Gregory Seymann, MD, SFHM

 

Case

A 50-year-old female presents with 3 days of cough, subjective fevers, myalgias, and dyspnea. She feels she “may have caught something” while volunteering at a preschool. She has hypertension, congestive heart failure, and 20 pack-years of smoking. Chest x-ray shows bibasilar consolidation versus atelectasis. Vital signs are notable for an O₂ saturation of 93%. White blood cell count and differential are normal. Procalcitonin level is 0.4 mcg/L.

Overview of the issue

Lower respiratory tract infections (LRTI) are common in the practice of hospital medicine; however, the primary symptoms of cough and dyspnea can be caused by a myriad of noninfectious conditions. Even when infection is suggested by the clinical presentation, the distinction between bacterial and viral etiologies can be challenging, complicating decisions about antibiotic use. Attention to antibiotic stewardship is a growing concern in U.S. hospitals, where the CDC estimates that as many as 50% of antibiotic orders are inappropriate or entirely unnecessary.¹ Antibiotic overuse is a driver of multidrug-resistant organisms and increasing rates of Clostridium difficile infection. A diagnostic test to enhance physicians’ ability to target patients who would benefit from antibiotics could be a useful tool to combat the complications of antibiotic overuse. (See Figure 1.)

Procalcitonin is produced in the thyroidal C-cells as a prohormone which is processed intracellularly and secreted as calcitonin in response to serum calcium levels. However, intact procalcitonin protein can be secreted from many other tissues in the presence of cytokines such as interleukin 1-beta, tumor necrosis factor-alpha, and lipopolysaccharide, typically released in response to systemic bacterial infections. Conversely, cytokines present in acute viral illness (interferon-gamma) suppress procalcitonin release. This dichotomy presents an opportunity to use procalcitonin to differentiate bacterial from nonbacterial etiologies in various clinical scenarios including LRTI.
 

Overview of the data

Multiple studies have demonstrated that procalcitonin can be safely used to guide antibiotic prescribing in patients with LRTI. The first large multicenter randomized controlled trial to address the topic was the Swiss PROHOSP study.² Investigators randomized 1,359 patients hospitalized with LRTI to procalcitonin (PCT) guided therapy or guideline-based therapy. After an initial PCT level was measured, antibiotic prescribing in the PCT arm of the study was directed by a prespecified protocol; specifically, clinicians were discouraged from prescribing antibiotics in patients with PCT levels less than 0.25 mcg/L. (See Figure 2.)

For patients who were particularly ill or unstable at admission, the protocol allowed for antibiotics despite a low PCT level, but repeat measurement within 24 hours and accompanying treatment recommendations were reinforced with the treatment team. Clinicians caring for patients in the control arm were presented with condition-specific clinical practice guidelines to reinforce antibiotic choices. In both arms, the final decision on antibiotic treatment remained with the physician.

Results from the PROHOSP study showed no difference in the combined outcome of death, intensive care unit admission, or complications in the ensuing 30 days, but antibiotic use was significantly reduced. Mean antibiotic exposure dropped from 8.7 to 5.7 days, a reduction of 35%, with the largest decrease among patients with chronic obstructive pulmonary disease (COPD) and acute bronchitis. Antibiotic-related adverse effects fell by 8.2%. Strengths of the study included a very high rate of protocol compliance (90%) by the treating clinicians.

A systematic review of all available studies of procalcitonin-guided therapy for LRTI was published in 2018 and included 26 randomized controlled trials encompassing 6,708 patients in 12 countries. Findings confirmed an overall reduction of 2.4 days in antibiotic exposure, 6% reduction in antibiotic-related adverse effects, and importantly a 17% relative risk reduction in mortality.³

Similar benefits of PCT-guided therapy have been demonstrated even among severely ill patients. A meta-analysis including 523 patients with bacteremia noted mean reduction in antibiotic exposure of 2.86 days, without excess mortality.⁴ A second meta-analysis of 4,482 critically ill patients admitted to the ICU with sepsis demonstrated not only a reduction in antibiotic exposure, but in mortality as well. Despite a relatively small decrease in antibiotic duration of 1.19 days, the investigators found an 11% reduction in mortality (P = .03) in the PCT-guided group.⁵

One notable outlier among the many positive studies on PCT-guided antibiotic therapy is the 2018 PROACT study performed in U.S. hospitals over 4 years.⁶ Its design was similar to the PROHOSP study, however, in contrast to the majority of other trials, the investigators were unable to demonstrate a reduction in antibiotic exposure, leading them to conclude that PCT guidance may not be a useful tool for antibiotic stewardship.

Unfortunately, significant differences in the compliance with the study protocol (90% in PROHOSP vs. 63% in PROACT), and a much healthier patient population (91% of the patients had a PCT less than 0.25, and a majority of patients had asthma which is not normally treated with antibiotics) hamper the generalizability of the PROACT findings. Rather than indicating a failure of PCT, the findings of the study underscore the fact that the utility of any lab test is limited unless it is applied in an appropriate diagnostic setting.

For hospitalists, the most clinically useful role for PCT testing is to guide the duration of antibiotic therapy. Although the literature supports short-course antibiotic therapy in many common conditions seen by hospitalists (Table 1), data suggest overprescribing remains prevalent. Several recent studies targeting LRTI underscore this point.

Despite guidelines advocating for treatment of uncomplicated community-acquired pneumonia (CAP) for no more than 5-7 days, two recent retrospective studies suggest most patients receive longer courses. A review of more than 150,000 patients across the United States with uncomplicated CAP documented a mean antibiotic duration of 9.5 days, with close to 70% of patients receiving more than 7 days of therapy.⁷ A multicenter study of CAP patients hospitalized in Michigan noted similar findings, with a mean 2-day excess duration of therapy or 2,526 excess days of treatment per 1,000 discharges.⁸ Though some who argue against procalcitonin’s utility cite the fact that existing guidelines already support short-course therapy, obviating the need for biomarker guidance, clinicians have not yet universally adopted this practice. Using a PCT algorithm can decrease duration of therapy and thereby reduce unnecessary antibiotic use. PCT levels less than 0.25 mcg/L support withholding or discontinuing antibiotics, or consideration of an alternative diagnosis.

The dynamics of the PCT assay must be considered in order to use it appropriately. Levels of PCT rise within 3-6 hours of infection, so patients presenting extremely early in the disease course may have falsely low levels. PCT levels correlate with severity of illness and should fall within 2-3 days of initiation of appropriate therapy. A repeat PCT in 2-3 days can be used to help time antibiotic cessation. Studies support stopping antibiotics in stable patients once the PCT level falls below 0.25 mcg/L or drops by 80% in patients with severe elevations. Lack of improvement suggests inadequate antibiotic therapy and is predictive of excess mortality.

Most drivers of false-positive PCT levels are rare and easily identifiable. (See Figure 3.) However, like troponin, patients with chronic kidney disease have delayed PCT clearance, so baseline levels may be about double the normal range. If a baseline is known, monitoring the rise and fall of PCT levels remains clinically useful in this population.

 

Application of data to case

In reviewing the case, the differential includes a viral upper respiratory infection, an acute exacerbation of COPD, decompensated heart failure, or bacterial pneumonia. The lab and imaging findings are nonspecific, but a PCT level less than 0.25 mcg/L raises concern for an acute bacterial pneumonia. Given that PCT levels rise in bacterial infection and are suppressed in viral infections, treating this patient with antibiotics seems prudent. In this case the relatively mild elevation suggests a less severe infection or a presentation early in the disease course. A repeat PCT in 2-3 days will guide timing for antibiotic cessation.

Bottom line

Thoughtful procalcitonin-guided antibiotic therapy for LRTI may further current antibiotic stewardship initiatives targeting reduction of inappropriate antimicrobial use, which may ultimately reduce rates of Clostridium difficile infections and the emergence of multidrug-resistant organisms.

Dr. Seymann and Dr. Ramos are clinical professors in the division of hospital medicine, department of medicine, at the University of California San Diego.

Key points

• Initial PCT level can help distinguish between viral and bacterial pneumonias.
• PCT levels rise in response to acute bacterial infections and are suppressed in viral infections.
• PCT levels below 0.25 mcg/L suggest that antibiotics can be safely withheld in otherwise stable patients.
• PCT levels correlate with severity of illness and prognosis.
• Rise of PCT is rapid (3-6 hours), and levels fall quickly with appropriate treatment (2-3 days).
• Serial PCT levels can be used to guide duration of antibiotic therapy.

References

1. CDC. Core elements of hospital antibiotic stewardship programs. Atlanta: U.S. Department of Health & Human Services. 2014. Available at www.cdc.gov/getsmart/healthcare/ implementation/core-elements.html.

2. Schuetz P et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: The ProHOSP randomized controlled trial. JAMA. 2009;302(10):1059-66. doi: 10.1001/jama.2009.1297.

3. Schuetz P et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. doi: 10.1016/S1473-3099(17)30592-3.

4. Meier MA et al. Procalcitonin-guided antibiotic treatment in patients with positive blood cultures: A patient-level meta-analysis of randomized trials. Clin Infect Dis. 2019;69(3):388-96. doi: 10.1093/cid/ciy917.

5. Wirz Y et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: A patient-level meta-analysis of randomized trials. Crit Care. 2018;22(1):191. doi: 10.1186/s13054-018-2125-7.

6. Huang DT et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018 Jul 19;379(3):236-49. doi: 10.1056/NEJMoa1802670.

7. Yi SH et al. Duration of antibiotic use among adults with uncomplicated community-acquired pneumonia requiring hospitalization in the United States. Clin Infect Dis. 2018;66(9):1333-41. doi: 10.1093/cid/cix986.

8. Vaughn V et al. Excess antibiotic treatment duration and adverse events in patients hospitalized with pneumonia: A multihospital cohort study. Ann Intern Med. 2019; 171(3):153-63. doi: 10.7326/M18-3640.

Quiz

1. A 57-year-old male is hospitalized for treatment of community-acquired pneumonia with IV azithromycin and ceftriaxone. PCT level on day 1 = 0.35 mcg/L. On day 4 of antibiotics the PCT level is 0.15 mcg/L. What should be done regarding the antibiotic course?

a. Continue antibiotics for a total course of 5 days.

b. Continue antibiotics for a total course of 7 days.

c. Stop antibiotics.

d. Continue antibiotics and repeat a PCT level the next day.

Answer: The best answer is c. Evidence suggests that 5 days of therapy is adequate treatment for uncomplicated community-acquired pneumonia. Procalcitonin-guided therapy allows for further tailoring of the regimen to the individual patient. Since this patient has clinically improved, and the PCT level is less than 0.25 mcg/L, it is reasonable to discontinue treatment and avoid unnecessary antibiotic days.

2. A 42-year-old female with known CKD stage 4 is hospitalized with suspected community-acquired pneumonia. Procalcitonin level is elevated at 0.6 mcg/L. How should the patient be treated?

a. Ignore the PCT as levels are falsely elevated due to CKD.

b. Treat with antibiotics for suspected community-acquired pneumonia.

c. Repeat PCT level in the morning.

d. Check a C-reactive protein level instead.

Answer: The best answer is b. Although decreased renal function can delay clearance of PCT, levels in CKD are typically about twice normal. In this case, when pneumonia is clinically suspected, the level of 0.6 mcg/L would correspond to a level of approximately 0.3 mcg/L and support a decision to treat with antibiotics.

3. A 36-year-old male develops sudden onset of dyspnea, cough, fever, and chills and proceeds rapidly to the emergency department. He is hypoxic, febrile, and has a leukocytosis. The PCT level is checked and found to be 0.2 mcg/L. Chest imaging shows a right middle lobe consolidation. How should the patient be treated?

a. Hold antibiotics.

b. Start antibiotic therapy.

c. Hold antibiotics and repeat PCT level in the morning.

Answer: The best answer is b. The clinical scenario suggests bacterial pneumonia. Given the sudden onset and early presentation to the ED, it is likely that the PCT level has not had time to peak. PCT levels typically begin to rise in 3-6 hours from the time of infection. Withholding antibiotics until the level exceeds 0.25 mcg/L would not be recommended when clinical judgment suggests otherwise.

4. Which of the following noninfectious scenarios does NOT cause an elevated PCT level?

a. Bone marrow transplant patient with acute graft versus host disease of the skin.

b. Patient presenting with paraneoplastic syndrome from small cell lung cancer.

c. Patient with cirrhosis presenting with hepatic encephalopathy.

d. Patient presenting with severe trauma from a motor vehicle accident.

Answer: The answer is c. Cirrhosis and/or hepatic encephalopathy does not cause a falsely elevated PCT level. Acute graft versus host disease, paraneoplastic syndrome from small cell lung cancer or medullary thyroid cancer, and massive stress such as severe trauma can cause elevations in PCT.
 

Additional reading

Spellberg B. The maturing antibiotic mantra: Shorter is still better. J Hosp Med. 2018;13:361-2. doi: 10.12788/jhm.2904.

Soni NJ et al. Procalcitonin-guided antibiotic therapy: A systematic review and meta-analysis. J Hosp Med. 2013;8:530-540. doi: 10.1002/jhm.2067.

Rhee C. Using procalcitonin to guide antibiotic therapy. Open Forum Infect Dis. 2017;4(1):ofw249. doi: 10.1093/ofid/ofw249.

Sager R et al. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med. 2017;15. doi: 10.1186/s12916-017-0795-7.

 

Case

A 50-year-old female presents with 3 days of cough, subjective fevers, myalgias, and dyspnea. She feels she “may have caught something” while volunteering at a preschool. She has hypertension, congestive heart failure, and 20 pack-years of smoking. Chest x-ray shows bibasilar consolidation versus atelectasis. Vital signs are notable for an O₂ saturation of 93%. White blood cell count and differential are normal. Procalcitonin level is 0.4 mcg/L.

Overview of the issue

Lower respiratory tract infections (LRTI) are common in the practice of hospital medicine; however, the primary symptoms of cough and dyspnea can be caused by a myriad of noninfectious conditions. Even when infection is suggested by the clinical presentation, the distinction between bacterial and viral etiologies can be challenging, complicating decisions about antibiotic use. Attention to antibiotic stewardship is a growing concern in U.S. hospitals, where the CDC estimates that as many as 50% of antibiotic orders are inappropriate or entirely unnecessary.¹ Antibiotic overuse is a driver of multidrug-resistant organisms and increasing rates of Clostridium difficile infection. A diagnostic test to enhance physicians’ ability to target patients who would benefit from antibiotics could be a useful tool to combat the complications of antibiotic overuse. (See Figure 1.)

Procalcitonin is produced in the thyroidal C-cells as a prohormone which is processed intracellularly and secreted as calcitonin in response to serum calcium levels. However, intact procalcitonin protein can be secreted from many other tissues in the presence of cytokines such as interleukin 1-beta, tumor necrosis factor-alpha, and lipopolysaccharide, typically released in response to systemic bacterial infections. Conversely, cytokines present in acute viral illness (interferon-gamma) suppress procalcitonin release. This dichotomy presents an opportunity to use procalcitonin to differentiate bacterial from nonbacterial etiologies in various clinical scenarios including LRTI.
 

Overview of the data

Multiple studies have demonstrated that procalcitonin can be safely used to guide antibiotic prescribing in patients with LRTI. The first large multicenter randomized controlled trial to address the topic was the Swiss PROHOSP study.² Investigators randomized 1,359 patients hospitalized with LRTI to procalcitonin (PCT) guided therapy or guideline-based therapy. After an initial PCT level was measured, antibiotic prescribing in the PCT arm of the study was directed by a prespecified protocol; specifically, clinicians were discouraged from prescribing antibiotics in patients with PCT levels less than 0.25 mcg/L. (See Figure 2.)

For patients who were particularly ill or unstable at admission, the protocol allowed for antibiotics despite a low PCT level, but repeat measurement within 24 hours and accompanying treatment recommendations were reinforced with the treatment team. Clinicians caring for patients in the control arm were presented with condition-specific clinical practice guidelines to reinforce antibiotic choices. In both arms, the final decision on antibiotic treatment remained with the physician.

Results from the PROHOSP study showed no difference in the combined outcome of death, intensive care unit admission, or complications in the ensuing 30 days, but antibiotic use was significantly reduced. Mean antibiotic exposure dropped from 8.7 to 5.7 days, a reduction of 35%, with the largest decrease among patients with chronic obstructive pulmonary disease (COPD) and acute bronchitis. Antibiotic-related adverse effects fell by 8.2%. Strengths of the study included a very high rate of protocol compliance (90%) by the treating clinicians.

A systematic review of all available studies of procalcitonin-guided therapy for LRTI was published in 2018 and included 26 randomized controlled trials encompassing 6,708 patients in 12 countries. Findings confirmed an overall reduction of 2.4 days in antibiotic exposure, 6% reduction in antibiotic-related adverse effects, and importantly a 17% relative risk reduction in mortality.³

Similar benefits of PCT-guided therapy have been demonstrated even among severely ill patients. A meta-analysis including 523 patients with bacteremia noted mean reduction in antibiotic exposure of 2.86 days, without excess mortality.⁴ A second meta-analysis of 4,482 critically ill patients admitted to the ICU with sepsis demonstrated not only a reduction in antibiotic exposure, but in mortality as well. Despite a relatively small decrease in antibiotic duration of 1.19 days, the investigators found an 11% reduction in mortality (P = .03) in the PCT-guided group.⁵

One notable outlier among the many positive studies on PCT-guided antibiotic therapy is the 2018 PROACT study performed in U.S. hospitals over 4 years.⁶ Its design was similar to the PROHOSP study, however, in contrast to the majority of other trials, the investigators were unable to demonstrate a reduction in antibiotic exposure, leading them to conclude that PCT guidance may not be a useful tool for antibiotic stewardship.

Unfortunately, significant differences in the compliance with the study protocol (90% in PROHOSP vs. 63% in PROACT), and a much healthier patient population (91% of the patients had a PCT less than 0.25, and a majority of patients had asthma which is not normally treated with antibiotics) hamper the generalizability of the PROACT findings. Rather than indicating a failure of PCT, the findings of the study underscore the fact that the utility of any lab test is limited unless it is applied in an appropriate diagnostic setting.

For hospitalists, the most clinically useful role for PCT testing is to guide the duration of antibiotic therapy. Although the literature supports short-course antibiotic therapy in many common conditions seen by hospitalists (Table 1), data suggest overprescribing remains prevalent. Several recent studies targeting LRTI underscore this point.

Despite guidelines advocating for treatment of uncomplicated community-acquired pneumonia (CAP) for no more than 5-7 days, two recent retrospective studies suggest most patients receive longer courses. A review of more than 150,000 patients across the United States with uncomplicated CAP documented a mean antibiotic duration of 9.5 days, with close to 70% of patients receiving more than 7 days of therapy.⁷ A multicenter study of CAP patients hospitalized in Michigan noted similar findings, with a mean 2-day excess duration of therapy or 2,526 excess days of treatment per 1,000 discharges.⁸ Though some who argue against procalcitonin’s utility cite the fact that existing guidelines already support short-course therapy, obviating the need for biomarker guidance, clinicians have not yet universally adopted this practice. Using a PCT algorithm can decrease duration of therapy and thereby reduce unnecessary antibiotic use. PCT levels less than 0.25 mcg/L support withholding or discontinuing antibiotics, or consideration of an alternative diagnosis.

The dynamics of the PCT assay must be considered in order to use it appropriately. Levels of PCT rise within 3-6 hours of infection, so patients presenting extremely early in the disease course may have falsely low levels. PCT levels correlate with severity of illness and should fall within 2-3 days of initiation of appropriate therapy. A repeat PCT in 2-3 days can be used to help time antibiotic cessation. Studies support stopping antibiotics in stable patients once the PCT level falls below 0.25 mcg/L or drops by 80% in patients with severe elevations. Lack of improvement suggests inadequate antibiotic therapy and is predictive of excess mortality.

Most drivers of false-positive PCT levels are rare and easily identifiable. (See Figure 3.) However, like troponin, patients with chronic kidney disease have delayed PCT clearance, so baseline levels may be about double the normal range. If a baseline is known, monitoring the rise and fall of PCT levels remains clinically useful in this population.

 

Application of data to case

In reviewing the case, the differential includes a viral upper respiratory infection, an acute exacerbation of COPD, decompensated heart failure, or bacterial pneumonia. The lab and imaging findings are nonspecific, but a PCT level less than 0.25 mcg/L raises concern for an acute bacterial pneumonia. Given that PCT levels rise in bacterial infection and are suppressed in viral infections, treating this patient with antibiotics seems prudent. In this case the relatively mild elevation suggests a less severe infection or a presentation early in the disease course. A repeat PCT in 2-3 days will guide timing for antibiotic cessation.

Bottom line

Thoughtful procalcitonin-guided antibiotic therapy for LRTI may further current antibiotic stewardship initiatives targeting reduction of inappropriate antimicrobial use, which may ultimately reduce rates of Clostridium difficile infections and the emergence of multidrug-resistant organisms.

Dr. Seymann and Dr. Ramos are clinical professors in the division of hospital medicine, department of medicine, at the University of California San Diego.

Key points

• Initial PCT level can help distinguish between viral and bacterial pneumonias.
• PCT levels rise in response to acute bacterial infections and are suppressed in viral infections.
• PCT levels below 0.25 mcg/L suggest that antibiotics can be safely withheld in otherwise stable patients.
• PCT levels correlate with severity of illness and prognosis.
• Rise of PCT is rapid (3-6 hours), and levels fall quickly with appropriate treatment (2-3 days).
• Serial PCT levels can be used to guide duration of antibiotic therapy.

References

1. CDC. Core elements of hospital antibiotic stewardship programs. Atlanta: U.S. Department of Health & Human Services. 2014. Available at www.cdc.gov/getsmart/healthcare/ implementation/core-elements.html.

2. Schuetz P et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: The ProHOSP randomized controlled trial. JAMA. 2009;302(10):1059-66. doi: 10.1001/jama.2009.1297.

3. Schuetz P et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. doi: 10.1016/S1473-3099(17)30592-3.

4. Meier MA et al. Procalcitonin-guided antibiotic treatment in patients with positive blood cultures: A patient-level meta-analysis of randomized trials. Clin Infect Dis. 2019;69(3):388-96. doi: 10.1093/cid/ciy917.

5. Wirz Y et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: A patient-level meta-analysis of randomized trials. Crit Care. 2018;22(1):191. doi: 10.1186/s13054-018-2125-7.

6. Huang DT et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018 Jul 19;379(3):236-49. doi: 10.1056/NEJMoa1802670.

7. Yi SH et al. Duration of antibiotic use among adults with uncomplicated community-acquired pneumonia requiring hospitalization in the United States. Clin Infect Dis. 2018;66(9):1333-41. doi: 10.1093/cid/cix986.

8. Vaughn V et al. Excess antibiotic treatment duration and adverse events in patients hospitalized with pneumonia: A multihospital cohort study. Ann Intern Med. 2019; 171(3):153-63. doi: 10.7326/M18-3640.

Quiz

1. A 57-year-old male is hospitalized for treatment of community-acquired pneumonia with IV azithromycin and ceftriaxone. PCT level on day 1 = 0.35 mcg/L. On day 4 of antibiotics the PCT level is 0.15 mcg/L. What should be done regarding the antibiotic course?

a. Continue antibiotics for a total course of 5 days.

b. Continue antibiotics for a total course of 7 days.

c. Stop antibiotics.

d. Continue antibiotics and repeat a PCT level the next day.

Answer: The best answer is c. Evidence suggests that 5 days of therapy is adequate treatment for uncomplicated community-acquired pneumonia. Procalcitonin-guided therapy allows for further tailoring of the regimen to the individual patient. Since this patient has clinically improved, and the PCT level is less than 0.25 mcg/L, it is reasonable to discontinue treatment and avoid unnecessary antibiotic days.

2. A 42-year-old female with known CKD stage 4 is hospitalized with suspected community-acquired pneumonia. Procalcitonin level is elevated at 0.6 mcg/L. How should the patient be treated?

a. Ignore the PCT as levels are falsely elevated due to CKD.

b. Treat with antibiotics for suspected community-acquired pneumonia.

c. Repeat PCT level in the morning.

d. Check a C-reactive protein level instead.

Answer: The best answer is b. Although decreased renal function can delay clearance of PCT, levels in CKD are typically about twice normal. In this case, when pneumonia is clinically suspected, the level of 0.6 mcg/L would correspond to a level of approximately 0.3 mcg/L and support a decision to treat with antibiotics.

3. A 36-year-old male develops sudden onset of dyspnea, cough, fever, and chills and proceeds rapidly to the emergency department. He is hypoxic, febrile, and has a leukocytosis. The PCT level is checked and found to be 0.2 mcg/L. Chest imaging shows a right middle lobe consolidation. How should the patient be treated?

a. Hold antibiotics.

b. Start antibiotic therapy.

c. Hold antibiotics and repeat PCT level in the morning.

Answer: The best answer is b. The clinical scenario suggests bacterial pneumonia. Given the sudden onset and early presentation to the ED, it is likely that the PCT level has not had time to peak. PCT levels typically begin to rise in 3-6 hours from the time of infection. Withholding antibiotics until the level exceeds 0.25 mcg/L would not be recommended when clinical judgment suggests otherwise.

4. Which of the following noninfectious scenarios does NOT cause an elevated PCT level?

a. Bone marrow transplant patient with acute graft versus host disease of the skin.

b. Patient presenting with paraneoplastic syndrome from small cell lung cancer.

c. Patient with cirrhosis presenting with hepatic encephalopathy.

d. Patient presenting with severe trauma from a motor vehicle accident.

Answer: The answer is c. Cirrhosis and/or hepatic encephalopathy does not cause a falsely elevated PCT level. Acute graft versus host disease, paraneoplastic syndrome from small cell lung cancer or medullary thyroid cancer, and massive stress such as severe trauma can cause elevations in PCT.
 

Additional reading

Spellberg B. The maturing antibiotic mantra: Shorter is still better. J Hosp Med. 2018;13:361-2. doi: 10.12788/jhm.2904.

Soni NJ et al. Procalcitonin-guided antibiotic therapy: A systematic review and meta-analysis. J Hosp Med. 2013;8:530-540. doi: 10.1002/jhm.2067.

Rhee C. Using procalcitonin to guide antibiotic therapy. Open Forum Infect Dis. 2017;4(1):ofw249. doi: 10.1093/ofid/ofw249.

Sager R et al. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med. 2017;15. doi: 10.1186/s12916-017-0795-7.

 

Case

A 50-year-old female presents with 3 days of cough, subjective fevers, myalgias, and dyspnea. She feels she “may have caught something” while volunteering at a preschool. She has hypertension, congestive heart failure, and 20 pack-years of smoking. Chest x-ray shows bibasilar consolidation versus atelectasis. Vital signs are notable for an O₂ saturation of 93%. White blood cell count and differential are normal. Procalcitonin level is 0.4 mcg/L.

Overview of the issue

Lower respiratory tract infections (LRTI) are common in the practice of hospital medicine; however, the primary symptoms of cough and dyspnea can be caused by a myriad of noninfectious conditions. Even when infection is suggested by the clinical presentation, the distinction between bacterial and viral etiologies can be challenging, complicating decisions about antibiotic use. Attention to antibiotic stewardship is a growing concern in U.S. hospitals, where the CDC estimates that as many as 50% of antibiotic orders are inappropriate or entirely unnecessary.¹ Antibiotic overuse is a driver of multidrug-resistant organisms and increasing rates of Clostridium difficile infection. A diagnostic test to enhance physicians’ ability to target patients who would benefit from antibiotics could be a useful tool to combat the complications of antibiotic overuse. (See Figure 1.)

Procalcitonin is produced in the thyroidal C-cells as a prohormone which is processed intracellularly and secreted as calcitonin in response to serum calcium levels. However, intact procalcitonin protein can be secreted from many other tissues in the presence of cytokines such as interleukin 1-beta, tumor necrosis factor-alpha, and lipopolysaccharide, typically released in response to systemic bacterial infections. Conversely, cytokines present in acute viral illness (interferon-gamma) suppress procalcitonin release. This dichotomy presents an opportunity to use procalcitonin to differentiate bacterial from nonbacterial etiologies in various clinical scenarios including LRTI.
 

Overview of the data

Multiple studies have demonstrated that procalcitonin can be safely used to guide antibiotic prescribing in patients with LRTI. The first large multicenter randomized controlled trial to address the topic was the Swiss PROHOSP study.² Investigators randomized 1,359 patients hospitalized with LRTI to procalcitonin (PCT) guided therapy or guideline-based therapy. After an initial PCT level was measured, antibiotic prescribing in the PCT arm of the study was directed by a prespecified protocol; specifically, clinicians were discouraged from prescribing antibiotics in patients with PCT levels less than 0.25 mcg/L. (See Figure 2.)

For patients who were particularly ill or unstable at admission, the protocol allowed for antibiotics despite a low PCT level, but repeat measurement within 24 hours and accompanying treatment recommendations were reinforced with the treatment team. Clinicians caring for patients in the control arm were presented with condition-specific clinical practice guidelines to reinforce antibiotic choices. In both arms, the final decision on antibiotic treatment remained with the physician.

Results from the PROHOSP study showed no difference in the combined outcome of death, intensive care unit admission, or complications in the ensuing 30 days, but antibiotic use was significantly reduced. Mean antibiotic exposure dropped from 8.7 to 5.7 days, a reduction of 35%, with the largest decrease among patients with chronic obstructive pulmonary disease (COPD) and acute bronchitis. Antibiotic-related adverse effects fell by 8.2%. Strengths of the study included a very high rate of protocol compliance (90%) by the treating clinicians.

A systematic review of all available studies of procalcitonin-guided therapy for LRTI was published in 2018 and included 26 randomized controlled trials encompassing 6,708 patients in 12 countries. Findings confirmed an overall reduction of 2.4 days in antibiotic exposure, 6% reduction in antibiotic-related adverse effects, and importantly a 17% relative risk reduction in mortality.³

Similar benefits of PCT-guided therapy have been demonstrated even among severely ill patients. A meta-analysis including 523 patients with bacteremia noted mean reduction in antibiotic exposure of 2.86 days, without excess mortality.⁴ A second meta-analysis of 4,482 critically ill patients admitted to the ICU with sepsis demonstrated not only a reduction in antibiotic exposure, but in mortality as well. Despite a relatively small decrease in antibiotic duration of 1.19 days, the investigators found an 11% reduction in mortality (P = .03) in the PCT-guided group.⁵

One notable outlier among the many positive studies on PCT-guided antibiotic therapy is the 2018 PROACT study performed in U.S. hospitals over 4 years.⁶ Its design was similar to the PROHOSP study, however, in contrast to the majority of other trials, the investigators were unable to demonstrate a reduction in antibiotic exposure, leading them to conclude that PCT guidance may not be a useful tool for antibiotic stewardship.

Unfortunately, significant differences in the compliance with the study protocol (90% in PROHOSP vs. 63% in PROACT), and a much healthier patient population (91% of the patients had a PCT less than 0.25, and a majority of patients had asthma which is not normally treated with antibiotics) hamper the generalizability of the PROACT findings. Rather than indicating a failure of PCT, the findings of the study underscore the fact that the utility of any lab test is limited unless it is applied in an appropriate diagnostic setting.

For hospitalists, the most clinically useful role for PCT testing is to guide the duration of antibiotic therapy. Although the literature supports short-course antibiotic therapy in many common conditions seen by hospitalists (Table 1), data suggest overprescribing remains prevalent. Several recent studies targeting LRTI underscore this point.

Despite guidelines advocating for treatment of uncomplicated community-acquired pneumonia (CAP) for no more than 5-7 days, two recent retrospective studies suggest most patients receive longer courses. A review of more than 150,000 patients across the United States with uncomplicated CAP documented a mean antibiotic duration of 9.5 days, with close to 70% of patients receiving more than 7 days of therapy.⁷ A multicenter study of CAP patients hospitalized in Michigan noted similar findings, with a mean 2-day excess duration of therapy or 2,526 excess days of treatment per 1,000 discharges.⁸ Though some who argue against procalcitonin’s utility cite the fact that existing guidelines already support short-course therapy, obviating the need for biomarker guidance, clinicians have not yet universally adopted this practice. Using a PCT algorithm can decrease duration of therapy and thereby reduce unnecessary antibiotic use. PCT levels less than 0.25 mcg/L support withholding or discontinuing antibiotics, or consideration of an alternative diagnosis.

The dynamics of the PCT assay must be considered in order to use it appropriately. Levels of PCT rise within 3-6 hours of infection, so patients presenting extremely early in the disease course may have falsely low levels. PCT levels correlate with severity of illness and should fall within 2-3 days of initiation of appropriate therapy. A repeat PCT in 2-3 days can be used to help time antibiotic cessation. Studies support stopping antibiotics in stable patients once the PCT level falls below 0.25 mcg/L or drops by 80% in patients with severe elevations. Lack of improvement suggests inadequate antibiotic therapy and is predictive of excess mortality.

Most drivers of false-positive PCT levels are rare and easily identifiable. (See Figure 3.) However, like troponin, patients with chronic kidney disease have delayed PCT clearance, so baseline levels may be about double the normal range. If a baseline is known, monitoring the rise and fall of PCT levels remains clinically useful in this population.

 

Application of data to case

In reviewing the case, the differential includes a viral upper respiratory infection, an acute exacerbation of COPD, decompensated heart failure, or bacterial pneumonia. The lab and imaging findings are nonspecific, but a PCT level less than 0.25 mcg/L raises concern for an acute bacterial pneumonia. Given that PCT levels rise in bacterial infection and are suppressed in viral infections, treating this patient with antibiotics seems prudent. In this case the relatively mild elevation suggests a less severe infection or a presentation early in the disease course. A repeat PCT in 2-3 days will guide timing for antibiotic cessation.

Bottom line

Thoughtful procalcitonin-guided antibiotic therapy for LRTI may further current antibiotic stewardship initiatives targeting reduction of inappropriate antimicrobial use, which may ultimately reduce rates of Clostridium difficile infections and the emergence of multidrug-resistant organisms.

Dr. Seymann and Dr. Ramos are clinical professors in the division of hospital medicine, department of medicine, at the University of California San Diego.

Key points

• Initial PCT level can help distinguish between viral and bacterial pneumonias.
• PCT levels rise in response to acute bacterial infections and are suppressed in viral infections.
• PCT levels below 0.25 mcg/L suggest that antibiotics can be safely withheld in otherwise stable patients.
• PCT levels correlate with severity of illness and prognosis.
• Rise of PCT is rapid (3-6 hours), and levels fall quickly with appropriate treatment (2-3 days).
• Serial PCT levels can be used to guide duration of antibiotic therapy.

References

1. CDC. Core elements of hospital antibiotic stewardship programs. Atlanta: U.S. Department of Health & Human Services. 2014. Available at www.cdc.gov/getsmart/healthcare/ implementation/core-elements.html.

2. Schuetz P et al. Effect of procalcitonin-based guidelines vs. standard guidelines on antibiotic use in lower respiratory tract infections: The ProHOSP randomized controlled trial. JAMA. 2009;302(10):1059-66. doi: 10.1001/jama.2009.1297.

3. Schuetz P et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: A patient level meta-analysis. Lancet Infect Dis. 2018;18(1):95-107. doi: 10.1016/S1473-3099(17)30592-3.

4. Meier MA et al. Procalcitonin-guided antibiotic treatment in patients with positive blood cultures: A patient-level meta-analysis of randomized trials. Clin Infect Dis. 2019;69(3):388-96. doi: 10.1093/cid/ciy917.

5. Wirz Y et al. Effect of procalcitonin-guided antibiotic treatment on clinical outcomes in intensive care unit patients with infection and sepsis patients: A patient-level meta-analysis of randomized trials. Crit Care. 2018;22(1):191. doi: 10.1186/s13054-018-2125-7.

6. Huang DT et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018 Jul 19;379(3):236-49. doi: 10.1056/NEJMoa1802670.

7. Yi SH et al. Duration of antibiotic use among adults with uncomplicated community-acquired pneumonia requiring hospitalization in the United States. Clin Infect Dis. 2018;66(9):1333-41. doi: 10.1093/cid/cix986.

8. Vaughn V et al. Excess antibiotic treatment duration and adverse events in patients hospitalized with pneumonia: A multihospital cohort study. Ann Intern Med. 2019; 171(3):153-63. doi: 10.7326/M18-3640.

Quiz

1. A 57-year-old male is hospitalized for treatment of community-acquired pneumonia with IV azithromycin and ceftriaxone. PCT level on day 1 = 0.35 mcg/L. On day 4 of antibiotics the PCT level is 0.15 mcg/L. What should be done regarding the antibiotic course?

a. Continue antibiotics for a total course of 5 days.

b. Continue antibiotics for a total course of 7 days.

c. Stop antibiotics.

d. Continue antibiotics and repeat a PCT level the next day.

Answer: The best answer is c. Evidence suggests that 5 days of therapy is adequate treatment for uncomplicated community-acquired pneumonia. Procalcitonin-guided therapy allows for further tailoring of the regimen to the individual patient. Since this patient has clinically improved, and the PCT level is less than 0.25 mcg/L, it is reasonable to discontinue treatment and avoid unnecessary antibiotic days.

2. A 42-year-old female with known CKD stage 4 is hospitalized with suspected community-acquired pneumonia. Procalcitonin level is elevated at 0.6 mcg/L. How should the patient be treated?

a. Ignore the PCT as levels are falsely elevated due to CKD.

b. Treat with antibiotics for suspected community-acquired pneumonia.

c. Repeat PCT level in the morning.

d. Check a C-reactive protein level instead.

Answer: The best answer is b. Although decreased renal function can delay clearance of PCT, levels in CKD are typically about twice normal. In this case, when pneumonia is clinically suspected, the level of 0.6 mcg/L would correspond to a level of approximately 0.3 mcg/L and support a decision to treat with antibiotics.

3. A 36-year-old male develops sudden onset of dyspnea, cough, fever, and chills and proceeds rapidly to the emergency department. He is hypoxic, febrile, and has a leukocytosis. The PCT level is checked and found to be 0.2 mcg/L. Chest imaging shows a right middle lobe consolidation. How should the patient be treated?

a. Hold antibiotics.

b. Start antibiotic therapy.

c. Hold antibiotics and repeat PCT level in the morning.

Answer: The best answer is b. The clinical scenario suggests bacterial pneumonia. Given the sudden onset and early presentation to the ED, it is likely that the PCT level has not had time to peak. PCT levels typically begin to rise in 3-6 hours from the time of infection. Withholding antibiotics until the level exceeds 0.25 mcg/L would not be recommended when clinical judgment suggests otherwise.

4. Which of the following noninfectious scenarios does NOT cause an elevated PCT level?

a. Bone marrow transplant patient with acute graft versus host disease of the skin.

b. Patient presenting with paraneoplastic syndrome from small cell lung cancer.

c. Patient with cirrhosis presenting with hepatic encephalopathy.

d. Patient presenting with severe trauma from a motor vehicle accident.

Answer: The answer is c. Cirrhosis and/or hepatic encephalopathy does not cause a falsely elevated PCT level. Acute graft versus host disease, paraneoplastic syndrome from small cell lung cancer or medullary thyroid cancer, and massive stress such as severe trauma can cause elevations in PCT.
 

Additional reading

Spellberg B. The maturing antibiotic mantra: Shorter is still better. J Hosp Med. 2018;13:361-2. doi: 10.12788/jhm.2904.

Soni NJ et al. Procalcitonin-guided antibiotic therapy: A systematic review and meta-analysis. J Hosp Med. 2013;8:530-540. doi: 10.1002/jhm.2067.

Rhee C. Using procalcitonin to guide antibiotic therapy. Open Forum Infect Dis. 2017;4(1):ofw249. doi: 10.1093/ofid/ofw249.

Sager R et al. Procalcitonin-guided diagnosis and antibiotic stewardship revisited. BMC Med. 2017;15. doi: 10.1186/s12916-017-0795-7.