Infectious Diseases

The Food and Drug Administration has approved Dengvaxia, the first vaccine indicated for the prevention of dengue virus disease caused by all viral serotypes. The vaccine was approved for children aged 9-16 years who live in endemic areas and have previously had laboratory-confirmed dengue disease.

Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands, according to an FDA statement announcing the approval.

While the first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu, a second infection can lead to a more severe form of the disease, including dengue hemorrhagic fever, which can be fatal. About 95% of hospitalized patients with dengue disease have a second dengue virus infection.

FDA approval of Dengvaxia is based on results from three randomized, placebo-controlled studies of 35,000 individuals in dengue-endemic areas. The vaccine was about 76% effective in preventing symptomatic, laboratory-confirmed dengue disease in people aged 9-16 years with a previous dengue diagnosis. The most common adverse events were headache, muscle pain, joint pain, fatigue, injection site pain, and low-grade fever; the frequency of adverse events decreased after each subsequent dose.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease. ... The FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement.

[email protected]

The Food and Drug Administration has approved Dengvaxia, the first vaccine indicated for the prevention of dengue virus disease caused by all viral serotypes. The vaccine was approved for children aged 9-16 years who live in endemic areas and have previously had laboratory-confirmed dengue disease.

Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands, according to an FDA statement announcing the approval.

While the first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu, a second infection can lead to a more severe form of the disease, including dengue hemorrhagic fever, which can be fatal. About 95% of hospitalized patients with dengue disease have a second dengue virus infection.

FDA approval of Dengvaxia is based on results from three randomized, placebo-controlled studies of 35,000 individuals in dengue-endemic areas. The vaccine was about 76% effective in preventing symptomatic, laboratory-confirmed dengue disease in people aged 9-16 years with a previous dengue diagnosis. The most common adverse events were headache, muscle pain, joint pain, fatigue, injection site pain, and low-grade fever; the frequency of adverse events decreased after each subsequent dose.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease. ... The FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement.

[email protected]

The Food and Drug Administration has approved Dengvaxia, the first vaccine indicated for the prevention of dengue virus disease caused by all viral serotypes. The vaccine was approved for children aged 9-16 years who live in endemic areas and have previously had laboratory-confirmed dengue disease.

Dengue is endemic in the U.S. territories of American Samoa, Guam, Puerto Rico, and the U.S. Virgin Islands, according to an FDA statement announcing the approval.

While the first infection with dengue virus typically results in either no symptoms or a mild illness that can be mistaken for the flu, a second infection can lead to a more severe form of the disease, including dengue hemorrhagic fever, which can be fatal. About 95% of hospitalized patients with dengue disease have a second dengue virus infection.

FDA approval of Dengvaxia is based on results from three randomized, placebo-controlled studies of 35,000 individuals in dengue-endemic areas. The vaccine was about 76% effective in preventing symptomatic, laboratory-confirmed dengue disease in people aged 9-16 years with a previous dengue diagnosis. The most common adverse events were headache, muscle pain, joint pain, fatigue, injection site pain, and low-grade fever; the frequency of adverse events decreased after each subsequent dose.

“Infection by one type of dengue virus usually provides immunity against that specific serotype, but a subsequent infection by any of the other three serotypes of the virus increases the risk of developing severe dengue disease. ... The FDA’s approval of this vaccine will help protect people previously infected with dengue virus from subsequent development of dengue disease,” Peter Marks, MD, director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement.

[email protected]

It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.

Getty Images

It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.

Do you ignore your training and treat these sick children with antibiotics?

If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?

A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).

The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.

In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?

Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.

We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.

Getty Images

It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.

Do you ignore your training and treat these sick children with antibiotics?

If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?

A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).

The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.

In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?

Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.

We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

It’s late on a Thursday afternoon. Even through the six walls that separate you from the waiting room you can feel the impatient throng of families as you struggle to see the tympanic membrane of a feverish and uncooperative 3-year-old. You already have scraped his auditory canal once with your curette. Your gut tells you that he must have an otitis but deeper in your soul there are other voices reminding you that to make the diagnosis you must visualize his ear drum. Your skill and the technology on hand has failed you.

Getty Images

It’s a Sunday morning, weekend hours, and you are seeing a 12-year-old with a sore throat and fever. Her physical exam suggests that she has strep pharyngitis but the team member in charge of restocking supplies has forgotten to reorder rapid strep kits and you used the last one yesterday afternoon.

Do you ignore your training and treat these sick children with antibiotics?

If you are someone who perceives the world in black and white, your response to these scenarios is simple because you NEVER prescribe antibiotics without seeing a tympanic membrane or confirming your suspicion with a rapid strep test. There are unrealistic solutions that could include requesting an immediate ear/nose/throat consult or sending the patient on an hour-long odyssey to the hospital lab. But for the rest of us who see in shades of gray, we may have to compromise our principles and temporarily become poor antibiotic stewards. The question is, how often do you compromise? Once a week, once a month, twice a year, or twice a day?

A study published in Pediatrics looks at the issue of antibiotic stewardship as it relates to telemedicine (“Antibiotic Prescribing During Pediatrics Direct-to-Consumer Telemedicine Visits,” Pediatrics. 2019 May. doi: 10.1542/peds.2018-2491).

The investigators found that children with acute respiratory infections were more likely to receive antibiotics and less likely to receive guideline concordant management at direct-to-consumer (DTC) telemedicine visits than when they were seen by their primary care physician or at an urgent care center.

In their discussion, the researchers note several possible explanations for the discrepancies they observed. DTC telemedicine visits are limited by the devices used by the families and physicians and generally lack availability of otoscopy and strep testing. The authors also wonder whether “there may be differential expectations for antibiotics among children and parents who use DTC telemedicine versus in person care.” Does this mean that families who utilize DTC telemedicine undervalue in-person care and/or are willing to compromise by accepting what they may suspect is substandard care for the convenience of DTC telemedicine?

Which brings me to my point. A physician who accepts the challenge of seeing pediatric patients with acute respiratory illnesses knowing that he or she will not be able to visualize tympanic membranes or perform strep testing also has accepted the fact that he or she will be compromising the principles of antibiotic stewardship he or she must have – or maybe should have – learned in medical school or residency.

We all occasionally compromise our principles when technology fails us or when the situations are extraordinary. But I am troubled that there some physicians who are willing to practice in an environment in which they are aware that they will be compromising their antibiotic stewardship on a daily or even hourly basis.
 

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

Yes, but with caution. Multiple randomized controlled trials showed that procalcitonin testing can help guide antibiotic management in a variety of clinical scenarios including sepsis, respiratory tract infection, and exacerbation of chronic obstructive pulmonary disease (COPD), and that procalcitonin guidance led to less antibiotic use with either unchanged or better outcomes. Moreover, observational studies have shown high negative predictive values for procalcitonin testing in other clinical situations such as bacteremia and bacterial meningitis, allowing clinicians to rule out these diagnoses if the clinical probability is low or moderate.

Nonetheless, clinical judgment must be exercised to consider the possibility of false- positive and false-negative results, especially if clinical suspicion for bacterial infection is high.

A RESPONSE TO BACTERIAL TOXIN

Procalcitonin is a peptide precursor of calcitonin that is produced by C cells of the thyroid and by neuroendocrine cells of the lung and intestine in response to bacterial toxin. In contrast, procalcitonin levels are down-regulated in viral infection.

Levels of procalcitonin increase 6 to 12 hours after stimulation, and the half-life is roughly 24 hours.¹ This suggests levels should decrease by one-half daily if an infection is controlled and is responding to therapy (assuming normal clearance).

The test costs about $25, with a turnaround time of 20 to 60 minutes, or longer at institutions that send the test out or run the tests in batches.

Point-of-care procalcitonin testing is emerging but not yet commercially available in the United States. Despite extensive observational studies and randomized controlled trials over the past 20 years, procalcitonin’s physiologic role remains unclear. The large body of evidence of the clinical utility of procalcitonin measurement has been summarized in several meta-analyses in different diseases.

PROCALCITONIN TESTING IN SEPSIS

Trials of procalcitonin testing have had slightly different inclusion criteria that commonly overlap with similar diagnoses. Sepsis is the broadest cohort studied.

The Procalcitonin to Reduce Antibiotic Treatments in Acutely Ill Patients (PRORATA) trial² randomized 621 patients admitted to the intensive care unit (ICU) with suspected bacterial infections to antibiotic therapy guided by procalcitonin concentrations or to antibiotic therapy based on current guidelines. The source of infection varied, but 73% of patients had pulmonary infections.The procalcitonin algorithm was as follows:

• Starting antibiotics was discouraged if the procalcitonin concentration was less than 0.5 ng/mL, and strongly discouraged if less than 0.25 ng/mL
• Starting antibiotics was encouraged if the concentration was 0.5 ng/mL or higher, and strongly encouraged if 1 ng/mL or higher
• Stopping antibiotics was encouraged if the concentration dropped by at least 80% from the peak level or to a level greater than or equal to 0.25 ng/mL; stopping was strongly encouraged if the concentration fell below 0.25 ng/mL.

There was also guidance to change antibiotics if procalcitonin increased on therapy and was above 0.5 ng/mL.

Although the study physicians generally followed the algorithm, they were allowed to override it based on clinical judgment. The main results were that the number of days without antibiotics was higher in the procalcitonin group than in the controls (14.3 vs 11.6 days), with no other statistically significant difference between groups. These findings supported the idea that procalcitonin can guide clinicians to safely “deprescribe” antibiotics.

The Stop Antibiotics on Guidance of Procalcitonin Study (SAPS),³ published in 2016, was a larger trial with similar design, in 1,575 patients admitted to the ICU with suspected infection. Antibiotic use was less and the 28-day mortality rate was lower with procalcitonin guidance: 20% vs 25% in the intention-to-treat analysis.

The Procalcitonin Guided Antibiotic Therapy and Hospitalisation in Patients With Lower Respiratory Tract Infections (ProHOSP) trial⁴ randomized 1,381 patients to antibiotic therapy guided by procalcitonin levels or standard guidelines. Most patients had community-acquired pneumonia, while the rest had exacerbations of COPD, acute bronchitis, or other lower respiratory tract infections.

In the study algorithm, starting or continuing antibiotics was discouraged if procalcitonin levels were 0.25 ng/mL or less, and strongly discouraged if less than 0.1 ng/mL. Starting or continuing antibiotics was encouraged if levels were greater than 0.25 ng/mL, and strongly encouraged if greater than 0.5 ng/mL.

The algorithm recommended stopping antibiotics if procalcitonin levels fell below 0.25 ng/mL or decreased by 80%, and strongly recommended stopping them if procalcitonin fell below 0.1 ng/mL or decreased by 90%.

The treating physician could override the algorithm if the patient was unstable, was in an ICU, or had Legionella infection.

Antibiotic use was less in the procalcitonin-guided arm (75.4% vs 87.7%; mean duration 5.7 days vs 8.7 days), as was the rate of adverse effects from antibiotics (19.8% vs 28.1%). Rates of recurrence or rehospitalization were also lower with procalcitonin guidance (3.7% vs 6.5%), presumably because of fewer antibiotic-related side effects or better diagnostic accuracy. Rates of death and ICU admission were similar in the 2 groups. These findings were similar to those of PRORATA and SAPS, demonstrating that guidance with procalcitonin levels decreased antibiotic utilization, with other outcomes either improved or unchanged.

Schuetz et al,⁵ in a 2018 meta-analysis, collected data on 6,708 patients from 26 trials in 12 countries and found that procalcitonin guidance decreased antibiotic exposure by 2.4 days and reduced the rate of antibiotic-related side effects (16% vs 22%). Although there was skepticism about the mortality benefit reported in the SAPS trial, a similar mortality benefit was found in this meta-analysis (30-day mortality rates were 9% vs 10%), suggesting that measuring procalcitonin not only reduces unnecessary antibiotic exposure, but also saves lives.

Although decreasing antibiotic exposure may not confer a survival benefit, procalcitonin guidance likely clarifies the diagnosis and thus expedites proper treatment in patients with sepsis-like syndromes that are actually due to a noninfectious pathology (eg, pulmonary embolism, myocardial infarction, adrenal insufficiency).

Negative findings in ProACT

The Procalcitonin Antibiotic Consensus Trial (ProACT)⁶ subsequently reported findings discordant with those above but was flawed in that adherence to the procalcitonin guideline by physicians was only 62% in the subgroup of patients with low procalcitonin results, which accounted for almost 90% of patients. Overall adherence by physicians to the procalcitonin guideline was 65%, much lower than in other trials (ProHOSP had over 90% adherence).⁴ Further, ProACT was done in American centers unfamiliar with procalcitonin, and it seems they did not trust low procalcitonin values as a reason to stop or avoid antibiotics.

ACUTE EXACERBATIONS OF COPD

Multiple small randomized controlled trials and subgroups of larger studies like ProHOSP have studied the use of procalcitonin in acute exacerbations of COPD. Most studies used a design similar to the algorithm in ProHOSP.

Mathioudakis et al,⁷ in a meta-analysis of 8 trials with a total of 1,062 patients with acute exacerbation of COPD, found that with procalcitonin guidance, prescription of antibiotics on admission decreased by almost one-half, and courses of antibiotics were approximately 4 days shorter without any statistically significant difference in rates of treatment failure, length of hospital stay, recurrence, rehospitalization, or overall mortality.

However, the quality of the studies included in the meta-analysis was deemed only low to moderate, and thus the authors concluded, “Procalcitonin-based protocols appear to be clinically effective; however, confirmatory trials with rigorous methodology are required.”⁷ Nonetheless, given the lack of data supporting current practices for patient selection for antibiotics in COPD exacerbations, a strategy involving procalcitonin seems to be reasonable.

Observational studies from as far as back as 1999 have examined the association of procalcitonin levels with bacteremia. The study designs were generally similar, with procalcitonin levels checked at time of blood culture, mostly in emergency rooms, and the procalcitonin value correlated with blood culture results. The general conclusion has been that procalcitonin has diagnostic value in ruling out bacteremia but should be used in the context of pretest probability rather than in isolation.

Hattori et al⁸ performed one of the largest studies, in 1,331 patients, using a procalcitonin level cutoff of 0.9 ng/mL. The sensitivity was 72% and specificity was 69%, which are not impressive; however, the negative predictive value was 95%, and even higher at lower cutoff values. Further, procalcitonin was significantly better at predicting bacteremia than either the white blood cell count or C-reactive protein level, with the latter two being hardly better than random chance.

Hoeboer et al⁹ performed a meta-analysis of various studies with a total of 16,514 patients. Using a cutoff of 0.5 ng/mL, they reported a sensitivity of 76% and a specificity of 69% with a negative predictive value of 97% in emergency rooms, 95% on regular wards, and 98% in ICUs. The high negative predictive value of procalcitonin can allow clinicians to stratify bacteremia risk to determine which patients need blood cultures, which in turn may help clinicians order blood cultures more appropriately and avoid unnecessary costs, delays, and harms associated with false-positive results, such as additional visits, additional testing, and unnecessary use of antibiotics.

MENINGITIS

As with bacteremia, observational studies have reported fairly high negative predictive values for procalcitonin in bacterial meningitis. The correlation is not surprising, given that most cases of bacterial meningitis occur due to hematogenous dissemination.

A 2015 meta-analysis of 9 studies and 725 patients reported a pooled sensitivity of 90%, specificity 90%, positive likelihood ratio 27.3, and negative likelihood ratio 0.13.¹⁰ Cutoffs for procalcitonin levels varied, but the most common value was 0.5 ng/mL. The authors also noted that the diagnostic utility of procalcitonin was far superior to C-reactive protein in this scenario, concluding that serum procalcitonin is a highly accurate test to distinguish between bacterial and viral causes in suspected meningitis.¹⁰

OTHER CLINICAL APPLICATIONS

Postoperative infection

Small studies have assessed procalcitonin as a marker to rule out postoperative infections,^11,12 but the heterogeneity of study designs and populations makes it difficult to combine the studies for meta-analysis. Nevertheless, the general trend is that there may be a role for procalcitonin, and that procalcitonin has better diagnostic yield than the white blood cell count or C-reactive protein level. The optimal cutoff depends on the surgery, since a small elevation in procalcitonin can be expected with the stress of surgery; and since the degree of elevation varies with type of surgery, the result must be interpreted with caution.

Malignancy

In malignancy-associated conditions such as neutropenic fever and tumor fever, the clinical utility of procalcitonin is somewhat diminished, as malignancy can cause elevated procalcitonin levels (especially in metastatic disease), but a low concentration still has a fair negative predictive value (approximately 90%) for bloodstream infections.¹³

A retrospective study suggested that the ratio of procalcitonin to C-reactive protein could improve diagnostic accuracy in patients with malignancies, presumably because an elevation of procalcitonin out of proportion to elevation in C-reactive protein favored a bacterial infection rather than nonspecific inflammation related to malignancy.¹⁴

Cardiac syndromes

In cardiac syndromes, dyspnea and abnormal chest imaging may make it difficult to exclude respiratory infections. Schuetz et al¹⁵ reviewed the potential value of procalcitonin testing in a variety of cardiac disorders, especially in acute cardiovascular conditions whose presentation resembles that of sepsis or acute respiratory tract infection. They concluded it may have a role in diagnosis and prognosis in these settings, as well as guiding drug therapy.

Localized infections

Though localized infections such as cystitis, cellulitis, and osteomyelitis often do not affect procalcitonin levels, the test may help assess illness severity and rule out associated bacteremia.

One study found that a low procalcitonin level was insufficient to rule out urinary tract infection, but procalcitonin levels predicted bacteremia better than any other variable or combination of variables; moreover, procalcitonin had a negative predictive value as high as 97% for ruling out bacteremia associated with urinary tract infection.¹⁶

In addition to being a useful marker for diagnosis of bacterial infections, the procalcitonin level has significant prognostic implications, as a high or persistently elevated level correlates with a higher rate of all-cause mortality.¹⁷ The prognostic capability may enhance triage decisions.

Because the procalcitonin level lacks specificity, clinicians need to be aware of noninfectious causes of elevations such as malignancy, surgery, impaired renal function,⁸ and myocardial infarction.¹⁸ In these scenarios, it is important to think critically about the procalcitonin result and consider an adjusted cutoff.

A study of procalcitonin to predict a positive blood culture in patients with renal disease suggested an optimal cutoff value of 1.06 ng/mL for patients with an estimated glomerular filtration rate of 30 to 60 mL/min/1.73m², and a value of 2.50 ng/mL for a rate less than 30 mL/min/1.73m².⁸

In a chronic process like malignancy, the procalcitonin level is usually not markedly elevated. But it can also remain persistently elevated, with no improvement associated with effective antibiotic treatment and no clinical deterioration associated with treatment failure.

Use of procalcitonin and troponin

For some patients, there may be diagnostic uncertainty about interpreting procalcitonin and troponin results, as both plaque-rupture myocardial infarction and demand ischemia from sepsis can cause elevation in both values. In a study of patients with acute myocardial infarction, the procalcitonin level peaked at 3.57 ng/mL and troponin peaked at 60 ng/mL at about 24 hours after admission.¹⁸ This suggests that a troponin-to-procalcitonin ratio may help distinguish acute myocardial infarction from demand ischemia, though the optimal cutoff is unknown.

Both troponin and procalcitonin levels can help rule out acute severe illness (eg, bloodstream infection, acute myocardial infarction). But both can be falsely negative in early presentation or in less severe disease (eg, localized infection, unstable angina), as well as in noninfectious inflammation and nonobstructive myocardial injury.

Both are important prognostic markers. Furthermore, both can be chronically elevated in patients with renal disease, but both still have a characteristic rise and fall in acute disease states. But neither should be used in isolation without information from electrocardiography, other tests, and the clinical context.

CAVEATS AND CHALLENGES

Based on clinical experience and reported studies, procalcitonin testing has proven valuable in the diagnosis, prognosis, and management of a range of diseases, particularly certain infections.

However, procalcitonin testing must be applied cautiously and judiciously. There is a potential for early false-negative results, and false-positive results can occur in conditions such as kidney disease, myocardial infarction, postoperative stress response, and malignancy, though there may be ways to factor these conditions into interpretation of procalcitonin results.

Widespread procalcitonin testing may lead to excessive costs, though the cost for each test is reasonable and probably offset by benefits of diagnostic clarification and decreased use of antibiotics, if appropriately applied.

The primary roles for procalcitonin testing are to rule out infection in patients with low probability of infection and to allow safe early cessation of antibiotic therapy in patients with presumed bacterial infection. Procalcitonin testing can enable providers to stop antibiotics safely, with the general trend showing decreased antibiotic utilization without patient harm. This can result in healthcare cost savings and improved patient outcomes such as decreased length of hospital stay, decreased readmission rates, fewer adverse effects from antibiotics, and possibly improved mortality rates.

Despite the potential benefits from procalcitonin testing, results must be interpreted within the clinical context because a host of factors can affect the values. Extreme values are more useful than intermediate values, which are difficult to interpret and have poor predictive value.

Although all current biomarkers for infection are imperfect, procalcitonin appears to have better diagnostic accuracy than other markers such as the white blood cell count and C-reactive protein in multiple clinical scenarios, and its appropriate use appears to improve important outcomes such as survival.

To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,¹ I was hoping for some clarification on a few points.

The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference² but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database³? The authors do cite an additional reference⁴ documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?

The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?

Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.³ This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.

To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,¹ I was hoping for some clarification on a few points.

The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference² but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database³? The authors do cite an additional reference⁴ documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?

The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?

Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.³ This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.

To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,¹ I was hoping for some clarification on a few points.

The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference² but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database³? The authors do cite an additional reference⁴ documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?

The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?

Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.³ This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.

The “human microbiota” describes all microorganisms within the human body, including bacteria, viruses, and eukaryotes. The related term “microbiome” refers to the complete catalog of these microbes and their genes.¹ There is a growing awareness that the human microbiota plays an important role in maintaining mental health, and that a disruption in its composition can contribute to manifestations of psychiatric disorders. A growing body of evidence has also linked mental health outcomes to the gut microbiome, suggesting that the gut microbiota can modulate the gut-brain axis.²

Numerous neurotransmitters, including dopamine, serotonin, gamma-aminobutyric acid, and acetylcholine, are produced in the gastrointestinal (GI) tract, and our diet is vital in sustaining and replenishing them. At the same time, our brain regulates our GI tract by secretion of hormones such as oxytocin, leptin, ghrelin, neuropeptide Y, corticotrophin-releasing factor, and a plethora of others. Dysregulation of this microbiome can lead to both physical and mental illnesses. Symptoms of psychiatric disorders, such as depression, psychosis, anxiety, and autism, can be a consequence of this dysregulation.²

Our diet can also modify the gut micro­organisms and therefore many of its metabolic pathways. More attention has been given to pre- and probiotics and their effects on DNA by epigenetic changes. One can quickly start to appreciate how this intricate crosstalk can lead to a variety of pathologic and psychiatric problems that have an adverse effect on autoimmune, inflammatory, metabolic, cognitive, and behavioral processes.^2,3

Thus far, links have mostly been reported in animal models, and human studies are limited.⁴ Researchers are just beginning to elucidate how the microbiota affect gut-brain signaling in humans. Such mechanisms may include alterations in microbial composition, immune activation, vagus nerve signaling, alterations in tryptophan metabolism, production of specific microbial neuroactive metabolites, and bacterial cell wall sugars.⁵ The microbiota-gut-brain axis plays a part in regulating/programming the hypothalamic-pituitary-adrenal (HPA) axis throughout the life span.³ The interactions between the gut microbiome, the immune system, and the CNS are regulated through pathways that involve endocrine functions (HPA axis), the immune system, and metabolic factors.^3,4 Recent research focusing on the gut microbiome has also given rise to international projects such as the Human Microbiome Project (Human Microbiome Project Consortium, 2012).³

Several studies have looked into psychiatry and inflammatory/immune pathways. Here we review 3 recent studies that have focused on the gut-brain axis (Table^6-8).

1. Rudzki L, Pawlak D, Pawlak K, et al. Immune suppression of IgG response against dairy proteins in major depression. BMC Psychiatry. 2017;17(1):268.

The aim of this study was to evaluate immunoglobulin G (IgG) response against 40 food products in patients with depression vs those in a control group, along with changes in inflammatory markers, psychological stress, and dietary variables.⁶

Study design

• N = 63, IgG levels against 44 food products, cortisol levels, tumor necrosis factor (TNF)-alpha, interleukin 6 (IL-6), and IL-1 beta levels were recorded. The psychological parameters of 34 participants with depression and 29 controls were compared using the Hamilton Depression Rating scale, (HAM-D-17), Perceived Stress scale, and Symptom Checklist scale. The study was conducted in Poland.

Continue to: Outcomes

Outcomes

• Patients who were depressed had lower IgG levels against dairy products compared to controls when there was high dairy consumption. However, there was no overall difference between patients and controls in mean IgG concentration against food products. 
• Patients who were depressed had higher levels of cortisol. Levels of cortisol had a positive correlation with HAM-D-17 score. Patients with depression had lower levels of TNF-alpha.

Conclusion

• Patients with depression had lower levels of IgG against dairy protein. Patients with depression had high cortisol levels but decreased levels of TNF-alpha, which could explain an immune suppression of IgG in these patients. There were no differences in IL-6 or IL-1beta levels.

Hypercortisolemia is present in approximately 60% of patients with depression. Elevated cortisol levels have a negative effect on lymphocyte function. B-lymphocytes (CD 10+ and CD 19+) are sensitive to glucocorticoids. Studies in mice have demonstrated that elevated glucocorticoid levels are associated with a 50% decrease in serum B-lymphocytes, and this can be explained by downregulation of c-myc protein, which plays a role in cell proliferation and cell survival. Glucocorticoids also decrease levels of protein kinases that are vital for the cell cycle to continue, and they upregulate p27 and p21, which are cell cycle inhibitors. Therefore, if high cortisol suppresses B-lymphocyte production, this can explain how patients with depression have low IgG levels, since B-lymphocytes differentiate into plasma cells that will produce antibodies.⁶

Depression can trigger an inflammatory response by increasing levels of inflammatory cytokines, acute phase reactants, and oxidative molecules. The inflammatory response can lead to intestinal wall disruption, and therefore bacteria can migrate across the GI barrier, along with food antigens, which could then lead to food antigen hypersensitivity.⁶

The significance of diet

Many studies have looked into specific types of diets, such as the Mediterranean diet, the ketogenic diet, and the addition of supplements such as probiotics, omega-3 fatty acids, zinc, and multivitamins.⁷ The Mediterranean diet is high in fiber, nuts, legumes, and fish.⁷ The ketogenic diet includes a controlled amount of fat, but is low in protein and carbohydrates.⁷ The main point is that a balanced diet can have a positive effect on mental health.⁷ The Mediterranean diet has shown to decrease the incidence of cardiovascular disease and lower the risk of depression.⁷ In animal studies, the ketogenic diet has improved anxiety, depression, and autism.⁷ Diet clearly affects gut microbiota and, as a consequence, the body’s level of inflammation.⁷ 

Continue to: The following review...

The following review highlighted the significance of diet on gut microbiome and mental health.⁷

2. Mörkl S, Wagner-Skacel J, Lahousen T, et al. The role of nutrition and the gut- brain axis in psychiatry: a review of the literature. Neuropsychobiology. 2018;17: 1-9.

Study design

• These researchers provided a narrative review of the significance of a healthy diet and nutritional supplements on the gut microbiome and the treatment of patients with psychiatric illness. 

Outcomes

• This review suggested dietary coaching as a nonpharmacologic treatment for patients with psychiatric illness. 

Conclusion

• The utilization of nutritional advice, along with medication management, therapy, and physical activity, can provide a holistic approach to the biopsychosocial treatment of patients with psychiatric illness.

This review also emphasized the poor dietary trends of Westernized countries, which include calorie-dense, genetically altered, processed meals. As Mörkl et al⁷ noted, we are overfed but undernourished. Mörkl et al⁷ reviewed studies that involve dietary coaching as part of the treatment plan of patients with mental illness. In one of these studies, patients who received nutritional advice and coaching over 6 weeks had a 40% to 50% decrease in depressive symptoms. These effects persisted for 2 more years. Mörkl et al⁷ also reviewed an Italian study that found that providing nutritional advice in patients with affective disorders and psychosis helped improve symptom severity and sleep.⁷

Continue to: Mörkl et al...

Mörkl et al⁷ also reviewed dietary supplements. Some studies have linked use of omega-3 fatty acids with improvement in affective disorders, Alzheimer’s disease, and posttraumatic stress disorder, as well as cardiovascular conditions. Omega-3 fatty acids may exert beneficial effects by enhancing brain-derived neurotrophic factor and neurogenesis as well as by decreasing inflammation.⁷

Zinc supplementation can also improve depression, as it has been linked to cytokine variation and hippocampal neuronal growth. Vitamin B₉ deficiency and vitamin D deficiency also have been associated with depression. Mörkl et al⁷ emphasized that a balanced diet that incorporates a variety of nutrients is more beneficial than supplementation of any individual vitamin alone.

Researchers have long emphasized the importance of a healthy balanced diet when treating patients with medical conditions such as cardiovascular or cerebrovascular diseases. Based on the studies Mörkl et al⁷ reviewed, the same emphasis should be communicated to our patients who suffer from psychiatric conditions.

The gut and anxiety

The gut microbiome has also been an area of research when studying generalized anxiety disorder (GAD).⁸

3. Jiang HY, Zhang X, Yu ZH, et al. Altered gut microbiota profile in patients with generalized anxiety disorder. J Psychiatr Res. 2018;104:130-136.

The aim of the study was to determine if there were changes in the composition of the gut microbiome in patients with GAD compared with healthy controls.⁸

Continue to: Study design

Study design

• A cross-sectional study of 76 patients in Zhejiang, China. Forty patients with GAD in the active state and 36 healthy controls were compared in terms of composition of GI microbacterial flora.
• Researchers also examined a subgroup of 12 patients who were treatment-naïve and 17 controls. Stool samples were collected from the 12 patients who were treatment-naïve before initiating medication.
• Researchers also conducted a prospective study in a subgroup of 9 patients with GAD in both the active state and remissive state. Two stool samples were collected from each patient—one during the active state of GAD and one during the remissive state—for a total of 18 samples. Stool samples analyzed with the use of polymerase chain reaction and microbial analysis.
• Patients completed the Hamilton Anxiety Rating (HAM-A) scale and were classified into groups. Those with HAM-A scores >14 were classified as being in the active state of GAD, and those with scores <7 were classified as being in the remissive state. 

Outcomes

• Among the samples collected, 8 bacterial taxa were found in different amounts in patients with GAD and healthy controls. Bacteroidetes, Ruminococcus gnavus, and Fusobacterium were increased in patients with GAD compared with controls, while Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus were increased in healthy controls.
• Bacterial variety was notably lower in the 12 patients who were treatment-naïve compared with the control group.
• There was no notable difference in microbial composition between patients in the active vs remissive state.

Conclusion

• Patients with GAD had less short chain fatty acid–producing bacteria (Faecalibacterium, Eubacterium rectale, Sutterella, Lachnospira, and Butyricicoccus) compared with controls. Decreased formation of short chain fatty acids could lead to GI barrier disruption. Fusobacterium and Ruminococcus were increased in patients with GAD. Fusobacterium can cause disease and be invasive when it disseminates within the body. The inflammatory characteristics of Fusobacterium contribute to the immunologic activation in GAD. Ruminococcus breaks down mucin, which could then increase GI permeability by mucous degradation of the GI lumen.

Changes in food processing and manufacturing have led to changes in our diets. Changes in our normal GI microbacterial flora could lead to increased gut permeability, bacterial dissemination, and subsequent systemic inflammation. Research has shown that the composition of the microbiota changes across the life span.⁹ A balanced intake of nutrients is important for both our physical and mental health and safeguards the basis of gut microbiome regulation. A well-regulated gut microbiome ensures low levels of inflammation in the brain and body. Lifestyle modifications and dietary coaching could be practical interventions for patients with psychiatric conditions.⁵ Current advances in technology now offer precise analyses of thousands of metabolites, enabling metabolomics to offer the promise of discovering new drug targets and biomarkers that may help pave a way to precision medicine.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

The Food and Drug Administration has approved glecaprevir/pibrentasvir tablets (Mavyret) for treating any of six identified genotypes of hepatitis C virus in children ages 12-17 years.

The agency noted in its press announcement that, although Mavyret is not the first treatment option for HCV in children, it is the first that can target any of six genotypes. Dosing information now will be provided for patients aged 12 years and older or weighing at least 99 lbs, without cirrhosis or who have compensated cirrhosis. It is not recommended for patients with moderate cirrhosis, and it is contraindicated in patients with severe cirrhosis, as well as patients taking atazanavir and rifampin.

In clinical trials of 47 patients with genotype 1, 2, 3, or 4 HCV without cirrhosis or with only mild cirrhosis, results at 12 weeks after 8 or 16 weeks’ treatment suggested patients’ infections had been cured – 100% had no virus detected in their blood. Adverse reactions observed were consistent with those previously observed in adults during clinical trials.

The most common reactions were headache and fatigue. Hepatitis B virus reactivation has been reported in coinfected adults during or after treatment with direct-acting antivirals, and in those who were not receiving HBV antiviral treatment. Full prescribing information can be found on the FDA website, and more information about this approval can be found in the agency’s announcement.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.

ORLANDO – Infections before the age of 4 are linked to the risk of nonaffective psychosis (NAP) in adulthood, according to a study presented at the annual congress of the Schizophrenia International Research Society. Researchers also found that a lower IQ seems to make the psychosis risk more likely.

It’s well-established in the literature that infections are tied to schizophrenia and that a premorbid IQ deficit is linked as well. Researchers looked to a huge data pool from the Swedish population to try to better define these risks.

“We know that there is an association between infection and schizophrenia,” said Golam Khandaker, MRCPsych, PhD, head of the inflammation and psychiatry research group at the University of Cambridge (England). “We know that there is premorbid IQ deficit in schizophrenia. So, we wanted to know, is there a sensitive period during childhood when exposure to infection is more harmful?”

Researchers analyzed data for 647,000 people in the Swedish population who were born between 1973 and 1997, and conscripted for military service through 2010. Exposure to infection was considered to be any hospitalization with any serious infection between birth and age 13. IQ measurements were taken during military conscription at the age of 18. And researchers looked for risk of nonaffective psychosis from the age of 18 on.

There was a significant increase in risk of nonaffective psychosis in adulthood among those who’d had an infection, with a hazard ratio of 1.16 (95% confidence interval, 1.08-1.24). But when researchers broke down this risk into smaller age spans, they found that only infection between birth and 1 year old (HR, 1.19; 95% CI, 1.06-1.33) and between age 2 and 4 (HR, 1.11; 95% CI, 1.02-1.22) was linked with a significantly elevated risk of NAP. Researchers also saw a link between infection and IQ.

“It seems that early childhood is a sensitive period with regards to the effects of infection on IQ and risk of psychosis in adult life,” Dr. Khandaker said.

Researchers assessed whether familial factors could be confounding this link. They looked at rates of NAP among those with an early infection and no early infection in the general population and found that it was no different statistically than among full siblings with an early infection, compared with those with no early infection. In other words, the infection-psychosis risk was the same – whether someone was a close family member or not.

Dr. Khandaker said the findings more definitively establish a link between infection and psychosis risk and suggest that the early years are when children are at their most vulnerable.

“The association between adult nonaffective psychosis with premorbid IQ and childhood infection are not explained by shared familial confounding,” he said. “So these associations could be causal.”

When they looked at the role of IQ and the link between infection and psychosis risk, researchers found an interaction: With every 1-point decrease in IQ score, there was a corresponding increased risk of NAP among those with childhood infections (odds ratio, 1.006; P = .02).

“Childhood infections,” Dr. Khandaker said, “increase psychosis risk partly by interfering with neurodevelopment, and partly by exaggerating the effects of cognitive vulnerability to psychosis.”

Dr. Khandaker disclosed no relevant financial relationships.

BALTIMORE – U.S. pediatricians feel comfortable providing patients with preventive information and travel advice related to Zika, but few feel prepared when it comes to testing and management of infants exposed prenatally to Zika infections, a study found.

Aunt_Spray/Thinkstock

“Areas where pediatricians were less likely to report preparedness included recommending testing, providing data to the Centers for Disease Control and Prevention’s Zika Pregnancy Registry, managing infants exposed to Zika prenatally, and informing parents of social services for Zika-infected infants,” senior author Amy J. Houtrow, MD, MPH, PhD, and colleagues reported at the Pediatric Academic Societies annual meeting.

“Results indicate that additional education efforts are needed to grow the overall Zika knowledge of pediatricians and boost preparedness, particularly around recommending Zika testing and providing data to CDC,” they concluded.

But these findings are not surprising given how rare congenital Zika virus syndrome is, explained Dr. Houtrow, an associate professor of physical medicine and rehabilitation and pediatrics at the University of Pittsburgh.

“For most rare conditions, pediatricians report better general than specific knowledge,” Dr. Houtrow said in an interview. “We expect pediatricians have a broad range of knowledge for a multitude of conditions and to be well versed in the care of infants and children with common conditions, coupled with the ability to access knowledge and expertise about rarer conditions such as congenital Zika syndrome.”

Dr. Houtrow and associates drew their findings from the 2018 AAP Periodic Survey of Fellows, which includes both primary care physicians and neonatologists. The survey’s response rate was 42%, with 672 of 1,599 surveys returned, but the researchers limited their analysis to 576 postresidency respondents who were providing direct patient care.

Overall, 39% of physicians reported being knowledgeable about Zika virus, and 47% said they wanted to learn more. More than half of responding doctors (57%) reported feeling moderately or very prepared when it came to informing patients of preventive measures to reduce risk of Zika infection, and nearly half (49%) felt confident about giving patients travel advice.

However, physicians’ preparedness gradually dropped for clinical situations requiring more direct experience with Zika. For example, 37% felt moderately or very prepared to provide clinical referrals for infant patients with an infection, and 33% felt prepared to talk with pregnant women about the risks of birth defects from Zika infection.

Just one in five physicians (22%) felt prepared for recommending Zika virus testing, and 16% felt prepared about providing data to the CDC’s U.S. Zika Pregnancy Registry or managing infants who had been prenatally exposed to Zika infection. Only 15% felt they had the preparedness to tell parents about social services for Zika-affected infants.

Preparedness did not differ by gender, specialty, practice setting, hours worked per week, or population density (urban, rural and suburban). However, differences did appear based on respondents’ age and U.S. region.

Older doctors reported greater knowledge about Zika than younger doctors. Compared with those aged 39 years or younger, those aged 40-49 and 50-59 reported feeling more knowledgeable (adjusted odds ratio, 1.74 and 1.72, respectively; P less than .05). The odds of feeling more knowledgeable was nearly triple among those aged at least 60 years, compared with those under 40 (aOR, 2.92; P less than .001).

Those practicing in the Northeast United States (aOR, 2.19; P less than .01) and in the South (aOR, 1.74; P less than .05) also reported feeling more knowledgeable than those in the West or Midwest.

“This makes sense because infants with a history of prenatal exposure to the Zika Virus are more likely to be seen in practices with more immigrants from the Caribbean and Latin America,” Dr. Houtrow said in an interview.

“There is definitely an opportunity to improve the dissemination of information about Zika virus to pediatricians, but the urgency of the need for education about Zika virus has diminished because the rates of new congenital Zika syndrome have dropped,” she continued.

Study limitations include the inability to generalize the findings beyond U.S. members of the AAP and the possibility that nonrespondents differed from respondents in terms of Zika knowledge and preparedness.

The research was funded by the AAP and CDC.

BALTIMORE – U.S. pediatricians feel comfortable providing patients with preventive information and travel advice related to Zika, but few feel prepared when it comes to testing and management of infants exposed prenatally to Zika infections, a study found.

Aunt_Spray/Thinkstock

“Areas where pediatricians were less likely to report preparedness included recommending testing, providing data to the Centers for Disease Control and Prevention’s Zika Pregnancy Registry, managing infants exposed to Zika prenatally, and informing parents of social services for Zika-infected infants,” senior author Amy J. Houtrow, MD, MPH, PhD, and colleagues reported at the Pediatric Academic Societies annual meeting.

“Results indicate that additional education efforts are needed to grow the overall Zika knowledge of pediatricians and boost preparedness, particularly around recommending Zika testing and providing data to CDC,” they concluded.

But these findings are not surprising given how rare congenital Zika virus syndrome is, explained Dr. Houtrow, an associate professor of physical medicine and rehabilitation and pediatrics at the University of Pittsburgh.

“For most rare conditions, pediatricians report better general than specific knowledge,” Dr. Houtrow said in an interview. “We expect pediatricians have a broad range of knowledge for a multitude of conditions and to be well versed in the care of infants and children with common conditions, coupled with the ability to access knowledge and expertise about rarer conditions such as congenital Zika syndrome.”

Dr. Houtrow and associates drew their findings from the 2018 AAP Periodic Survey of Fellows, which includes both primary care physicians and neonatologists. The survey’s response rate was 42%, with 672 of 1,599 surveys returned, but the researchers limited their analysis to 576 postresidency respondents who were providing direct patient care.

Overall, 39% of physicians reported being knowledgeable about Zika virus, and 47% said they wanted to learn more. More than half of responding doctors (57%) reported feeling moderately or very prepared when it came to informing patients of preventive measures to reduce risk of Zika infection, and nearly half (49%) felt confident about giving patients travel advice.

However, physicians’ preparedness gradually dropped for clinical situations requiring more direct experience with Zika. For example, 37% felt moderately or very prepared to provide clinical referrals for infant patients with an infection, and 33% felt prepared to talk with pregnant women about the risks of birth defects from Zika infection.

Just one in five physicians (22%) felt prepared for recommending Zika virus testing, and 16% felt prepared about providing data to the CDC’s U.S. Zika Pregnancy Registry or managing infants who had been prenatally exposed to Zika infection. Only 15% felt they had the preparedness to tell parents about social services for Zika-affected infants.

Preparedness did not differ by gender, specialty, practice setting, hours worked per week, or population density (urban, rural and suburban). However, differences did appear based on respondents’ age and U.S. region.

Older doctors reported greater knowledge about Zika than younger doctors. Compared with those aged 39 years or younger, those aged 40-49 and 50-59 reported feeling more knowledgeable (adjusted odds ratio, 1.74 and 1.72, respectively; P less than .05). The odds of feeling more knowledgeable was nearly triple among those aged at least 60 years, compared with those under 40 (aOR, 2.92; P less than .001).

Those practicing in the Northeast United States (aOR, 2.19; P less than .01) and in the South (aOR, 1.74; P less than .05) also reported feeling more knowledgeable than those in the West or Midwest.

“This makes sense because infants with a history of prenatal exposure to the Zika Virus are more likely to be seen in practices with more immigrants from the Caribbean and Latin America,” Dr. Houtrow said in an interview.

“There is definitely an opportunity to improve the dissemination of information about Zika virus to pediatricians, but the urgency of the need for education about Zika virus has diminished because the rates of new congenital Zika syndrome have dropped,” she continued.

Study limitations include the inability to generalize the findings beyond U.S. members of the AAP and the possibility that nonrespondents differed from respondents in terms of Zika knowledge and preparedness.

The research was funded by the AAP and CDC.

BALTIMORE – U.S. pediatricians feel comfortable providing patients with preventive information and travel advice related to Zika, but few feel prepared when it comes to testing and management of infants exposed prenatally to Zika infections, a study found.

Aunt_Spray/Thinkstock

“Areas where pediatricians were less likely to report preparedness included recommending testing, providing data to the Centers for Disease Control and Prevention’s Zika Pregnancy Registry, managing infants exposed to Zika prenatally, and informing parents of social services for Zika-infected infants,” senior author Amy J. Houtrow, MD, MPH, PhD, and colleagues reported at the Pediatric Academic Societies annual meeting.

“Results indicate that additional education efforts are needed to grow the overall Zika knowledge of pediatricians and boost preparedness, particularly around recommending Zika testing and providing data to CDC,” they concluded.

But these findings are not surprising given how rare congenital Zika virus syndrome is, explained Dr. Houtrow, an associate professor of physical medicine and rehabilitation and pediatrics at the University of Pittsburgh.

“For most rare conditions, pediatricians report better general than specific knowledge,” Dr. Houtrow said in an interview. “We expect pediatricians have a broad range of knowledge for a multitude of conditions and to be well versed in the care of infants and children with common conditions, coupled with the ability to access knowledge and expertise about rarer conditions such as congenital Zika syndrome.”

Dr. Houtrow and associates drew their findings from the 2018 AAP Periodic Survey of Fellows, which includes both primary care physicians and neonatologists. The survey’s response rate was 42%, with 672 of 1,599 surveys returned, but the researchers limited their analysis to 576 postresidency respondents who were providing direct patient care.

Overall, 39% of physicians reported being knowledgeable about Zika virus, and 47% said they wanted to learn more. More than half of responding doctors (57%) reported feeling moderately or very prepared when it came to informing patients of preventive measures to reduce risk of Zika infection, and nearly half (49%) felt confident about giving patients travel advice.

However, physicians’ preparedness gradually dropped for clinical situations requiring more direct experience with Zika. For example, 37% felt moderately or very prepared to provide clinical referrals for infant patients with an infection, and 33% felt prepared to talk with pregnant women about the risks of birth defects from Zika infection.

Just one in five physicians (22%) felt prepared for recommending Zika virus testing, and 16% felt prepared about providing data to the CDC’s U.S. Zika Pregnancy Registry or managing infants who had been prenatally exposed to Zika infection. Only 15% felt they had the preparedness to tell parents about social services for Zika-affected infants.

Preparedness did not differ by gender, specialty, practice setting, hours worked per week, or population density (urban, rural and suburban). However, differences did appear based on respondents’ age and U.S. region.

Older doctors reported greater knowledge about Zika than younger doctors. Compared with those aged 39 years or younger, those aged 40-49 and 50-59 reported feeling more knowledgeable (adjusted odds ratio, 1.74 and 1.72, respectively; P less than .05). The odds of feeling more knowledgeable was nearly triple among those aged at least 60 years, compared with those under 40 (aOR, 2.92; P less than .001).

Those practicing in the Northeast United States (aOR, 2.19; P less than .01) and in the South (aOR, 1.74; P less than .05) also reported feeling more knowledgeable than those in the West or Midwest.

“This makes sense because infants with a history of prenatal exposure to the Zika Virus are more likely to be seen in practices with more immigrants from the Caribbean and Latin America,” Dr. Houtrow said in an interview.

“There is definitely an opportunity to improve the dissemination of information about Zika virus to pediatricians, but the urgency of the need for education about Zika virus has diminished because the rates of new congenital Zika syndrome have dropped,” she continued.

Study limitations include the inability to generalize the findings beyond U.S. members of the AAP and the possibility that nonrespondents differed from respondents in terms of Zika knowledge and preparedness.

The research was funded by the AAP and CDC.