Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

Case Presentation: A 62-year-old male presented with shortness of breath and a cough productive of green sputum. He had a history of hyperlipidemia, posttraumatic stress disorder, bipolar disorder, obstructive sleep apnea, and a 50 pack-year history of smoking. His medications included prazosin, melatonin, lithium, and gabapentin. He also had a significant exposure history including asbestos and chemical paints following his leave from the military. At the initial evaluation, laboratory work revealed a leukocytosis with white blood cell (WBC) count 20 k/cm³and otherwise normal transaminases, albumin, and electrolytes. A chest X-ray revealed a new left hilar mass.

►Manisha Apte, MD, Chief Medical Resident, VA Boston Healthcare System (VABHS) and Boston Medical Center (BMC): To work up his new left hilar mass, a computed tomography (CT) of the chest was ordered (Figure 1), which revealed an apical left lower lobe mass extending into the left hilum encasing part of the ascending aorta. Enlarged mediastinal subcentimeter paratracheal and superior mediastinal lymph nodes also were identified and the pattern raised the concern for lymphangitic carcinomatosis. Dr. Fine, what do you make of the CT findings?

►Dr. Apte: Four weeks later, the patient presented with continued shortness of breath, fatigue, and fever. A repeat chest CT showed an opacity suggestive of pneumonia. Given the continued concern for cancer a CT-guided needle biopsy was performed and was once again negative for malignancy. The decision was made to pursue a video-assisted thorascopic surgery (VATS). Following the VATS, the patient developed rigors, fever, and tachycardia with new atrial fibrillation. While being evaluated hypercalcemia was identified, with further workup revealing a low parathyroid hormone (PTH) and low PTH-related peptide. Dr. Fine, the presence of hypercalcemia and a new arrythmia raised the possibility of sarcoidosis. Could this be sarcoidosis?


►Dr. Fine: Sarcoidosis is one of the great masqueraders in medicine. There is a type of sarcoidosis called nodular sarcoidosis where you see masslike distribution in the lung, but generally there are multiple masses and so this presentation would be atypical.³ There is also a phenomenon called sarcoidal reactions usually in the presence of cancer. Again, one tends to see multiple tiny lesions in the lung. It is certainly on the differential, but I would consider it to be less likely than cancer. It is also relatively common to develop atrial fibrillation after manipulation from a lung surgery.⁴ The other possibility I am concerned about is whether the mass is invading the mediastinum and involving the pericardium.


►Dr. Apte: Results from the VATS biopsy once again returned negative for malignancy and instead showed signs of focal micro-abscesses, atypical pneumocytes, and prominent neutrophils. A diagnosis of acute fibrinous organizing pneumonia (AFOP) was offered. Dr. Fine, what is AFOP?


►Dr. Fine: This is the first case of AFOP I had seen and probably the first case many in our department have seen. This is a relatively new entity with limited reported cases in the literature and is a pathological diagnosis originally recorded in autopsies from patients at the National Institutes of Health.^5,6 Given the complexity of the lesion, the diagnosis is difficult to make. Most commonly, AFOP is associated with other systemic entities, most commonly hematologic malignancies like lymphomas and leukemias. It has also been associated with vasculitis and certain drugs. The mechanism is poorly understood, and although pneumonia is a part of the term, this just implies there is inflammation of the lung (ie, pneumonitis).


► Dr. Apte: Given the association of AFOP with underlying hematologic malignancies, an emphasis was placed on another finding: the patient’s increasing WBC count. The total WBC count had been 20 k/cm³ at the time of his lung mass discovery but had increased to > 40 k/cm³ with a differential of neutrophils > 80%. Flow cytometry was negative, and his peripheral smear was read as normal. Dr. Gilbert, what might explain this patient’s leukocytosis?

►Gary Gilbert, MD, Section of Hematology and Oncology, VABHS and Associate Professor of Medicine, Harvard Medical School (HMS): This patient had an elevated WBC for 4 months. Initially, the cause was likely lithium as this is known to cause a leukocytosis.⁷ More recently, the total WBC had increased and there were a couple of other abnormalities: A consistently elevated absolute monocyte count and a markedly elevated mature neutrophil count. These findings are consistent with a leukemoid reaction (ie, a WBC count > 50,000/µL from causes other than leukemia). The question becomes what is this a leukemoid reaction in response to? Once we have excluded a lung malignancy (a well-known common cause of a leukemoid reaction) we must consider a clonal myeloproliferative disorder. This is particularly true because many things that cause a leukemoid reaction (eg, lobar pneumonia) do not cause a persistently elevated neutrophil count. That this patient does have a persistently elevated neutrophil count suggests something abnormal about the neutrophils themselves.

► Dr. Apte: A bone marrow biopsy was performed. Dr. Gilbert, can you comment on this patient’s bone marrow biopsy and whether a myeloproliferative disorder may have played a role in the marked leukocytosis?

► Dr. Gilbert: The bone marrow biopsy was hyperplastic with myeloid predominance and normal maturation in all lineages. A deep sequencing analysis demonstrated the absence of chromosomal abnormalities or genetic mutations that are associated with myeloproliferative disorders. This excludes the possibility of a myeloproliferative disorder.


► Dr. Apte: The patient was started on 60 mg of prednisone daily, which led to marked improvement in his symptoms. He was discharged in stable condition but presented again with abdominal pain. A complete blood count once again showed increased WBC and new thrombocytosis. A CT angiogram (CTA) showed the prior lung mass with new signs of central necrosis. In the abdomen, new splenic and renal infarct were identified, along with signs of multiple arterial thrombi in the abdomen and internal and external iliac vessel wall thickening. These findings were read as concerning for a medium vessel vasculitis. Dr. Kaur, what are some of the imaging findings you would expect to see in vasculitis, and what about this patient’s CT is consistent with a medium vessel vasculitis?


► Maneet Kaur, MD, Section of Rheumatology, VABHS: Vasculitis is inflammation of the vessel wall that can lead to vascular injury and activation of the coagulation cascade. Sometimes these findings can be seen on imaging with evidence of stenosis, microaneurysms, and thrombosis distal to the stenosis. The nomenclature of vasculitis is not simple and has been revised many times. Medium-vessel vasculitis does not just affect the medium vessels (eg, visceral arteries) but can overlap with distal large vessels and smaller cutaneous vessels.

The first thing that comes to mind in this case is polyarteritis nodosa (PAN), an immune complex-mediated medium vessel disease that can involve large and small vessels in muscle, nerve, and skin. It can also present with masses.

►Dr. Apte: To address the arterial thrombi seen on CTA, arterial-brachial indices were obtained and showed bilateral occlusive disease in his distal extremities; findings that could be explained by vasculitis. His VATS biopsy pathology was reviewed for signs of vasculitis. Dr. Huang, can you review these slides for us please?

►Qin Huang, MD, Department of Pathology and Laboratory Medicine, VABHS and Assistant Professor of Pathology, HMS: This patient had a history of smoking, and there are many black pigment-laden macrophages present in the lung tissue. There were areas of hemorrhage and fibrin deposition and an overall picture of organizing pneumonia. At a lower power, you can see neutrophils everywhere, some in the form of micro-abscesses. The arterial walls did not show signs of vasculitis (Figure 2). Based on the clinical information and radiology findings, we suspected an acute infection-related pneumonia or a primary lung malignancy causing obstruction pneumonia. We suggested a rebiopsy of the lung mass to rule out a primary lung malignancy.

► Dr. Apte: Given his CT findings, a serologic rheumatologic workup including antineutrophil cytoplasmic antibody, antinuclear antibody, and rheumatoid factors were sent and returned negative. The location of arterial wall inflammation on imaging made it unamenable for biopsy. The patient began to experience bilateral temporal pain, which raised the concern for a large vessel vasculitis, specifically giant cell arteritis. Bilateral temporal artery biopsies were obtained and were not suggestive of vasculitis. Dr. Kaur, we still do not have any serologic or biopsy confirmation to support a diagnosis of vasculitis. Can we still call this a vasculitis?

►Dr. Kaur: Few things can cause the picture that was seen radiographically. A few noninflammatory causes like fibromuscular dysplasia can cause both large and small vessel stenosis, but the elevations in erythrocyte sedimentation rate and C-reactive protein along with response to steroids makes these diagnoses unlikely. Sometimes we must make a clinical diagnosis for vasculitis based on the clinical picture, and I would feel comfortable treating this patient for vasculitis.

With that said, I remain concerned that this patient also has a malignancy. His WBC increased to > 70 k/cm³ and his calcium to > 13 mg/dL. These findings are hard to explain by vasculitis alone. There are cancer-associated vasculitis, and I suspect this is the explanation here.⁸ His temporal pain was pointing to large vessel involvement, so he could have an undifferentiated vasculitis.

► Dr. Apte: A decision was made to empirically treat with tocilizumab, an IL-6 receptor antagonist, for an undifferentiated autoimmune disease, in addition to tapering steroids. The patient underwent a second VATS, which again revealed AFOP but no signs of malignancy. Unfortunately, he developed multiple complications over the subsequent weeks and passed away. An autopsy was requested by family members and pathology from his lung mass was reviewed. (Figure 3). Dr. Huang, can you review these slides for us?

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

About 40% of patients with heart failure (HF) also have type 2 diabetes mellitus (T2DM).¹ Certain sodium-glucose cotransporter-2 (SGLT2) inhibitors have benefited patients with HF.² We report a case of a patient with T2DM who had signs and symptoms of hypervolemia after discontinuing the SGLT2 inhibitor empagliflozin. The patient was found to have previously undiagnosed HF. This case highlights the relationship between T2DM and HF and the benefits of treatment with SGLT2 inhibitors.

Case Presentation

A 58-year-old male presented for care at Malcolm Randall Veterans Affairs Medical Center in Gainseville, Florida, diabetes clinic. The patient was diagnosed with T2DM at age 32 years. At 36 years, he was started on subcutaneous insulin injections, and was switched to insulin pump therapy in his early 40s. At the time of evaluation, the T2DM was managed using an insulin pump, metformin, and acarbose. He had been prescribed empagliflozin 10 mg several months before presentation, but the medication ran out about 1 month prior to evaluation, and additional refills were unavailable.

The patient reported a 1-month history of worsening exertional shortness of breath, decreased exercise tolerance, and lower extremity swelling. Vitals signs, including respiratory rate and oxygen saturation were within normal limits. Bibasilar crackles and bilateral 2+ pitting pedal edema were noted. The remaining examination was unrevealing. His most recent glycated hemoglobin A_1c level from 1 month prior to the presentation was 6.4%.

Given the patient’s shortness of breath and evidence of fluid overload on examination, brain natriuretic peptide was obtained and was significantly elevated at 5,895 pg/mL. A transthoracic echocardiogram revealed left ventricular ejection fraction < 20%. The patient was started on furosemide 40 mg, pending receipt of empagliflozin. A cardiology evaluation also was recommended.

Cardiac catheterization identified significant obstructions to the left anterior descending and left circumflex arteries. The patient underwent successful percutaneous coronary intervention to these areas. Following initiation of medications and coronary revascularization, the patient reported significant symptom improvement. At the follow-up evaluation 8 weeks later, he was symptom free, and his physical examination was consistent with euvolemia.

Discussion

T2DM has been associated with adverse cardiovascular outcomes, including atherosclerotic heart disease and HF. There are several theories about the relationship between T2DM and HF, though the exact pathophysiology of this relationship is unknown.^3,4 One theory suggests diabetic cardiomyopathy as the cause. In patients with diabetic cardiomyopathy, there is early development of diastolic dysfunction, which eventually progresses to ventricular dysfunction. There is continued stimulation of the renin-angiotensin-aldosterone system that leads to death of cardiomyocytes, fibrosis, and remodeling, which worsens pump failure.⁵

SGLT2 inhibitors decrease hyperglycemia and hyperinsulinemia, potentially reducing HF risk. SGLT2 inhibitors decrease blood glucose levels by inhibiting SGLT2 in the proximal tubule, leading to a decrease of glucose reabsorption and an increase in excretion.^6,7 The EMPA-REG OUTCOME trial looked at cardiovascular outcomes in patients with T2DM at high risk for adverse cardiac events. There was a significant risk reduction in deaths and hospitalizations for HF in patients treated with empagliflozin.⁸

Conclusions

SGLT2 inhibitors have been shown to have a role in the management of HF in patients with T2DM. There is a risk of exacerbation or unmasking of HF when discontinuing SGLT2 inhibitors. To our knowledge, this is the first paper describing the discovery of HF following interruption of SGLT2 inhibitor treatment. The clinician and patient should monitor for signs and symptoms of fluid overload when stopping therapy. Further research into the benefits of a more comprehensive evaluation is needed.

Schizophrenia patients with parkinsonism show distinctive patterns of cortical surface markers, compared with schizophrenia patients without parkinsonism and healthy controls, results of a multimodal magnetic resonance imaging study suggest.

Sensorimotor abnormalities are common in schizophrenia patients, however, “the neurobiological mechanisms underlying parkinsonism in [schizophrenia], which in treated samples represents the unity of interplay between spontaneous and antipsychotic drug-exacerbated movement disorder, are poorly understood,” wrote Robert Christian Wolf, MD, of Heidelberg (Germany) University, and colleagues.

In a study published in Schizophrenia Research (2021 May;231:54-60), the investigators examined brain imaging findings from 20 healthy controls, 38 schizophrenia patients with parkinsonism (SZ-P), and 35 schizophrenia patients without parkinsonism (SZ-nonP). Dr. Wolf and colleagues examined three cortical surface markers: cortical thickness, complexity of cortical folding, and sulcus depth.

Compared with SZ-nonP patients, the SZ-P patients showed significantly increased complexity of cortical folding in the left supplementary motor cortex (SMC) and significantly decreased left postcentral sulcus (PCS) depth. In addition, left SMC activity was higher in both SZ-P and SZ-nonP patient groups, compared with controls.

In a regression analysis, the researchers examined relationships between parkinsonism severity and brain structure. They found that parkinsonism severity was negatively associated with left middle frontal complexity of cortical folding and left anterior cingulate cortex cortical thickness.

“Overall, the data support the notion that cortical features of distinct neurodevelopmental origin, particularly cortical folding indices such as [complexity of cortical folding] and sulcus depth, contribute to the pathogenesis of parkinsonism in SZ,” the researchers wrote.

The study findings were limited by several factors, including the cross-sectional design, the potential limitations of the Simpson-Angus Scale in characterizing parkinsonism, the inability to record lifetime antibiotics exposure in the patient population, and the inability to identify changes in brain stem nuclei, the researchers noted. However, the results were strengthened by the well-matched study groups and use of multimodal MRI, they said.

Consequently, “these data provide novel insights into different trajectories of cortical development in SZ patients evidencing parkinsonism,” and suggest a link between abnormal neurodevelopmental processes and an increased risk for movement disorders in schizophrenia, they concluded.

The study was funded by the German Research Foundation and the German Federal Ministry of Education and Research. Dr. Wolf and colleagues disclosed no conflicts.

Schizophrenia patients with parkinsonism show distinctive patterns of cortical surface markers, compared with schizophrenia patients without parkinsonism and healthy controls, results of a multimodal magnetic resonance imaging study suggest.

Sensorimotor abnormalities are common in schizophrenia patients, however, “the neurobiological mechanisms underlying parkinsonism in [schizophrenia], which in treated samples represents the unity of interplay between spontaneous and antipsychotic drug-exacerbated movement disorder, are poorly understood,” wrote Robert Christian Wolf, MD, of Heidelberg (Germany) University, and colleagues.

In a study published in Schizophrenia Research (2021 May;231:54-60), the investigators examined brain imaging findings from 20 healthy controls, 38 schizophrenia patients with parkinsonism (SZ-P), and 35 schizophrenia patients without parkinsonism (SZ-nonP). Dr. Wolf and colleagues examined three cortical surface markers: cortical thickness, complexity of cortical folding, and sulcus depth.

Compared with SZ-nonP patients, the SZ-P patients showed significantly increased complexity of cortical folding in the left supplementary motor cortex (SMC) and significantly decreased left postcentral sulcus (PCS) depth. In addition, left SMC activity was higher in both SZ-P and SZ-nonP patient groups, compared with controls.

In a regression analysis, the researchers examined relationships between parkinsonism severity and brain structure. They found that parkinsonism severity was negatively associated with left middle frontal complexity of cortical folding and left anterior cingulate cortex cortical thickness.

“Overall, the data support the notion that cortical features of distinct neurodevelopmental origin, particularly cortical folding indices such as [complexity of cortical folding] and sulcus depth, contribute to the pathogenesis of parkinsonism in SZ,” the researchers wrote.

The study findings were limited by several factors, including the cross-sectional design, the potential limitations of the Simpson-Angus Scale in characterizing parkinsonism, the inability to record lifetime antibiotics exposure in the patient population, and the inability to identify changes in brain stem nuclei, the researchers noted. However, the results were strengthened by the well-matched study groups and use of multimodal MRI, they said.

Consequently, “these data provide novel insights into different trajectories of cortical development in SZ patients evidencing parkinsonism,” and suggest a link between abnormal neurodevelopmental processes and an increased risk for movement disorders in schizophrenia, they concluded.

The study was funded by the German Research Foundation and the German Federal Ministry of Education and Research. Dr. Wolf and colleagues disclosed no conflicts.

Schizophrenia patients with parkinsonism show distinctive patterns of cortical surface markers, compared with schizophrenia patients without parkinsonism and healthy controls, results of a multimodal magnetic resonance imaging study suggest.

Sensorimotor abnormalities are common in schizophrenia patients, however, “the neurobiological mechanisms underlying parkinsonism in [schizophrenia], which in treated samples represents the unity of interplay between spontaneous and antipsychotic drug-exacerbated movement disorder, are poorly understood,” wrote Robert Christian Wolf, MD, of Heidelberg (Germany) University, and colleagues.

In a study published in Schizophrenia Research (2021 May;231:54-60), the investigators examined brain imaging findings from 20 healthy controls, 38 schizophrenia patients with parkinsonism (SZ-P), and 35 schizophrenia patients without parkinsonism (SZ-nonP). Dr. Wolf and colleagues examined three cortical surface markers: cortical thickness, complexity of cortical folding, and sulcus depth.

Compared with SZ-nonP patients, the SZ-P patients showed significantly increased complexity of cortical folding in the left supplementary motor cortex (SMC) and significantly decreased left postcentral sulcus (PCS) depth. In addition, left SMC activity was higher in both SZ-P and SZ-nonP patient groups, compared with controls.

In a regression analysis, the researchers examined relationships between parkinsonism severity and brain structure. They found that parkinsonism severity was negatively associated with left middle frontal complexity of cortical folding and left anterior cingulate cortex cortical thickness.

“Overall, the data support the notion that cortical features of distinct neurodevelopmental origin, particularly cortical folding indices such as [complexity of cortical folding] and sulcus depth, contribute to the pathogenesis of parkinsonism in SZ,” the researchers wrote.

The study findings were limited by several factors, including the cross-sectional design, the potential limitations of the Simpson-Angus Scale in characterizing parkinsonism, the inability to record lifetime antibiotics exposure in the patient population, and the inability to identify changes in brain stem nuclei, the researchers noted. However, the results were strengthened by the well-matched study groups and use of multimodal MRI, they said.

Consequently, “these data provide novel insights into different trajectories of cortical development in SZ patients evidencing parkinsonism,” and suggest a link between abnormal neurodevelopmental processes and an increased risk for movement disorders in schizophrenia, they concluded.

The study was funded by the German Research Foundation and the German Federal Ministry of Education and Research. Dr. Wolf and colleagues disclosed no conflicts.

The workload of individual hospitalists has long been a hot-button issue. In a 2013 survey of hospitalists, 40% felt workloads were unsafe on a monthly basis, and 22% reported ordering unnecessary testing or procedures because of time pressure.¹ In a 2014 analysis of over 20,000 admissions to an academic hospital medicine service, increasing workload led to increased length of stay and cost per case.² Although these studies suggest a “sweet spot” for hospitalist workload, many groups face constant pressure to increase revenue.

Over the past decade there has been a significant change in how hospital medicine programs are financed. In the 2010 State of Hospital Medicine (SoHM), the median financial support per physician hospitalist in adult hospital medicine groups (HMGs) was $98,253. By the 2020 SoHM, the financial support was $198,750, an increase of $100,497 in just 10 years. When this is combined with the explosive growth in the number of hospitalists, there is one inescapable conclusion – hospital medicine is expensive.

Over this same 10 years, net collections per hospitalist grew from $194,440 in 2010 to $216,779 in 2020, an increase of $22,339. The increase was caused by higher collections per encounter, not more encounters. Additionally, median compensation for adult/internal medicine hospitalists increased over the same period from $215,000 to $307,336, an increase of $92,336, or 43%. That is an increase of 3.7% per year, more than twice the rate of inflation or wage growth in the general economy over the same period. About 75% of this increase was funded by hospital support. It is clear – health care systems continue to find value in investing in hospitalists and hospital medicine programs.

With mounting costs for hospitals, there is pressure for the hospitalist model of care to change or for yearly billable encounters per hospitalist full-time equivalent to increase. Yet, the productivity of hospitalists, as measured by median billable encounters per year has remained flat. The 2010 SoHM listed median number of billable encounters per year for an internal medicine hospitalist as 2,230. In 2020, the number is 2,246 – a trivial 0.7% increase per decade, what amounts to a rounding error. There has been wiggle up and down over the years, but I suspect these are not trends but noise.

So the question is why. I think it is partly because hospital medicine leaders together with the leaders of their health care systems seem to be reaching an equilibrium. Productivity will always remain an expectation. This expectation will vary based on local circumstances. But for many HMGs, the days when productivity is pushed as the primary objective seem to be disappearing. Most hospital leaders seem to now understand that high productivity can be detrimental to other program goals.

But if productivity is flat, do 40% of hospitalists still feel they are providing unsafe care on a monthly basis? Without another study we don’t know, but here are some reasons why I’m hopeful. First, the hospitalist workforce is more experienced than 10 years ago and may be more efficient. Second, hospital medicine groups are larger and are therefore enabled to schedule more flexibly or enact jeopardy systems to level out workload on busy days. And lastly, hospitalists who feel they are providing unsafe care find greener pastures. The 2010 SoHM reported adult hospital medicine programs had a median 14.3% turnover rate. The 2020 SoHM turnover was 10.9%. While this is up from 2018 (7.4%) and 2016 (6.9%), the general trend is down.

Additionally, we all need to consider the possibility that there will be a disruptive innovation that will allow greater productivity for individual hospitalists while maintaining value. It is apparent the EHR is not yet that breakthrough. We all need to keep our eyes open, stay flexible, and be prepared to meet evolving demands on our programs.

We will see constant demands on hospitalists. But I’m hopeful that going forward expectations will increasingly shift away from simply working harder and seeing more patients, toward goals related to improving performance. Training programs generally produce excellent clinicians, but they often do not equip physicians to be excellent hospitalists. Successful hospital medicine programs will recruit lifelong learners and career hospitalists who are flexible and willing to innovate and adapt. The best programs will have structures in place to help excellent clinicians mature into the role of excellent hospitalists, and leaders that create and foster an environment of excellence.

Discover more 2020 SoHM Report data at www.hospitalmedicine.org/sohm.

Dr. Frederickson is medical director, hospital medicine and palliative care, at CHI Health, Omaha, Neb., and assistant professor at Creighton University, Omaha.

References

1. Michtalik HJ et al. Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists. JAMA Intern Med. 2013;173(5):375-7. doi: 10.1001/jamainternmed.2013.1864.

2. Elliott DJ et al. Effect of Hospitalist Workload on the Quality and Efficiency of Care. JAMA Intern Med. 2014;174(5):786-93. doi: 10.1001/jamainternmed.2014.300.

The workload of individual hospitalists has long been a hot-button issue. In a 2013 survey of hospitalists, 40% felt workloads were unsafe on a monthly basis, and 22% reported ordering unnecessary testing or procedures because of time pressure.¹ In a 2014 analysis of over 20,000 admissions to an academic hospital medicine service, increasing workload led to increased length of stay and cost per case.² Although these studies suggest a “sweet spot” for hospitalist workload, many groups face constant pressure to increase revenue.

Over the past decade there has been a significant change in how hospital medicine programs are financed. In the 2010 State of Hospital Medicine (SoHM), the median financial support per physician hospitalist in adult hospital medicine groups (HMGs) was $98,253. By the 2020 SoHM, the financial support was $198,750, an increase of $100,497 in just 10 years. When this is combined with the explosive growth in the number of hospitalists, there is one inescapable conclusion – hospital medicine is expensive.

Over this same 10 years, net collections per hospitalist grew from $194,440 in 2010 to $216,779 in 2020, an increase of $22,339. The increase was caused by higher collections per encounter, not more encounters. Additionally, median compensation for adult/internal medicine hospitalists increased over the same period from $215,000 to $307,336, an increase of $92,336, or 43%. That is an increase of 3.7% per year, more than twice the rate of inflation or wage growth in the general economy over the same period. About 75% of this increase was funded by hospital support. It is clear – health care systems continue to find value in investing in hospitalists and hospital medicine programs.

With mounting costs for hospitals, there is pressure for the hospitalist model of care to change or for yearly billable encounters per hospitalist full-time equivalent to increase. Yet, the productivity of hospitalists, as measured by median billable encounters per year has remained flat. The 2010 SoHM listed median number of billable encounters per year for an internal medicine hospitalist as 2,230. In 2020, the number is 2,246 – a trivial 0.7% increase per decade, what amounts to a rounding error. There has been wiggle up and down over the years, but I suspect these are not trends but noise.

So the question is why. I think it is partly because hospital medicine leaders together with the leaders of their health care systems seem to be reaching an equilibrium. Productivity will always remain an expectation. This expectation will vary based on local circumstances. But for many HMGs, the days when productivity is pushed as the primary objective seem to be disappearing. Most hospital leaders seem to now understand that high productivity can be detrimental to other program goals.

But if productivity is flat, do 40% of hospitalists still feel they are providing unsafe care on a monthly basis? Without another study we don’t know, but here are some reasons why I’m hopeful. First, the hospitalist workforce is more experienced than 10 years ago and may be more efficient. Second, hospital medicine groups are larger and are therefore enabled to schedule more flexibly or enact jeopardy systems to level out workload on busy days. And lastly, hospitalists who feel they are providing unsafe care find greener pastures. The 2010 SoHM reported adult hospital medicine programs had a median 14.3% turnover rate. The 2020 SoHM turnover was 10.9%. While this is up from 2018 (7.4%) and 2016 (6.9%), the general trend is down.

Additionally, we all need to consider the possibility that there will be a disruptive innovation that will allow greater productivity for individual hospitalists while maintaining value. It is apparent the EHR is not yet that breakthrough. We all need to keep our eyes open, stay flexible, and be prepared to meet evolving demands on our programs.

We will see constant demands on hospitalists. But I’m hopeful that going forward expectations will increasingly shift away from simply working harder and seeing more patients, toward goals related to improving performance. Training programs generally produce excellent clinicians, but they often do not equip physicians to be excellent hospitalists. Successful hospital medicine programs will recruit lifelong learners and career hospitalists who are flexible and willing to innovate and adapt. The best programs will have structures in place to help excellent clinicians mature into the role of excellent hospitalists, and leaders that create and foster an environment of excellence.

Discover more 2020 SoHM Report data at www.hospitalmedicine.org/sohm.

Dr. Frederickson is medical director, hospital medicine and palliative care, at CHI Health, Omaha, Neb., and assistant professor at Creighton University, Omaha.

References

1. Michtalik HJ et al. Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists. JAMA Intern Med. 2013;173(5):375-7. doi: 10.1001/jamainternmed.2013.1864.

2. Elliott DJ et al. Effect of Hospitalist Workload on the Quality and Efficiency of Care. JAMA Intern Med. 2014;174(5):786-93. doi: 10.1001/jamainternmed.2014.300.

The workload of individual hospitalists has long been a hot-button issue. In a 2013 survey of hospitalists, 40% felt workloads were unsafe on a monthly basis, and 22% reported ordering unnecessary testing or procedures because of time pressure.¹ In a 2014 analysis of over 20,000 admissions to an academic hospital medicine service, increasing workload led to increased length of stay and cost per case.² Although these studies suggest a “sweet spot” for hospitalist workload, many groups face constant pressure to increase revenue.

Over the past decade there has been a significant change in how hospital medicine programs are financed. In the 2010 State of Hospital Medicine (SoHM), the median financial support per physician hospitalist in adult hospital medicine groups (HMGs) was $98,253. By the 2020 SoHM, the financial support was $198,750, an increase of $100,497 in just 10 years. When this is combined with the explosive growth in the number of hospitalists, there is one inescapable conclusion – hospital medicine is expensive.

Over this same 10 years, net collections per hospitalist grew from $194,440 in 2010 to $216,779 in 2020, an increase of $22,339. The increase was caused by higher collections per encounter, not more encounters. Additionally, median compensation for adult/internal medicine hospitalists increased over the same period from $215,000 to $307,336, an increase of $92,336, or 43%. That is an increase of 3.7% per year, more than twice the rate of inflation or wage growth in the general economy over the same period. About 75% of this increase was funded by hospital support. It is clear – health care systems continue to find value in investing in hospitalists and hospital medicine programs.

With mounting costs for hospitals, there is pressure for the hospitalist model of care to change or for yearly billable encounters per hospitalist full-time equivalent to increase. Yet, the productivity of hospitalists, as measured by median billable encounters per year has remained flat. The 2010 SoHM listed median number of billable encounters per year for an internal medicine hospitalist as 2,230. In 2020, the number is 2,246 – a trivial 0.7% increase per decade, what amounts to a rounding error. There has been wiggle up and down over the years, but I suspect these are not trends but noise.

So the question is why. I think it is partly because hospital medicine leaders together with the leaders of their health care systems seem to be reaching an equilibrium. Productivity will always remain an expectation. This expectation will vary based on local circumstances. But for many HMGs, the days when productivity is pushed as the primary objective seem to be disappearing. Most hospital leaders seem to now understand that high productivity can be detrimental to other program goals.

But if productivity is flat, do 40% of hospitalists still feel they are providing unsafe care on a monthly basis? Without another study we don’t know, but here are some reasons why I’m hopeful. First, the hospitalist workforce is more experienced than 10 years ago and may be more efficient. Second, hospital medicine groups are larger and are therefore enabled to schedule more flexibly or enact jeopardy systems to level out workload on busy days. And lastly, hospitalists who feel they are providing unsafe care find greener pastures. The 2010 SoHM reported adult hospital medicine programs had a median 14.3% turnover rate. The 2020 SoHM turnover was 10.9%. While this is up from 2018 (7.4%) and 2016 (6.9%), the general trend is down.

Additionally, we all need to consider the possibility that there will be a disruptive innovation that will allow greater productivity for individual hospitalists while maintaining value. It is apparent the EHR is not yet that breakthrough. We all need to keep our eyes open, stay flexible, and be prepared to meet evolving demands on our programs.

We will see constant demands on hospitalists. But I’m hopeful that going forward expectations will increasingly shift away from simply working harder and seeing more patients, toward goals related to improving performance. Training programs generally produce excellent clinicians, but they often do not equip physicians to be excellent hospitalists. Successful hospital medicine programs will recruit lifelong learners and career hospitalists who are flexible and willing to innovate and adapt. The best programs will have structures in place to help excellent clinicians mature into the role of excellent hospitalists, and leaders that create and foster an environment of excellence.

Discover more 2020 SoHM Report data at www.hospitalmedicine.org/sohm.

Dr. Frederickson is medical director, hospital medicine and palliative care, at CHI Health, Omaha, Neb., and assistant professor at Creighton University, Omaha.

References

1. Michtalik HJ et al. Impact of Attending Physician Workload on Patient Care: A Survey of Hospitalists. JAMA Intern Med. 2013;173(5):375-7. doi: 10.1001/jamainternmed.2013.1864.

2. Elliott DJ et al. Effect of Hospitalist Workload on the Quality and Efficiency of Care. JAMA Intern Med. 2014;174(5):786-93. doi: 10.1001/jamainternmed.2014.300.

Testing COVID-19 vaccines in young children is going to be tricky. Deciding how to approve them and who should get them may be even more difficult.

So far, the vaccines available to Americans ages 12 and up have sailed through the U.S. Food and Drug Administration’s regulatory checks, taking advantage of an accelerated clearance process called an Emergency Use Authorization (EUA). 

EUAs set a lower bar for effectiveness, saying the vaccines may be safe and effective based on just a few months of data. 

But with COVID cases plummeting in the United States and children historically seeing far less serious disease than adults, a panel of expert advisors to the FDA was asked to deliberate on Thursday whether the agency could consider vaccines for this age group under the same standard. 

Stated another way: Is COVID an emergency for kids? 

There’s another wrinkle in the mix, too – heart inflammation, which appears to be a very rare emerging adverse event tied to vaccination. It seems to happen more often in teens and young adults. To date, cases of myocarditis and pericarditis appear to be happening in 16 to 30 people for every 1 million doses given. 

But if it is conclusively linked to the shots, some wonder whether it might tip the balance between benefits and risks for kids.

That left some of the experts who sit on the FDA’s advisory committee for vaccines and related biological products urging the FDA to take its time and more thoroughly study the shots before they’re given to millions of children.
 

Vaccine studies different in children?

Clinical studies of the vaccines in teens and adults have thus far relied on some straightforward math. You take two groups of similar people. You give half the vaccine and half a placebo. Then you wait and see which group has more symptomatic infections. To date, the vaccines have dramatically cut the risk of getting severely ill with COVID for every age group tested.

But COVID infections are falling rapidly in the U.S., and that may make it more difficult for researchers to conduct a similar kind of experiment in children.

The FDA is considering different approaches to figure out whether a vaccine would be effective in kids, including something called an “immunobridging trial.” 

In bridging trials, researchers don’t look for infections; rather, they look for proven signs that someone has developed immunity, like antibody levels. Those biomarkers are then compared to the immune responses of younger adults who have demonstrated good protection against infection.

The main advantage of bridging studies is speed. It’s possible to get a snapshot of how the immune system responds to a vaccine within weeks of the final dose.

The drawback is that researchers don’t know exactly what to look for to judge how well the shots are generating protection. 

That’s made even more difficult because kids’ immune systems are still developing, so it may be tough to draw direct parallels to adults.

“We don’t know what the serologic correlate of immunity is now. We don’t know how much antibody you have to get in order to be protected. We don’t know what the role of T cells will be,” said H. Cody Meissner, MD, chief of the division of pediatric infectious disease at Tufts Medical Center, Boston.

“I have so much sympathy for the FDA because these are enormous problems, and you have to make a decision,” said Dr. Meissner, who is a member of the FDA’s vaccines and related biological products advisory committee.
 

Speed vaccines to market, or gather more data?

The plummeting rate of infections in the United States also means that it may be more difficult for the FDA to justify allowing a vaccine on the market for emergency use for children under age 12.

In its recent advisory committee meeting, the agency asked the panel whether it should consider COVID vaccines for children under an EUA or a biologics license application (BLA), aka full approval. 

A BLA typically means the agency considers a year or two of data on a new product, rather than just 2 months’ worth. Emergency use also allows products on the market under a looser standard – they “may be” safe and effective, instead of has been proven to be safe and effective.

Several committee members said they didn’t feel the United States was still in an emergency with COVID and couldn’t see the FDA allowing a vaccine to be used in kids that wasn’t given the agency’s highest level of scrutiny, particularly with reports of adverse events like myocarditis coming to light.

“I just want to be sure the price we pay for vaccinating millions of children justifies the side effects, and I don’t think we know that yet,” Dr. Meissner said.

Others acknowledged that there was little risk to kids now with infections on the decline but said that picture could change as variants spread, schools reopen, and colder temperatures force people indoors. 

The FDA must decide whether to act based on where we are now or where we could be in a few months.

“I think it’s the million-dollar question right now,” said Hannah Kirking, MD, a medical epidemiologist with the Centers for Disease Control and Prevention who presented new and unpublished data on COVID’s impact in children to the FDA’s advisory committee.

She said prospective studies tracking the way COVID moves through a household with weekly testing from New York City and Utah had found that children catch and transmit COVID almost as readily as adults. But they don’t usually get as sick as adults do, so their cases are easy to miss. 

She also presented the results of blood tests from samples around the country looking for evidence of past infection. In these seroprevalence studies, about 27% of children under age 17 had antibodies to COVID – the most of any age group. So more than 1 in 4 kids already has some natural immunity.

That means the main benefit of vaccinating children might be the protection of others, while they still bear the risks – however tiny.

Some experts felt that wasn’t enough reason to justify mass distribution of the vaccines to kids, and from a regulatory standpoint, it might not be permissible.

“FDA can only approve a medical product in a population if the benefits outweigh the risks in that population,” said Peter Doshi, PhD, assistant professor of pharmaceutical health services research in the University of Maryland’s school of pharmacy, Baltimore.

“If benefits don’t outweigh risks in children, it can’t be indicated for children. Full stop,” said Dr. Doshi, who is also an editor at the BMJ.

He said there’s another way to give children access to vaccines, through an expanded access or compassionate use program. Because most COVID deaths have been in children with underlying health conditions, Dr. Doshi and others said it might make sense to allow expanded access – which would get vaccines to children at high risk for complications – without turning them loose on millions before they are more thoroughly studied.

“It’s not a particularly attractive option for industry, because there’s no money to be made. Your medicine can’t be commercialized under expanded access. The most you can reap is manufacturing cost, which is not a lot,” he said.

Art Caplan, a professor of bioethics at New York University’s Langone medical center, said the argument for vaccinating children for flu falls along the same lines. The benefit-to-risk ratio is finely balanced in children.  The main value of protecting them is to protect others.

“Flu rarely kills young folks. But you’re really trying to protect old folks and that’s the classic example,” he said.

What’s more, he said the idea that children would take on some risk with a vaccine for little personal benefit is oversimplified.

“Yes, you might get vaccinated to prevent harm to others, but those others are providing benefits to you. It’s not a one-way street. I think that’s a little morally distorted,” Mr. Caplan said. “Being able to keep society open benefits kids and adults alike.”

Other committee members felt like it was too early to sound the all-clear on COVID and said the FDA should authorize vaccines for children as quickly as it had for other age groups.

“We are still, I believe, in an emergency situation. I think that when this virus goes into our children, which is what it’s going to do, that will give it an incubator to change,” said Oveta Fuller, PhD, associate professor of microbiology and immunology at the University of Michigan, Ann Arbor.

Fuller said that for the good of the world, Americans needed to vaccinate children to prevent the virus from mutating and creating new and potentially more dangerous variants.
 

Weighing risk over safety

Beth Thielen, MD, PhD, pediatric infectious disease specialist and virologist at the University of Minnesota, Minneapolis, said she had not followed the committee’s discussions, but about once a month she treats kids who are very sick because of the virus – either because of a COVID infection or because of multisystem inflammatory syndrome (MIS-C), an inflammatory reaction that strikes after infection.

She’s worried about how the virus has already changed. She said the kind of disease she’s seeing in kids now is different than what she saw in the early months of the pandemic.

“In the last couple of months, I’ve actually seen a few cases of severe pulmonary disease, more similar to adult disease in children,” Dr. Thielen said. “I see on the horizon that we could start seeing more significant disease in young people, and then the risks of being unvaccinated go up substantially.” 

But she also knows nobody has a crystal ball, and right now, everything seems to be trending in the right direction with COVID. That makes the risk-to-benefit consideration murkier.

“The question in my mind is, what is the risk of side effects from the vaccine?” she said. “I think we really need to know what the safety profile of vaccine looks like in children because we do have a decent understanding now what risk from disease looks like, because it’s small, but we are seeing it.”

Dr. Thielen said she’ll be keeping an eye on the next meeting of the CDC’s Advisory Committee on Immunization Practices for more answers.

A version of this article first appeared on Medscape.com.

Testing COVID-19 vaccines in young children is going to be tricky. Deciding how to approve them and who should get them may be even more difficult.

So far, the vaccines available to Americans ages 12 and up have sailed through the U.S. Food and Drug Administration’s regulatory checks, taking advantage of an accelerated clearance process called an Emergency Use Authorization (EUA). 

EUAs set a lower bar for effectiveness, saying the vaccines may be safe and effective based on just a few months of data. 

But with COVID cases plummeting in the United States and children historically seeing far less serious disease than adults, a panel of expert advisors to the FDA was asked to deliberate on Thursday whether the agency could consider vaccines for this age group under the same standard. 

Stated another way: Is COVID an emergency for kids? 

There’s another wrinkle in the mix, too – heart inflammation, which appears to be a very rare emerging adverse event tied to vaccination. It seems to happen more often in teens and young adults. To date, cases of myocarditis and pericarditis appear to be happening in 16 to 30 people for every 1 million doses given. 

But if it is conclusively linked to the shots, some wonder whether it might tip the balance between benefits and risks for kids.

That left some of the experts who sit on the FDA’s advisory committee for vaccines and related biological products urging the FDA to take its time and more thoroughly study the shots before they’re given to millions of children.
 

Vaccine studies different in children?

Clinical studies of the vaccines in teens and adults have thus far relied on some straightforward math. You take two groups of similar people. You give half the vaccine and half a placebo. Then you wait and see which group has more symptomatic infections. To date, the vaccines have dramatically cut the risk of getting severely ill with COVID for every age group tested.

But COVID infections are falling rapidly in the U.S., and that may make it more difficult for researchers to conduct a similar kind of experiment in children.

The FDA is considering different approaches to figure out whether a vaccine would be effective in kids, including something called an “immunobridging trial.” 

In bridging trials, researchers don’t look for infections; rather, they look for proven signs that someone has developed immunity, like antibody levels. Those biomarkers are then compared to the immune responses of younger adults who have demonstrated good protection against infection.

The main advantage of bridging studies is speed. It’s possible to get a snapshot of how the immune system responds to a vaccine within weeks of the final dose.

The drawback is that researchers don’t know exactly what to look for to judge how well the shots are generating protection. 

That’s made even more difficult because kids’ immune systems are still developing, so it may be tough to draw direct parallels to adults.

“We don’t know what the serologic correlate of immunity is now. We don’t know how much antibody you have to get in order to be protected. We don’t know what the role of T cells will be,” said H. Cody Meissner, MD, chief of the division of pediatric infectious disease at Tufts Medical Center, Boston.

“I have so much sympathy for the FDA because these are enormous problems, and you have to make a decision,” said Dr. Meissner, who is a member of the FDA’s vaccines and related biological products advisory committee.
 

Speed vaccines to market, or gather more data?

The plummeting rate of infections in the United States also means that it may be more difficult for the FDA to justify allowing a vaccine on the market for emergency use for children under age 12.

In its recent advisory committee meeting, the agency asked the panel whether it should consider COVID vaccines for children under an EUA or a biologics license application (BLA), aka full approval. 

A BLA typically means the agency considers a year or two of data on a new product, rather than just 2 months’ worth. Emergency use also allows products on the market under a looser standard – they “may be” safe and effective, instead of has been proven to be safe and effective.

Several committee members said they didn’t feel the United States was still in an emergency with COVID and couldn’t see the FDA allowing a vaccine to be used in kids that wasn’t given the agency’s highest level of scrutiny, particularly with reports of adverse events like myocarditis coming to light.

“I just want to be sure the price we pay for vaccinating millions of children justifies the side effects, and I don’t think we know that yet,” Dr. Meissner said.

Others acknowledged that there was little risk to kids now with infections on the decline but said that picture could change as variants spread, schools reopen, and colder temperatures force people indoors. 

The FDA must decide whether to act based on where we are now or where we could be in a few months.

“I think it’s the million-dollar question right now,” said Hannah Kirking, MD, a medical epidemiologist with the Centers for Disease Control and Prevention who presented new and unpublished data on COVID’s impact in children to the FDA’s advisory committee.

She said prospective studies tracking the way COVID moves through a household with weekly testing from New York City and Utah had found that children catch and transmit COVID almost as readily as adults. But they don’t usually get as sick as adults do, so their cases are easy to miss. 

She also presented the results of blood tests from samples around the country looking for evidence of past infection. In these seroprevalence studies, about 27% of children under age 17 had antibodies to COVID – the most of any age group. So more than 1 in 4 kids already has some natural immunity.

That means the main benefit of vaccinating children might be the protection of others, while they still bear the risks – however tiny.

Some experts felt that wasn’t enough reason to justify mass distribution of the vaccines to kids, and from a regulatory standpoint, it might not be permissible.

“FDA can only approve a medical product in a population if the benefits outweigh the risks in that population,” said Peter Doshi, PhD, assistant professor of pharmaceutical health services research in the University of Maryland’s school of pharmacy, Baltimore.

“If benefits don’t outweigh risks in children, it can’t be indicated for children. Full stop,” said Dr. Doshi, who is also an editor at the BMJ.

He said there’s another way to give children access to vaccines, through an expanded access or compassionate use program. Because most COVID deaths have been in children with underlying health conditions, Dr. Doshi and others said it might make sense to allow expanded access – which would get vaccines to children at high risk for complications – without turning them loose on millions before they are more thoroughly studied.

“It’s not a particularly attractive option for industry, because there’s no money to be made. Your medicine can’t be commercialized under expanded access. The most you can reap is manufacturing cost, which is not a lot,” he said.

Art Caplan, a professor of bioethics at New York University’s Langone medical center, said the argument for vaccinating children for flu falls along the same lines. The benefit-to-risk ratio is finely balanced in children.  The main value of protecting them is to protect others.

“Flu rarely kills young folks. But you’re really trying to protect old folks and that’s the classic example,” he said.

What’s more, he said the idea that children would take on some risk with a vaccine for little personal benefit is oversimplified.

“Yes, you might get vaccinated to prevent harm to others, but those others are providing benefits to you. It’s not a one-way street. I think that’s a little morally distorted,” Mr. Caplan said. “Being able to keep society open benefits kids and adults alike.”

Other committee members felt like it was too early to sound the all-clear on COVID and said the FDA should authorize vaccines for children as quickly as it had for other age groups.

“We are still, I believe, in an emergency situation. I think that when this virus goes into our children, which is what it’s going to do, that will give it an incubator to change,” said Oveta Fuller, PhD, associate professor of microbiology and immunology at the University of Michigan, Ann Arbor.

Fuller said that for the good of the world, Americans needed to vaccinate children to prevent the virus from mutating and creating new and potentially more dangerous variants.
 

Weighing risk over safety

Beth Thielen, MD, PhD, pediatric infectious disease specialist and virologist at the University of Minnesota, Minneapolis, said she had not followed the committee’s discussions, but about once a month she treats kids who are very sick because of the virus – either because of a COVID infection or because of multisystem inflammatory syndrome (MIS-C), an inflammatory reaction that strikes after infection.

She’s worried about how the virus has already changed. She said the kind of disease she’s seeing in kids now is different than what she saw in the early months of the pandemic.

“In the last couple of months, I’ve actually seen a few cases of severe pulmonary disease, more similar to adult disease in children,” Dr. Thielen said. “I see on the horizon that we could start seeing more significant disease in young people, and then the risks of being unvaccinated go up substantially.” 

But she also knows nobody has a crystal ball, and right now, everything seems to be trending in the right direction with COVID. That makes the risk-to-benefit consideration murkier.

“The question in my mind is, what is the risk of side effects from the vaccine?” she said. “I think we really need to know what the safety profile of vaccine looks like in children because we do have a decent understanding now what risk from disease looks like, because it’s small, but we are seeing it.”

Dr. Thielen said she’ll be keeping an eye on the next meeting of the CDC’s Advisory Committee on Immunization Practices for more answers.

A version of this article first appeared on Medscape.com.

Testing COVID-19 vaccines in young children is going to be tricky. Deciding how to approve them and who should get them may be even more difficult.

So far, the vaccines available to Americans ages 12 and up have sailed through the U.S. Food and Drug Administration’s regulatory checks, taking advantage of an accelerated clearance process called an Emergency Use Authorization (EUA). 

EUAs set a lower bar for effectiveness, saying the vaccines may be safe and effective based on just a few months of data. 

But with COVID cases plummeting in the United States and children historically seeing far less serious disease than adults, a panel of expert advisors to the FDA was asked to deliberate on Thursday whether the agency could consider vaccines for this age group under the same standard. 

Stated another way: Is COVID an emergency for kids? 

There’s another wrinkle in the mix, too – heart inflammation, which appears to be a very rare emerging adverse event tied to vaccination. It seems to happen more often in teens and young adults. To date, cases of myocarditis and pericarditis appear to be happening in 16 to 30 people for every 1 million doses given. 

But if it is conclusively linked to the shots, some wonder whether it might tip the balance between benefits and risks for kids.

That left some of the experts who sit on the FDA’s advisory committee for vaccines and related biological products urging the FDA to take its time and more thoroughly study the shots before they’re given to millions of children.
 

Vaccine studies different in children?

Clinical studies of the vaccines in teens and adults have thus far relied on some straightforward math. You take two groups of similar people. You give half the vaccine and half a placebo. Then you wait and see which group has more symptomatic infections. To date, the vaccines have dramatically cut the risk of getting severely ill with COVID for every age group tested.

But COVID infections are falling rapidly in the U.S., and that may make it more difficult for researchers to conduct a similar kind of experiment in children.

The FDA is considering different approaches to figure out whether a vaccine would be effective in kids, including something called an “immunobridging trial.” 

In bridging trials, researchers don’t look for infections; rather, they look for proven signs that someone has developed immunity, like antibody levels. Those biomarkers are then compared to the immune responses of younger adults who have demonstrated good protection against infection.

The main advantage of bridging studies is speed. It’s possible to get a snapshot of how the immune system responds to a vaccine within weeks of the final dose.

The drawback is that researchers don’t know exactly what to look for to judge how well the shots are generating protection. 

That’s made even more difficult because kids’ immune systems are still developing, so it may be tough to draw direct parallels to adults.

“We don’t know what the serologic correlate of immunity is now. We don’t know how much antibody you have to get in order to be protected. We don’t know what the role of T cells will be,” said H. Cody Meissner, MD, chief of the division of pediatric infectious disease at Tufts Medical Center, Boston.

“I have so much sympathy for the FDA because these are enormous problems, and you have to make a decision,” said Dr. Meissner, who is a member of the FDA’s vaccines and related biological products advisory committee.
 

Speed vaccines to market, or gather more data?

The plummeting rate of infections in the United States also means that it may be more difficult for the FDA to justify allowing a vaccine on the market for emergency use for children under age 12.

In its recent advisory committee meeting, the agency asked the panel whether it should consider COVID vaccines for children under an EUA or a biologics license application (BLA), aka full approval. 

A BLA typically means the agency considers a year or two of data on a new product, rather than just 2 months’ worth. Emergency use also allows products on the market under a looser standard – they “may be” safe and effective, instead of has been proven to be safe and effective.

Several committee members said they didn’t feel the United States was still in an emergency with COVID and couldn’t see the FDA allowing a vaccine to be used in kids that wasn’t given the agency’s highest level of scrutiny, particularly with reports of adverse events like myocarditis coming to light.

“I just want to be sure the price we pay for vaccinating millions of children justifies the side effects, and I don’t think we know that yet,” Dr. Meissner said.

Others acknowledged that there was little risk to kids now with infections on the decline but said that picture could change as variants spread, schools reopen, and colder temperatures force people indoors. 

The FDA must decide whether to act based on where we are now or where we could be in a few months.

“I think it’s the million-dollar question right now,” said Hannah Kirking, MD, a medical epidemiologist with the Centers for Disease Control and Prevention who presented new and unpublished data on COVID’s impact in children to the FDA’s advisory committee.

She said prospective studies tracking the way COVID moves through a household with weekly testing from New York City and Utah had found that children catch and transmit COVID almost as readily as adults. But they don’t usually get as sick as adults do, so their cases are easy to miss. 

She also presented the results of blood tests from samples around the country looking for evidence of past infection. In these seroprevalence studies, about 27% of children under age 17 had antibodies to COVID – the most of any age group. So more than 1 in 4 kids already has some natural immunity.

That means the main benefit of vaccinating children might be the protection of others, while they still bear the risks – however tiny.

Some experts felt that wasn’t enough reason to justify mass distribution of the vaccines to kids, and from a regulatory standpoint, it might not be permissible.

“FDA can only approve a medical product in a population if the benefits outweigh the risks in that population,” said Peter Doshi, PhD, assistant professor of pharmaceutical health services research in the University of Maryland’s school of pharmacy, Baltimore.

“If benefits don’t outweigh risks in children, it can’t be indicated for children. Full stop,” said Dr. Doshi, who is also an editor at the BMJ.

He said there’s another way to give children access to vaccines, through an expanded access or compassionate use program. Because most COVID deaths have been in children with underlying health conditions, Dr. Doshi and others said it might make sense to allow expanded access – which would get vaccines to children at high risk for complications – without turning them loose on millions before they are more thoroughly studied.

“It’s not a particularly attractive option for industry, because there’s no money to be made. Your medicine can’t be commercialized under expanded access. The most you can reap is manufacturing cost, which is not a lot,” he said.

Art Caplan, a professor of bioethics at New York University’s Langone medical center, said the argument for vaccinating children for flu falls along the same lines. The benefit-to-risk ratio is finely balanced in children.  The main value of protecting them is to protect others.

“Flu rarely kills young folks. But you’re really trying to protect old folks and that’s the classic example,” he said.

What’s more, he said the idea that children would take on some risk with a vaccine for little personal benefit is oversimplified.

“Yes, you might get vaccinated to prevent harm to others, but those others are providing benefits to you. It’s not a one-way street. I think that’s a little morally distorted,” Mr. Caplan said. “Being able to keep society open benefits kids and adults alike.”

Other committee members felt like it was too early to sound the all-clear on COVID and said the FDA should authorize vaccines for children as quickly as it had for other age groups.

“We are still, I believe, in an emergency situation. I think that when this virus goes into our children, which is what it’s going to do, that will give it an incubator to change,” said Oveta Fuller, PhD, associate professor of microbiology and immunology at the University of Michigan, Ann Arbor.

Fuller said that for the good of the world, Americans needed to vaccinate children to prevent the virus from mutating and creating new and potentially more dangerous variants.
 

Weighing risk over safety

Beth Thielen, MD, PhD, pediatric infectious disease specialist and virologist at the University of Minnesota, Minneapolis, said she had not followed the committee’s discussions, but about once a month she treats kids who are very sick because of the virus – either because of a COVID infection or because of multisystem inflammatory syndrome (MIS-C), an inflammatory reaction that strikes after infection.

She’s worried about how the virus has already changed. She said the kind of disease she’s seeing in kids now is different than what she saw in the early months of the pandemic.

“In the last couple of months, I’ve actually seen a few cases of severe pulmonary disease, more similar to adult disease in children,” Dr. Thielen said. “I see on the horizon that we could start seeing more significant disease in young people, and then the risks of being unvaccinated go up substantially.” 

But she also knows nobody has a crystal ball, and right now, everything seems to be trending in the right direction with COVID. That makes the risk-to-benefit consideration murkier.

“The question in my mind is, what is the risk of side effects from the vaccine?” she said. “I think we really need to know what the safety profile of vaccine looks like in children because we do have a decent understanding now what risk from disease looks like, because it’s small, but we are seeing it.”

Dr. Thielen said she’ll be keeping an eye on the next meeting of the CDC’s Advisory Committee on Immunization Practices for more answers.

A version of this article first appeared on Medscape.com.

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Difficulty falling asleep may be predictive of future cognitive impairment in older adults – and depressive symptoms and vascular disease may partially drive this association, new research suggests.

Trouble falling asleep “may be a modifiable risk factor for later-life cognitive impairment and dementia,” said lead author Afsara Zaheed, a PhD candidate in clinical science, department of psychology, University of Michigan, Ann Arbor.

“Patients should also be aware of the importance of insomnia on cognitive functioning so that they can bring up these concerns with their providers early,” she said.

The findings were presented at Virtual SLEEP 2021, the 35th Annual Meeting of the Associated Professional Sleep Societies.
 

Poor sleep common with age

As many as one-half of older adults report having poor sleep quality and insomnia, and growing evidence suggests that insomnia may be a unique risk factor for cognitive decline in later life, Ms. Zaheed explained.

To investigate further, the researchers analyzed data on 2,496 adults aged 51 years and older who were participants in the Health and Retirement Study, a longitudinal study of aging in a nationally representative population of older adults.

In 2002, participants were asked how often they had trouble falling asleep, woke up during the night, woke up too early, and were not able to fall asleep again and how often they felt really rested when they woke up in the morning.

In 2016, participants’ cognition was assessed using a battery of neuropsychological tests that gauged episodic memory, executive function, language, visuospatial/construction, and processing speed.

Analyses controlled for sociodemographics, baseline global cognitive performance, and the influence of depressive symptoms and vascular disease.

Compared with other insomnia symptoms, having difficulty falling asleep in 2002 was the main insomnia symptom that was predictive of cognitive impairment 14 years later, in 2016.

More frequent trouble falling asleep was predictive of poorer episodic memory, executive function, language, processing speed, and visuospatial performance.

The associations between sleep initiation and later cognitive impairment were partially explained by depressive symptoms and vascular disease burden for all domains except episodic memory, which was only partially explained by depressive symptoms.
 

Unclear mechanism

Ms. Zaheed said research is needed to uncover neurophysiologic mechanisms underlying the observed associations. “It may be that chronic difficulty with falling asleep is associated with inflammatory or metabolic processes that negatively affect brain structure and function over time,” she said.

“Insomnia has also been linked with higher accumulation of protein aggregates in the brain that disrupt cell communication and are characteristic of late-life disorders such as Alzheimer’s disease,” she added.

“While our project did not directly investigate these potential causal pathways between insomnia and cognition, our results suggest that investigating these potential mechanisms is an important area for future research,” Ms. Zaheed said.

“While additional intervention research is needed to determine whether targeting insomnia in older patients can have lasting cognitive benefits, results from this study suggest that discussing insomnia symptoms at the primary care level may be beneficial for both doctors and patients,” she added.

“By targeting insomnia – for example, through an evidence-based cognitive–behavioral therapy approach – individuals may improve various mental and physical health outcomes in addition to improving their sleep quality,” Ms. Zaheed said.

Reached for comment, Shaheen E. Lakhan, MD, PhD, neurologist in Newton, Massachusetts, said, “There is a strong link between chronic sleep disturbances and cognitive impairment, including dementia.”

“This study further supports this link and specifically calls out initiating sleep (as opposed to staying asleep) as the culprit. It also raises the hypothesis that the link is primarily mediated by depression and vascular disease; however, the verdict is still out,” said Dr. Lakhan.

The study was funded by the National Institute on Aging. Ms. Zaheed and Dr. Lakhan have disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

A version of this article first appeared on Medscape.com.

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

A version of this article first appeared on Medscape.com.

Insomnia in childhood persists into adulthood and may raise the risk for internalizing disorders in young adults, new research indicates. However, insomnia symptoms in childhood that remit in the transition to adolescence do not confer increased risk of mood or anxiety disorders later on, the study found.

“As insomnia symptoms may precipitate or maintain internalizing disorders, our findings further reinforce the need for early sleep interventions to prevent future mental health disorders,” said lead investigator Julio Fernandez-Mendoza, PhD, associate professor at Penn State University, Hershey.

He presented his research at Virtual SLEEP 2021, the 35th annual meeting of the Associated Professional Sleep Societies.
 

Results ‘very clear’

The findings are based on data from the Penn State Child Cohort, a longitudinal, population-based sample of 700 children with a median age of 9 years, including 421 who were followed up 8 years later as adolescents (median age, 16 years) and 502 who were followed up 15 years later as young adults (median age, 24 years).

The data are “very clear that the risk of having internalizing disorders in young adulthood associated with having persistent insomnia symptoms, since childhood through adolescence into young adulthood,” Dr. Fernandez-Mendoza said in his presentation.

A persistent developmental trajectory was associated with a threefold increased risk of adult internalizing disorder (hazard ratio, 3.19).

The risk of having an internalizing disorder in young adulthood associated with newly developing (incident) insomnia symptoms is about twofold higher (HR, 1.94), whereas the risk associated with the waxing and waning pattern of insomnia is 1.5-fold (HR, 1.53) higher and only marginally significant, he reported.

An equally important finding, said Dr. Fernandez-Mendoza, is that those who had remitted insomnia symptoms in the transition to adolescence and throughout young adulthood were not at increased risk of having an internalizing disorder in young adulthood.

“Insomnia symptoms in a persistent manner associated with long-term adverse mental health outcomes, but remission of those insomnia symptoms associated with a good prognosis,” he said.

It’s also important to note, he said, that about 40% of children do not outgrow their insomnia symptoms in the transition to adolescence and are at risk of developing mental health disorders later on during early adulthood.

Reached for comment, Nitun Verma, MD, a spokesperson for the American Academy of Sleep Medicine, said: “There is a connection with mood and anxiety disorders with sleep, especially insomnia. This is a good reminder that reviewing someone’s sleep habits should always be a part of assessing someone’s mental health.”

A version of this article first appeared on Medscape.com.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

An in vitro study that used mouse endothelial cells to simulate the blood-brain barrier (BBB) suggests that specific proteins may be involved in destabilization of the protective barrier during a cortical spreading depression (CSD) event.

CSD has been linked to migraine aura, but a connection to pain symptoms is uncertain. “There’s just a lack of knowledge. We don’t understand migraine pathophysiology,” said Michael G. Harrington, MBChB, who was asked to comment on the study.

“The evidence for altered transport across the barrier in cortical spreading depression and the associated aura of migraine is pretty strong. The evidence for regular migraine, not so. In fact, there’s really no strong evidence for leakage in those people, and so it is still unresolved whether this initial cortical spreading depression that occurs in aura then triggers migraine afterwards, because it’s occurring during the aura. And in people who do not have the aura, is there a silent cortical spreading depression phenomenon with some leakage that triggers the migraine? That question is definitely not answered,” said Dr. Harrington, a research professor of neurology at the University of Southern California, Los Angeles.

Leakage of the BBB might allow passage of nociceptive compounds that could trigger migraine. Loss of BBB integrity has also been seen in other central nervous system pain disorders, suggesting that alterations to BBB functioning could have broader implications.

“In this model that we’re using, we’re seeing loss of overall barrier integrity, which lends itself to a whole cascade of further pathological possibilities,” Jared Wahl, a PhD candidate at the University of Arizona, Tucson, said in an interview. He presented the research at the American Headache Society’s 2021 annual meeting.

A leaky BBB could allow infiltration of a range of substances, but the potential for such a mechanism in migraine pathology is not well understood.

The researchers specifically investigated the potential role of claudin-5 in the tight junction (TJ) region of the BBB. The decision was made in part because the proteins involved in the BBB are difficult to study, and there is some familiarity with claudin-5, according to Mr. Wahl. ”Of all the proteins that are out there, for claudin-5 (there are) somewhat better techniques and products available to work with, and there’s been some previous research done to show that it’s implicated in blood brain barrier pathology. So it seemed like a good candidate to start with investigating this whole possible pathophysiological link between barrier disruption and migration of pronociceptive substances into the CNS during migraine attacks,” he said. The claudin proteins are also the major components of the tight junctions that seal off gaps between endothelial cells along the BBB.
 

Dynamic changes seen in the in vitro model

To simulate a CSD event, the researchers pulsed cultured cells for 5 minutes with astrocyte-conditioned media, artificial cerebrospinal fluid, KCl, glutamate, altered pH, or adenosine triphosphate (ATP). They used trans endothelial electrical resistance (TEER) to quickly and qualitatively screen for loss of barrier integrity, which is characterized by loss of electrical resistance. To quantify the magnitude of a breach, the researchers applied carbon-14 (C14)–labeled sucrose to one side of the barrier, and determined the amount of labeled sucrose transmitted to the other side of the barrier.

ATP and pH pulses that were outside normal physiological limits led to permeability. The team then used immunocytochemistry assays to visualize the condition of the model BBB, and found discontinuity of the tight junction membranes. Imaging of claudin-5 showed organizational changes within the tight junction, but there was no change in expression level, suggesting that the alterations were due to dynamic reorganization, according to Mr. Wahl.

Transient openings could allow passage of molecules such as bradykinin, calcitonin gene-related peptide (CGRP), and substance P, which could go on to affect the trigeminal nerve complex and trigger a migraine. “That’s sort of the crux of a lot of this migraine research, is gluing this physiological (mechanism) to how it is actually activating the CNS. And this is sort of where we’re going with it at the moment,” said Mr. Wahl.
 

Next steps

The researchers next plan to generate a cell line with claudin-5 linked to green fluorescent protein, then use confocal microscopy to image claudin-5 in real time as the BBB model responds to a simulated CSD.

Another important step will be to link physiological findings like those presented by Mr. Wahl to migraine-specific mechanisms. The results from this model will need to be expanded to include more than endothelial cells, especially astrocytes, pericytes, and neurons, as well as organoids, brain slices, or in vivo animal models, according to Dr. Harrington. “I think you could try and block the changes in occludin [another protein in the tight junction] or claudin-5 to see if, under the same provocation, that prevented the changes in a migraine model. That would be a direct way of connecting from CSD to migraine,” said Dr. Harrington.

If BBB disruption is confirmed to play an important role in migraine, and claudin-5 or other specific proteins are confirmed to be the cause, it could have clinical implications. A drug that could prevent those changes in the proteins and prevent a leak in the BBB could be a migraine preventative. “That could help prevent things like nociceptive substances migrating into the CNS, and could possibly be a well-tolerated drug target that doesn’t have the side effects or the overuse problems that a lot of stuff on the market has today,” said Mr. Wahl.

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

A version of this article first appeared on Medscape.com.

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

A version of this article first appeared on Medscape.com.

The migraine medication erenumab appears to pose no increased risk of hypertension, easing earlier concerns that this may be one of the drug’s adverse events, an analysis of postmarketing data shows. Nevertheless, investigators noted that more research is needed to confirm that this is the case.

While randomized clinical trials have shown no increased risk of hypertension related to the drug, it has been reported in postmarketing data. However, many of these events occurred in patients with previously documented hypertension or risk factors for the disorder, the investigators noted.

The rate of hypertension adverse events in postmarketing data was 0.144 per 100 person-years. Most such reports described only one instance of elevated blood pressure. In April 2020, the prescribing information for the drug was updated to include a mention of the risk of hypertension.

“Given the limitations of postmarketing reports, including incomplete information, lack of a control arm, and others, additional data are certainly needed to fully characterize the nature, the timing, and the extent to which hypertension is a risk associated with erenumab, and indeed other [calcitonin-gene-related peptide (CGRP)] pathway antagonists,” said study investigator David W. Dodick, MD, professor of neurology at the Mayo Clinic College of Medicine, Phoenix.

The findings were presented at the American Headache Society’s 2021 annual meeting.
 

No increased risk over time

A monoclonal antibody and CGRP antagonist, erenumab is approved in the United States for migraine prevention in adults. CGRP medications are vasodilators, and, therefore, migraine treatments that target this pathway could theoretically have hypertensive effects.

To assess the risk of hypertension in migraine patients treated with erenumab, investigators examined clinical trial and postmarketing data. The analysis included cases with limited information and patients with a different etiology for the development of hypertension.

Using Amgen Clinical Trial data, the researchers performed a pooled safety analysis of four placebo-controlled, double-blind phase 2 or 3 studies of the drug. Participants had episodic or chronic migraine and were between ages 18 and 60 years or age 65 years. The doses studied were 70 mg and 140 mg.

In these studies, blood pressure data for each patient were based on an average of at least two measurements taken after patients were in rested state for at least 5 minutes. The position used for blood pressure measurement for each patient was consistent throughout the study.

The investigators also analyzed postmarketing reports of hypertension from May 17, 2018, to Jan. 31, 2020, identified in Amgen Global Safety data.

The pooled studies included 1,043 participants receiving placebo, 893 receiving 70 mg of erenumab, and 507 receiving 140 mg of the drug. During the treatment phase, the incidence of hypertension was 0.9% among controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group. The proportion of patients who started a new antihypertensive medication was 1.2% in controls, 0.8% in the 70-mg group, and 0.2% in the 140-mg group.

In a long-term, open-label study, patients with episodic migraine received erenumab treatment for up to 5 years. The incidence of hypertension did not increase with time in this population.

The postmarketing data encompassed 245,682 person-years of erenumab exposure. The researchers identified 362 hypertension events (355 cases). The rate of these events was 0.144 per 100 person-years. The exposure-adjusted incidence of hypertension was 1.9 per 100 patient-years for erenumab.

Of the 362 hypertensive events, 158 (43.6%) were in patients with a medical history of hypertension or risk factors for hypertension. Information about the time to onset of hypertension was available for 121 (33.4%) adverse events.

Of this group, 56 (46.2%) occurred within 1 week of erenumab initiation, including 43 (35.5%) that occurred within 1 day. This rapid time to hypertension onset “is inconsistent with the pharmacokinetic profile of once-monthly erenumab 70 mg or 140 mg, which has a peak serum concentration in approximately 6 days,” said Dr. Dodick.
 

Hypertension ‘not a barrier’ to treatment

Commenting on the findings, Richard B. Lipton, MD, Edwin S. Lowe professor and vice chair of neurology at Albert Einstein College of Medicine, New York, noted that in theory blocking CGRP could increase blood pressure. However, he noted that the data and clinical experience do not suggest erenumab poses a serious risk.

“I have rarely seen new-onset hypertension with erenumab in the patients treated at our medical center. The few cases I have seen were in older adults with pre-existing hypertension,” he said.

The investigators’ review of clinical trial data together with global safety databases was a strength of their study, said Dr. Lipton. In clinical trials, patients are monitored carefully, and a placebo control group aids in the determination of background rates.

“In the trials, the incidence of new-onset hypertension or hypertension exacerbation was 0.9%, while the placebo rate was 0.2%,” said Dr. Lipton. “The absolute increase in the risk of hypertension was 0.6% or six cases per thousand: A low rate.” But clinical trials enroll carefully selected patients who do not represent the broad group of people treated with erenumab in clinical practice, he added.

The global safety data are more representative of patients who receive erenumab in real-world settings. The weaknesses of these data, though, are the lack of a control group and the incomplete ascertainment of data associated with spontaneous reporting.

Yet both types of studies, with their complementary strengths and weaknesses, indicated low rates of hypertension.

“The low incidence of hypertension, in my view, is not a barrier to the use of erenumab, though checking blood pressure after starting any new migraine therapy is prudent,” Dr. Lipton concluded.

The study was funded by Amgen. Dr. Dodick had no relevant disclosures. Dr. Lipton has consulted for and conducted studies funded by Amgen and by other companies that manufacture CGRP drugs. He has stock options in Biohaven.

A version of this article first appeared on Medscape.com.

Severe complications at 5 years were no different for patients with perforated purulent diverticulitis who underwent laparoscopic peritoneal lavage or colon resection, according to data from 199 individuals treated at 21 hospitals in Norway and Sweden. But it may yet prove appropriate in the right patient.

Acute perforated diverticulitis with peritonitis remains a challenging complication with high morbidity and mortality among patients with diverticular disease, and bowel resection remains the standard of treatment, Najia Azhar, MD, of Skåne University Hospital, Malmö, Sweden, and colleagues wrote.

Short-term data suggest that laparoscopic lavage with drainage and antibiotics might be a viable alternative, but long-term data are lacking, they said.

In the Scandinavian Diverticulitis (SCANDIV) trial, published in JAMA Surgery, researchers randomized 101 patients to laparoscopic peritoneal lavage and 98 to colon resection. With 3 patients lost to follow-up, the final analysis included 73 patients who underwent laparoscopic lavage and 69 who underwent resection. The mean age of the lavage patients was 66.4 years, and 39 were men. The mean age of the resection patients was 63.5 years, and 36 were men. The primary outcome was severe complications – excluding stoma reversals and elective sigmoid resections because of recurrence – at an average of 5 years’ follow-up. Secondary outcomes included stoma prevalence, diverticulitis recurrence, and secondary sigmoid resection.

Severe complications were similar for the lavage and resection groups (36% and 35%, respectively), as were the overall mortality rates (32% and 25%, respectively).

The prevalence of stoma was significantly lower in the lavage group, compared with the resection group (8% vs. 33%, P = .002). However, secondary operations (including reversal of stoma) were similar between the lavage and resection groups, performed in 26 lavage patients (36%) versus 24 resection patients (35%).

Diverticulitis recurrence was significantly more common in the lavage, compared with the resection group (21% vs. 4%, P = .004), the researchers noted.

In the laparoscopic lavage group, 30% (n = 21) underwent a sigmoid resection; all but one of these occurred within a year of the index procedure, the researchers wrote. In addition, overall length of hospital stay was similar for both groups.

No significant differences in quality of life were noted between the groups, based on the EuroQoL-5D questionnaire or Cleveland Global Quality of Life scores.
 

Balance secondary pros and cons

Laparoscopic lavage is not common practice today in the United States, the researchers noted. In clinical practice guidelines issued in 2020, the American Society of Colon and Rectal Surgeons strongly recommend colectomy over laparoscopic lavage for the treatment of left-sided colonic diverticulitis. However, the European Society of Coloproctology’s guidelines state that laparoscopic lavage is feasible for patients with peritonitis at Hinchey stage III.

The findings of the current study were limited primarily by the exclusion of 50% of eligible patients because of challenges associated with conducting randomized trials in emergency settings, the researchers noted. However, the number of excluded patients and their baseline characteristics after exclusion were very similar in the two groups, and the study represents the largest randomized trial to date to examine long-term outcomes in patients with perforated diverticulitis.

“Laparoscopic lavage is faster and cost-effective but leads to a higher reoperation rate and recurrence rate, often requiring secondary sigmoid resection,” the researchers emphasized. Consequently, patients undergoing lavage should have consented for resection surgery.

The similar rates of severe complications and quality of life scores support laparoscopic lavage as an option for perforated purulent diverticulitis, but shared decision-making will be essential for better optimal patient management, the researchers concluded.
 

Similar outcomes, but unanswered questions

Even though the primary outcome of disease-related morbidity was similar for both groups, “the issue still remains regarding when and how, if ever, this therapeutic approach should be considered for purulent peritonitis,” Kellie E. Cunningham, MD, and Brian S. Zuckerbraun, MD, both of the University of Pittsburgh, wrote in an accompanying editorial.

Although laparoscopic lavage has the obvious advantages of avoiding a laparotomy and stoma, previous studies have shown a higher rate of early reoperations and recurrent diverticulitis, despite lower stoma prevalence and equal mortality rates, they said. In addition, “patients who are immunosuppressed or would be expected to have a higher mortality rate with failure to achieve definitive source control should likely not be offered this therapy.”

A “philosophical” argument could be made in favor of laparoscopic lavage based on the potential consequences of early treatment failure, they wrote.

“Although one may consider the need for early reoperation a complication, some would argue it affects the minority of patients, thus avoiding the more morbid procedure with creation of a stoma at the index operation in the majority of patients,” they noted. “Additionally, patients who underwent lavage that subsequently proceed to colectomy would have otherwise been offered this therapy initially at the time of the index operation.”

More research is needed to answer questions such as which, if any, operative findings are associated with failure. In addition, an analysis of long-term cost benefits between the two options should be explored, the authors wrote.

Based on current evidence, shared decision-making is necessary, with individualized care and short and long-term trade-offs taken into account, they wrote.
 

Gastroenterologist perspective: Study fills gap in follow-up data

In an interview, David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia School of Medicine, Norfolk, said the study is important because data have been lacking on outcomes of a laparoscopic lavage without a resection.

The findings represent “a major shift” in the growing consensus among surgeons that laparoscopic lavage is a viable option in appropriate patients, he said.

A key issue is the high rate of morbidity in patients who undergo traditional diverticulitis surgery. Complications can include wound infection and poor quality of life associated with stoma, Dr. Johnson said. Consequently, “a nonoperative approach from a patient perspective is certainly refreshing.”

Dr. Johnson said he was surprised by how well the patients fared after lavage given the severity of the diverticulitis in the patient population. However, this may be in part because of the relatively small numbers of patients at highest risk for complications, such as those with diabetes or immunocompromising conditions.

Dr. Johnson also said he was struck by the fact that the adenocarcinomas in the lavage group were diagnosed within the first year after the procedure. “The cancer diagnosis shouldn’t reflect on the lavage group,” but emphasizes the importance of having an earlier colonoscopy, he noted.

Next steps for research might include identifying a standardized endpoint for lavage, and determining how expanded use of the procedure might impact community practice, Dr. Johnson said. In addition, more research is needed to more clearly define patients most likely to benefit from laparoscopic lavage.

The study was supported in part by the department of surgery at Skåne University Hospital, Akershus University Hospital, and a fellowship to one of the study coauthors from the Southeastern Norway Regional Health Authority. Lead author Dr. Azhar disclosed grants from the department of surgery of Skåne University Hospital. Dr. Cunningham and Dr. Zuckerbraun had no financial conflicts to disclose. Dr. Johnson had no relevant financial disclosures.

Severe complications at 5 years were no different for patients with perforated purulent diverticulitis who underwent laparoscopic peritoneal lavage or colon resection, according to data from 199 individuals treated at 21 hospitals in Norway and Sweden. But it may yet prove appropriate in the right patient.

Acute perforated diverticulitis with peritonitis remains a challenging complication with high morbidity and mortality among patients with diverticular disease, and bowel resection remains the standard of treatment, Najia Azhar, MD, of Skåne University Hospital, Malmö, Sweden, and colleagues wrote.

Short-term data suggest that laparoscopic lavage with drainage and antibiotics might be a viable alternative, but long-term data are lacking, they said.

In the Scandinavian Diverticulitis (SCANDIV) trial, published in JAMA Surgery, researchers randomized 101 patients to laparoscopic peritoneal lavage and 98 to colon resection. With 3 patients lost to follow-up, the final analysis included 73 patients who underwent laparoscopic lavage and 69 who underwent resection. The mean age of the lavage patients was 66.4 years, and 39 were men. The mean age of the resection patients was 63.5 years, and 36 were men. The primary outcome was severe complications – excluding stoma reversals and elective sigmoid resections because of recurrence – at an average of 5 years’ follow-up. Secondary outcomes included stoma prevalence, diverticulitis recurrence, and secondary sigmoid resection.

Severe complications were similar for the lavage and resection groups (36% and 35%, respectively), as were the overall mortality rates (32% and 25%, respectively).

The prevalence of stoma was significantly lower in the lavage group, compared with the resection group (8% vs. 33%, P = .002). However, secondary operations (including reversal of stoma) were similar between the lavage and resection groups, performed in 26 lavage patients (36%) versus 24 resection patients (35%).

Diverticulitis recurrence was significantly more common in the lavage, compared with the resection group (21% vs. 4%, P = .004), the researchers noted.

In the laparoscopic lavage group, 30% (n = 21) underwent a sigmoid resection; all but one of these occurred within a year of the index procedure, the researchers wrote. In addition, overall length of hospital stay was similar for both groups.

No significant differences in quality of life were noted between the groups, based on the EuroQoL-5D questionnaire or Cleveland Global Quality of Life scores.
 

Balance secondary pros and cons

Laparoscopic lavage is not common practice today in the United States, the researchers noted. In clinical practice guidelines issued in 2020, the American Society of Colon and Rectal Surgeons strongly recommend colectomy over laparoscopic lavage for the treatment of left-sided colonic diverticulitis. However, the European Society of Coloproctology’s guidelines state that laparoscopic lavage is feasible for patients with peritonitis at Hinchey stage III.

The findings of the current study were limited primarily by the exclusion of 50% of eligible patients because of challenges associated with conducting randomized trials in emergency settings, the researchers noted. However, the number of excluded patients and their baseline characteristics after exclusion were very similar in the two groups, and the study represents the largest randomized trial to date to examine long-term outcomes in patients with perforated diverticulitis.

“Laparoscopic lavage is faster and cost-effective but leads to a higher reoperation rate and recurrence rate, often requiring secondary sigmoid resection,” the researchers emphasized. Consequently, patients undergoing lavage should have consented for resection surgery.

The similar rates of severe complications and quality of life scores support laparoscopic lavage as an option for perforated purulent diverticulitis, but shared decision-making will be essential for better optimal patient management, the researchers concluded.
 

Similar outcomes, but unanswered questions

Even though the primary outcome of disease-related morbidity was similar for both groups, “the issue still remains regarding when and how, if ever, this therapeutic approach should be considered for purulent peritonitis,” Kellie E. Cunningham, MD, and Brian S. Zuckerbraun, MD, both of the University of Pittsburgh, wrote in an accompanying editorial.

Although laparoscopic lavage has the obvious advantages of avoiding a laparotomy and stoma, previous studies have shown a higher rate of early reoperations and recurrent diverticulitis, despite lower stoma prevalence and equal mortality rates, they said. In addition, “patients who are immunosuppressed or would be expected to have a higher mortality rate with failure to achieve definitive source control should likely not be offered this therapy.”

A “philosophical” argument could be made in favor of laparoscopic lavage based on the potential consequences of early treatment failure, they wrote.

“Although one may consider the need for early reoperation a complication, some would argue it affects the minority of patients, thus avoiding the more morbid procedure with creation of a stoma at the index operation in the majority of patients,” they noted. “Additionally, patients who underwent lavage that subsequently proceed to colectomy would have otherwise been offered this therapy initially at the time of the index operation.”

More research is needed to answer questions such as which, if any, operative findings are associated with failure. In addition, an analysis of long-term cost benefits between the two options should be explored, the authors wrote.

Based on current evidence, shared decision-making is necessary, with individualized care and short and long-term trade-offs taken into account, they wrote.
 

Gastroenterologist perspective: Study fills gap in follow-up data

In an interview, David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia School of Medicine, Norfolk, said the study is important because data have been lacking on outcomes of a laparoscopic lavage without a resection.

The findings represent “a major shift” in the growing consensus among surgeons that laparoscopic lavage is a viable option in appropriate patients, he said.

A key issue is the high rate of morbidity in patients who undergo traditional diverticulitis surgery. Complications can include wound infection and poor quality of life associated with stoma, Dr. Johnson said. Consequently, “a nonoperative approach from a patient perspective is certainly refreshing.”

Dr. Johnson said he was surprised by how well the patients fared after lavage given the severity of the diverticulitis in the patient population. However, this may be in part because of the relatively small numbers of patients at highest risk for complications, such as those with diabetes or immunocompromising conditions.

Dr. Johnson also said he was struck by the fact that the adenocarcinomas in the lavage group were diagnosed within the first year after the procedure. “The cancer diagnosis shouldn’t reflect on the lavage group,” but emphasizes the importance of having an earlier colonoscopy, he noted.

Next steps for research might include identifying a standardized endpoint for lavage, and determining how expanded use of the procedure might impact community practice, Dr. Johnson said. In addition, more research is needed to more clearly define patients most likely to benefit from laparoscopic lavage.

The study was supported in part by the department of surgery at Skåne University Hospital, Akershus University Hospital, and a fellowship to one of the study coauthors from the Southeastern Norway Regional Health Authority. Lead author Dr. Azhar disclosed grants from the department of surgery of Skåne University Hospital. Dr. Cunningham and Dr. Zuckerbraun had no financial conflicts to disclose. Dr. Johnson had no relevant financial disclosures.

Severe complications at 5 years were no different for patients with perforated purulent diverticulitis who underwent laparoscopic peritoneal lavage or colon resection, according to data from 199 individuals treated at 21 hospitals in Norway and Sweden. But it may yet prove appropriate in the right patient.

Acute perforated diverticulitis with peritonitis remains a challenging complication with high morbidity and mortality among patients with diverticular disease, and bowel resection remains the standard of treatment, Najia Azhar, MD, of Skåne University Hospital, Malmö, Sweden, and colleagues wrote.

Short-term data suggest that laparoscopic lavage with drainage and antibiotics might be a viable alternative, but long-term data are lacking, they said.

In the Scandinavian Diverticulitis (SCANDIV) trial, published in JAMA Surgery, researchers randomized 101 patients to laparoscopic peritoneal lavage and 98 to colon resection. With 3 patients lost to follow-up, the final analysis included 73 patients who underwent laparoscopic lavage and 69 who underwent resection. The mean age of the lavage patients was 66.4 years, and 39 were men. The mean age of the resection patients was 63.5 years, and 36 were men. The primary outcome was severe complications – excluding stoma reversals and elective sigmoid resections because of recurrence – at an average of 5 years’ follow-up. Secondary outcomes included stoma prevalence, diverticulitis recurrence, and secondary sigmoid resection.

Severe complications were similar for the lavage and resection groups (36% and 35%, respectively), as were the overall mortality rates (32% and 25%, respectively).

The prevalence of stoma was significantly lower in the lavage group, compared with the resection group (8% vs. 33%, P = .002). However, secondary operations (including reversal of stoma) were similar between the lavage and resection groups, performed in 26 lavage patients (36%) versus 24 resection patients (35%).

Diverticulitis recurrence was significantly more common in the lavage, compared with the resection group (21% vs. 4%, P = .004), the researchers noted.

In the laparoscopic lavage group, 30% (n = 21) underwent a sigmoid resection; all but one of these occurred within a year of the index procedure, the researchers wrote. In addition, overall length of hospital stay was similar for both groups.

No significant differences in quality of life were noted between the groups, based on the EuroQoL-5D questionnaire or Cleveland Global Quality of Life scores.
 

Balance secondary pros and cons

Laparoscopic lavage is not common practice today in the United States, the researchers noted. In clinical practice guidelines issued in 2020, the American Society of Colon and Rectal Surgeons strongly recommend colectomy over laparoscopic lavage for the treatment of left-sided colonic diverticulitis. However, the European Society of Coloproctology’s guidelines state that laparoscopic lavage is feasible for patients with peritonitis at Hinchey stage III.

The findings of the current study were limited primarily by the exclusion of 50% of eligible patients because of challenges associated with conducting randomized trials in emergency settings, the researchers noted. However, the number of excluded patients and their baseline characteristics after exclusion were very similar in the two groups, and the study represents the largest randomized trial to date to examine long-term outcomes in patients with perforated diverticulitis.

“Laparoscopic lavage is faster and cost-effective but leads to a higher reoperation rate and recurrence rate, often requiring secondary sigmoid resection,” the researchers emphasized. Consequently, patients undergoing lavage should have consented for resection surgery.

The similar rates of severe complications and quality of life scores support laparoscopic lavage as an option for perforated purulent diverticulitis, but shared decision-making will be essential for better optimal patient management, the researchers concluded.
 

Similar outcomes, but unanswered questions

Even though the primary outcome of disease-related morbidity was similar for both groups, “the issue still remains regarding when and how, if ever, this therapeutic approach should be considered for purulent peritonitis,” Kellie E. Cunningham, MD, and Brian S. Zuckerbraun, MD, both of the University of Pittsburgh, wrote in an accompanying editorial.

Although laparoscopic lavage has the obvious advantages of avoiding a laparotomy and stoma, previous studies have shown a higher rate of early reoperations and recurrent diverticulitis, despite lower stoma prevalence and equal mortality rates, they said. In addition, “patients who are immunosuppressed or would be expected to have a higher mortality rate with failure to achieve definitive source control should likely not be offered this therapy.”

A “philosophical” argument could be made in favor of laparoscopic lavage based on the potential consequences of early treatment failure, they wrote.

“Although one may consider the need for early reoperation a complication, some would argue it affects the minority of patients, thus avoiding the more morbid procedure with creation of a stoma at the index operation in the majority of patients,” they noted. “Additionally, patients who underwent lavage that subsequently proceed to colectomy would have otherwise been offered this therapy initially at the time of the index operation.”

More research is needed to answer questions such as which, if any, operative findings are associated with failure. In addition, an analysis of long-term cost benefits between the two options should be explored, the authors wrote.

Based on current evidence, shared decision-making is necessary, with individualized care and short and long-term trade-offs taken into account, they wrote.
 

Gastroenterologist perspective: Study fills gap in follow-up data

In an interview, David A. Johnson, MD, professor of medicine and chief of gastroenterology at Eastern Virginia School of Medicine, Norfolk, said the study is important because data have been lacking on outcomes of a laparoscopic lavage without a resection.

The findings represent “a major shift” in the growing consensus among surgeons that laparoscopic lavage is a viable option in appropriate patients, he said.

A key issue is the high rate of morbidity in patients who undergo traditional diverticulitis surgery. Complications can include wound infection and poor quality of life associated with stoma, Dr. Johnson said. Consequently, “a nonoperative approach from a patient perspective is certainly refreshing.”

Dr. Johnson said he was surprised by how well the patients fared after lavage given the severity of the diverticulitis in the patient population. However, this may be in part because of the relatively small numbers of patients at highest risk for complications, such as those with diabetes or immunocompromising conditions.

Dr. Johnson also said he was struck by the fact that the adenocarcinomas in the lavage group were diagnosed within the first year after the procedure. “The cancer diagnosis shouldn’t reflect on the lavage group,” but emphasizes the importance of having an earlier colonoscopy, he noted.

Next steps for research might include identifying a standardized endpoint for lavage, and determining how expanded use of the procedure might impact community practice, Dr. Johnson said. In addition, more research is needed to more clearly define patients most likely to benefit from laparoscopic lavage.

The study was supported in part by the department of surgery at Skåne University Hospital, Akershus University Hospital, and a fellowship to one of the study coauthors from the Southeastern Norway Regional Health Authority. Lead author Dr. Azhar disclosed grants from the department of surgery of Skåne University Hospital. Dr. Cunningham and Dr. Zuckerbraun had no financial conflicts to disclose. Dr. Johnson had no relevant financial disclosures.