates. We agreed in advance that any count that deviated by more than 7 (approximately half the effect the study was powered to detect) from the gold standard would require another investigator to intervene. This proved unnecessary as no such deviation was found.

Coagulase studies were performed on all plates with bacterial isolates, and gram staining was performed on selected plates, along with identification of gram-negative stains, using the Microscan (Siemens, New York, NY). An “honest broker”—the only person authorized to match the plates with the stethoscopes’ ID numbers—then matched the prewash and post-wash data by stethoscope and type of health care provider. Another investigator analyzed the final data sheet for accuracy.

Power and sample size

A pilot study was performed to obtain estimates of the average and variance of the bacterial counts in a control group of stethoscopes and to determine whether the act of imprinting the stethoscope itself would significantly reduce the colony counts. The results established that there was no statistical change in either the summary statistics or the distribution of the bacterial counts over the course of multiple imprinting.

Estimates obtained from the pilot study indicated that 58 stethoscopes would be sufficient to yield 80% power (alpha=0.05, 2-tailed) for detecting an average difference of 15 colony counts between the prewash and post-wash samples. Seventy-eight stethoscopes would increase the power to 90%. We ultimately tested 92 stethoscopes.

Statistical analysis

Descriptive statistical measures were calculated to examine the bacterial counts. Linear regression analysis was used to compute the correlation in the validation data. This before-and-after design results in “paired data,” and both parametric and nonparametric statistical tests were used. We used a paired t-test to test the mean difference in bacterial counts between the pre- and post-wash samples, and a random effects model to estimate the individual components of variance. The difference in the median bacterial counts was tested using the signed rank test. We used various diagnostic measures to examine the assumptions of the statistical tests; and means, medians, 95% confidence intervals (CIs), and P-values (using P<.05 as statistical significance) to report the results. The Bonferroni multiple comparisons procedure was used to determine whether the bacterial counts were statistically different among subgroups of health care providers. All statistical analyses were performed using SAS (Cary, NC) software.

Results

A total of 184 culture plates showing before and after samples for 92 stethoscopes were analyzed. The provider breakdown of the sample consisted of nurses (39%), residents (30%), attending physicians (15%), faculty (13%), and medical students (3%). Thirty-five (approximately 1 in 6) of the 184 plates were randomly sampled for validation. There was a high degree of reliability between the investigator’s bacterial counts and the bacterial counts of the gold standard (r=+0.98, P<.001).

Bacterial counts. The distribution of the bacterial colony counts skewed right in both the prewash (0-198) and post-wash (0-48) samples. The FIGURE shows the skewed distributions in the actual bacterial counts for the 92 pairs of plates before and after hand and stethoscope washing. In the prewash sample, the mean bacterial count was 28.4 (95% CI, 20.2-36.6), vs a post-wash mean of 3.2 (95% CI, 1.8-4.6; P<.001). This resulted in an estimated difference in mean bacterial counts of 25.2 (95% CI, 17.2-33.3). The difference in the medians was also significant, with a prewash median of 11.5 and a post-wash median of 1.0 (P<.001). The difference between the pre- and post-wash periods remained significant even after using various transformations to normalize the data. Random effects modeling showed that very little (<5%) of the total variation was related to the type of health care provider.

Types of bacteria. The TABLE gives the breakdown and frequency of the various types of bacteria that we identified on the stethoscopes. Many were of low pathogenic potential, such as coagulase-negative staph species, which would not cause disease in healthy individuals. However, in hospitalized or immunocompromised patients, they could well induce illness. There were also several clearly pathogenic bacterial isolates, including 3 MRSA colonies (each on a different stethoscope), as well as Pseudomonas and Klebsiella. All of these isolates were killed by scrubbing with foam.

Considering only the MRSA colonies, the number needed to treat is 31 (95% CI, 18-89), indicating that for approximately every 31 hand- and stethoscope-washings with the alcohol-based foam, 1 MRSA colony could potentially be eliminated from a stethoscope head.

FIGURE
Bacterial counts: Prewash and post-wash

TABLE
What we found on the stethoscopes

Discussion

The findings of this study suggest that the use of alcohol-based hand foam to simultaneously sterilize the hands and a stethoscope head significantly reduces the number of bacterial colonies, including MRSA. The quantifiable risk of clinical infection with MRSA in patients through brief contact with a contaminated fomite such as a stethoscope is unknown. However, the transmission of the bacteria itself from contaminated surfaces and hands through brief contacts has been well established.^11,12

A new standard for cleaning stethoscopes?

Swiping stethoscopes with alcohol pads is currently the gold standard for cleaning these instruments, but physicians do not consistently use alcohol pads for this purpose. Moreover, the pads must be purchased and available for use, require an extra step, and produce waste that must be disposed of—and clinicians still have to cleanse their hands, often using alcohol-based hand foam. Using the foam to cleanse the stethoscope while cleaning hands requires no added cost or additional time, and may reduce or prevent serious nosocomial and community-based infections.

Limitations of the study

One limitation of this study was the lack of control of the washing procedure. But because our goal was to see how the technique fared in actual use among all participants, uniform technique was not required. Knowing they were in a study may have altered the way the participants washed their hands and stethoscopes. If this were true, however, we would expect a much larger proportion of the total variation to be due to differences among clinicians than the 5% that was found.

This technique does not eliminate all bacteria—for instance, sporulating organisms such as Clostridium difficile are not killed by alcohol products.¹⁸ Yet friction alone has been found to reduce the number of these pathogens (A.S., unpublished data, 2007).

This study utilized alcohol-based hand foam because it was available at the study institution, so we cannot make any claims for nonalcohol-based products. It does appear, however, that alcohol-based foam may not be susceptible to bacterial resistance, as had previously been found in triclosan-containing products.¹⁹

It is not known whether the alcohol-based foam will damage stethoscope diaphragms. Previous studies have suggested that alcohol pads do cause damage to the rubber components of stethoscopes,¹⁶ but the foam studied here, like most similar products, contains emollients that may or may not have a protective effect. Another study would be necessary to fully assess this question.

While it is impossible to destroy all bacteria or eliminate all infections by simultaneous hand and stethoscope cleansing, many infections could potentially be prevented with this simple component of a comprehensive infection control program. Alcohol-based hand foam is already in use for hand cleansing between patients in many inpatient and outpatient settings, and this procedure requires no added cost and no additional time. Further research is necessary to determine whether the reduction of bacterial growth also corresponds to a reduction in clinically related disease. The results of this study provide evidence that hand foam, when used to simultaneously sterilize the hands and stethoscope, can significantly reduce the number of bacterial colonies on stethoscopes.

CORRESPONDENCE
Maryellen A. Schroeder, MD, MPH, UPMC St. Margaret, 815 Freeport Road, Pittsburgh, PA 15201; [email protected]

Background Studies have shown that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, but alcohol pads are used infrequently used and not always available.

Methods We conducted a prospective, single-blinded study to investigate whether simultaneously scrubbing hands and stethoscope head with alcohol-based hand foam would significantly reduce bacterial counts on the stethoscope. Using their own stethoscope, participants imprinted the stethoscope head onto a chocolate agar plate, then used alcohol-based hand foam to cleanse their hands while simultaneously rubbing the stethoscope head. Once the stethoscope heads were dry, the participants imprinted their stethoscope heads onto a second plate. After 48 hours’ incubation, we determined the bacterial counts for the prewash and post-wash plates, and compared the 2.

Results We analyzed a total of 184 cultures (from 92 stethoscopes). Both the mean (28 prewash vs 3 post-wash, P=.001) and median (11 prewash vs 1 post-wash, P=.001) colony counts were significantly greater before being cleansed. Three methicillin-resistant Staphylococcus aureus (MRSA) colonies were identified in the prewash period; all were destroyed by the foam. The estimated number of hand washes needed to prevent 1 MRSA colony is 31 (95% confidence interval [CI], 18-89).

Conclusion Simultaneously using hand foam to clean hands and stethoscope heads reduces bacterial counts on stethoscopes. Further research is needed to determine whether this intervention can reduce morbidity and mortality associated with bacterial infection.

More than 160 years after a Hungarian physician introduced a protocol of strict handwashing and instrument sterilization to hospital wards,¹ many clinicians still don’t wash their hands regularly or properly sterilize their medical equipment.^2,3 The lack of stringent infection control, both in inpatient and office settings, is exacerbated by the rise in antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, including community-acquired MRSA, accounts for infections ranging from severe skin lesions to sepsis, and an estimated 18,650 deaths annually.^4,5

Waterless hand cleansers, such as alcohol-based foams and gels, improve handwashing compliance.^6-8 These products are effective in reducing both bacterial and viral agents, are convenient to use, and may even be good for caregivers’ skin.⁹ But would they work on stethoscopes? Our study was designed to find out.

An often-neglected source of bacteria

Infection can spread from patient to patient, not only on hands, but also via fomites such as ventilators, computer keyboards, pagers, and stethoscopes.^10-14 Antimicrobial stethoscope covers, including those impregnated with silver ions, do not decrease bacterial colonization; evidence suggests that their use may actually increase it.¹⁵ Studies indicate that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, and it has been suggested that cleansing of stethoscopes daily may be as effective as more frequent cleaning.¹⁶ Unfortunately, many clinicians do not clean their stethoscopes on a regular basis.¹⁷ In addition, alcohol pads are not always available, and using them requires an extra step and produces waste.

An earlier study by a member of our research team (A.S., unpublished data, 2007) indicated that rubbing stethoscopes exposed to nonpathogenic Staphylococcus epidermidis with alcohol-based hand foam was comparable to using alcohol wipes in reducing bacterial counts. The primary objective of this study was to determine whether clinicians can simultaneously reduce bacteria on stethoscope heads and clean their hands with alcohol-based foam.

Methods

This study was a prospective, single-blinded, “before-and-after” trial—a design in which each participant served as his or her own control and used foam that was already available on site. The study was conducted at 1 community-based hospital and 1 satellite family health center; the study was approved by the hospital Institutional Review Board. A grant from St. Margaret’s Foundation covered the cost of the agar plates.

We began by asking the attending physicians, faculty, nurses, residents, and medical students who attended a grand rounds program to participate; we visited the satellite health facility to recruit participants, as well. We started with 93 participants, but 1 stethoscope was damaged during the study, so we ended up with 92 participants and 184 cultures.

Interventions

In the prewash, or “before” portion of the study, all participants imprinted the head of their stethoscope onto a chocolate agar plate. The clinicians then used a 62.5% ethyl alcohol-based foam to cleanse their hands, simultaneously rubbing the stethoscope head between their hands. After a brief drying time, the clinicians imprinted their stethoscope head onto a separate agar plate (the post-wash, or “after” component).

We did not tell participants how to wash their hands or for how long. We simply told them to cleanse their hands as they normally would and to rub the foam onto the stethoscope head, as well.

Randomization and measurement

Prior to data collection, randomly assigned ID numbers were recorded on the bottom of 200 agar plates, which were then placed in a box. One member of our research team gave each clinician 2 plates. Participants imprinted their stethoscope head onto the first plate and handed it to another investigator, who recorded the prewash ID numbers. Participants then performed the handwashing and stethoscope rub and repeated the imprinting procedure with the second plate. This time, the investigator recorded the professional role of each participant (eg, resident, attending, nurse, faculty) as well as the post-wash ID numbers.

After 48 hours at 35°C incubation, the plates were arranged in numerical order. A member of the research team then counted the number and identified the type of bacterial colonies on each plate and recorded the findings on a data sheet by ID number.

Validation

In order to validate the bacterial counts, the supervisor of the hospital laboratory—who had 20 years’ experience in examining cultures and served as the gold standard—independently examined a random sample of plates. We agreed in advance that any count that deviated by more than 7 (approximately half the effect the study was powered to detect) from the gold standard would require another investigator to intervene. This proved unnecessary as no such deviation was found.

Coagulase studies were performed on all plates with bacterial isolates, and gram staining was performed on selected plates, along with identification of gram-negative stains, using the Microscan (Siemens, New York, NY). An “honest broker”—the only person authorized to match the plates with the stethoscopes’ ID numbers—then matched the prewash and post-wash data by stethoscope and type of health care provider. Another investigator analyzed the final data sheet for accuracy.

Power and sample size

A pilot study was performed to obtain estimates of the average and variance of the bacterial counts in a control group of stethoscopes and to determine whether the act of imprinting the stethoscope itself would significantly reduce the colony counts. The results established that there was no statistical change in either the summary statistics or the distribution of the bacterial counts over the course of multiple imprinting.

Estimates obtained from the pilot study indicated that 58 stethoscopes would be sufficient to yield 80% power (alpha=0.05, 2-tailed) for detecting an average difference of 15 colony counts between the prewash and post-wash samples. Seventy-eight stethoscopes would increase the power to 90%. We ultimately tested 92 stethoscopes.

Statistical analysis

Descriptive statistical measures were calculated to examine the bacterial counts. Linear regression analysis was used to compute the correlation in the validation data. This before-and-after design results in “paired data,” and both parametric and nonparametric statistical tests were used. We used a paired t-test to test the mean difference in bacterial counts between the pre- and post-wash samples, and a random effects model to estimate the individual components of variance. The difference in the median bacterial counts was tested using the signed rank test. We used various diagnostic measures to examine the assumptions of the statistical tests; and means, medians, 95% confidence intervals (CIs), and P-values (using P<.05 as statistical significance) to report the results. The Bonferroni multiple comparisons procedure was used to determine whether the bacterial counts were statistically different among subgroups of health care providers. All statistical analyses were performed using SAS (Cary, NC) software.

Results

A total of 184 culture plates showing before and after samples for 92 stethoscopes were analyzed. The provider breakdown of the sample consisted of nurses (39%), residents (30%), attending physicians (15%), faculty (13%), and medical students (3%). Thirty-five (approximately 1 in 6) of the 184 plates were randomly sampled for validation. There was a high degree of reliability between the investigator’s bacterial counts and the bacterial counts of the gold standard (r=+0.98, P<.001).

Bacterial counts. The distribution of the bacterial colony counts skewed right in both the prewash (0-198) and post-wash (0-48) samples. The FIGURE shows the skewed distributions in the actual bacterial counts for the 92 pairs of plates before and after hand and stethoscope washing. In the prewash sample, the mean bacterial count was 28.4 (95% CI, 20.2-36.6), vs a post-wash mean of 3.2 (95% CI, 1.8-4.6; P<.001). This resulted in an estimated difference in mean bacterial counts of 25.2 (95% CI, 17.2-33.3). The difference in the medians was also significant, with a prewash median of 11.5 and a post-wash median of 1.0 (P<.001). The difference between the pre- and post-wash periods remained significant even after using various transformations to normalize the data. Random effects modeling showed that very little (<5%) of the total variation was related to the type of health care provider.

Types of bacteria. The TABLE gives the breakdown and frequency of the various types of bacteria that we identified on the stethoscopes. Many were of low pathogenic potential, such as coagulase-negative staph species, which would not cause disease in healthy individuals. However, in hospitalized or immunocompromised patients, they could well induce illness. There were also several clearly pathogenic bacterial isolates, including 3 MRSA colonies (each on a different stethoscope), as well as Pseudomonas and Klebsiella. All of these isolates were killed by scrubbing with foam.

Considering only the MRSA colonies, the number needed to treat is 31 (95% CI, 18-89), indicating that for approximately every 31 hand- and stethoscope-washings with the alcohol-based foam, 1 MRSA colony could potentially be eliminated from a stethoscope head.

FIGURE
Bacterial counts: Prewash and post-wash

TABLE
What we found on the stethoscopes

Discussion

The findings of this study suggest that the use of alcohol-based hand foam to simultaneously sterilize the hands and a stethoscope head significantly reduces the number of bacterial colonies, including MRSA. The quantifiable risk of clinical infection with MRSA in patients through brief contact with a contaminated fomite such as a stethoscope is unknown. However, the transmission of the bacteria itself from contaminated surfaces and hands through brief contacts has been well established.^11,12

A new standard for cleaning stethoscopes?

Swiping stethoscopes with alcohol pads is currently the gold standard for cleaning these instruments, but physicians do not consistently use alcohol pads for this purpose. Moreover, the pads must be purchased and available for use, require an extra step, and produce waste that must be disposed of—and clinicians still have to cleanse their hands, often using alcohol-based hand foam. Using the foam to cleanse the stethoscope while cleaning hands requires no added cost or additional time, and may reduce or prevent serious nosocomial and community-based infections.

Limitations of the study

One limitation of this study was the lack of control of the washing procedure. But because our goal was to see how the technique fared in actual use among all participants, uniform technique was not required. Knowing they were in a study may have altered the way the participants washed their hands and stethoscopes. If this were true, however, we would expect a much larger proportion of the total variation to be due to differences among clinicians than the 5% that was found.

This technique does not eliminate all bacteria—for instance, sporulating organisms such as Clostridium difficile are not killed by alcohol products.¹⁸ Yet friction alone has been found to reduce the number of these pathogens (A.S., unpublished data, 2007).

This study utilized alcohol-based hand foam because it was available at the study institution, so we cannot make any claims for nonalcohol-based products. It does appear, however, that alcohol-based foam may not be susceptible to bacterial resistance, as had previously been found in triclosan-containing products.¹⁹

It is not known whether the alcohol-based foam will damage stethoscope diaphragms. Previous studies have suggested that alcohol pads do cause damage to the rubber components of stethoscopes,¹⁶ but the foam studied here, like most similar products, contains emollients that may or may not have a protective effect. Another study would be necessary to fully assess this question.

While it is impossible to destroy all bacteria or eliminate all infections by simultaneous hand and stethoscope cleansing, many infections could potentially be prevented with this simple component of a comprehensive infection control program. Alcohol-based hand foam is already in use for hand cleansing between patients in many inpatient and outpatient settings, and this procedure requires no added cost and no additional time. Further research is necessary to determine whether the reduction of bacterial growth also corresponds to a reduction in clinically related disease. The results of this study provide evidence that hand foam, when used to simultaneously sterilize the hands and stethoscope, can significantly reduce the number of bacterial colonies on stethoscopes.

CORRESPONDENCE
Maryellen A. Schroeder, MD, MPH, UPMC St. Margaret, 815 Freeport Road, Pittsburgh, PA 15201; [email protected]

Background Studies have shown that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, but alcohol pads are used infrequently used and not always available.

Methods We conducted a prospective, single-blinded study to investigate whether simultaneously scrubbing hands and stethoscope head with alcohol-based hand foam would significantly reduce bacterial counts on the stethoscope. Using their own stethoscope, participants imprinted the stethoscope head onto a chocolate agar plate, then used alcohol-based hand foam to cleanse their hands while simultaneously rubbing the stethoscope head. Once the stethoscope heads were dry, the participants imprinted their stethoscope heads onto a second plate. After 48 hours’ incubation, we determined the bacterial counts for the prewash and post-wash plates, and compared the 2.

Results We analyzed a total of 184 cultures (from 92 stethoscopes). Both the mean (28 prewash vs 3 post-wash, P=.001) and median (11 prewash vs 1 post-wash, P=.001) colony counts were significantly greater before being cleansed. Three methicillin-resistant Staphylococcus aureus (MRSA) colonies were identified in the prewash period; all were destroyed by the foam. The estimated number of hand washes needed to prevent 1 MRSA colony is 31 (95% confidence interval [CI], 18-89).

Conclusion Simultaneously using hand foam to clean hands and stethoscope heads reduces bacterial counts on stethoscopes. Further research is needed to determine whether this intervention can reduce morbidity and mortality associated with bacterial infection.

More than 160 years after a Hungarian physician introduced a protocol of strict handwashing and instrument sterilization to hospital wards,¹ many clinicians still don’t wash their hands regularly or properly sterilize their medical equipment.^2,3 The lack of stringent infection control, both in inpatient and office settings, is exacerbated by the rise in antibiotic-resistant bacteria. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, including community-acquired MRSA, accounts for infections ranging from severe skin lesions to sepsis, and an estimated 18,650 deaths annually.^4,5

Waterless hand cleansers, such as alcohol-based foams and gels, improve handwashing compliance.^6-8 These products are effective in reducing both bacterial and viral agents, are convenient to use, and may even be good for caregivers’ skin.⁹ But would they work on stethoscopes? Our study was designed to find out.

An often-neglected source of bacteria

Infection can spread from patient to patient, not only on hands, but also via fomites such as ventilators, computer keyboards, pagers, and stethoscopes.^10-14 Antimicrobial stethoscope covers, including those impregnated with silver ions, do not decrease bacterial colonization; evidence suggests that their use may actually increase it.¹⁵ Studies indicate that rubbing alcohol pads on stethoscope diaphragms can reduce bacterial colonization, and it has been suggested that cleansing of stethoscopes daily may be as effective as more frequent cleaning.¹⁶ Unfortunately, many clinicians do not clean their stethoscopes on a regular basis.¹⁷ In addition, alcohol pads are not always available, and using them requires an extra step and produces waste.

An earlier study by a member of our research team (A.S., unpublished data, 2007) indicated that rubbing stethoscopes exposed to nonpathogenic Staphylococcus epidermidis with alcohol-based hand foam was comparable to using alcohol wipes in reducing bacterial counts. The primary objective of this study was to determine whether clinicians can simultaneously reduce bacteria on stethoscope heads and clean their hands with alcohol-based foam.

Methods

This study was a prospective, single-blinded, “before-and-after” trial—a design in which each participant served as his or her own control and used foam that was already available on site. The study was conducted at 1 community-based hospital and 1 satellite family health center; the study was approved by the hospital Institutional Review Board. A grant from St. Margaret’s Foundation covered the cost of the agar plates.

We began by asking the attending physicians, faculty, nurses, residents, and medical students who attended a grand rounds program to participate; we visited the satellite health facility to recruit participants, as well. We started with 93 participants, but 1 stethoscope was damaged during the study, so we ended up with 92 participants and 184 cultures.

Interventions

In the prewash, or “before” portion of the study, all participants imprinted the head of their stethoscope onto a chocolate agar plate. The clinicians then used a 62.5% ethyl alcohol-based foam to cleanse their hands, simultaneously rubbing the stethoscope head between their hands. After a brief drying time, the clinicians imprinted their stethoscope head onto a separate agar plate (the post-wash, or “after” component).

We did not tell participants how to wash their hands or for how long. We simply told them to cleanse their hands as they normally would and to rub the foam onto the stethoscope head, as well.

Randomization and measurement

Prior to data collection, randomly assigned ID numbers were recorded on the bottom of 200 agar plates, which were then placed in a box. One member of our research team gave each clinician 2 plates. Participants imprinted their stethoscope head onto the first plate and handed it to another investigator, who recorded the prewash ID numbers. Participants then performed the handwashing and stethoscope rub and repeated the imprinting procedure with the second plate. This time, the investigator recorded the professional role of each participant (eg, resident, attending, nurse, faculty) as well as the post-wash ID numbers.

After 48 hours at 35°C incubation, the plates were arranged in numerical order. A member of the research team then counted the number and identified the type of bacterial colonies on each plate and recorded the findings on a data sheet by ID number.

Validation

In order to validate the bacterial counts, the supervisor of the hospital laboratory—who had 20 years’ experience in examining cultures and served as the gold standard—independently examined a random sample of plates. We agreed in advance that any count that deviated by more than 7 (approximately half the effect the study was powered to detect) from the gold standard would require another investigator to intervene. This proved unnecessary as no such deviation was found.

Coagulase studies were performed on all plates with bacterial isolates, and gram staining was performed on selected plates, along with identification of gram-negative stains, using the Microscan (Siemens, New York, NY). An “honest broker”—the only person authorized to match the plates with the stethoscopes’ ID numbers—then matched the prewash and post-wash data by stethoscope and type of health care provider. Another investigator analyzed the final data sheet for accuracy.

Power and sample size

A pilot study was performed to obtain estimates of the average and variance of the bacterial counts in a control group of stethoscopes and to determine whether the act of imprinting the stethoscope itself would significantly reduce the colony counts. The results established that there was no statistical change in either the summary statistics or the distribution of the bacterial counts over the course of multiple imprinting.

Estimates obtained from the pilot study indicated that 58 stethoscopes would be sufficient to yield 80% power (alpha=0.05, 2-tailed) for detecting an average difference of 15 colony counts between the prewash and post-wash samples. Seventy-eight stethoscopes would increase the power to 90%. We ultimately tested 92 stethoscopes.

Statistical analysis

Descriptive statistical measures were calculated to examine the bacterial counts. Linear regression analysis was used to compute the correlation in the validation data. This before-and-after design results in “paired data,” and both parametric and nonparametric statistical tests were used. We used a paired t-test to test the mean difference in bacterial counts between the pre- and post-wash samples, and a random effects model to estimate the individual components of variance. The difference in the median bacterial counts was tested using the signed rank test. We used various diagnostic measures to examine the assumptions of the statistical tests; and means, medians, 95% confidence intervals (CIs), and P-values (using P<.05 as statistical significance) to report the results. The Bonferroni multiple comparisons procedure was used to determine whether the bacterial counts were statistically different among subgroups of health care providers. All statistical analyses were performed using SAS (Cary, NC) software.

Results

A total of 184 culture plates showing before and after samples for 92 stethoscopes were analyzed. The provider breakdown of the sample consisted of nurses (39%), residents (30%), attending physicians (15%), faculty (13%), and medical students (3%). Thirty-five (approximately 1 in 6) of the 184 plates were randomly sampled for validation. There was a high degree of reliability between the investigator’s bacterial counts and the bacterial counts of the gold standard (r=+0.98, P<.001).

Bacterial counts. The distribution of the bacterial colony counts skewed right in both the prewash (0-198) and post-wash (0-48) samples. The FIGURE shows the skewed distributions in the actual bacterial counts for the 92 pairs of plates before and after hand and stethoscope washing. In the prewash sample, the mean bacterial count was 28.4 (95% CI, 20.2-36.6), vs a post-wash mean of 3.2 (95% CI, 1.8-4.6; P<.001). This resulted in an estimated difference in mean bacterial counts of 25.2 (95% CI, 17.2-33.3). The difference in the medians was also significant, with a prewash median of 11.5 and a post-wash median of 1.0 (P<.001). The difference between the pre- and post-wash periods remained significant even after using various transformations to normalize the data. Random effects modeling showed that very little (<5%) of the total variation was related to the type of health care provider.

Types of bacteria. The TABLE gives the breakdown and frequency of the various types of bacteria that we identified on the stethoscopes. Many were of low pathogenic potential, such as coagulase-negative staph species, which would not cause disease in healthy individuals. However, in hospitalized or immunocompromised patients, they could well induce illness. There were also several clearly pathogenic bacterial isolates, including 3 MRSA colonies (each on a different stethoscope), as well as Pseudomonas and Klebsiella. All of these isolates were killed by scrubbing with foam.

Considering only the MRSA colonies, the number needed to treat is 31 (95% CI, 18-89), indicating that for approximately every 31 hand- and stethoscope-washings with the alcohol-based foam, 1 MRSA colony could potentially be eliminated from a stethoscope head.

FIGURE
Bacterial counts: Prewash and post-wash

TABLE
What we found on the stethoscopes

Discussion

The findings of this study suggest that the use of alcohol-based hand foam to simultaneously sterilize the hands and a stethoscope head significantly reduces the number of bacterial colonies, including MRSA. The quantifiable risk of clinical infection with MRSA in patients through brief contact with a contaminated fomite such as a stethoscope is unknown. However, the transmission of the bacteria itself from contaminated surfaces and hands through brief contacts has been well established.^11,12

A new standard for cleaning stethoscopes?

Swiping stethoscopes with alcohol pads is currently the gold standard for cleaning these instruments, but physicians do not consistently use alcohol pads for this purpose. Moreover, the pads must be purchased and available for use, require an extra step, and produce waste that must be disposed of—and clinicians still have to cleanse their hands, often using alcohol-based hand foam. Using the foam to cleanse the stethoscope while cleaning hands requires no added cost or additional time, and may reduce or prevent serious nosocomial and community-based infections.

Limitations of the study

One limitation of this study was the lack of control of the washing procedure. But because our goal was to see how the technique fared in actual use among all participants, uniform technique was not required. Knowing they were in a study may have altered the way the participants washed their hands and stethoscopes. If this were true, however, we would expect a much larger proportion of the total variation to be due to differences among clinicians than the 5% that was found.

This technique does not eliminate all bacteria—for instance, sporulating organisms such as Clostridium difficile are not killed by alcohol products.¹⁸ Yet friction alone has been found to reduce the number of these pathogens (A.S., unpublished data, 2007).

This study utilized alcohol-based hand foam because it was available at the study institution, so we cannot make any claims for nonalcohol-based products. It does appear, however, that alcohol-based foam may not be susceptible to bacterial resistance, as had previously been found in triclosan-containing products.¹⁹

It is not known whether the alcohol-based foam will damage stethoscope diaphragms. Previous studies have suggested that alcohol pads do cause damage to the rubber components of stethoscopes,¹⁶ but the foam studied here, like most similar products, contains emollients that may or may not have a protective effect. Another study would be necessary to fully assess this question.

While it is impossible to destroy all bacteria or eliminate all infections by simultaneous hand and stethoscope cleansing, many infections could potentially be prevented with this simple component of a comprehensive infection control program. Alcohol-based hand foam is already in use for hand cleansing between patients in many inpatient and outpatient settings, and this procedure requires no added cost and no additional time. Further research is necessary to determine whether the reduction of bacterial growth also corresponds to a reduction in clinically related disease. The results of this study provide evidence that hand foam, when used to simultaneously sterilize the hands and stethoscope, can significantly reduce the number of bacterial colonies on stethoscopes.

CORRESPONDENCE
Maryellen A. Schroeder, MD, MPH, UPMC St. Margaret, 815 Freeport Road, Pittsburgh, PA 15201; [email protected]

Dear Dr. Mossman,

A psychiatrist retires from practice and goes into some other line of work—perhaps managing a restaurant. He then has an “affair” with a former patient whom he had not treated for several years. Could the retired psychiatrist’s conduct be the basis of a successful lawsuit?—Submitted by “Dr. D”

Evidence tells us that the retired psychiatrist’s behavior likely could do emotional harm to his former patient. If the former patient suffers some injury, a successful suit could follow—if not on grounds of malpractice, then on other grounds. In this article we’ll see why by looking at:

• rates of doctor-patient sex
• potential harm from doctor-patient sex
• ethical bans on sex with former patients
• possible legal actions.

Sex with patients: Rates and risk

Doctors and patients often develop erotic thoughts about each other.^1,2 But as Sigmund Freud noted almost a century ago, an actual love relationship between a doctor and a psychotherapy patient can cause a “complete defeat for the treatment” and destroy the patient’s chance for recovery.³

More than 5 decades later, surveys of medical professionals supplemented Freud’s observations with data about the frequency and impact of doctor-patient sex. In a 1973 survey, 11% of physicians said they had erotic contact with patients, and 5% reported intercourse.⁴ In a 1986 survey of psychiatrists, 3% of women and 7% of men acknowledged having sexual contact with patients.⁵ In a 1992 study of 10,000 nonpsychiatric physicians, 9% of respondents reported having sex with patients.⁶ Actual rates of doctor-patient sex probably are much higher than reported because physicians may be reluctant to admit to having erotic contact with patients, even in anonymous surveys.⁷ The typical therapist-patient sex scenario involves a male doctor and an adult female patient, but same-sex encounters and sexual contact with minors occur, too.⁸

Sex between a therapist and a patient is likely to cause emotional injury. For example, a 1991 study found that 90% of psychotherapy patients who had sexual involvement with a prior therapist had been harmed by the experience.⁹ Books, articles, and Web sites offer vivid individual accounts of harm patients have suffered ( Table ). Doctors who have sex with patients could face public opprobrium, civil lawsuits, actions against their medical licenses, and prosecution in states that make sex with psychiatric patients a criminal offense.¹⁰

Table

How sexual relationships can harm patients

What about former patients?

Sex between providers and current patients is opposed by all major healthcare organizations, including the American Psychiatric Association (APA),¹¹ American Medical Association,¹² and American Psychological Association.¹³ The last 2 groups strongly discourage sex with former patients, but the APA’s ethics code states that such activity is always unethical.

The APA’s position reflects 2 general truths of psychiatric practice:

• Psychiatric patients often return for care years after initial treatment has ended. “Former patients” are really “possible future patients.” Improper relationships with former patients disrupt the doctor’s obligation to remain available for future care.
• Even if a patient never returns to treatment, intense feelings about a doctor can last for years. A psychiatrist who engages in sex with a former patient may evoke and manipulate feelings “left over” from therapy.

Psychiatrists therefore “have only one kind of relationship with a patient—that is, a doctor-patient relationship.”¹⁴ Moreover, as Simon and Shuman observe, “[N]o patient [is] strong enough, no pause is long enough, and no love is true enough to justify compromising this boundary.”¹⁵

Legal actions

If a physician no longer practices medicine, can any of his activities—including with a former patient—be malpractice? In fact, sex between practicing doctors and current patients might not always be malpractice. If a psychiatrist gains sexual access to a patient by saying that the sex will be therapeutic, the psychiatrist has perpetrated fraud and this intentional action might not be covered by malpractice insurance.¹⁶

In several cases involving nonpsychiatric physicians,¹⁷ courts have held that consensual doctor-patient sex is not malpractice, though it might represent some other form of wrongdoing. The argument is that sex with a patient is an intentional act that is never a professional service, whereas malpractice by definition arises unintentionally from negligence while rendering professional services. Other courts, however, have held that doctor-patient sex can be malpractice because it breaches the physician’s fiduciary relationship and can constitute an abuse of power.¹⁸

After retirement, physicians still have responsibilities to former patients: to protect records, to respect confidentiality, and to release information upon proper requests. Some fiduciary duties to patients survive the conclusion of treatment, and behavior that breaches those responsibilities can bring legal action.

Psychiatrists should realize that many former patients remain vulnerable because of feelings “left over” from therapy. Therefore, potential civil actions against a retired psychiatrist might include:

A suit for intentional infliction of emotional distress. This tort action requires proving more than mere insults or indignities; it occurs only when someone “by extreme and outrageous conduct intentionally or recklessly causes severe emotional distress to another.”¹⁹ Initiating sex with a former patient is strongly disapproved and meets the legal criterion of having a high probability of causing mental distress.²⁰

A suit for negligent infliction of emotional distress. Modern law permits recourse for negligently inflicted emotional distress when harm occurs in “the course of specified categories of activities, undertakings, or relationships in which the negligent conduct is especially likely to cause emotional disturbance.”²¹

Suits for exploitation. Some jurisdictions allow suits against therapists who have sex with former patients, irrespective of therapists’ license status. For example, Minnesota allows lawsuits for “sexual exploitation” if the former patient’s capacity to consent was impaired by emotional dependence on the psychotherapist.²²

Actions by licensing boards. Many retired practitioners maintain their medical licenses. Retired-but-still-licensed psychiatrists can be subject to professional disciplinary actions.

Dear Dr. Mossman,

A psychiatrist retires from practice and goes into some other line of work—perhaps managing a restaurant. He then has an “affair” with a former patient whom he had not treated for several years. Could the retired psychiatrist’s conduct be the basis of a successful lawsuit?—Submitted by “Dr. D”

Evidence tells us that the retired psychiatrist’s behavior likely could do emotional harm to his former patient. If the former patient suffers some injury, a successful suit could follow—if not on grounds of malpractice, then on other grounds. In this article we’ll see why by looking at:

• rates of doctor-patient sex
• potential harm from doctor-patient sex
• ethical bans on sex with former patients
• possible legal actions.

Sex with patients: Rates and risk

Doctors and patients often develop erotic thoughts about each other.^1,2 But as Sigmund Freud noted almost a century ago, an actual love relationship between a doctor and a psychotherapy patient can cause a “complete defeat for the treatment” and destroy the patient’s chance for recovery.³

More than 5 decades later, surveys of medical professionals supplemented Freud’s observations with data about the frequency and impact of doctor-patient sex. In a 1973 survey, 11% of physicians said they had erotic contact with patients, and 5% reported intercourse.⁴ In a 1986 survey of psychiatrists, 3% of women and 7% of men acknowledged having sexual contact with patients.⁵ In a 1992 study of 10,000 nonpsychiatric physicians, 9% of respondents reported having sex with patients.⁶ Actual rates of doctor-patient sex probably are much higher than reported because physicians may be reluctant to admit to having erotic contact with patients, even in anonymous surveys.⁷ The typical therapist-patient sex scenario involves a male doctor and an adult female patient, but same-sex encounters and sexual contact with minors occur, too.⁸

Sex between a therapist and a patient is likely to cause emotional injury. For example, a 1991 study found that 90% of psychotherapy patients who had sexual involvement with a prior therapist had been harmed by the experience.⁹ Books, articles, and Web sites offer vivid individual accounts of harm patients have suffered ( Table ). Doctors who have sex with patients could face public opprobrium, civil lawsuits, actions against their medical licenses, and prosecution in states that make sex with psychiatric patients a criminal offense.¹⁰

Table

How sexual relationships can harm patients

What about former patients?

Sex between providers and current patients is opposed by all major healthcare organizations, including the American Psychiatric Association (APA),¹¹ American Medical Association,¹² and American Psychological Association.¹³ The last 2 groups strongly discourage sex with former patients, but the APA’s ethics code states that such activity is always unethical.

The APA’s position reflects 2 general truths of psychiatric practice:

• Psychiatric patients often return for care years after initial treatment has ended. “Former patients” are really “possible future patients.” Improper relationships with former patients disrupt the doctor’s obligation to remain available for future care.
• Even if a patient never returns to treatment, intense feelings about a doctor can last for years. A psychiatrist who engages in sex with a former patient may evoke and manipulate feelings “left over” from therapy.

Psychiatrists therefore “have only one kind of relationship with a patient—that is, a doctor-patient relationship.”¹⁴ Moreover, as Simon and Shuman observe, “[N]o patient [is] strong enough, no pause is long enough, and no love is true enough to justify compromising this boundary.”¹⁵

Legal actions

If a physician no longer practices medicine, can any of his activities—including with a former patient—be malpractice? In fact, sex between practicing doctors and current patients might not always be malpractice. If a psychiatrist gains sexual access to a patient by saying that the sex will be therapeutic, the psychiatrist has perpetrated fraud and this intentional action might not be covered by malpractice insurance.¹⁶

In several cases involving nonpsychiatric physicians,¹⁷ courts have held that consensual doctor-patient sex is not malpractice, though it might represent some other form of wrongdoing. The argument is that sex with a patient is an intentional act that is never a professional service, whereas malpractice by definition arises unintentionally from negligence while rendering professional services. Other courts, however, have held that doctor-patient sex can be malpractice because it breaches the physician’s fiduciary relationship and can constitute an abuse of power.¹⁸

After retirement, physicians still have responsibilities to former patients: to protect records, to respect confidentiality, and to release information upon proper requests. Some fiduciary duties to patients survive the conclusion of treatment, and behavior that breaches those responsibilities can bring legal action.

Psychiatrists should realize that many former patients remain vulnerable because of feelings “left over” from therapy. Therefore, potential civil actions against a retired psychiatrist might include:

A suit for intentional infliction of emotional distress. This tort action requires proving more than mere insults or indignities; it occurs only when someone “by extreme and outrageous conduct intentionally or recklessly causes severe emotional distress to another.”¹⁹ Initiating sex with a former patient is strongly disapproved and meets the legal criterion of having a high probability of causing mental distress.²⁰

A suit for negligent infliction of emotional distress. Modern law permits recourse for negligently inflicted emotional distress when harm occurs in “the course of specified categories of activities, undertakings, or relationships in which the negligent conduct is especially likely to cause emotional disturbance.”²¹

Suits for exploitation. Some jurisdictions allow suits against therapists who have sex with former patients, irrespective of therapists’ license status. For example, Minnesota allows lawsuits for “sexual exploitation” if the former patient’s capacity to consent was impaired by emotional dependence on the psychotherapist.²²

Actions by licensing boards. Many retired practitioners maintain their medical licenses. Retired-but-still-licensed psychiatrists can be subject to professional disciplinary actions.

Dear Dr. Mossman,

A psychiatrist retires from practice and goes into some other line of work—perhaps managing a restaurant. He then has an “affair” with a former patient whom he had not treated for several years. Could the retired psychiatrist’s conduct be the basis of a successful lawsuit?—Submitted by “Dr. D”

Evidence tells us that the retired psychiatrist’s behavior likely could do emotional harm to his former patient. If the former patient suffers some injury, a successful suit could follow—if not on grounds of malpractice, then on other grounds. In this article we’ll see why by looking at:

• rates of doctor-patient sex
• potential harm from doctor-patient sex
• ethical bans on sex with former patients
• possible legal actions.

Sex with patients: Rates and risk

Doctors and patients often develop erotic thoughts about each other.^1,2 But as Sigmund Freud noted almost a century ago, an actual love relationship between a doctor and a psychotherapy patient can cause a “complete defeat for the treatment” and destroy the patient’s chance for recovery.³

More than 5 decades later, surveys of medical professionals supplemented Freud’s observations with data about the frequency and impact of doctor-patient sex. In a 1973 survey, 11% of physicians said they had erotic contact with patients, and 5% reported intercourse.⁴ In a 1986 survey of psychiatrists, 3% of women and 7% of men acknowledged having sexual contact with patients.⁵ In a 1992 study of 10,000 nonpsychiatric physicians, 9% of respondents reported having sex with patients.⁶ Actual rates of doctor-patient sex probably are much higher than reported because physicians may be reluctant to admit to having erotic contact with patients, even in anonymous surveys.⁷ The typical therapist-patient sex scenario involves a male doctor and an adult female patient, but same-sex encounters and sexual contact with minors occur, too.⁸

Sex between a therapist and a patient is likely to cause emotional injury. For example, a 1991 study found that 90% of psychotherapy patients who had sexual involvement with a prior therapist had been harmed by the experience.⁹ Books, articles, and Web sites offer vivid individual accounts of harm patients have suffered ( Table ). Doctors who have sex with patients could face public opprobrium, civil lawsuits, actions against their medical licenses, and prosecution in states that make sex with psychiatric patients a criminal offense.¹⁰

Table

How sexual relationships can harm patients

What about former patients?

Sex between providers and current patients is opposed by all major healthcare organizations, including the American Psychiatric Association (APA),¹¹ American Medical Association,¹² and American Psychological Association.¹³ The last 2 groups strongly discourage sex with former patients, but the APA’s ethics code states that such activity is always unethical.

The APA’s position reflects 2 general truths of psychiatric practice:

• Psychiatric patients often return for care years after initial treatment has ended. “Former patients” are really “possible future patients.” Improper relationships with former patients disrupt the doctor’s obligation to remain available for future care.
• Even if a patient never returns to treatment, intense feelings about a doctor can last for years. A psychiatrist who engages in sex with a former patient may evoke and manipulate feelings “left over” from therapy.

Psychiatrists therefore “have only one kind of relationship with a patient—that is, a doctor-patient relationship.”¹⁴ Moreover, as Simon and Shuman observe, “[N]o patient [is] strong enough, no pause is long enough, and no love is true enough to justify compromising this boundary.”¹⁵

Legal actions

If a physician no longer practices medicine, can any of his activities—including with a former patient—be malpractice? In fact, sex between practicing doctors and current patients might not always be malpractice. If a psychiatrist gains sexual access to a patient by saying that the sex will be therapeutic, the psychiatrist has perpetrated fraud and this intentional action might not be covered by malpractice insurance.¹⁶

In several cases involving nonpsychiatric physicians,¹⁷ courts have held that consensual doctor-patient sex is not malpractice, though it might represent some other form of wrongdoing. The argument is that sex with a patient is an intentional act that is never a professional service, whereas malpractice by definition arises unintentionally from negligence while rendering professional services. Other courts, however, have held that doctor-patient sex can be malpractice because it breaches the physician’s fiduciary relationship and can constitute an abuse of power.¹⁸

After retirement, physicians still have responsibilities to former patients: to protect records, to respect confidentiality, and to release information upon proper requests. Some fiduciary duties to patients survive the conclusion of treatment, and behavior that breaches those responsibilities can bring legal action.

Psychiatrists should realize that many former patients remain vulnerable because of feelings “left over” from therapy. Therefore, potential civil actions against a retired psychiatrist might include:

A suit for intentional infliction of emotional distress. This tort action requires proving more than mere insults or indignities; it occurs only when someone “by extreme and outrageous conduct intentionally or recklessly causes severe emotional distress to another.”¹⁹ Initiating sex with a former patient is strongly disapproved and meets the legal criterion of having a high probability of causing mental distress.²⁰

A suit for negligent infliction of emotional distress. Modern law permits recourse for negligently inflicted emotional distress when harm occurs in “the course of specified categories of activities, undertakings, or relationships in which the negligent conduct is especially likely to cause emotional disturbance.”²¹

Suits for exploitation. Some jurisdictions allow suits against therapists who have sex with former patients, irrespective of therapists’ license status. For example, Minnesota allows lawsuits for “sexual exploitation” if the former patient’s capacity to consent was impaired by emotional dependence on the psychotherapist.²²

Actions by licensing boards. Many retired practitioners maintain their medical licenses. Retired-but-still-licensed psychiatrists can be subject to professional disciplinary actions.

A thorough differential diagnosis, primarily based on history and physical examination, is essential when a child presents with a suspicious cough. Certain imaging modalities are also useful for diagnosis.

Identification of an underlying cause is crucial. When doing your history and physical exam, look for something that does not fit a routine presentation. For example, a cough in the presence of a constitutional change, such as weight loss, can indicate a more serious problem. In addition, a cough with a relatively sudden onset or one associated with labored breathing can be worrisome. Also, a choking episode followed by sudden cough, for example, can indicate the presence of a foreign body.

Asthma is the most common cause of chronic cough in the pediatric population, but also consider less common etiologies such as tracheoesophageal fistula, cystic fibrosis (CF), and bronchopulmonary dysplasia. Failure to thrive, clubbing, cardiac signs, and persistent stridor suggest alternative diagnoses.

Patient age offers some guidance in your differential diagnosis. In a neonate (younger than 28 days), persistent cough might suggest an infection or a congenital anomaly such as compression of the esophagus and trachea by a vascular ring. Infectious etiologies include rhinovirus, adenovirus, respiratory syncytial virus, and pertussis.

In preschool children, think upper or lower respiratory tract infection, rhinitis, postnasal drip syndrome, gastroesophageal reflux, an irritant source (such as passive smoking or air pollution), and, of course, asthma.

Among school-age children and adolescents, consider the same possibilities, but add inhalant or other substance abuse to your list of possible irritant causes. In addition, these older children can develop psychogenic or “habit” cough, one that is absent during sleep, distraction, or periods of concentration. Vocal cord dysfunction, also known as laryngeal wheeze, is another possibility in this group.

General pediatricians commonly treat children with a cough that lasts 5-10 days in the context of an upper respiratory tract illness, such as a cold. If a child still coughs incessantly after other cold symptoms have resolved, I would be concerned. This is not necessarily a call to refer the patient to a specialist, but this scenario is a call to do further diagnostic evaluation.

If the child already is diagnosed with asthma and develops a cough, determine whether the patient is taking the appropriate medication and/or is compliant with therapy. Also, ask about the child's environment, particularly the presence of passive smoking, dust, and pets.

In terms of allergy testing, I recommend a radioallergosorbent allergen-specific IgE antibody assay. This is indicated if a child has other lateral symptoms, such as eczema, and/or during peak times for seasonal allergies.

It is helpful when pediatricians do spirometry for a child with a suspicious cough. Nationwide, about 20%-25% of general pediatricians do pulmonary function testing. Pediatric pulmonologists like me would like to see more pediatricians perform these tests. Sinus x-rays also can be helpful, and are within the purview of the general pediatrician. Some might consider this an unnecessary test, however, or one for which you need a high index of suspicion before ordering.

A test that is generally unnecessary is a sweat test for cystic fibrosis. A lot of pediatricians get this test, and I would not tell them not to because often the child with CF has other symptoms that are more diagnostic.

A thorough differential diagnosis, primarily based on history and physical examination, is essential when a child presents with a suspicious cough. Certain imaging modalities are also useful for diagnosis.

Identification of an underlying cause is crucial. When doing your history and physical exam, look for something that does not fit a routine presentation. For example, a cough in the presence of a constitutional change, such as weight loss, can indicate a more serious problem. In addition, a cough with a relatively sudden onset or one associated with labored breathing can be worrisome. Also, a choking episode followed by sudden cough, for example, can indicate the presence of a foreign body.

Asthma is the most common cause of chronic cough in the pediatric population, but also consider less common etiologies such as tracheoesophageal fistula, cystic fibrosis (CF), and bronchopulmonary dysplasia. Failure to thrive, clubbing, cardiac signs, and persistent stridor suggest alternative diagnoses.

Patient age offers some guidance in your differential diagnosis. In a neonate (younger than 28 days), persistent cough might suggest an infection or a congenital anomaly such as compression of the esophagus and trachea by a vascular ring. Infectious etiologies include rhinovirus, adenovirus, respiratory syncytial virus, and pertussis.

In preschool children, think upper or lower respiratory tract infection, rhinitis, postnasal drip syndrome, gastroesophageal reflux, an irritant source (such as passive smoking or air pollution), and, of course, asthma.

Among school-age children and adolescents, consider the same possibilities, but add inhalant or other substance abuse to your list of possible irritant causes. In addition, these older children can develop psychogenic or “habit” cough, one that is absent during sleep, distraction, or periods of concentration. Vocal cord dysfunction, also known as laryngeal wheeze, is another possibility in this group.

General pediatricians commonly treat children with a cough that lasts 5-10 days in the context of an upper respiratory tract illness, such as a cold. If a child still coughs incessantly after other cold symptoms have resolved, I would be concerned. This is not necessarily a call to refer the patient to a specialist, but this scenario is a call to do further diagnostic evaluation.

If the child already is diagnosed with asthma and develops a cough, determine whether the patient is taking the appropriate medication and/or is compliant with therapy. Also, ask about the child's environment, particularly the presence of passive smoking, dust, and pets.

In terms of allergy testing, I recommend a radioallergosorbent allergen-specific IgE antibody assay. This is indicated if a child has other lateral symptoms, such as eczema, and/or during peak times for seasonal allergies.

It is helpful when pediatricians do spirometry for a child with a suspicious cough. Nationwide, about 20%-25% of general pediatricians do pulmonary function testing. Pediatric pulmonologists like me would like to see more pediatricians perform these tests. Sinus x-rays also can be helpful, and are within the purview of the general pediatrician. Some might consider this an unnecessary test, however, or one for which you need a high index of suspicion before ordering.

A test that is generally unnecessary is a sweat test for cystic fibrosis. A lot of pediatricians get this test, and I would not tell them not to because often the child with CF has other symptoms that are more diagnostic.

A thorough differential diagnosis, primarily based on history and physical examination, is essential when a child presents with a suspicious cough. Certain imaging modalities are also useful for diagnosis.

Identification of an underlying cause is crucial. When doing your history and physical exam, look for something that does not fit a routine presentation. For example, a cough in the presence of a constitutional change, such as weight loss, can indicate a more serious problem. In addition, a cough with a relatively sudden onset or one associated with labored breathing can be worrisome. Also, a choking episode followed by sudden cough, for example, can indicate the presence of a foreign body.

Asthma is the most common cause of chronic cough in the pediatric population, but also consider less common etiologies such as tracheoesophageal fistula, cystic fibrosis (CF), and bronchopulmonary dysplasia. Failure to thrive, clubbing, cardiac signs, and persistent stridor suggest alternative diagnoses.

Patient age offers some guidance in your differential diagnosis. In a neonate (younger than 28 days), persistent cough might suggest an infection or a congenital anomaly such as compression of the esophagus and trachea by a vascular ring. Infectious etiologies include rhinovirus, adenovirus, respiratory syncytial virus, and pertussis.

In preschool children, think upper or lower respiratory tract infection, rhinitis, postnasal drip syndrome, gastroesophageal reflux, an irritant source (such as passive smoking or air pollution), and, of course, asthma.

Among school-age children and adolescents, consider the same possibilities, but add inhalant or other substance abuse to your list of possible irritant causes. In addition, these older children can develop psychogenic or “habit” cough, one that is absent during sleep, distraction, or periods of concentration. Vocal cord dysfunction, also known as laryngeal wheeze, is another possibility in this group.

General pediatricians commonly treat children with a cough that lasts 5-10 days in the context of an upper respiratory tract illness, such as a cold. If a child still coughs incessantly after other cold symptoms have resolved, I would be concerned. This is not necessarily a call to refer the patient to a specialist, but this scenario is a call to do further diagnostic evaluation.

If the child already is diagnosed with asthma and develops a cough, determine whether the patient is taking the appropriate medication and/or is compliant with therapy. Also, ask about the child's environment, particularly the presence of passive smoking, dust, and pets.

In terms of allergy testing, I recommend a radioallergosorbent allergen-specific IgE antibody assay. This is indicated if a child has other lateral symptoms, such as eczema, and/or during peak times for seasonal allergies.

It is helpful when pediatricians do spirometry for a child with a suspicious cough. Nationwide, about 20%-25% of general pediatricians do pulmonary function testing. Pediatric pulmonologists like me would like to see more pediatricians perform these tests. Sinus x-rays also can be helpful, and are within the purview of the general pediatrician. Some might consider this an unnecessary test, however, or one for which you need a high index of suspicion before ordering.

A test that is generally unnecessary is a sweat test for cystic fibrosis. A lot of pediatricians get this test, and I would not tell them not to because often the child with CF has other symptoms that are more diagnostic.