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.

A 74-year-old man presented to the gastroenterology clinic with a 2-day history of retrosternal discomfort. His vital signs were normal, and laboratory testing showed a normal leukocyte count.

Esophagogastroduodenoscopy (EGD) revealed longitudinal sloughing mucosal casts in the middle and lower esophagus (Figure 1).

The patient had been taking dabigatran 110 mg twice daily for 2 years because of nonvalvular atrial fibrillation. He was also taking amlodipine 2.5 mg/day for hypertension.

DABIGATRAN-INDUCED ESOPHAGITIS

Although no study has investigated the overall prevalence of dabigatran-induced esophagitis, a retrospective database review of 91 patients taking dabigatran and undergoing upper-gastrointestinal endoscopy reported that 19 (20.9%) had endoscopic signs of dabigatran-induced esophagitis.²

Typical symptoms are the acute onset of chest pain, epigastralgia, odynophagia, and dysphagia. But patients can also have no symptoms or only mild symptoms.^2,3

Despite dabigatran’s anticoagulant activity, there have been few reports of bleeding, perhaps because  the lesions tend to be superficial on the surface of the esophageal mucosa.

Symptoms usually resolve within 1 week after stopping dabigatran and starting a proton pump inhibitor. To prevent mucosal injury, patients should be instructed to take dabigatran with sufficient water and to remain in an upright position for at least 30 minutes afterward.⁴

A 74-year-old man presented to the gastroenterology clinic with a 2-day history of retrosternal discomfort. His vital signs were normal, and laboratory testing showed a normal leukocyte count.

Esophagogastroduodenoscopy (EGD) revealed longitudinal sloughing mucosal casts in the middle and lower esophagus (Figure 1).

The patient had been taking dabigatran 110 mg twice daily for 2 years because of nonvalvular atrial fibrillation. He was also taking amlodipine 2.5 mg/day for hypertension.

DABIGATRAN-INDUCED ESOPHAGITIS

Although no study has investigated the overall prevalence of dabigatran-induced esophagitis, a retrospective database review of 91 patients taking dabigatran and undergoing upper-gastrointestinal endoscopy reported that 19 (20.9%) had endoscopic signs of dabigatran-induced esophagitis.²

Typical symptoms are the acute onset of chest pain, epigastralgia, odynophagia, and dysphagia. But patients can also have no symptoms or only mild symptoms.^2,3

Despite dabigatran’s anticoagulant activity, there have been few reports of bleeding, perhaps because  the lesions tend to be superficial on the surface of the esophageal mucosa.

Symptoms usually resolve within 1 week after stopping dabigatran and starting a proton pump inhibitor. To prevent mucosal injury, patients should be instructed to take dabigatran with sufficient water and to remain in an upright position for at least 30 minutes afterward.⁴

A 74-year-old man presented to the gastroenterology clinic with a 2-day history of retrosternal discomfort. His vital signs were normal, and laboratory testing showed a normal leukocyte count.

Esophagogastroduodenoscopy (EGD) revealed longitudinal sloughing mucosal casts in the middle and lower esophagus (Figure 1).

The patient had been taking dabigatran 110 mg twice daily for 2 years because of nonvalvular atrial fibrillation. He was also taking amlodipine 2.5 mg/day for hypertension.

DABIGATRAN-INDUCED ESOPHAGITIS

Although no study has investigated the overall prevalence of dabigatran-induced esophagitis, a retrospective database review of 91 patients taking dabigatran and undergoing upper-gastrointestinal endoscopy reported that 19 (20.9%) had endoscopic signs of dabigatran-induced esophagitis.²

Typical symptoms are the acute onset of chest pain, epigastralgia, odynophagia, and dysphagia. But patients can also have no symptoms or only mild symptoms.^2,3

Despite dabigatran’s anticoagulant activity, there have been few reports of bleeding, perhaps because  the lesions tend to be superficial on the surface of the esophageal mucosa.

Symptoms usually resolve within 1 week after stopping dabigatran and starting a proton pump inhibitor. To prevent mucosal injury, patients should be instructed to take dabigatran with sufficient water and to remain in an upright position for at least 30 minutes afterward.⁴

A 55-year-old man with type 2 diabetes mellitus, hypertension, anemia, and ulcerative colitis presented to the emergency department with an ulcer on his left leg (Figure 1). He said the lesion had started as a “large pimple” that ruptured one night while he was sleeping and then became drastically worse over the past week. He said the lesion was painful and was “oozing blood.”

On examination, the lesion was 7 cm by 6.5 cm, with fibrinous, necrotic tissue, purulence, and a violaceous tint at the borders. The patient’s body temperature was 100.5°F (38.1°C) and the white blood cell count was 8.1 x 10⁹/L (reference range 4.0–11.0).

Based on the patient’s medical history, the lesion was initially diagnosed as an infected diabetic ulcer. He was admitted to the hospital and intravenous (IV) vancomycin and clindamycin were started. During this time, the lesion expanded in size, and a second lesion appeared on the right anterior thigh, in similar fashion to how the original lesion had started. The original lesion expanded to 8 cm by 8.5 cm by hospital day 2. The patient continued to have episodes of low-grade fever without leukocytosis.

Cultures of blood and tissue from the lesions were negative, ruling out bacterial infection. Magnetic resonance imaging of the left tibia was negative for osteomyelitis. Punch biopsy of the ulcer border was done on day 3 to evaluate for pyoderma gangrenosum.

On hospital day 5, the patient developed acute kidney injury, with a creatinine increase to 2.17 mg/dL over 24 hours from a baseline value of 0.82 mg/dL. The IV antibiotics were discontinued, and IV fluid hydration was started. At this time, diabetic ulcer secondary to infection and osteomyelitis were ruled out. The lesions were diagnosed as pyoderma gangrenosum.

The patient was started on prednisone 30 mg twice daily. After 2 days, the low-grade fevers resolved, both lesions began to heal, and his creatinine level returned to baseline (Figure 2). He was discharged on hospital day 10. The prednisone was tapered over 1 month, with wet-to-dry dressing changes for wound care.

After discharge, he remained adherent to his steroid regimen. At a follow-up visit to his dermatologist, the ulcers had fully closed, and the skin had begun to heal. Results of the punch biopsy study came back 2 days after the patient was discharged and further confirmed the diagnosis, with a mixed lymphocytic composition composed primarily of neutrophils.

APPROACH TO DIAGNOSIS

Pyoderma gangrenosum is rare, with an incidence of 3 to 10 cases per million people per year.¹ It is a rapidly progressive ulcerative condition typically associated with inflammatory bowel disease.² Despite its name, the condition involves neither gangrene nor infection. The ulcer typically appears on the legs and is rapidly growing, painful, and purulent, with tissue necrosis and a violaceous border.³

Pyoderma gangrenosum is often misdiagnosed as infective ulcer and inappropriately treated with antibiotics.² It can also be mistreated with surgical debridement, which can result in severe complications such as pathergy.¹

The differential diagnosis includes diabetic ulcer, peripheral vascular disease, vasculitis, bacterial infection, osteomyelitis, and malignancy. Because it presents as an open, necrotic ulcer, ruling out infection is a top priority.³ However, an initial workup to rule out infection or other conditions can delay diagnosis and treatment,¹ and treatment with broad-spectrum antibiotics poses the risk of nephrotoxicity and new complications during the hospital stay.

Diagnosis requires meeting 2 major criteria—ie, presence of the characteristic ulcerous lesion, and exclusion of other causes of skin ulceration—and at least 2 minor criteria including histologic confirmation of neutrophil infiltrate at the ulcer border, the presence of a systemic disease associated with pyoderma gangrenosum, and a rapid response to steroid treatment.^4,5

Our patient was at high risk for an infected diabetic ulcer. After infection was ruled out, clinical suspicion for pyoderma gangrenosum was high, given the patient’s presentation and his history of ulcerative colitis.

TREATMENT

Treatment of pyoderma gangrenosum begins with systemic corticosteroids, as was done in this patient. Additional measures depend on whether the disease is localized or extensive and can include wound care, topical treatments, immunosuppressants, and immunomodulators.¹

A 55-year-old man with type 2 diabetes mellitus, hypertension, anemia, and ulcerative colitis presented to the emergency department with an ulcer on his left leg (Figure 1). He said the lesion had started as a “large pimple” that ruptured one night while he was sleeping and then became drastically worse over the past week. He said the lesion was painful and was “oozing blood.”

On examination, the lesion was 7 cm by 6.5 cm, with fibrinous, necrotic tissue, purulence, and a violaceous tint at the borders. The patient’s body temperature was 100.5°F (38.1°C) and the white blood cell count was 8.1 x 10⁹/L (reference range 4.0–11.0).

Based on the patient’s medical history, the lesion was initially diagnosed as an infected diabetic ulcer. He was admitted to the hospital and intravenous (IV) vancomycin and clindamycin were started. During this time, the lesion expanded in size, and a second lesion appeared on the right anterior thigh, in similar fashion to how the original lesion had started. The original lesion expanded to 8 cm by 8.5 cm by hospital day 2. The patient continued to have episodes of low-grade fever without leukocytosis.

Cultures of blood and tissue from the lesions were negative, ruling out bacterial infection. Magnetic resonance imaging of the left tibia was negative for osteomyelitis. Punch biopsy of the ulcer border was done on day 3 to evaluate for pyoderma gangrenosum.

On hospital day 5, the patient developed acute kidney injury, with a creatinine increase to 2.17 mg/dL over 24 hours from a baseline value of 0.82 mg/dL. The IV antibiotics were discontinued, and IV fluid hydration was started. At this time, diabetic ulcer secondary to infection and osteomyelitis were ruled out. The lesions were diagnosed as pyoderma gangrenosum.

The patient was started on prednisone 30 mg twice daily. After 2 days, the low-grade fevers resolved, both lesions began to heal, and his creatinine level returned to baseline (Figure 2). He was discharged on hospital day 10. The prednisone was tapered over 1 month, with wet-to-dry dressing changes for wound care.

After discharge, he remained adherent to his steroid regimen. At a follow-up visit to his dermatologist, the ulcers had fully closed, and the skin had begun to heal. Results of the punch biopsy study came back 2 days after the patient was discharged and further confirmed the diagnosis, with a mixed lymphocytic composition composed primarily of neutrophils.

APPROACH TO DIAGNOSIS

Pyoderma gangrenosum is rare, with an incidence of 3 to 10 cases per million people per year.¹ It is a rapidly progressive ulcerative condition typically associated with inflammatory bowel disease.² Despite its name, the condition involves neither gangrene nor infection. The ulcer typically appears on the legs and is rapidly growing, painful, and purulent, with tissue necrosis and a violaceous border.³

Pyoderma gangrenosum is often misdiagnosed as infective ulcer and inappropriately treated with antibiotics.² It can also be mistreated with surgical debridement, which can result in severe complications such as pathergy.¹

The differential diagnosis includes diabetic ulcer, peripheral vascular disease, vasculitis, bacterial infection, osteomyelitis, and malignancy. Because it presents as an open, necrotic ulcer, ruling out infection is a top priority.³ However, an initial workup to rule out infection or other conditions can delay diagnosis and treatment,¹ and treatment with broad-spectrum antibiotics poses the risk of nephrotoxicity and new complications during the hospital stay.

Diagnosis requires meeting 2 major criteria—ie, presence of the characteristic ulcerous lesion, and exclusion of other causes of skin ulceration—and at least 2 minor criteria including histologic confirmation of neutrophil infiltrate at the ulcer border, the presence of a systemic disease associated with pyoderma gangrenosum, and a rapid response to steroid treatment.^4,5

Our patient was at high risk for an infected diabetic ulcer. After infection was ruled out, clinical suspicion for pyoderma gangrenosum was high, given the patient’s presentation and his history of ulcerative colitis.

TREATMENT

Treatment of pyoderma gangrenosum begins with systemic corticosteroids, as was done in this patient. Additional measures depend on whether the disease is localized or extensive and can include wound care, topical treatments, immunosuppressants, and immunomodulators.¹

A 55-year-old man with type 2 diabetes mellitus, hypertension, anemia, and ulcerative colitis presented to the emergency department with an ulcer on his left leg (Figure 1). He said the lesion had started as a “large pimple” that ruptured one night while he was sleeping and then became drastically worse over the past week. He said the lesion was painful and was “oozing blood.”

On examination, the lesion was 7 cm by 6.5 cm, with fibrinous, necrotic tissue, purulence, and a violaceous tint at the borders. The patient’s body temperature was 100.5°F (38.1°C) and the white blood cell count was 8.1 x 10⁹/L (reference range 4.0–11.0).

Based on the patient’s medical history, the lesion was initially diagnosed as an infected diabetic ulcer. He was admitted to the hospital and intravenous (IV) vancomycin and clindamycin were started. During this time, the lesion expanded in size, and a second lesion appeared on the right anterior thigh, in similar fashion to how the original lesion had started. The original lesion expanded to 8 cm by 8.5 cm by hospital day 2. The patient continued to have episodes of low-grade fever without leukocytosis.

Cultures of blood and tissue from the lesions were negative, ruling out bacterial infection. Magnetic resonance imaging of the left tibia was negative for osteomyelitis. Punch biopsy of the ulcer border was done on day 3 to evaluate for pyoderma gangrenosum.

On hospital day 5, the patient developed acute kidney injury, with a creatinine increase to 2.17 mg/dL over 24 hours from a baseline value of 0.82 mg/dL. The IV antibiotics were discontinued, and IV fluid hydration was started. At this time, diabetic ulcer secondary to infection and osteomyelitis were ruled out. The lesions were diagnosed as pyoderma gangrenosum.

The patient was started on prednisone 30 mg twice daily. After 2 days, the low-grade fevers resolved, both lesions began to heal, and his creatinine level returned to baseline (Figure 2). He was discharged on hospital day 10. The prednisone was tapered over 1 month, with wet-to-dry dressing changes for wound care.

After discharge, he remained adherent to his steroid regimen. At a follow-up visit to his dermatologist, the ulcers had fully closed, and the skin had begun to heal. Results of the punch biopsy study came back 2 days after the patient was discharged and further confirmed the diagnosis, with a mixed lymphocytic composition composed primarily of neutrophils.

APPROACH TO DIAGNOSIS

Pyoderma gangrenosum is rare, with an incidence of 3 to 10 cases per million people per year.¹ It is a rapidly progressive ulcerative condition typically associated with inflammatory bowel disease.² Despite its name, the condition involves neither gangrene nor infection. The ulcer typically appears on the legs and is rapidly growing, painful, and purulent, with tissue necrosis and a violaceous border.³

Pyoderma gangrenosum is often misdiagnosed as infective ulcer and inappropriately treated with antibiotics.² It can also be mistreated with surgical debridement, which can result in severe complications such as pathergy.¹

The differential diagnosis includes diabetic ulcer, peripheral vascular disease, vasculitis, bacterial infection, osteomyelitis, and malignancy. Because it presents as an open, necrotic ulcer, ruling out infection is a top priority.³ However, an initial workup to rule out infection or other conditions can delay diagnosis and treatment,¹ and treatment with broad-spectrum antibiotics poses the risk of nephrotoxicity and new complications during the hospital stay.

Diagnosis requires meeting 2 major criteria—ie, presence of the characteristic ulcerous lesion, and exclusion of other causes of skin ulceration—and at least 2 minor criteria including histologic confirmation of neutrophil infiltrate at the ulcer border, the presence of a systemic disease associated with pyoderma gangrenosum, and a rapid response to steroid treatment.^4,5

Our patient was at high risk for an infected diabetic ulcer. After infection was ruled out, clinical suspicion for pyoderma gangrenosum was high, given the patient’s presentation and his history of ulcerative colitis.

TREATMENT

Treatment of pyoderma gangrenosum begins with systemic corticosteroids, as was done in this patient. Additional measures depend on whether the disease is localized or extensive and can include wound care, topical treatments, immunosuppressants, and immunomodulators.¹

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.

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

To the Editor: I read with great interest the article “Aleukemic leukemia cutis” by Abraham et al,¹ as we recently had a case of this at my institution. The case is unique and quite intriguing; however, I found the pathologic description confusing and imprecise.

The authors state, “The findings were consistent with leukemic T cells with monocytic differentiation.”¹ This is based on their findings that the tumor cells expressed CD4, CD43, CD68, and lysozyme. However, the cells were negative for CD30, ALK-1, CD2, and CD3.

First, I must contest the authors’ claim that “the cells co-expressed T-cell markers (CD4 and CD43)”: CD4 and CD43 are not specific for T cells and are almost invariably seen on monocytes, especially in acute monoblastic/monocytic leukemia (AMoL; also known as M5 in the French-American-British classification system).^2,3 Therefore, the immunophenotype is perfect for an AMoL, but since there was no significant blood or bone marrow involvement and it was limited to the skin, this would best fit with a myeloid sarcoma, which frequently has a monocytic immunoprofile.^3,4

Additionally, this would not be a mixed-phenotype acute leukemia, T/myeloid, not otherwise specified, as that requires positivity for cytoplasmic CD3 or surface CD3, and that was conspicuously absent.⁵ Therefore, the appropriate workup and treatment should have essentially followed the course for acute myeloid leukemia,⁴ which is unclear from the present report as there is no mention of a molecular workup (eg, for FLT3 and NPM1 mutations). This would, in turn, have important treatment and prognostic implications.⁶

The reason for my comments is to bring to light the importance of exact pathologic diagnosis, especially when dealing with leukemia. We currently have a host of treatment options and prognostic tools for the various types of acute myeloid leukemia, but only when a clear and precise pathologic diagnosis is given.⁵

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

In Reply: We greatly appreciate our reader’s interest and response. He brings up a very good point. We have reviewed the reports and discussed it with our pathologists. On page 85, the sentence that begins, “The findings were consistent with leukemic T cells with monocytic differentiation” should actually read, “The findings were consistent with leukemic cells with monocytic differentiation.” The patient was appropriately treated for acute myeloid leukemia.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“The most radical act anyone can commit is to be happy.”
—Patch Adams

Patch Adams understood that laughter was important not only in healing, but also for filling the souls of those who care for patients. Each of us has a well within us, full of compassion, caring, and healing. Yet we daily face fear, pain, frustration, exhaustion, grief, and loss. All of these can deplete us while our patients are expecting more. There is perhaps no quicker way to replenish our wells than by the simple act of laughing.

As we take on the responsibilities of the world, many of us come to believe that laughter is something only children do. Research shows that children laugh about 400 times a day, but adults on average laugh only about 15 times. Especially in a healthcare environment plagued by burnout, we tend to become serious and don a stoic professional face. Some of us even believe that laughing makes us less professional.

As already mentioned, laughter brings physiological benefits to the body. It lessens people’s pain, so if anything, we need to be spreading more healing laughter in all of our interactions. It is like a bee pollinating flowers and bringing them to life. But how can you as a busy hospitalist do this? Here are five ways to bring smiles and giggles to the health care:

• Smile. Smiling is contagious. So called “mirror neurons” (important in early human development) allow babies to mimic facial and emotional responses and fire in response to sensory input. Have you ever noticed when someone yawns, others in a room will yawn as well? Those are mirror neurons at work. Smiling and laughter activate mirror neurons in the brain of primates and humans.1 This is why sitcoms often include laugh tracks—hearing the laughter makes us laugh. So laugh and watch: others will join you.
• Have some jokes ready. According to research those who can tell a good joke are viewed as more competent. Some data even suggests that employees with a good sense of humor are more likely to get a raise or promotion.2 However, humor can be tricky, as it is subjective. So, keep your jokes simple, nonoffensive, and short. Remember to know and read your audience.
• Plan silly times. Theme days replete with outfits or with sundries that may reflect your patients tastes or those of your inpatient teams can add smiles and joy while breaking a dismal routine.
• Be a good sport. Self-deprecation can be a way not only to bring a smile or two, but can help diffuse a tense situation. Being a good sport not only helps people spread joy to others but is a good way to be seen in a positive light by employers.
• Celebrate success and fun. Encourage smiling, pleasure, and laughing. When managers and administrators look like they are enjoying themselves, they set the company culture that it is a fun place to work.

Laughter is the best medicine. It not only heals others, but also helps lighten our daily loads, and brings a smile to our face and everyone we meet. Consider trying this opportunity to bring you and those around you a world of good.

Disclosures

The author has nothing to disclose.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.

“What is my veteran status?” “Should I receive any benefits from VA, like the GI Bill?”

Now women veterans have another convenient way to get answers to questions like those. Texting 855.829.6636 (855.VA.WOMEN) connects women veterans to the Women Veterans Call Center, where they will find information about VA benefits, health care, and resources. The new texting feature aligns the service with those of other VA call centers, the VA says.

Women are among the fastest-growing veteran demographics , the VA says, accounting for > 30% of the increase in veterans who served between 2014 and 2018. The number of women using VA health care services has tripled since 2000 from about 160,000 to > 500,000. But the VA has found that women veterans underuse VA care, largely due to a lack of knowledge about benefits, services, and their eligibility for them. As the number of women veterans continues to grow, the VA says, it is expanding its outreach to ensure they receive enrollment and benefits information through user-friendly and responsive means. The VA says it works to meet the unique requirements of women, “offering privacy, dignity, and sensitivity to gender-specific needs.” In addition to linking callers to information, the call center staff make direct referrals to Women Veteran Program Managers at every VAMC.

Since 2013, the call center has received nearly 83,000 inbound calls and has initiated almost 1.3 million outbound calls, resulting in communication with > 650,000 veterans.

Staffed by trained, compassionate female VA employees (many are also veterans), the call center is available Monday through Friday 8 am to 10 pm ET and Saturdays from 8 am to 6:30 pm ET. Veterans can call for themselves or on behalf of another woman veteran. Calls are free and confidential, texts and chats are anonymous. Veterans can call as often as they like, the VA says—“until you have the answer to your questions.”

For more information about the Women Veterans Call Center, visit https://www.womenshealth.va.gov/programoverview/wvcc.asp.